Lung Cancer

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The question has been lingering for years in medical science circles. Since 2020, when the artificial intelligence (AI) model AlphaFold made it possible to predict protein structures, would the technology open the drug discovery floodgates?

Short answer: No. At least not yet.

The longer answer goes something like this:

A drug target (such as a mutation) is like a lock. The right drug (a protein designed to bind to the mutation, stopping its activity) is the key. But proteins are fidgety and flexible.

“They’re basically molecular springs,” said Gabriel Monteiro da Silva, PhD, a computational chemistry research scientist at Genesis Therapeutics. “Your key can bend and alter the shape of the lock, and if you don’t account for that, your key might fail.”

This is the protein problem in drug development. Another issue making this challenge so vexing is that proteins don’t act in isolation. Their interactions with other proteins, ribonucleic acid, and DNA can affect how they bind to molecules and the shapes they adopt.

Newer versions of AlphaFold, such as AlphaFold Multimer and AlphaFold 3 (the code for which was recently revealed for academic use), can predict many interactions among proteins and between proteins and other molecules. But these tools still have weak points scientists are trying to overcome or work around.

“Those kinds of dynamics and multiple conformations are still quite challenging for the AI models to predict,” said James Zou, PhD, associate professor of biomedical data science at Stanford University in California.

“We’re finding more and more that the only way we can make these structures useful for drug discovery is if we incorporate dynamics, if we incorporate more physics into the model,” said Monteiro da Silva.

Monteiro da Silva spent 3 years during his PhD at Brown University, Providence, Rhode Island, running physics-based simulations in the lab, trying to understand why proteins carrying certain mutations are drug resistant. His results showed how “the changing landscape of shapes that a protein can take” prevented the drug from binding.

It took him 3 years to model just four mutations.

AI can do better — and the struggle is fascinating. By developing models that build on the predictive power of AlphaFold, scientists are uncovering new details about protein activity — insights that can lead to new therapeutics and reveal why existing ones stop working — much faster than they could with traditional methods or AlphaFold alone.

 

New Windows into Protein Dynamics

By predicting protein structural details, AlphaFold models also made it possible to predict pockets where drugs could bind.

A notable step, “but that’s just the starting point,” said Pedro Beltrao, PhD, an associate professor at Institute of Molecular Systems Biology, ETH Zurich in Switzerland. “It’s still very difficult, given a pocket, to actually design the drug or figure out what the pocket binds.”

Going back to the lock-and-key analogy: While he was at Brown, with a team of researchers in the Rubenstein Group, Monteiro da Silva helped create a model to better understand how mutations affect “the shape and dynamics of the lock.” They manipulated the amino acid sequences of proteins, guiding their evolution. This enabled them to use AlphaFold to predict “protein ensembles” and how frequently those ensembles appear. Each ensemble represents the many different shapes a protein can take under given conditions.

“Essentially, it tries to find the most common shapes that a protein will take over an arbitrary amount of time,” Monteiro da Silva said. “If we can predict these ensembles at scale and fast, then we can screen many mutations that cause resistance and develop drugs that will not be affected by that resistance.”

To evaluate their method, the researchers focused on ABL1, a well-studied kinase that causes leukemia. ABL1 can be drugged – unless it carries or develops a mutation that causes drug resistance. Currently there are no drugs that work against proteins carrying those mutations, according to Monteiro da Silva. The researchers used their hybrid AI-meets-physics method to investigate how drugs bind to different ABL1 mutations, screening 100 mutations in just 1 month.

“It’s not going to be perfect for every one of them. But if we have 100 and we get 20 with good accuracy, that’s better than doing four over 3 years,” Monteiro da Silva said.

A forthcoming paper will make their model publicly available in “an easy-to-use graphical interface” that they hope clinicians and medicinal chemists will try out. It can also complement other AI-based tools that dig into protein dynamics, according to Monteiro da Silva.

 

Complementary Tools to Speed Up Discovery 

Another aspect of the protein problem is scale. One protein can interact with hundreds of other proteins, which in turn may interact with hundreds more, all of which comprise the human interactome.

Feixiong Cheng, PhD, helped build PIONEER, a deep learning model that predicts the three-dimensional (3D) structure of interactions between proteins across the interactome.

Most disease mutations disrupt specific interactions between proteins, making their affinity stronger or weaker, explained Cheng. To treat a disease without causing major side effects, scientists need a precise understanding of those interactions.

“From the drug discovery perspective, we cannot just focus on single proteins. We have to understand the protein environment, in particular how the protein interacts with other proteins,” said Cheng, director of Cleveland Clinic Genome Center, Cleveland.

PIONEER helps by blending AlphaFold’s protein structure predictions with next-generation sequencing, a type of genomic research that identifies mutations in the human genome. The model predicts the 3D structure of the places where proteins interact — the binding sites, or interfaces — across the interactome.

“We tell you not only that a binds b, but where on a and where on b the two proteins interact,” said Haiyuan Yu, PhD, director of the Center for Innovative Proteomics, Cornell University, and co-creator of PIONEER.

This can help scientists understand “why a mutation, protein, or even network is a good target for therapeutic discovery,” Cheng said.

The researchers validated PIONEER’s predictions in the lab, testing the impacts of roughly 3000 mutations on 7000 pairs of interacting proteins. Based on their findings, they plan to develop and test treatments for lung and endometrial cancer.

PIONEER can also help scientists home in on how a mutation causes a disease, such as by showing recurrent mutations.

“If you find cancer mutations hitting an interface again and again and again, it means that this is likely to be driving cancer progression,” said Beltrao.

Beltrao’s lab and others have looked for recurrent mutations by using AlphaFold Multimer and AlphaFold 3 to directly model protein interactions. It’s a much slower approach (Pioneer is more than 5000 faster than AlphaFold Multimer, according to Cheng). But it could allow scientists to model interfaces that are not shown by PIONEER.

“You will need many different things to try to come up with a structural modeling of the interactome, and all these will have limitations,” said Beltrao. “Their method is a very good step forward, and there’ll be other approaches that are complementary, to continue to add details.”

 

And It Wouldn’t be an AI Mission Without ChatGPT

Large language models, such as ChatGPT, are another way that scientists are adding details to protein structure predictions. Zou used GPT-4 to “fine tune” a protein language model, called evolutionary scale modeling (ESM-2), which predicts protein structures directly from a protein sequence.

First, they trained ChatGPT on thousands of papers and studies containing information about the functions, biophysical properties, and disease relevance of different mutations. Next, they used the trained model to “teach” ESM-2, boosting its ability “to predict which mutations are likely to have larger effects or smaller effects,” Zou said. The same could be done for a model like AlphaFold, according to Zou.

“They are quite complementary in that the large language model contains a lot more information about the functions and the biophysics of different mutations and proteins as captured in text,” he said, whereas “you can’t give AlphaFold a piece of paper.”

Exactly how AlphaFold makes its predictions is another mystery. “It will somehow learn protein dynamics phenomenologically,” said Monteiro da Silva. He and others are trying to understand how that happens, in hopes of creating even more accurate predictive models. But for the time being, AI-based methods still need assistance from physics.

“The dream is that we achieve a state where we rely on just the fast methods, and they’re accurate enough,” he said. “But we’re so far from that.”

A version of this article first appeared on Medscape.com.

The question has been lingering for years in medical science circles. Since 2020, when the artificial intelligence (AI) model AlphaFold made it possible to predict protein structures, would the technology open the drug discovery floodgates?

Short answer: No. At least not yet.

The longer answer goes something like this:

A drug target (such as a mutation) is like a lock. The right drug (a protein designed to bind to the mutation, stopping its activity) is the key. But proteins are fidgety and flexible.

“They’re basically molecular springs,” said Gabriel Monteiro da Silva, PhD, a computational chemistry research scientist at Genesis Therapeutics. “Your key can bend and alter the shape of the lock, and if you don’t account for that, your key might fail.”

This is the protein problem in drug development. Another issue making this challenge so vexing is that proteins don’t act in isolation. Their interactions with other proteins, ribonucleic acid, and DNA can affect how they bind to molecules and the shapes they adopt.

Newer versions of AlphaFold, such as AlphaFold Multimer and AlphaFold 3 (the code for which was recently revealed for academic use), can predict many interactions among proteins and between proteins and other molecules. But these tools still have weak points scientists are trying to overcome or work around.

“Those kinds of dynamics and multiple conformations are still quite challenging for the AI models to predict,” said James Zou, PhD, associate professor of biomedical data science at Stanford University in California.

“We’re finding more and more that the only way we can make these structures useful for drug discovery is if we incorporate dynamics, if we incorporate more physics into the model,” said Monteiro da Silva.

Monteiro da Silva spent 3 years during his PhD at Brown University, Providence, Rhode Island, running physics-based simulations in the lab, trying to understand why proteins carrying certain mutations are drug resistant. His results showed how “the changing landscape of shapes that a protein can take” prevented the drug from binding.

It took him 3 years to model just four mutations.

AI can do better — and the struggle is fascinating. By developing models that build on the predictive power of AlphaFold, scientists are uncovering new details about protein activity — insights that can lead to new therapeutics and reveal why existing ones stop working — much faster than they could with traditional methods or AlphaFold alone.

 

New Windows into Protein Dynamics

By predicting protein structural details, AlphaFold models also made it possible to predict pockets where drugs could bind.

