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Personalized cancer vaccine shows early promise across tumor types
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
FROM AACR 2021
Rankings of most common cancers to shift over next 20 years
The next 20 years will see a big shift in cancer type rankings, researchers predict.
At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.
the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.
These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.
The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.
Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.
“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.
The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.
The projected, estimated numbers are not ironclad, the researchers acknowledged.
“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.
“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.
Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.
“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
Difference in opinion on prostate cancer
The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.
“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.
“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.
Dr. Miller casts doubt on this prediction.
Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”
Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.
For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.
The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The next 20 years will see a big shift in cancer type rankings, researchers predict.
At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.
the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.
These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.
The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.
Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.
“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.
The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.
The projected, estimated numbers are not ironclad, the researchers acknowledged.
“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.
“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.
Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.
“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
Difference in opinion on prostate cancer
The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.
“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.
“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.
Dr. Miller casts doubt on this prediction.
Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”
Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.
For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.
The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The next 20 years will see a big shift in cancer type rankings, researchers predict.
At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.
the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.
These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.
The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.
Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.
“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.
The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.
The projected, estimated numbers are not ironclad, the researchers acknowledged.
“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.
“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.
Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.
“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
Difference in opinion on prostate cancer
The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.
“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.
“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.
Dr. Miller casts doubt on this prediction.
Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”
Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.
For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.
The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Presurgical nivo/chemo boosts pCR rates in NSCLC
Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.
However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.
Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.
Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.
This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.
This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.
“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.
Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).
The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.
The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
Change in trial design
Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.
However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).
“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.
Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”
She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.
“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
CheckMate 816 particulars
CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.
Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.
Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.
In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.
Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).
In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
Safety similar
“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.
The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.
Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.
Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.
The investigators are continuing to assess event-free survival and overall survival.
CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.
A version of this article first appeared on Medscape.com.
Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.
However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.
Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.
Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.
This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.
This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.
“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.
Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).
The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.
The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
Change in trial design
Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.
However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).
“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.
Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”
She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.
“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
CheckMate 816 particulars
CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.
Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.
Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.
In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.
Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).
In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
Safety similar
“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.
The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.
Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.
Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.
The investigators are continuing to assess event-free survival and overall survival.
CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.
A version of this article first appeared on Medscape.com.
Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.
However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.
Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.
Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.
This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.
This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.
“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.
Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).
The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.
The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
Change in trial design
Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.
However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).
“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.
Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”
She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.
“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
CheckMate 816 particulars
CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.
Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.
Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.
In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.
Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).
In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
Safety similar
“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.
The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.
Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.
Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.
The investigators are continuing to assess event-free survival and overall survival.
CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.
A version of this article first appeared on Medscape.com.
FROM AACR 2021
Steroid-refractory pneumonitis from ICIs: Experience at major centers
Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.
The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
The Johns Hopkins experience
Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.
Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.
Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.
Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.
Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.
The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.
Overall, clinically relevant findings were:
- Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
- Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
- Some patients improved clinically after IVIg therapy, but mortality was high overall.
- Infliximab therapy, alone or in combination with IVIg, was ineffective.
The Memorial Sloan Kettering experience
Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.
Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.
Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.
The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).
A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.
Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.
The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.
In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.
Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.
Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.
Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.
Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.
Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.
The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
Lessons for clinicians
The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.
Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.
This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.
The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.
Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.
Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.
Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.
Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.
Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.
The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.
The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.
The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
The Johns Hopkins experience
Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.
Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.
Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.
Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.
Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.
The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.
Overall, clinically relevant findings were:
- Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
- Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
- Some patients improved clinically after IVIg therapy, but mortality was high overall.
- Infliximab therapy, alone or in combination with IVIg, was ineffective.
The Memorial Sloan Kettering experience
Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.
Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.
Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.
The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).
A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.
Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.
The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.
In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.
Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.
Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.
Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.
Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.
Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.
The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
Lessons for clinicians
The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.
Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.
This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.
The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.
Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.
Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.
Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.
Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.
Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.
The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.
The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.
The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
The Johns Hopkins experience
Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.
Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.
Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.
Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.
Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.
The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.
Overall, clinically relevant findings were:
- Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
- Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
- Some patients improved clinically after IVIg therapy, but mortality was high overall.
- Infliximab therapy, alone or in combination with IVIg, was ineffective.
The Memorial Sloan Kettering experience
Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.
Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.
Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.
The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).
A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.
Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.
The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.
In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.
Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.
Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.
Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.
Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.
Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.
The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
Lessons for clinicians
The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.
Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.
This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.
The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.
Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.
Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.
Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.
Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.
Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.
The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.
The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Increased cancer risk from night shift due to gene dysregulation?
Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”
But why night shift should elevate the risk for cancer has been unclear.
A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.
“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.
The study was published online in the Journal of Pineal Research.
Study conducted among volunteers
The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.
The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).
After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).
Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.
The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.
The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:
- 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
- 113 (15.6%) were rhythmic in day shift only.
- 96 (13.2%) were rhythmic during night shift only.
- 48 (6.6%) were rhythmic during both shifts.
A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.
Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.
Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
Next steps
The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.
If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.
“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”
The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”
But why night shift should elevate the risk for cancer has been unclear.
A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.
“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.
The study was published online in the Journal of Pineal Research.
Study conducted among volunteers
The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.
The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).
After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).
Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.
The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.
The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:
- 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
- 113 (15.6%) were rhythmic in day shift only.
- 96 (13.2%) were rhythmic during night shift only.
- 48 (6.6%) were rhythmic during both shifts.
A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.
Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.
Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
Next steps
The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.
If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.
“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”
The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”
But why night shift should elevate the risk for cancer has been unclear.
A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.
“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.
The study was published online in the Journal of Pineal Research.
Study conducted among volunteers
The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.
The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).
After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).
Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.
The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.
The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:
- 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
- 113 (15.6%) were rhythmic in day shift only.
- 96 (13.2%) were rhythmic during night shift only.
- 48 (6.6%) were rhythmic during both shifts.
A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.
Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.
Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
Next steps
The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.
If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.
“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”
The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Cancer screening stopped by pandemic: Repercussions to come?
Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.
Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.
“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.
She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).
In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.
“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.
A similar picture has emerged elsewhere.
In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.
In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).
Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.
The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.
There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.
“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.
In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.
By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.
Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.
After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.
The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.
The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.
His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.
In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.
Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.
Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.
“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”
He suspects that there is more at play than screening cancellations.
In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.
“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.
She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.
Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.
Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.
“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.
Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.
Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.
“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”
In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.
Public health initiatives to rebalance the messaging are now underway.
Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”
In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”
“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”
Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.
Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.
“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.
She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).
In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.
“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.
A similar picture has emerged elsewhere.
In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.
In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).
Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.
The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.
There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.
“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.
In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.
By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.
Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.
After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.
The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.
The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.
His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.
In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.
Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.
Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.
“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”
He suspects that there is more at play than screening cancellations.
In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.
“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.
She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.
Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.
Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.
“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.
Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.
Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.
“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”
In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.
Public health initiatives to rebalance the messaging are now underway.
Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”
In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”
“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”
Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.
Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.
“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.
She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).
In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.
“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.
A similar picture has emerged elsewhere.
In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.
In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).
Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.
The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.
There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.
“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.
In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.
By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.
Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.
After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.
The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.
The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.
His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.
In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.
Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.
Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.
“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”
He suspects that there is more at play than screening cancellations.
In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.
“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.
She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.
Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.
Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.
“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.
Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.
Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.
“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”
In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.
Public health initiatives to rebalance the messaging are now underway.
Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”
In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”
“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”
Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Hypofractionated radiotherapy: New normal for lung cancer?
The U.K.-based study showed that patients with stage I-III lung cancer who were set to undergo radiotherapy with curative intent were more likely to receive fewer fractions at higher doses when treated between April and October 2020. During that period, 19% of patients had their radiotherapy dose or fractionation schedule changed to deviate from standard care.
In addition, 8% of patients who were set to undergo surgery ultimately received radiotherapy instead, presumably to ease pressures on already struggling intensive care services, said Kathryn Banfill, MBChB, of Christie NHS Foundation Trust in Manchester, England.
Dr. Banfill presented results from the COVID-RT Lung study at the European Lung Cancer Virtual Congress 2021 (Abstract 203MO).
New guidelines prompt study
When the COVID-19 pandemic began, European and joint European and North American guidelines were issued to try to ensure that lung cancer patients would continue to receive the best possible treatment under the circumstances. This included guidance on how and when to use treatments such as radiotherapy.
