Lung Cancer

Adding aggressive local radiotherapy to treatment with tyrosine kinase inhibitor (TKI) significantly improved progression-free and overall survival in patients with previously untreated, EGFR-mutated, oligometastatic non–small cell lung cancer (NSCLC) in a phase 3 trial presented as part of the American Society of Clinical Oncology virtual scientific program.

Sixty-eight patients were randomized at diagnosis to receive a first-generation TKI plus stereotactic body radiation therapy (SBRT) to all disease sites. The other 68 patients were randomized to receive a TKI alone, but 3 patients were lost follow-up and not included in the analysis. The TKIs used were gefitinib, erlotinib, and icotinib.

At baseline, patients had a maximum of two lesions in any one organ and no more than five metastases overall. Patients with brain metastases were excluded.

The median progression-free survival was 20.2 months in the SBRT arm and 12.5 months in the TKI-only arm (hazard ratio, 0.618; P < .001). The median overall survival was 25.5 months and 17.4 months, respectively (HR, 0.682; P < .001).

There were no grade 4/5 adverse events nor any statistically significant between-group differences in grade 3 events.
 

‘Compelling’ data with caveats

The study results suggest that “aggressive local therapy to sites at diagnosis should be explored further in large cohort phase 3 trials as a standard treatment option in this clinical scenario,” said investigator Xiao-shan Wang, MD, PhD, of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital in Chengdu.

“The data are compelling,” Dr. Wang added. “As we attempt to maximize the benefits of EGFR-directed targeted therapies, we are likely going to be moving away from a sequentially administered approach to treatment and considering combinations.”

The new findings, combined with prior phase 2 results, support “incorporation of upfront SBRT with TKI into practice for selected patients with oligometastatic disease, with the open question remaining of how many metastases are too many,” said study discussant Rachel Sanborn, MD, of Providence Cancer Institute Franz Clinic in Portland, Ore.

However, “it’s important to make note of the baseline characteristics of the patients enrolled,” she said.

Twelve percent of patients in the control arm and 4% of those in the SBRT group had EGFR exon 20 insertions. This “imbalance could have negatively impacted the outcomes in the TKI-alone arm,” Dr. Sanborn said.

Also, a higher proportion of patients in the TKI-alone arm received gefitinib, and “there was no information offered on second-line therapies in the study, which might have also affected outcomes,” Dr. Sanborn added.
 

Additional details

The study (NCT02893332) enrolled NSCLC patients with a life expectancy of at least 6 months and an Eastern Cooperative Oncology Group performance status score of 0-2. NSCLC was confirmed by pathology and EGFR mutations by gene sequencing.

The radiation dose was 25-40 Gy in five fractions. Gefitinib was used in 47% of patients in the SBRT arm and 58% of the control group. Erlotinib was used in 44% of the SBRT arm and 35% of controls. Icotinib was used by less than 10% of patients in each group.

Grade 3 skin rash occurred in 50% of patients in the SBRT arm and 62% of those in the TKI-alone arm. Grade 3 pneumonitis occurred in 30% and 15%, respectively. Grade 3 esophagitis occurred in 15% of patients in both arms.

One patient in the TKI arm had severe liver injury. One patient in the SBRT arm fractured a rib, which was considered probably related to the radiation.

Multivariate analysis revealed that, in addition to SBRT, lower baseline performance status score (0 vs. 1-2) and fewer metastases (<2 vs. ≥3) were protective for progression-free survival. Lower performance scores, fewer metastases, lower T stage (T1-2 vs. T3-4), and exon 19 versus exon 20 and 21 mutations were protective for overall survival.

The study arms were well balanced at baseline. The mean patient age was 66.9 years in the SBRT arm and 63.32 years in the TKI-only arm. In both arms, most patients were women (63% and 60%, respectively).

The study was sponsored by Sichuan Provincial People’s Hospital. The investigators and Dr. Sanborn have no relevant disclosures.

aotto@mdedge.com

SOURCE: Wang X et al. ASCO 2020, Abstract 9508.

Adding aggressive local radiotherapy to treatment with tyrosine kinase inhibitor (TKI) significantly improved progression-free and overall survival in patients with previously untreated, EGFR-mutated, oligometastatic non–small cell lung cancer (NSCLC) in a phase 3 trial presented as part of the American Society of Clinical Oncology virtual scientific program.