A notable step, “but that’s just the starting point,” said Pedro Beltrao, PhD, an associate professor at Institute of Molecular Systems Biology, ETH Zurich in Switzerland. “It’s still very difficult, given a pocket, to actually design the drug or figure out what the pocket binds.”

Going back to the lock-and-key analogy: While he was at Brown, with a team of researchers in the Rubenstein Group, Monteiro da Silva helped create a model to better understand how mutations affect “the shape and dynamics of the lock.” They manipulated the amino acid sequences of proteins, guiding their evolution. This enabled them to use AlphaFold to predict “protein ensembles” and how frequently those ensembles appear. Each ensemble represents the many different shapes a protein can take under given conditions.

“Essentially, it tries to find the most common shapes that a protein will take over an arbitrary amount of time,” Monteiro da Silva said. “If we can predict these ensembles at scale and fast, then we can screen many mutations that cause resistance and develop drugs that will not be affected by that resistance.”

To evaluate their method, the researchers focused on ABL1, a well-studied kinase that causes leukemia. ABL1 can be drugged – unless it carries or develops a mutation that causes drug resistance. Currently there are no drugs that work against proteins carrying those mutations, according to Monteiro da Silva. The researchers used their hybrid AI-meets-physics method to investigate how drugs bind to different ABL1 mutations, screening 100 mutations in just 1 month.

“It’s not going to be perfect for every one of them. But if we have 100 and we get 20 with good accuracy, that’s better than doing four over 3 years,” Monteiro da Silva said.

A forthcoming paper will make their model publicly available in “an easy-to-use graphical interface” that they hope clinicians and medicinal chemists will try out. It can also complement other AI-based tools that dig into protein dynamics, according to Monteiro da Silva.

 

Complementary Tools to Speed Up Discovery 

Another aspect of the protein problem is scale. One protein can interact with hundreds of other proteins, which in turn may interact with hundreds more, all of which comprise the human interactome.

Feixiong Cheng, PhD, helped build PIONEER, a deep learning model that predicts the three-dimensional (3D) structure of interactions between proteins across the interactome.

Most disease mutations disrupt specific interactions between proteins, making their affinity stronger or weaker, explained Cheng. To treat a disease without causing major side effects, scientists need a precise understanding of those interactions.

“From the drug discovery perspective, we cannot just focus on single proteins. We have to understand the protein environment, in particular how the protein interacts with other proteins,” said Cheng, director of Cleveland Clinic Genome Center, Cleveland.

PIONEER helps by blending AlphaFold’s protein structure predictions with next-generation sequencing, a type of genomic research that identifies mutations in the human genome. The model predicts the 3D structure of the places where proteins interact — the binding sites, or interfaces — across the interactome.

“We tell you not only that a binds b, but where on a and where on b the two proteins interact,” said Haiyuan Yu, PhD, director of the Center for Innovative Proteomics, Cornell University, and co-creator of PIONEER.

This can help scientists understand “why a mutation, protein, or even network is a good target for therapeutic discovery,” Cheng said.

The researchers validated PIONEER’s predictions in the lab, testing the impacts of roughly 3000 mutations on 7000 pairs of interacting proteins. Based on their findings, they plan to develop and test treatments for lung and endometrial cancer.

PIONEER can also help scientists home in on how a mutation causes a disease, such as by showing recurrent mutations.

“If you find cancer mutations hitting an interface again and again and again, it means that this is likely to be driving cancer progression,” said Beltrao.

Beltrao’s lab and others have looked for recurrent mutations by using AlphaFold Multimer and AlphaFold 3 to directly model protein interactions. It’s a much slower approach (Pioneer is more than 5000 faster than AlphaFold Multimer, according to Cheng). But it could allow scientists to model interfaces that are not shown by PIONEER.

“You will need many different things to try to come up with a structural modeling of the interactome, and all these will have limitations,” said Beltrao. “Their method is a very good step forward, and there’ll be other approaches that are complementary, to continue to add details.”

 

And It Wouldn’t be an AI Mission Without ChatGPT

Large language models, such as ChatGPT, are another way that scientists are adding details to protein structure predictions. Zou used GPT-4 to “fine tune” a protein language model, called evolutionary scale modeling (ESM-2), which predicts protein structures directly from a protein sequence.

First, they trained ChatGPT on thousands of papers and studies containing information about the functions, biophysical properties, and disease relevance of different mutations. Next, they used the trained model to “teach” ESM-2, boosting its ability “to predict which mutations are likely to have larger effects or smaller effects,” Zou said. The same could be done for a model like AlphaFold, according to Zou.

“They are quite complementary in that the large language model contains a lot more information about the functions and the biophysics of different mutations and proteins as captured in text,” he said, whereas “you can’t give AlphaFold a piece of paper.”

Exactly how AlphaFold makes its predictions is another mystery. “It will somehow learn protein dynamics phenomenologically,” said Monteiro da Silva. He and others are trying to understand how that happens, in hopes of creating even more accurate predictive models. But for the time being, AI-based methods still need assistance from physics.

“The dream is that we achieve a state where we rely on just the fast methods, and they’re accurate enough,” he said. “But we’re so far from that.”

A version of this article first appeared on Medscape.com.

The question has been lingering for years in medical science circles. Since 2020, when the artificial intelligence (AI) model AlphaFold made it possible to predict protein structures, would the technology open the drug discovery floodgates?

Short answer: No. At least not yet.

The longer answer goes something like this:

A drug target (such as a mutation) is like a lock. The right drug (a protein designed to bind to the mutation, stopping its activity) is the key. But proteins are fidgety and flexible.

“They’re basically molecular springs,” said Gabriel Monteiro da Silva, PhD, a computational chemistry research scientist at Genesis Therapeutics. “Your key can bend and alter the shape of the lock, and if you don’t account for that, your key might fail.”

This is the protein problem in drug development. Another issue making this challenge so vexing is that proteins don’t act in isolation. Their interactions with other proteins, ribonucleic acid, and DNA can affect how they bind to molecules and the shapes they adopt.

Newer versions of AlphaFold, such as AlphaFold Multimer and AlphaFold 3 (the code for which was recently revealed for academic use), can predict many interactions among proteins and between proteins and other molecules. But these tools still have weak points scientists are trying to overcome or work around.

“Those kinds of dynamics and multiple conformations are still quite challenging for the AI models to predict,” said James Zou, PhD, associate professor of biomedical data science at Stanford University in California.

“We’re finding more and more that the only way we can make these structures useful for drug discovery is if we incorporate dynamics, if we incorporate more physics into the model,” said Monteiro da Silva.

Monteiro da Silva spent 3 years during his PhD at Brown University, Providence, Rhode Island, running physics-based simulations in the lab, trying to understand why proteins carrying certain mutations are drug resistant. His results showed how “the changing landscape of shapes that a protein can take” prevented the drug from binding.

It took him 3 years to model just four mutations.

AI can do better — and the struggle is fascinating. By developing models that build on the predictive power of AlphaFold, scientists are uncovering new details about protein activity — insights that can lead to new therapeutics and reveal why existing ones stop working — much faster than they could with traditional methods or AlphaFold alone.

 

New Windows into Protein Dynamics

By predicting protein structural details, AlphaFold models also made it possible to predict pockets where drugs could bind.

A notable step, “but that’s just the starting point,” said Pedro Beltrao, PhD, an associate professor at Institute of Molecular Systems Biology, ETH Zurich in Switzerland. “It’s still very difficult, given a pocket, to actually design the drug or figure out what the pocket binds.”

Going back to the lock-and-key analogy: While he was at Brown, with a team of researchers in the Rubenstein Group, Monteiro da Silva helped create a model to better understand how mutations affect “the shape and dynamics of the lock.” They manipulated the amino acid sequences of proteins, guiding their evolution. This enabled them to use AlphaFold to predict “protein ensembles” and how frequently those ensembles appear. Each ensemble represents the many different shapes a protein can take under given conditions.

“Essentially, it tries to find the most common shapes that a protein will take over an arbitrary amount of time,” Monteiro da Silva said. “If we can predict these ensembles at scale and fast, then we can screen many mutations that cause resistance and develop drugs that will not be affected by that resistance.”

To evaluate their method, the researchers focused on ABL1, a well-studied kinase that causes leukemia. ABL1 can be drugged – unless it carries or develops a mutation that causes drug resistance. Currently there are no drugs that work against proteins carrying those mutations, according to Monteiro da Silva. The researchers used their hybrid AI-meets-physics method to investigate how drugs bind to different ABL1 mutations, screening 100 mutations in just 1 month.

“It’s not going to be perfect for every one of them. But if we have 100 and we get 20 with good accuracy, that’s better than doing four over 3 years,” Monteiro da Silva said.

A forthcoming paper will make their model publicly available in “an easy-to-use graphical interface” that they hope clinicians and medicinal chemists will try out. It can also complement other AI-based tools that dig into protein dynamics, according to Monteiro da Silva.

 

Complementary Tools to Speed Up Discovery 

Another aspect of the protein problem is scale. One protein can interact with hundreds of other proteins, which in turn may interact with hundreds more, all of which comprise the human interactome.

Feixiong Cheng, PhD, helped build PIONEER, a deep learning model that predicts the three-dimensional (3D) structure of interactions between proteins across the interactome.