One U.K. guideline included recommendations on the use of hypofractionation in the COVID-19 era. The recommendations focused on altering the dosage or length of radiotherapy treatments to try to reduce the number of hospital visits, thereby reducing the risk of exposing patients to SARS-CoV-2.
“The aim of these guidelines is very much to reduce the risk to patients,” Dr. Banfill said. “These patients are often at higher risk of serious COVID-19, both as a result of their cancer and also as a result of many of the coexisting medical conditions that they have, such as COPD [chronic obstructive pulmonary disease],” she explained.
The COVID-RT Lung study was essentially born out of these guidelines. The goals of the study were to see what changes to radiotherapy practice occurred as a result of the guidelines and to assess how the changes have affected patient outcomes.
Changes to diagnosis and treatment
COVID-RT Lung is an ongoing, prospective study of patients with biopsy- or imaging-proven stage I–III lung cancer who were referred for, or treated with, radical radiotherapy at one of 26 oncology centers in the United Kingdom between April and October 2020.
Records on 1,117 patients were available for the initial analysis. The patients’ median age was 72 years (range, 38-93 years), and half were women.
The records showed changes to diagnostic investigations in 14% of patients (n = 160). Changes included not obtaining histology (4.6%, n = 51), not conducting nodal sampling (3.1%, n = 35), not performing pulmonary function tests (1.8%, n = 20), not conducting brain imaging (2.9%, n = 32), not performing PET/CT scans or having out-of-date scans (4.2%, n = 47), and delays in diagnosis (0.6%, n = 7).
Changes to treatment – deviations from standard care – occurred in 37% of patients (n = 415). This included 19% of patients (n = 210) having changes to radiotherapy dose or fractionation schedule, 8% (n = 86) undergoing radiotherapy instead of surgery, and 13% (n = 143) having their chemotherapy omitted or reduced.
The median number of radiotherapy fractions was 15 for patients who had their radiotherapy adjusted and 20 for those who had no treatment amendments.
“Those who had their treatment changed were more likely to have hypofractionated or ultra-hypofractionated radiotherapy,” Dr. Banfill said.
This was particularly true for patients with early-stage disease, she noted, where there was an increase in the percentage of patients getting more than 15 Gy per fraction. Even in stage III disease, there was an increased use of 3–5 Gy per fraction, although “virtually nobody” who had a change in treatment received less than 2 Gy per fraction, Dr. Banfill said.
“The changes are in line with what was reported in international recommendations,” observed Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium, who discussed the findings at the meeting.
Few patients had COVID-19
“It was striking to me to see that so few patients developed COVID-19 prior to radiotherapy or during radiotherapy,” Dr. Lievens noted. “This is actually something that we’ve also experienced in our setting.”
Indeed, just 15 patients (1%) were diagnosed with COVID-19, 10 of whom were diagnosed before receiving radiotherapy.
Dr. Banfill observed that the COVID-19 diagnosis had been “a reasonable time” before the patients started radiotherapy, and some had been diagnosed with lung cancer as a result of having a chest x-ray for suspected COVID-19.
Of the four patients who were diagnosed during treatment, two had their radiotherapy interrupted as a result.
The low COVID-19 rate is perhaps a result of the protective measures recommended in the United Kingdom, such as advising patients to shield from others, Dr. Banfill said.
Are changes to practice likely to hold?
“Part of the reason we actually stopped the data collection in October was that people were starting to go, ‘Well, is this actually a change?’ because they’d been doing it for 6 months,” Dr. Banfill observed during the discussion session.
“It was becoming almost normal for some of these hypofractionated changes. I think there is potential for these to become more embedded going forward,” she said. Data on how these changes might affect patients in the long term is going to be the focus of a future analysis.
“There is ongoing data collection on recurrence and survival and toxicity, which will hopefully provide more information on the outcomes of this patient group,” Dr. Banfill said.
The COVID-RT Lung project is supported by the NIHR Manchester Biomedical Research Centre. Dr. Banfill and Dr. Lievens reported no relevant conflicts of interest.
The U.K.-based study showed that patients with stage I-III lung cancer who were set to undergo radiotherapy with curative intent were more likely to receive fewer fractions at higher doses when treated between April and October 2020. During that period, 19% of patients had their radiotherapy dose or fractionation schedule changed to deviate from standard care.