Most disease mutations disrupt specific interactions between proteins, making their affinity stronger or weaker, explained Cheng. To treat a disease without causing major side effects, scientists need a precise understanding of those interactions.

“From the drug discovery perspective, we cannot just focus on single proteins. We have to understand the protein environment, in particular how the protein interacts with other proteins,” said Cheng, director of Cleveland Clinic Genome Center, Cleveland.

PIONEER helps by blending AlphaFold’s protein structure predictions with next-generation sequencing, a type of genomic research that identifies mutations in the human genome. The model predicts the 3D structure of the places where proteins interact — the binding sites, or interfaces — across the interactome.

“We tell you not only that a binds b, but where on a and where on b the two proteins interact,” said Haiyuan Yu, PhD, director of the Center for Innovative Proteomics, Cornell University, and co-creator of PIONEER.

This can help scientists understand “why a mutation, protein, or even network is a good target for therapeutic discovery,” Cheng said.

The researchers validated PIONEER’s predictions in the lab, testing the impacts of roughly 3000 mutations on 7000 pairs of interacting proteins. Based on their findings, they plan to develop and test treatments for lung and endometrial cancer.

PIONEER can also help scientists home in on how a mutation causes a disease, such as by showing recurrent mutations.

“If you find cancer mutations hitting an interface again and again and again, it means that this is likely to be driving cancer progression,” said Beltrao.

Beltrao’s lab and others have looked for recurrent mutations by using AlphaFold Multimer and AlphaFold 3 to directly model protein interactions. It’s a much slower approach (Pioneer is more than 5000 faster than AlphaFold Multimer, according to Cheng). But it could allow scientists to model interfaces that are not shown by PIONEER.

“You will need many different things to try to come up with a structural modeling of the interactome, and all these will have limitations,” said Beltrao. “Their method is a very good step forward, and there’ll be other approaches that are complementary, to continue to add details.”

 

And It Wouldn’t be an AI Mission Without ChatGPT

Large language models, such as ChatGPT, are another way that scientists are adding details to protein structure predictions. Zou used GPT-4 to “fine tune” a protein language model, called evolutionary scale modeling (ESM-2), which predicts protein structures directly from a protein sequence.

First, they trained ChatGPT on thousands of papers and studies containing information about the functions, biophysical properties, and disease relevance of different mutations. Next, they used the trained model to “teach” ESM-2, boosting its ability “to predict which mutations are likely to have larger effects or smaller effects,” Zou said. The same could be done for a model like AlphaFold, according to Zou.

“They are quite complementary in that the large language model contains a lot more information about the functions and the biophysics of different mutations and proteins as captured in text,” he said, whereas “you can’t give AlphaFold a piece of paper.”

Exactly how AlphaFold makes its predictions is another mystery. “It will somehow learn protein dynamics phenomenologically,” said Monteiro da Silva. He and others are trying to understand how that happens, in hopes of creating even more accurate predictive models. But for the time being, AI-based methods still need assistance from physics.

“The dream is that we achieve a state where we rely on just the fast methods, and they’re accurate enough,” he said. “But we’re so far from that.”

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

I would like to briefly talk about a very interesting paper and one that probably has about as much to inform the doctor-patient relationship as any paper you can think of. 

The title itself gives you a little bit of that answer before I even discuss the outcome. The paper is “The Benefits of Quitting Smoking at Different Ages,” recently published in The American Journal of Preventive Medicine.

I’m not going to even begin to attempt to explore the statistics of the analysis, but I think the conclusions are both fascinating and important. I will read the first sentence of the results and then just comment on some of the others because there’s just so much data here and I really want to focus on the punchline. 

The results section said that, compared with people who never smoked, those who smoke currently, aged 35, 45, 55, 65, or 75, (those were all the groups they looked at), and who have smoked throughout adulthood until that age will lose an average of 9.1, 8.3, 7.3, 5.9, and 4.4 years of life, respectively — obviously, it’s a lot — if they continue to smoke for the rest of their lives. 

If somebody is smoking at age 35 and they continue to smoke, they could lose 9 years of life on average. We know that. It’s terrible. That’s why people should never smoke. Period. End of story. There’s no social value. There’s no health value of smoking. It’s a deadly recreational activity for multiple illnesses, and obviously, cancer is prominent among them.

Here’s the conclusion of the paper that I think is interesting. That doctor, whether it’s a primary care doctor, an oncologist, an ob/gyn, or a family doctor, is seeing Mr Smith or Mrs Jones in the office today, whether they know that patient well or not very well, and they’re still smoking. However, if the person we’re describing here quits smoking at these ages, how much life do they add back, compared with if they continued?

They may say: “Oh, I’ve been smoking all my life. What difference does it make? The die is cast.” Wrong! If you’ve been smoking your whole adult life — so let’s just say that you started at age 18, age 20, age 15, or even age 12 — but you quit smoking at the age of 35, you’re going to add 8 years of life on average. If you quit smoking when you’re 65, having smoked your whole adult life, you will add 1.7 years of life. That’s 1.7 years to be with your family, to be with your grandchildren, and enjoy life. If you ask, “Oh, what difference does it make?” It makes a big difference. 

I’ll share another statistic and I’ll be done. I think this is really an interesting one. The chances of gaining at least a year of life among those who quit smoking at the age of 65 was 23.4%. There is a 1 out of 4 chance that you’re going to live an additional year if you stop at age 65. Even if you stop smoking at age 75, you have a 14% chance of living at least an additional year longer than you would have if you didn’t stop smoking. 

There is much to think about here, much to consider, and much to discuss potentially with patients.

Dr. Markman is Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix. He reported conflicts of interest with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

I would like to briefly talk about a very interesting paper and one that probably has about as much to inform the doctor-patient relationship as any paper you can think of. 

The title itself gives you a little bit of that answer before I even discuss the outcome. The paper is “The Benefits of Quitting Smoking at Different Ages,” recently published in The American Journal of Preventive Medicine.

I’m not going to even begin to attempt to explore the statistics of the analysis, but I think the conclusions are both fascinating and important. I will read the first sentence of the results and then just comment on some of the others because there’s just so much data here and I really want to focus on the punchline. 

The results section said that, compared with people who never smoked, those who smoke currently, aged 35, 45, 55, 65, or 75, (those were all the groups they looked at), and who have smoked throughout adulthood until that age will lose an average of 9.1, 8.3, 7.3, 5.9, and 4.4 years of life, respectively — obviously, it’s a lot — if they continue to smoke for the rest of their lives. 

If somebody is smoking at age 35 and they continue to smoke, they could lose 9 years of life on average. We know that. It’s terrible. That’s why people should never smoke. Period. End of story. There’s no social value. There’s no health value of smoking. It’s a deadly recreational activity for multiple illnesses, and obviously, cancer is prominent among them.

Here’s the conclusion of the paper that I think is interesting. That doctor, whether it’s a primary care doctor, an oncologist, an ob/gyn, or a family doctor, is seeing Mr Smith or Mrs Jones in the office today, whether they know that patient well or not very well, and they’re still smoking. However, if the person we’re describing here quits smoking at these ages, how much life do they add back, compared with if they continued?

They may say: “Oh, I’ve been smoking all my life. What difference does it make? The die is cast.” Wrong! If you’ve been smoking your whole adult life — so let’s just say that you started at age 18, age 20, age 15, or even age 12 — but you quit smoking at the age of 35, you’re going to add 8 years of life on average. If you quit smoking when you’re 65, having smoked your whole adult life, you will add 1.7 years of life. That’s 1.7 years to be with your family, to be with your grandchildren, and enjoy life. If you ask, “Oh, what difference does it make?” It makes a big difference. 

I’ll share another statistic and I’ll be done. I think this is really an interesting one. The chances of gaining at least a year of life among those who quit smoking at the age of 65 was 23.4%. There is a 1 out of 4 chance that you’re going to live an additional year if you stop at age 65. Even if you stop smoking at age 75, you have a 14% chance of living at least an additional year longer than you would have if you didn’t stop smoking. 

There is much to think about here, much to consider, and much to discuss potentially with patients.

Dr. Markman is Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix. He reported conflicts of interest with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

I would like to briefly talk about a very interesting paper and one that probably has about as much to inform the doctor-patient relationship as any paper you can think of. 

The title itself gives you a little bit of that answer before I even discuss the outcome. The paper is “The Benefits of Quitting Smoking at Different Ages,” recently published in The American Journal of Preventive Medicine.

I’m not going to even begin to attempt to explore the statistics of the analysis, but I think the conclusions are both fascinating and important. I will read the first sentence of the results and then just comment on some of the others because there’s just so much data here and I really want to focus on the punchline. 

The results section said that, compared with people who never smoked, those who smoke currently, aged 35, 45, 55, 65, or 75, (those were all the groups they looked at), and who have smoked throughout adulthood until that age will lose an average of 9.1, 8.3, 7.3, 5.9, and 4.4 years of life, respectively — obviously, it’s a lot — if they continue to smoke for the rest of their lives. 

If somebody is smoking at age 35 and they continue to smoke, they could lose 9 years of life on average. We know that. It’s terrible. That’s why people should never smoke. Period. End of story. There’s no social value. There’s no health value of smoking. It’s a deadly recreational activity for multiple illnesses, and obviously, cancer is prominent among them.

Here’s the conclusion of the paper that I think is interesting. That doctor, whether it’s a primary care doctor, an oncologist, an ob/gyn, or a family doctor, is seeing Mr Smith or Mrs Jones in the office today, whether they know that patient well or not very well, and they’re still smoking. However, if the person we’re describing here quits smoking at these ages, how much life do they add back, compared with if they continued?

They may say: “Oh, I’ve been smoking all my life. What difference does it make? The die is cast.” Wrong! If you’ve been smoking your whole adult life — so let’s just say that you started at age 18, age 20, age 15, or even age 12 — but you quit smoking at the age of 35, you’re going to add 8 years of life on average. If you quit smoking when you’re 65, having smoked your whole adult life, you will add 1.7 years of life. That’s 1.7 years to be with your family, to be with your grandchildren, and enjoy life. If you ask, “Oh, what difference does it make?” It makes a big difference. 

I’ll share another statistic and I’ll be done. I think this is really an interesting one. The chances of gaining at least a year of life among those who quit smoking at the age of 65 was 23.4%. There is a 1 out of 4 chance that you’re going to live an additional year if you stop at age 65. Even if you stop smoking at age 75, you have a 14% chance of living at least an additional year longer than you would have if you didn’t stop smoking. 

There is much to think about here, much to consider, and much to discuss potentially with patients.

Dr. Markman is Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix. He reported conflicts of interest with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

Introduction
Large cell neuroendocrine carcinomas (LCNEC) of the lung are sufficiently rare that large trials to establish a standard of care are impractical. Treatment strategies effective for related malignancies, particularly small-cell lung cancer (SCLC), have been commonly applied to LCNEC of the lung, but it is important to recognize the unique features of LCNEC in order to make a diagnosis and to individualize treatment. As current long-term survival in patients with LCNEC of the lung remains poor, participation in clinical trials should be encouraged. Therapies under investigation include those targeted at the delta-like ligand 3 (DLL3), an antigen highly expressed in neuroendocrine (NE) tumors, and Seneca Valley oncolytic viral (SVV) therapy. Early introduction of palliative care should also be offered to optimize quality of life. High-quality data for LCNEC of the lung and novel breakthrough drugs are much needed.

Background
NE tumors can develop from NE cells in almost any organ.¹ After the gastrointestinal tract, the lung is the most common site of NE malignancies. They account for only about 2% of all lung cancers but 25% of NE tumors.² Criteria for differentiating NE tumors from other tumors in the lung were first proposed in 1991.³ In 2022, the World Health Organization described 5 major subtypes of NE lung malignancies.⁴ On a spectrum ranging from best to worst outcome among lung cancers, LCNEC has a significantly more aggressive course compared with typical carcinoids (TC) and atypical carcinoids (AC), approaching that of SCLC, which arguably has the worst outcome (Table).⁵

Table. Comparing NSCLC, SCLC, and LCNEC of the Lung

Similarities exist between LCNEC of the lung and other non-small cell lung cancer (NSCLC) types, but there are more parallels with SCLC. Both are more common in male patients and both are associated with a history of smoking.⁶ They also share a poor prognosis. If diagnosed at an advanced stage, 5-year survival rates for LCNEC of the lung and SCLC have been reported to be as low as 5% to 15%.⁶

The risk of a delay in establishing the correct diagnosis of LCNEC of the lung, even by experienced pathologists, is considerable. The key diagnostic criteria include expression of at least 1 NE marker, such as chromogranin-A or synaptophysin, a high proliferation rate (> 10 mitoses per high-power field), extensive necrosis, and NE morphology features, such as trabeculae and palisading and rosette formations.⁷ However, other lung cancers can also express NE markers and some features might be missed without relatively large tissue specimens.⁷

To improve diagnostic accuracy, additional criteria, such as absence of squamous or adenocarcinoma features or the demonstration of 2 or more NE markers are now being advocated in some reports,⁸ while others have advocated that terms such as “combined NSCLC/SCLC” should not be accepted as a substitute for differentiating and finalizing a diagnosis of LCNEC of the lung.⁷ Excisional or resection biopsies, as opposed to needle biopsies, might be required to obtain an adequate tissue sample to reach a definitive diagnosis.

Illustrating the potential for confusion with other lung cancers, LCNEC of the lung can be characterized by 2 subtypes.⁹ Type 1 is characterized by TP53 and STK11/KEAP1 alternations—similar to adenocarcinomas and squamous cell lung cancers—and it is associated with a higher expression of NE markers, such as ASCL1 and DLL3. Type 2 is typically characterized by inactivation of TP53 and RB1. Ultimately, type I LCNEC of the lung has a mutational pattern similar to NSCLC and type II has a pattern similar to SCLC. While LCNEC is typically located in the periphery of the lung, SCLC is typically centrally located and NSCLC can be found in either location. Complicated further by the fact that a proportion of these tumors have features shared with SCLC and rarer cancers, such as spindle-cell carcinoma and giant cell carcinoma, LCNEC should be considered in the differential diagnosis of any lung cancer with ambiguous features.⁷

For these reasons, a pathology review should be performed at a high-volume center whenever possible. As part of the diagnostic process, molecular testing should be gathered for all patients whether or not it is required to make or confirm the diagnosis. This information will be informative for guiding treatment, particularly second- and third-line interventions. Rather than being unique and definitive, the individual features of LCNEC of the lung—including the genetic, molecular, histologic, and morphologic characteristics—cumulatively support the diagnosis. After establishing a pathological diagnosis, staging of LCNEC of the lung is paramount. In addition, distinctions between the grades of LCNEC of the lung are relative. For example, tumors with a better relative prognosis typically have fewer gene mutations than tumors with a worse relative prognosis, but mutations are generally found in both.

Bronchoscopy with endobronchial ultrasound can be considered for both diagnosis and staging of locally advanced tumors, but a surgical specimen might still be required for a definitive diagnosis. Differentiating local LCNEC, which has been reported in about 25% of cases, from locally advanced and metastatic disease is critical for planning treatment. Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) plays an important role in staging LCNEC of the lung. Unlike TC and AC, for LCNEC of the lung there is a very limited role of somatostatin receptor agonist-based imaging or tetraazacyclododecanetetraacetic acid-DPhel-Tyr3-octreotate (DOTATATE) PET during diagnostic workup.

Therapeutic Strategies
In early stages, resection followed by adjuvant chemotherapy has long been used for LCNEC of the lung. Studies evaluating this approach, such as one that combined cisplatin and etoposide,¹⁰ suggest doublet chemotherapy after surgery offers a benefit in LCNEC of the lung comparable to that seen in SCLC. There is limited support for adjunctive radiotherapy in early-stage LCNEC of the lung,⁵ even if radiotherapy has shown benefit for patients ineligible for surgery.¹¹

In locally advanced and advanced LCNEC (≥ stage III-B) ineligible for resection, chemoradiation has been associated with a survival advantage over chemotherapy alone,¹² but due to the high rates of relapse and limited survival, efforts to move to novel therapies have been expanding for both LCNEC of the lung and SCLC. This includes immunotherapies used before or after chemoradiation. Again, much of the interest in immunotherapies has been derived from studies in SCLC, but several small studies have associated checkpoint inhibitors with substantial antitumor activity in patients with LCNEC.^13,14 There are no large scale prospective trials to determine the optimal treatment in the first line setting for LCNEC of the lung and most data is extrapolated from treatment of ES-SCLC. In a retrospective study, however, comparing survival of palliative chemotherapy with a SCLC versus a NSCLC regimen, the SCLC regimen was favored.¹⁵

Following a pivotal trial of tarlatamab-dlle, that led to an accelerated approval for extensive-stage SCLC in May 2024,¹⁶ this drug has also been evaluated in a small group of patients with LCNEC of the lung. The parallels between LCNEC and SCLC have raised hope that this drug, which is a bispecific T-cell engager (BiTE) that binds to the DLL3 ligand and CD3, may provide benefit in LCNEC of the lung that is commensurate with the benefit seen in SCLC. A recently published LCNEC case study supports this potential.¹⁷ A high-grade NE-carcinoma-specific oncolytic virus called Seneca Valley virus holds promise. Preclinical data suggest encouraging anticancer activity when SVV is combined with immune checkpoint inhibitor therapy.¹⁸ SVV seems to attack cancer cells that express tumor endothelial marker 8 (TEM-8), making it an interesting target in future efforts for screening and tailoring treatment.¹⁹ Human studies are in development.

Due to the high frequency of relapse regardless of frontline therapies, there is also growing interest in maintenance strategies to extend disease control. Maintenance regimens that have been evaluated or are being considered include immunotherapies, even if the optimal sequence of treatment modalities remains unknown. The high rate of relapse also encourages early planning of sequential therapies based on molecular testing. Numerous studies of LCNEC of the lung have now identified activating mutations in targetable pathways, such as P13K/AKT/mTOR, KRAS, and FGFR1.¹⁸ Patients may also harbor a high tumor mutation burden, a characteristic that might favor treatment with immunotherapy. Each mutation is relevant to only a small proportion of patients with LCNEC. However, when all potentially targetable mutations are considered together, the proportion of patients with LCNEC who would benefit from an individualized therapy is substantial, thus supporting trials of individualized therapy, particularly in the second line.

The high rate of relapse with currently available therapies encourages enrollment in clinical trials, particularly among patients who have already failed a first-line strategy. In the United States, studies are enrolling patients with LCNEC of the lung for checkpoint inhibitors with or without combination chemotherapy, novel BiTE therapies, and novel therapies targeting specific activating pathways. Many of these trials offer enrollment to patients with either SCLC or LCNEC.