In addition, 8% of patients who were set to undergo surgery ultimately received radiotherapy instead, presumably to ease pressures on already struggling intensive care services, said Kathryn Banfill, MBChB, of Christie NHS Foundation Trust in Manchester, England.
Dr. Banfill presented results from the COVID-RT Lung study at the European Lung Cancer Virtual Congress 2021 (Abstract 203MO).
New guidelines prompt study
When the COVID-19 pandemic began, European and joint European and North American guidelines were issued to try to ensure that lung cancer patients would continue to receive the best possible treatment under the circumstances. This included guidance on how and when to use treatments such as radiotherapy.
One U.K. guideline included recommendations on the use of hypofractionation in the COVID-19 era. The recommendations focused on altering the dosage or length of radiotherapy treatments to try to reduce the number of hospital visits, thereby reducing the risk of exposing patients to SARS-CoV-2.
“The aim of these guidelines is very much to reduce the risk to patients,” Dr. Banfill said. “These patients are often at higher risk of serious COVID-19, both as a result of their cancer and also as a result of many of the coexisting medical conditions that they have, such as COPD [chronic obstructive pulmonary disease],” she explained.
The COVID-RT Lung study was essentially born out of these guidelines. The goals of the study were to see what changes to radiotherapy practice occurred as a result of the guidelines and to assess how the changes have affected patient outcomes.
Changes to diagnosis and treatment
COVID-RT Lung is an ongoing, prospective study of patients with biopsy- or imaging-proven stage I–III lung cancer who were referred for, or treated with, radical radiotherapy at one of 26 oncology centers in the United Kingdom between April and October 2020.
Records on 1,117 patients were available for the initial analysis. The patients’ median age was 72 years (range, 38-93 years), and half were women.
The records showed changes to diagnostic investigations in 14% of patients (n = 160). Changes included not obtaining histology (4.6%, n = 51), not conducting nodal sampling (3.1%, n = 35), not performing pulmonary function tests (1.8%, n = 20), not conducting brain imaging (2.9%, n = 32), not performing PET/CT scans or having out-of-date scans (4.2%, n = 47), and delays in diagnosis (0.6%, n = 7).
Changes to treatment – deviations from standard care – occurred in 37% of patients (n = 415). This included 19% of patients (n = 210) having changes to radiotherapy dose or fractionation schedule, 8% (n = 86) undergoing radiotherapy instead of surgery, and 13% (n = 143) having their chemotherapy omitted or reduced.
The median number of radiotherapy fractions was 15 for patients who had their radiotherapy adjusted and 20 for those who had no treatment amendments.
“Those who had their treatment changed were more likely to have hypofractionated or ultra-hypofractionated radiotherapy,” Dr. Banfill said.
This was particularly true for patients with early-stage disease, she noted, where there was an increase in the percentage of patients getting more than 15 Gy per fraction. Even in stage III disease, there was an increased use of 3–5 Gy per fraction, although “virtually nobody” who had a change in treatment received less than 2 Gy per fraction, Dr. Banfill said.
“The changes are in line with what was reported in international recommendations,” observed Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium, who discussed the findings at the meeting.
Few patients had COVID-19
“It was striking to me to see that so few patients developed COVID-19 prior to radiotherapy or during radiotherapy,” Dr. Lievens noted. “This is actually something that we’ve also experienced in our setting.”
Indeed, just 15 patients (1%) were diagnosed with COVID-19, 10 of whom were diagnosed before receiving radiotherapy.
Dr. Banfill observed that the COVID-19 diagnosis had been “a reasonable time” before the patients started radiotherapy, and some had been diagnosed with lung cancer as a result of having a chest x-ray for suspected COVID-19.
Of the four patients who were diagnosed during treatment, two had their radiotherapy interrupted as a result.
The low COVID-19 rate is perhaps a result of the protective measures recommended in the United Kingdom, such as advising patients to shield from others, Dr. Banfill said.
Are changes to practice likely to hold?
“Part of the reason we actually stopped the data collection in October was that people were starting to go, ‘Well, is this actually a change?’ because they’d been doing it for 6 months,” Dr. Banfill observed during the discussion session.
“It was becoming almost normal for some of these hypofractionated changes. I think there is potential for these to become more embedded going forward,” she said. Data on how these changes might affect patients in the long term is going to be the focus of a future analysis.