Due to poor survival, patients with advancing LCNEC of the lung should be considered for palliative care. Although no guideline protocol exists for palliative care, the American Society of Clinical Oncology recommends palliative care for all individuals with advanced cancer based on evidence of improved quality of life and, in some cases, survival.²⁰ 

Summary
LCNEC is an uncommon lung malignancy with a poor prognosis in the advanced stages at which it is most often recognized. The risk of overlooking this cancer in the initial diagnosis emphasizes the need for an adequate index of suspicion and familiarity with its distinguishing characteristics. Treatments of LCNEC of the lung have been largely based on those used for SCLC, but there has been an evolution in the understanding of this disease, which includes a greater appreciation for heterogeneity among driving mutations, a growing interest in maintenance therapies to extend the time to relapse, and trials of a growing array of novel therapies, including immunotherapies and BiTEs. Early intervention with these novel therapies and an emphasis on palliative care is needed because LCNEC has such an aggressive course.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Large cell neuroendocrine carcinomas (LCNEC) of the lung are sufficiently rare that large trials to establish a standard of care are impractical. Treatment strategies effective for related malignancies, particularly small-cell lung cancer (SCLC), have been commonly applied to LCNEC of the lung, but it is important to recognize the unique features of LCNEC in order to make a diagnosis and to individualize treatment. As current long-term survival in patients with LCNEC of the lung remains poor, participation in clinical trials should be encouraged. Therapies under investigation include those targeted at the delta-like ligand 3 (DLL3), an antigen highly expressed in neuroendocrine (NE) tumors, and Seneca Valley oncolytic viral (SVV) therapy. Early introduction of palliative care should also be offered to optimize quality of life. High-quality data for LCNEC of the lung and novel breakthrough drugs are much needed.

Background
NE tumors can develop from NE cells in almost any organ.¹ After the gastrointestinal tract, the lung is the most common site of NE malignancies. They account for only about 2% of all lung cancers but 25% of NE tumors.² Criteria for differentiating NE tumors from other tumors in the lung were first proposed in 1991.³ In 2022, the World Health Organization described 5 major subtypes of NE lung malignancies.⁴ On a spectrum ranging from best to worst outcome among lung cancers, LCNEC has a significantly more aggressive course compared with typical carcinoids (TC) and atypical carcinoids (AC), approaching that of SCLC, which arguably has the worst outcome (Table).⁵

Table. Comparing NSCLC, SCLC, and LCNEC of the Lung

Similarities exist between LCNEC of the lung and other non-small cell lung cancer (NSCLC) types, but there are more parallels with SCLC. Both are more common in male patients and both are associated with a history of smoking.⁶ They also share a poor prognosis. If diagnosed at an advanced stage, 5-year survival rates for LCNEC of the lung and SCLC have been reported to be as low as 5% to 15%.⁶

The risk of a delay in establishing the correct diagnosis of LCNEC of the lung, even by experienced pathologists, is considerable. The key diagnostic criteria include expression of at least 1 NE marker, such as chromogranin-A or synaptophysin, a high proliferation rate (> 10 mitoses per high-power field), extensive necrosis, and NE morphology features, such as trabeculae and palisading and rosette formations.⁷ However, other lung cancers can also express NE markers and some features might be missed without relatively large tissue specimens.⁷

To improve diagnostic accuracy, additional criteria, such as absence of squamous or adenocarcinoma features or the demonstration of 2 or more NE markers are now being advocated in some reports,⁸ while others have advocated that terms such as “combined NSCLC/SCLC” should not be accepted as a substitute for differentiating and finalizing a diagnosis of LCNEC of the lung.⁷ Excisional or resection biopsies, as opposed to needle biopsies, might be required to obtain an adequate tissue sample to reach a definitive diagnosis.

Illustrating the potential for confusion with other lung cancers, LCNEC of the lung can be characterized by 2 subtypes.⁹ Type 1 is characterized by TP53 and STK11/KEAP1 alternations—similar to adenocarcinomas and squamous cell lung cancers—and it is associated with a higher expression of NE markers, such as ASCL1 and DLL3. Type 2 is typically characterized by inactivation of TP53 and RB1. Ultimately, type I LCNEC of the lung has a mutational pattern similar to NSCLC and type II has a pattern similar to SCLC. While LCNEC is typically located in the periphery of the lung, SCLC is typically centrally located and NSCLC can be found in either location. Complicated further by the fact that a proportion of these tumors have features shared with SCLC and rarer cancers, such as spindle-cell carcinoma and giant cell carcinoma, LCNEC should be considered in the differential diagnosis of any lung cancer with ambiguous features.⁷

For these reasons, a pathology review should be performed at a high-volume center whenever possible. As part of the diagnostic process, molecular testing should be gathered for all patients whether or not it is required to make or confirm the diagnosis. This information will be informative for guiding treatment, particularly second- and third-line interventions. Rather than being unique and definitive, the individual features of LCNEC of the lung—including the genetic, molecular, histologic, and morphologic characteristics—cumulatively support the diagnosis. After establishing a pathological diagnosis, staging of LCNEC of the lung is paramount. In addition, distinctions between the grades of LCNEC of the lung are relative. For example, tumors with a better relative prognosis typically have fewer gene mutations than tumors with a worse relative prognosis, but mutations are generally found in both.

Bronchoscopy with endobronchial ultrasound can be considered for both diagnosis and staging of locally advanced tumors, but a surgical specimen might still be required for a definitive diagnosis. Differentiating local LCNEC, which has been reported in about 25% of cases, from locally advanced and metastatic disease is critical for planning treatment. Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) plays an important role in staging LCNEC of the lung. Unlike TC and AC, for LCNEC of the lung there is a very limited role of somatostatin receptor agonist-based imaging or tetraazacyclododecanetetraacetic acid-DPhel-Tyr3-octreotate (DOTATATE) PET during diagnostic workup.

Therapeutic Strategies
In early stages, resection followed by adjuvant chemotherapy has long been used for LCNEC of the lung. Studies evaluating this approach, such as one that combined cisplatin and etoposide,¹⁰ suggest doublet chemotherapy after surgery offers a benefit in LCNEC of the lung comparable to that seen in SCLC. There is limited support for adjunctive radiotherapy in early-stage LCNEC of the lung,⁵ even if radiotherapy has shown benefit for patients ineligible for surgery.¹¹

In locally advanced and advanced LCNEC (≥ stage III-B) ineligible for resection, chemoradiation has been associated with a survival advantage over chemotherapy alone,¹² but due to the high rates of relapse and limited survival, efforts to move to novel therapies have been expanding for both LCNEC of the lung and SCLC. This includes immunotherapies used before or after chemoradiation. Again, much of the interest in immunotherapies has been derived from studies in SCLC, but several small studies have associated checkpoint inhibitors with substantial antitumor activity in patients with LCNEC.^13,14 There are no large scale prospective trials to determine the optimal treatment in the first line setting for LCNEC of the lung and most data is extrapolated from treatment of ES-SCLC. In a retrospective study, however, comparing survival of palliative chemotherapy with a SCLC versus a NSCLC regimen, the SCLC regimen was favored.¹⁵

Following a pivotal trial of tarlatamab-dlle, that led to an accelerated approval for extensive-stage SCLC in May 2024,¹⁶ this drug has also been evaluated in a small group of patients with LCNEC of the lung. The parallels between LCNEC and SCLC have raised hope that this drug, which is a bispecific T-cell engager (BiTE) that binds to the DLL3 ligand and CD3, may provide benefit in LCNEC of the lung that is commensurate with the benefit seen in SCLC. A recently published LCNEC case study supports this potential.¹⁷ A high-grade NE-carcinoma-specific oncolytic virus called Seneca Valley virus holds promise. Preclinical data suggest encouraging anticancer activity when SVV is combined with immune checkpoint inhibitor therapy.¹⁸ SVV seems to attack cancer cells that express tumor endothelial marker 8 (TEM-8), making it an interesting target in future efforts for screening and tailoring treatment.¹⁹ Human studies are in development.

Due to the high frequency of relapse regardless of frontline therapies, there is also growing interest in maintenance strategies to extend disease control. Maintenance regimens that have been evaluated or are being considered include immunotherapies, even if the optimal sequence of treatment modalities remains unknown. The high rate of relapse also encourages early planning of sequential therapies based on molecular testing. Numerous studies of LCNEC of the lung have now identified activating mutations in targetable pathways, such as P13K/AKT/mTOR, KRAS, and FGFR1.¹⁸ Patients may also harbor a high tumor mutation burden, a characteristic that might favor treatment with immunotherapy. Each mutation is relevant to only a small proportion of patients with LCNEC. However, when all potentially targetable mutations are considered together, the proportion of patients with LCNEC who would benefit from an individualized therapy is substantial, thus supporting trials of individualized therapy, particularly in the second line.

The high rate of relapse with currently available therapies encourages enrollment in clinical trials, particularly among patients who have already failed a first-line strategy. In the United States, studies are enrolling patients with LCNEC of the lung for checkpoint inhibitors with or without combination chemotherapy, novel BiTE therapies, and novel therapies targeting specific activating pathways. Many of these trials offer enrollment to patients with either SCLC or LCNEC.

Due to poor survival, patients with advancing LCNEC of the lung should be considered for palliative care. Although no guideline protocol exists for palliative care, the American Society of Clinical Oncology recommends palliative care for all individuals with advanced cancer based on evidence of improved quality of life and, in some cases, survival.²⁰ 

Summary
LCNEC is an uncommon lung malignancy with a poor prognosis in the advanced stages at which it is most often recognized. The risk of overlooking this cancer in the initial diagnosis emphasizes the need for an adequate index of suspicion and familiarity with its distinguishing characteristics. Treatments of LCNEC of the lung have been largely based on those used for SCLC, but there has been an evolution in the understanding of this disease, which includes a greater appreciation for heterogeneity among driving mutations, a growing interest in maintenance therapies to extend the time to relapse, and trials of a growing array of novel therapies, including immunotherapies and BiTEs. Early intervention with these novel therapies and an emphasis on palliative care is needed because LCNEC has such an aggressive course.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Large cell neuroendocrine carcinomas (LCNEC) of the lung are sufficiently rare that large trials to establish a standard of care are impractical. Treatment strategies effective for related malignancies, particularly small-cell lung cancer (SCLC), have been commonly applied to LCNEC of the lung, but it is important to recognize the unique features of LCNEC in order to make a diagnosis and to individualize treatment. As current long-term survival in patients with LCNEC of the lung remains poor, participation in clinical trials should be encouraged. Therapies under investigation include those targeted at the delta-like ligand 3 (DLL3), an antigen highly expressed in neuroendocrine (NE) tumors, and Seneca Valley oncolytic viral (SVV) therapy. Early introduction of palliative care should also be offered to optimize quality of life. High-quality data for LCNEC of the lung and novel breakthrough drugs are much needed.

Background
NE tumors can develop from NE cells in almost any organ.¹ After the gastrointestinal tract, the lung is the most common site of NE malignancies. They account for only about 2% of all lung cancers but 25% of NE tumors.² Criteria for differentiating NE tumors from other tumors in the lung were first proposed in 1991.³ In 2022, the World Health Organization described 5 major subtypes of NE lung malignancies.⁴ On a spectrum ranging from best to worst outcome among lung cancers, LCNEC has a significantly more aggressive course compared with typical carcinoids (TC) and atypical carcinoids (AC), approaching that of SCLC, which arguably has the worst outcome (Table).⁵

Table. Comparing NSCLC, SCLC, and LCNEC of the Lung

Similarities exist between LCNEC of the lung and other non-small cell lung cancer (NSCLC) types, but there are more parallels with SCLC. Both are more common in male patients and both are associated with a history of smoking.⁶ They also share a poor prognosis. If diagnosed at an advanced stage, 5-year survival rates for LCNEC of the lung and SCLC have been reported to be as low as 5% to 15%.⁶

The risk of a delay in establishing the correct diagnosis of LCNEC of the lung, even by experienced pathologists, is considerable. The key diagnostic criteria include expression of at least 1 NE marker, such as chromogranin-A or synaptophysin, a high proliferation rate (> 10 mitoses per high-power field), extensive necrosis, and NE morphology features, such as trabeculae and palisading and rosette formations.⁷ However, other lung cancers can also express NE markers and some features might be missed without relatively large tissue specimens.⁷

To improve diagnostic accuracy, additional criteria, such as absence of squamous or adenocarcinoma features or the demonstration of 2 or more NE markers are now being advocated in some reports,⁸ while others have advocated that terms such as “combined NSCLC/SCLC” should not be accepted as a substitute for differentiating and finalizing a diagnosis of LCNEC of the lung.⁷ Excisional or resection biopsies, as opposed to needle biopsies, might be required to obtain an adequate tissue sample to reach a definitive diagnosis.

Illustrating the potential for confusion with other lung cancers, LCNEC of the lung can be characterized by 2 subtypes.⁹ Type 1 is characterized by TP53 and STK11/KEAP1 alternations—similar to adenocarcinomas and squamous cell lung cancers—and it is associated with a higher expression of NE markers, such as ASCL1 and DLL3. Type 2 is typically characterized by inactivation of TP53 and RB1. Ultimately, type I LCNEC of the lung has a mutational pattern similar to NSCLC and type II has a pattern similar to SCLC. While LCNEC is typically located in the periphery of the lung, SCLC is typically centrally located and NSCLC can be found in either location. Complicated further by the fact that a proportion of these tumors have features shared with SCLC and rarer cancers, such as spindle-cell carcinoma and giant cell carcinoma, LCNEC should be considered in the differential diagnosis of any lung cancer with ambiguous features.⁷

For these reasons, a pathology review should be performed at a high-volume center whenever possible. As part of the diagnostic process, molecular testing should be gathered for all patients whether or not it is required to make or confirm the diagnosis. This information will be informative for guiding treatment, particularly second- and third-line interventions. Rather than being unique and definitive, the individual features of LCNEC of the lung—including the genetic, molecular, histologic, and morphologic characteristics—cumulatively support the diagnosis. After establishing a pathological diagnosis, staging of LCNEC of the lung is paramount. In addition, distinctions between the grades of LCNEC of the lung are relative. For example, tumors with a better relative prognosis typically have fewer gene mutations than tumors with a worse relative prognosis, but mutations are generally found in both.

Bronchoscopy with endobronchial ultrasound can be considered for both diagnosis and staging of locally advanced tumors, but a surgical specimen might still be required for a definitive diagnosis. Differentiating local LCNEC, which has been reported in about 25% of cases, from locally advanced and metastatic disease is critical for planning treatment. Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) plays an important role in staging LCNEC of the lung. Unlike TC and AC, for LCNEC of the lung there is a very limited role of somatostatin receptor agonist-based imaging or tetraazacyclododecanetetraacetic acid-DPhel-Tyr3-octreotate (DOTATATE) PET during diagnostic workup.

Therapeutic Strategies
In early stages, resection followed by adjuvant chemotherapy has long been used for LCNEC of the lung. Studies evaluating this approach, such as one that combined cisplatin and etoposide,¹⁰ suggest doublet chemotherapy after surgery offers a benefit in LCNEC of the lung comparable to that seen in SCLC. There is limited support for adjunctive radiotherapy in early-stage LCNEC of the lung,⁵ even if radiotherapy has shown benefit for patients ineligible for surgery.¹¹

In locally advanced and advanced LCNEC (≥ stage III-B) ineligible for resection, chemoradiation has been associated with a survival advantage over chemotherapy alone,¹² but due to the high rates of relapse and limited survival, efforts to move to novel therapies have been expanding for both LCNEC of the lung and SCLC. This includes immunotherapies used before or after chemoradiation. Again, much of the interest in immunotherapies has been derived from studies in SCLC, but several small studies have associated checkpoint inhibitors with substantial antitumor activity in patients with LCNEC.^13,14 There are no large scale prospective trials to determine the optimal treatment in the first line setting for LCNEC of the lung and most data is extrapolated from treatment of ES-SCLC. In a retrospective study, however, comparing survival of palliative chemotherapy with a SCLC versus a NSCLC regimen, the SCLC regimen was favored.¹⁵

Following a pivotal trial of tarlatamab-dlle, that led to an accelerated approval for extensive-stage SCLC in May 2024,¹⁶ this drug has also been evaluated in a small group of patients with LCNEC of the lung. The parallels between LCNEC and SCLC have raised hope that this drug, which is a bispecific T-cell engager (BiTE) that binds to the DLL3 ligand and CD3, may provide benefit in LCNEC of the lung that is commensurate with the benefit seen in SCLC. A recently published LCNEC case study supports this potential.¹⁷ A high-grade NE-carcinoma-specific oncolytic virus called Seneca Valley virus holds promise. Preclinical data suggest encouraging anticancer activity when SVV is combined with immune checkpoint inhibitor therapy.¹⁸ SVV seems to attack cancer cells that express tumor endothelial marker 8 (TEM-8), making it an interesting target in future efforts for screening and tailoring treatment.¹⁹ Human studies are in development.

Due to the high frequency of relapse regardless of frontline therapies, there is also growing interest in maintenance strategies to extend disease control. Maintenance regimens that have been evaluated or are being considered include immunotherapies, even if the optimal sequence of treatment modalities remains unknown. The high rate of relapse also encourages early planning of sequential therapies based on molecular testing. Numerous studies of LCNEC of the lung have now identified activating mutations in targetable pathways, such as P13K/AKT/mTOR, KRAS, and FGFR1.¹⁸ Patients may also harbor a high tumor mutation burden, a characteristic that might favor treatment with immunotherapy. Each mutation is relevant to only a small proportion of patients with LCNEC. However, when all potentially targetable mutations are considered together, the proportion of patients with LCNEC who would benefit from an individualized therapy is substantial, thus supporting trials of individualized therapy, particularly in the second line.

The high rate of relapse with currently available therapies encourages enrollment in clinical trials, particularly among patients who have already failed a first-line strategy. In the United States, studies are enrolling patients with LCNEC of the lung for checkpoint inhibitors with or without combination chemotherapy, novel BiTE therapies, and novel therapies targeting specific activating pathways. Many of these trials offer enrollment to patients with either SCLC or LCNEC.