“There is ongoing data collection on recurrence and survival and toxicity, which will hopefully provide more information on the outcomes of this patient group,” Dr. Banfill said.
The COVID-RT Lung project is supported by the NIHR Manchester Biomedical Research Centre. Dr. Banfill and Dr. Lievens reported no relevant conflicts of interest.
The U.K.-based study showed that patients with stage I-III lung cancer who were set to undergo radiotherapy with curative intent were more likely to receive fewer fractions at higher doses when treated between April and October 2020. During that period, 19% of patients had their radiotherapy dose or fractionation schedule changed to deviate from standard care.
In addition, 8% of patients who were set to undergo surgery ultimately received radiotherapy instead, presumably to ease pressures on already struggling intensive care services, said Kathryn Banfill, MBChB, of Christie NHS Foundation Trust in Manchester, England.
Dr. Banfill presented results from the COVID-RT Lung study at the European Lung Cancer Virtual Congress 2021 (Abstract 203MO).
New guidelines prompt study
When the COVID-19 pandemic began, European and joint European and North American guidelines were issued to try to ensure that lung cancer patients would continue to receive the best possible treatment under the circumstances. This included guidance on how and when to use treatments such as radiotherapy.
One U.K. guideline included recommendations on the use of hypofractionation in the COVID-19 era. The recommendations focused on altering the dosage or length of radiotherapy treatments to try to reduce the number of hospital visits, thereby reducing the risk of exposing patients to SARS-CoV-2.
“The aim of these guidelines is very much to reduce the risk to patients,” Dr. Banfill said. “These patients are often at higher risk of serious COVID-19, both as a result of their cancer and also as a result of many of the coexisting medical conditions that they have, such as COPD [chronic obstructive pulmonary disease],” she explained.
The COVID-RT Lung study was essentially born out of these guidelines. The goals of the study were to see what changes to radiotherapy practice occurred as a result of the guidelines and to assess how the changes have affected patient outcomes.
Changes to diagnosis and treatment
COVID-RT Lung is an ongoing, prospective study of patients with biopsy- or imaging-proven stage I–III lung cancer who were referred for, or treated with, radical radiotherapy at one of 26 oncology centers in the United Kingdom between April and October 2020.
Records on 1,117 patients were available for the initial analysis. The patients’ median age was 72 years (range, 38-93 years), and half were women.
The records showed changes to diagnostic investigations in 14% of patients (n = 160). Changes included not obtaining histology (4.6%, n = 51), not conducting nodal sampling (3.1%, n = 35), not performing pulmonary function tests (1.8%, n = 20), not conducting brain imaging (2.9%, n = 32), not performing PET/CT scans or having out-of-date scans (4.2%, n = 47), and delays in diagnosis (0.6%, n = 7).
Changes to treatment – deviations from standard care – occurred in 37% of patients (n = 415). This included 19% of patients (n = 210) having changes to radiotherapy dose or fractionation schedule, 8% (n = 86) undergoing radiotherapy instead of surgery, and 13% (n = 143) having their chemotherapy omitted or reduced.
The median number of radiotherapy fractions was 15 for patients who had their radiotherapy adjusted and 20 for those who had no treatment amendments.
“Those who had their treatment changed were more likely to have hypofractionated or ultra-hypofractionated radiotherapy,” Dr. Banfill said.
This was particularly true for patients with early-stage disease, she noted, where there was an increase in the percentage of patients getting more than 15 Gy per fraction. Even in stage III disease, there was an increased use of 3–5 Gy per fraction, although “virtually nobody” who had a change in treatment received less than 2 Gy per fraction, Dr. Banfill said.
“The changes are in line with what was reported in international recommendations,” observed Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium, who discussed the findings at the meeting.
Few patients had COVID-19
“It was striking to me to see that so few patients developed COVID-19 prior to radiotherapy or during radiotherapy,” Dr. Lievens noted. “This is actually something that we’ve also experienced in our setting.”
Indeed, just 15 patients (1%) were diagnosed with COVID-19, 10 of whom were diagnosed before receiving radiotherapy.