Due to poor survival, patients with advancing LCNEC of the lung should be considered for palliative care. Although no guideline protocol exists for palliative care, the American Society of Clinical Oncology recommends palliative care for all individuals with advanced cancer based on evidence of improved quality of life and, in some cases, survival.²⁰ 

Summary
LCNEC is an uncommon lung malignancy with a poor prognosis in the advanced stages at which it is most often recognized. The risk of overlooking this cancer in the initial diagnosis emphasizes the need for an adequate index of suspicion and familiarity with its distinguishing characteristics. Treatments of LCNEC of the lung have been largely based on those used for SCLC, but there has been an evolution in the understanding of this disease, which includes a greater appreciation for heterogeneity among driving mutations, a growing interest in maintenance therapies to extend the time to relapse, and trials of a growing array of novel therapies, including immunotherapies and BiTEs. Early intervention with these novel therapies and an emphasis on palliative care is needed because LCNEC has such an aggressive course.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

National Organization for Rare Disorders: Strengthening Rare Cancer Advocacy
By Alli Ward
NORD's Rare Cancer Coalition has transformed advocacy and awareness efforts, offering education and fostering research to address the challenges of rare cancers.

Treatment of Glioblastoma: A Potential Shift in Paradigm
By Jeffrey N. Bruce, MD
Immunotherapies and molecular profiling are paving the way for more targeted approaches in treating glioblastoma.

Emerging Insights and Therapeutic Strategies for Large Cell Neuroendocrine Carcinoma of the Lung
By Robert A. Ramirez, DO, FACP, and Aman Chauhan, MD 
New diagnostic tools and precision medicine approaches are addressing the unique challenges of this aggressive neuroendocrine cancer.

Advancements in the Treatment of Malignant PEComas with mTOR Inhibitors
By Richard F. Riedel, MD
The use of mTOR inhibitors marks significant progress in managing advanced malignant PEComas, offering new hope for patients.

Cutaneous T-Cell Lymphomas Update: Benefits of a Multidisciplinary Care Approach
By Jina Chung, MD, and Eric Mou, MD
A multidisciplinary care model ensures optimal outcomes for patients with cutaneous T-cell lymphomas, addressing both medical and emotional needs.

Optimizing Myelofibrosis Care in the Age of JAK Inhibitors
By Douglas Tremblay, MD
JAK inhibitors are central to myelofibrosis management, with personalized strategies helping to navigate resistance and improve quality of life.

Current Management and Future Directions in the Treatment of Gallbladder Cancer
By Ghassan K. Abou-Alfa, MD, MBA, JD, FASCO
Molecular profiling and immunotherapy are reshaping the treatment paradigm for gallbladder cancer, improving survival outcomes.

Improving Prognosis in Hepatoblastoma: Evolving Risk Stratification and Treatment Strategies
By Greg M. Tiao, MD
Risk stratification and individualized therapies are driving progress in treating hepatoblastoma, with promising advancements on the horizon.

National Organization for Rare Disorders: Strengthening Rare Cancer Advocacy
By Alli Ward
NORD's Rare Cancer Coalition has transformed advocacy and awareness efforts, offering education and fostering research to address the challenges of rare cancers.

Treatment of Glioblastoma: A Potential Shift in Paradigm
By Jeffrey N. Bruce, MD
Immunotherapies and molecular profiling are paving the way for more targeted approaches in treating glioblastoma.

Emerging Insights and Therapeutic Strategies for Large Cell Neuroendocrine Carcinoma of the Lung
By Robert A. Ramirez, DO, FACP, and Aman Chauhan, MD 
New diagnostic tools and precision medicine approaches are addressing the unique challenges of this aggressive neuroendocrine cancer.

Advancements in the Treatment of Malignant PEComas with mTOR Inhibitors
By Richard F. Riedel, MD
The use of mTOR inhibitors marks significant progress in managing advanced malignant PEComas, offering new hope for patients.

Cutaneous T-Cell Lymphomas Update: Benefits of a Multidisciplinary Care Approach
By Jina Chung, MD, and Eric Mou, MD
A multidisciplinary care model ensures optimal outcomes for patients with cutaneous T-cell lymphomas, addressing both medical and emotional needs.

Optimizing Myelofibrosis Care in the Age of JAK Inhibitors
By Douglas Tremblay, MD
JAK inhibitors are central to myelofibrosis management, with personalized strategies helping to navigate resistance and improve quality of life.

Current Management and Future Directions in the Treatment of Gallbladder Cancer
By Ghassan K. Abou-Alfa, MD, MBA, JD, FASCO
Molecular profiling and immunotherapy are reshaping the treatment paradigm for gallbladder cancer, improving survival outcomes.

Improving Prognosis in Hepatoblastoma: Evolving Risk Stratification and Treatment Strategies
By Greg M. Tiao, MD
Risk stratification and individualized therapies are driving progress in treating hepatoblastoma, with promising advancements on the horizon.

National Organization for Rare Disorders: Strengthening Rare Cancer Advocacy
By Alli Ward
NORD's Rare Cancer Coalition has transformed advocacy and awareness efforts, offering education and fostering research to address the challenges of rare cancers.

Treatment of Glioblastoma: A Potential Shift in Paradigm
By Jeffrey N. Bruce, MD
Immunotherapies and molecular profiling are paving the way for more targeted approaches in treating glioblastoma.

Emerging Insights and Therapeutic Strategies for Large Cell Neuroendocrine Carcinoma of the Lung
By Robert A. Ramirez, DO, FACP, and Aman Chauhan, MD 
New diagnostic tools and precision medicine approaches are addressing the unique challenges of this aggressive neuroendocrine cancer.

Advancements in the Treatment of Malignant PEComas with mTOR Inhibitors
By Richard F. Riedel, MD
The use of mTOR inhibitors marks significant progress in managing advanced malignant PEComas, offering new hope for patients.

Cutaneous T-Cell Lymphomas Update: Benefits of a Multidisciplinary Care Approach
By Jina Chung, MD, and Eric Mou, MD
A multidisciplinary care model ensures optimal outcomes for patients with cutaneous T-cell lymphomas, addressing both medical and emotional needs.

Optimizing Myelofibrosis Care in the Age of JAK Inhibitors
By Douglas Tremblay, MD
JAK inhibitors are central to myelofibrosis management, with personalized strategies helping to navigate resistance and improve quality of life.

Current Management and Future Directions in the Treatment of Gallbladder Cancer
By Ghassan K. Abou-Alfa, MD, MBA, JD, FASCO
Molecular profiling and immunotherapy are reshaping the treatment paradigm for gallbladder cancer, improving survival outcomes.

Improving Prognosis in Hepatoblastoma: Evolving Risk Stratification and Treatment Strategies
By Greg M. Tiao, MD
Risk stratification and individualized therapies are driving progress in treating hepatoblastoma, with promising advancements on the horizon.

When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them. 

The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials. 

During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities. 

In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.

Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.

But is that really the case? 

A recent survey published in The Lancet Oncology aimed to tease out people’s preferences for confirmed clinical benefit vs speedier access. The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works. 

In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios. 

The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).

The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).

The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios. 

Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty. 

Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.

“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.

Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview. 

In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.

“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.

Bishal Gyawali, MD, PhD, was not surprised by the findings. 

“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview. 

“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”

However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added. 

What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.

The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.

A version of this article first appeared on Medscape.com.

When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them. 

The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials. 

During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities. 

In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.

Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.

But is that really the case? 

A recent survey published in The Lancet Oncology aimed to tease out people’s preferences for confirmed clinical benefit vs speedier access. The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works. 

In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios. 

The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).

The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).

The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios. 

Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty. 

Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.

“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.

Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview. 

In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.

“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.

Bishal Gyawali, MD, PhD, was not surprised by the findings. 

“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview. 

“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”

However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added. 

What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.

The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.

A version of this article first appeared on Medscape.com.

When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them. 

The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials. 

During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities. 

In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.

Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.

But is that really the case? 

A recent survey published in The Lancet Oncology aimed to tease out people’s preferences for confirmed clinical benefit vs speedier access. The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works. 

In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios. 

The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).

The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).

The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios. 

Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty. 

Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.

“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.

Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview. 

In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.

“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.

Bishal Gyawali, MD, PhD, was not surprised by the findings. 

“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview. 

“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”

However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added. 

What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.

The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.

A version of this article first appeared on Medscape.com.

More than a third of all patients with cancer die in hospitals, a figure that has increased slightly in recent years, while deaths at home have decreased. These findings come from a recent study published in Cancer Epidemiology, which analyzed data on the different places in Italy where end of life occurs.

“Place of death is relevant both for individuals and for the society. Home is universally considered the optimal place of death, while dying in a hospital may be a signal of inappropriate end-of-life care,” wrote the authors, led by Gianmauro Numico, MD, head of the Oncology Department at the Santa Croce e Carle General Hospital in Cuneo, Italy.

“Despite the general trend toward strengthening community-based networks and the increasing number of hospice and long-term care facilities, we oncologists are facing an opposite trend, with many patients spending their last days in the hospital,” Numico explained to Univadis Italy. This observation led to the questions that prompted the study: Is this only a perception among doctors, or is it a real phenomenon? If the latter, why is it happening? As the expert points out, it is a commonly held belief that people today should not die in the hospital, and numerous studies conducted on healthy individuals suggest that 70%-80% of the population would prefer to die at home.

 

What’s Preferable

For their analysis, Numico and colleagues relied on death certificates published by the Italian National Institute of Statistics from 2015 to 2019, excluding data from the pandemic years to avoid potential biases.

The analysis of data pertaining to cancer deaths revealed that approximately 35% of Italian patients with cancer die in hospitals, with a slight increase over the study period. Of the patients who die elsewhere, 40% die at home and 20% die in hospice or other long-term care facilities. Home deaths have decreased by 3.09%, while those in hospices and long-term care facilities have increased by 2.71%, and hospital deaths have risen by 0.3%.

The study also highlighted notable geographical differences: Hospital deaths are more frequent in the north, while in the south, home deaths remain predominant, although hospital admissions are on the rise. “These differences reflect not only access to facilities but also cultural and social variables,” explained Numico. “Some end-of-life issues with cancer patients are more straightforward, while others are difficult to manage outside the hospital,” he said, recalling that many family members and caregivers are afraid they won’t be able to care for their loved ones properly without the support of an appropriate facility and skilled personnel.

Social factors also contribute to the increased use of hospitals for end-of-life care: Without a social and family network, it is often impossible to manage the final stages of life at home. “We cannot guarantee that dying at home is better for everyone; in some cases, the home cannot provide the necessary care and emotional support,” Numico added.

 

Attitudes Need Change

Looking beyond Italy, it is clear that this trend exists in other countries as well. For example, in the Netherlands — where community-based care is highly developed and includes practices such as euthanasia — hospital death rates are higher than those in Italy. In the United States, the trend is different, but this is largely due to the structure of the US healthcare system, where patients bear much of the financial burden of hospital admissions.

“The basic requests of patients and families are clear: They want a safe place that is adequately staffed and where the patient won’t suffer,” said Numico, questioning whether the home is truly the best place to die. “In reality, this is not always the case, and it’s important to focus on the quality of care in the final days rather than just the place of care,” he added.

Ruling out hospitals a priori as a place to die is not a winning strategy, according to the expert. Instead of trying to reverse the trend, he suggests integrating the hospital into a care network that prioritizes the patient’s well-being, regardless of the setting. “Our goal should not be to eliminate hospital deaths — a common request from hospital administrations — but rather to ensure that end-of-life care in hospitals is a dignified experience that respects the needs of the dying and their loved ones,” Numico said. “We must ensure that, wherever the end-of-life process occurs, it should happen in the best way possible, and the hospital must be a part of this overall framework,” he concluded.

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

More than a third of all patients with cancer die in hospitals, a figure that has increased slightly in recent years, while deaths at home have decreased. These findings come from a recent study published in Cancer Epidemiology, which analyzed data on the different places in Italy where end of life occurs.

“Place of death is relevant both for individuals and for the society. Home is universally considered the optimal place of death, while dying in a hospital may be a signal of inappropriate end-of-life care,” wrote the authors, led by Gianmauro Numico, MD, head of the Oncology Department at the Santa Croce e Carle General Hospital in Cuneo, Italy.

“Despite the general trend toward strengthening community-based networks and the increasing number of hospice and long-term care facilities, we oncologists are facing an opposite trend, with many patients spending their last days in the hospital,” Numico explained to Univadis Italy. This observation led to the questions that prompted the study: Is this only a perception among doctors, or is it a real phenomenon? If the latter, why is it happening? As the expert points out, it is a commonly held belief that people today should not die in the hospital, and numerous studies conducted on healthy individuals suggest that 70%-80% of the population would prefer to die at home.

 

What’s Preferable

For their analysis, Numico and colleagues relied on death certificates published by the Italian National Institute of Statistics from 2015 to 2019, excluding data from the pandemic years to avoid potential biases.

The analysis of data pertaining to cancer deaths revealed that approximately 35% of Italian patients with cancer die in hospitals, with a slight increase over the study period. Of the patients who die elsewhere, 40% die at home and 20% die in hospice or other long-term care facilities. Home deaths have decreased by 3.09%, while those in hospices and long-term care facilities have increased by 2.71%, and hospital deaths have risen by 0.3%.

The study also highlighted notable geographical differences: Hospital deaths are more frequent in the north, while in the south, home deaths remain predominant, although hospital admissions are on the rise. “These differences reflect not only access to facilities but also cultural and social variables,” explained Numico. “Some end-of-life issues with cancer patients are more straightforward, while others are difficult to manage outside the hospital,” he said, recalling that many family members and caregivers are afraid they won’t be able to care for their loved ones properly without the support of an appropriate facility and skilled personnel.

Social factors also contribute to the increased use of hospitals for end-of-life care: Without a social and family network, it is often impossible to manage the final stages of life at home. “We cannot guarantee that dying at home is better for everyone; in some cases, the home cannot provide the necessary care and emotional support,” Numico added.

 

Attitudes Need Change

Looking beyond Italy, it is clear that this trend exists in other countries as well. For example, in the Netherlands — where community-based care is highly developed and includes practices such as euthanasia — hospital death rates are higher than those in Italy. In the United States, the trend is different, but this is largely due to the structure of the US healthcare system, where patients bear much of the financial burden of hospital admissions.

“The basic requests of patients and families are clear: They want a safe place that is adequately staffed and where the patient won’t suffer,” said Numico, questioning whether the home is truly the best place to die. “In reality, this is not always the case, and it’s important to focus on the quality of care in the final days rather than just the place of care,” he added.

Ruling out hospitals a priori as a place to die is not a winning strategy, according to the expert. Instead of trying to reverse the trend, he suggests integrating the hospital into a care network that prioritizes the patient’s well-being, regardless of the setting. “Our goal should not be to eliminate hospital deaths — a common request from hospital administrations — but rather to ensure that end-of-life care in hospitals is a dignified experience that respects the needs of the dying and their loved ones,” Numico said. “We must ensure that, wherever the end-of-life process occurs, it should happen in the best way possible, and the hospital must be a part of this overall framework,” he concluded.

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

More than a third of all patients with cancer die in hospitals, a figure that has increased slightly in recent years, while deaths at home have decreased. These findings come from a recent study published in Cancer Epidemiology, which analyzed data on the different places in Italy where end of life occurs.

“Place of death is relevant both for individuals and for the society. Home is universally considered the optimal place of death, while dying in a hospital may be a signal of inappropriate end-of-life care,” wrote the authors, led by Gianmauro Numico, MD, head of the Oncology Department at the Santa Croce e Carle General Hospital in Cuneo, Italy.

“Despite the general trend toward strengthening community-based networks and the increasing number of hospice and long-term care facilities, we oncologists are facing an opposite trend, with many patients spending their last days in the hospital,” Numico explained to Univadis Italy. This observation led to the questions that prompted the study: Is this only a perception among doctors, or is it a real phenomenon? If the latter, why is it happening? As the expert points out, it is a commonly held belief that people today should not die in the hospital, and numerous studies conducted on healthy individuals suggest that 70%-80% of the population would prefer to die at home.

 

What’s Preferable

For their analysis, Numico and colleagues relied on death certificates published by the Italian National Institute of Statistics from 2015 to 2019, excluding data from the pandemic years to avoid potential biases.

The analysis of data pertaining to cancer deaths revealed that approximately 35% of Italian patients with cancer die in hospitals, with a slight increase over the study period. Of the patients who die elsewhere, 40% die at home and 20% die in hospice or other long-term care facilities. Home deaths have decreased by 3.09%, while those in hospices and long-term care facilities have increased by 2.71%, and hospital deaths have risen by 0.3%.

The study also highlighted notable geographical differences: Hospital deaths are more frequent in the north, while in the south, home deaths remain predominant, although hospital admissions are on the rise. “These differences reflect not only access to facilities but also cultural and social variables,” explained Numico. “Some end-of-life issues with cancer patients are more straightforward, while others are difficult to manage outside the hospital,” he said, recalling that many family members and caregivers are afraid they won’t be able to care for their loved ones properly without the support of an appropriate facility and skilled personnel.

Social factors also contribute to the increased use of hospitals for end-of-life care: Without a social and family network, it is often impossible to manage the final stages of life at home. “We cannot guarantee that dying at home is better for everyone; in some cases, the home cannot provide the necessary care and emotional support,” Numico added.

 

Attitudes Need Change

Looking beyond Italy, it is clear that this trend exists in other countries as well. For example, in the Netherlands — where community-based care is highly developed and includes practices such as euthanasia — hospital death rates are higher than those in Italy. In the United States, the trend is different, but this is largely due to the structure of the US healthcare system, where patients bear much of the financial burden of hospital admissions.

“The basic requests of patients and families are clear: They want a safe place that is adequately staffed and where the patient won’t suffer,” said Numico, questioning whether the home is truly the best place to die. “In reality, this is not always the case, and it’s important to focus on the quality of care in the final days rather than just the place of care,” he added.

Ruling out hospitals a priori as a place to die is not a winning strategy, according to the expert. Instead of trying to reverse the trend, he suggests integrating the hospital into a care network that prioritizes the patient’s well-being, regardless of the setting. “Our goal should not be to eliminate hospital deaths — a common request from hospital administrations — but rather to ensure that end-of-life care in hospitals is a dignified experience that respects the needs of the dying and their loved ones,” Numico said. “We must ensure that, wherever the end-of-life process occurs, it should happen in the best way possible, and the hospital must be a part of this overall framework,” he concluded.

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

A version of this article first appeared on Medscape.com.

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

A version of this article first appeared on Medscape.com.

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

A version of this article first appeared on Medscape.com.