Dr. Banfill observed that the COVID-19 diagnosis had been “a reasonable time” before the patients started radiotherapy, and some had been diagnosed with lung cancer as a result of having a chest x-ray for suspected COVID-19.
Of the four patients who were diagnosed during treatment, two had their radiotherapy interrupted as a result.
The low COVID-19 rate is perhaps a result of the protective measures recommended in the United Kingdom, such as advising patients to shield from others, Dr. Banfill said.
Are changes to practice likely to hold?
“Part of the reason we actually stopped the data collection in October was that people were starting to go, ‘Well, is this actually a change?’ because they’d been doing it for 6 months,” Dr. Banfill observed during the discussion session.
“It was becoming almost normal for some of these hypofractionated changes. I think there is potential for these to become more embedded going forward,” she said. Data on how these changes might affect patients in the long term is going to be the focus of a future analysis.
“There is ongoing data collection on recurrence and survival and toxicity, which will hopefully provide more information on the outcomes of this patient group,” Dr. Banfill said.
The COVID-RT Lung project is supported by the NIHR Manchester Biomedical Research Centre. Dr. Banfill and Dr. Lievens reported no relevant conflicts of interest.
FROM ELCC 2021
List of COVID-19 high-risk comorbidities expanded
The list of medical according to the Centers for Disease Control and Prevention.
The CDC’s latest list consists of 17 conditions or groups of related conditions that may increase patients’ risk of developing severe outcomes of COVID-19, the CDC said on a web page intended for the general public.
On a separate page, the CDC defines severe outcomes “as hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death.”
Asthma is included in the newly expanded list with other chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis; the list’s heart disease entry covers coronary artery disease, heart failure, cardiomyopathies, and hypertension, the CDC said.
The list of medical according to the Centers for Disease Control and Prevention.
The CDC’s latest list consists of 17 conditions or groups of related conditions that may increase patients’ risk of developing severe outcomes of COVID-19, the CDC said on a web page intended for the general public.
On a separate page, the CDC defines severe outcomes “as hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death.”
Asthma is included in the newly expanded list with other chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis; the list’s heart disease entry covers coronary artery disease, heart failure, cardiomyopathies, and hypertension, the CDC said.
The list of medical according to the Centers for Disease Control and Prevention.
The CDC’s latest list consists of 17 conditions or groups of related conditions that may increase patients’ risk of developing severe outcomes of COVID-19, the CDC said on a web page intended for the general public.
On a separate page, the CDC defines severe outcomes “as hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death.”
Asthma is included in the newly expanded list with other chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis; the list’s heart disease entry covers coronary artery disease, heart failure, cardiomyopathies, and hypertension, the CDC said.
Technique combines ‘best of both worlds’ to target lung nodules
The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.
“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).
Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.
Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.
“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.
Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
Study results
Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.
The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.
The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.
In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.
The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).
The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.
In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.
It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.
“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”
The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.
The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.
“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).
Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.
Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.
“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.
Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
Study results
Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.
The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.
The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.
In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.
The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).
The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.
In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.
It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.
“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”
The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.
The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.
“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).
Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.
Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.
“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.
Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
Study results
Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.
The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.
The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.
In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.
The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).
The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.
In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.
It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.
“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”
The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.
FROM ELCC 2021
Camrelizumab ‘another brick in the wall’ against squamous NSCLC
.
Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).
Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).
The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.
“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”
“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.
Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
Patients and treatment
CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.
Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.
This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.
The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
Efficacy and safety
The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).
The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.
Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.
The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).
The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.
Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.
Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.
“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
Putting CAMEL-sq into perspective
Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.
In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.
Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.
“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.
That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.
“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.
She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.
CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.
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Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).
Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).
The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.
“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”
“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.
Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
Patients and treatment
CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.
Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.
This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.
The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
Efficacy and safety
The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).
The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.
Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.
The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).
The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.
Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.
Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.
“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
Putting CAMEL-sq into perspective
Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.
In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.
Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.
“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.
That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.
“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.
She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.
CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.
.
Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).
Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).
The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.
“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”
“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.
Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
Patients and treatment
CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.
Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.
This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.
The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
Efficacy and safety
The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).
The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.
Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.
The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).
The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.
Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.
Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.
“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
Putting CAMEL-sq into perspective
Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.
In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.
Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.
“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.
That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.
“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.
She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.
CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.
FROM ELCC 2021