Sixty-eight patients were randomized at diagnosis to receive a first-generation TKI plus stereotactic body radiation therapy (SBRT) to all disease sites. The other 68 patients were randomized to receive a TKI alone, but 3 patients were lost follow-up and not included in the analysis. The TKIs used were gefitinib, erlotinib, and icotinib.

At baseline, patients had a maximum of two lesions in any one organ and no more than five metastases overall. Patients with brain metastases were excluded.

The median progression-free survival was 20.2 months in the SBRT arm and 12.5 months in the TKI-only arm (hazard ratio, 0.618; P < .001). The median overall survival was 25.5 months and 17.4 months, respectively (HR, 0.682; P < .001).

There were no grade 4/5 adverse events nor any statistically significant between-group differences in grade 3 events.
 

‘Compelling’ data with caveats

The study results suggest that “aggressive local therapy to sites at diagnosis should be explored further in large cohort phase 3 trials as a standard treatment option in this clinical scenario,” said investigator Xiao-shan Wang, MD, PhD, of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital in Chengdu.

“The data are compelling,” Dr. Wang added. “As we attempt to maximize the benefits of EGFR-directed targeted therapies, we are likely going to be moving away from a sequentially administered approach to treatment and considering combinations.”

The new findings, combined with prior phase 2 results, support “incorporation of upfront SBRT with TKI into practice for selected patients with oligometastatic disease, with the open question remaining of how many metastases are too many,” said study discussant Rachel Sanborn, MD, of Providence Cancer Institute Franz Clinic in Portland, Ore.

However, “it’s important to make note of the baseline characteristics of the patients enrolled,” she said.

Twelve percent of patients in the control arm and 4% of those in the SBRT group had EGFR exon 20 insertions. This “imbalance could have negatively impacted the outcomes in the TKI-alone arm,” Dr. Sanborn said.

Also, a higher proportion of patients in the TKI-alone arm received gefitinib, and “there was no information offered on second-line therapies in the study, which might have also affected outcomes,” Dr. Sanborn added.
 

Additional details

The study (NCT02893332) enrolled NSCLC patients with a life expectancy of at least 6 months and an Eastern Cooperative Oncology Group performance status score of 0-2. NSCLC was confirmed by pathology and EGFR mutations by gene sequencing.

The radiation dose was 25-40 Gy in five fractions. Gefitinib was used in 47% of patients in the SBRT arm and 58% of the control group. Erlotinib was used in 44% of the SBRT arm and 35% of controls. Icotinib was used by less than 10% of patients in each group.

Grade 3 skin rash occurred in 50% of patients in the SBRT arm and 62% of those in the TKI-alone arm. Grade 3 pneumonitis occurred in 30% and 15%, respectively. Grade 3 esophagitis occurred in 15% of patients in both arms.

One patient in the TKI arm had severe liver injury. One patient in the SBRT arm fractured a rib, which was considered probably related to the radiation.

Multivariate analysis revealed that, in addition to SBRT, lower baseline performance status score (0 vs. 1-2) and fewer metastases (<2 vs. ≥3) were protective for progression-free survival. Lower performance scores, fewer metastases, lower T stage (T1-2 vs. T3-4), and exon 19 versus exon 20 and 21 mutations were protective for overall survival.

The study arms were well balanced at baseline. The mean patient age was 66.9 years in the SBRT arm and 63.32 years in the TKI-only arm. In both arms, most patients were women (63% and 60%, respectively).

The study was sponsored by Sichuan Provincial People’s Hospital. The investigators and Dr. Sanborn have no relevant disclosures.

aotto@mdedge.com

SOURCE: Wang X et al. ASCO 2020, Abstract 9508.

Adding aggressive local radiotherapy to treatment with tyrosine kinase inhibitor (TKI) significantly improved progression-free and overall survival in patients with previously untreated, EGFR-mutated, oligometastatic non–small cell lung cancer (NSCLC) in a phase 3 trial presented as part of the American Society of Clinical Oncology virtual scientific program.

Sixty-eight patients were randomized at diagnosis to receive a first-generation TKI plus stereotactic body radiation therapy (SBRT) to all disease sites. The other 68 patients were randomized to receive a TKI alone, but 3 patients were lost follow-up and not included in the analysis. The TKIs used were gefitinib, erlotinib, and icotinib.

At baseline, patients had a maximum of two lesions in any one organ and no more than five metastases overall. Patients with brain metastases were excluded.

The median progression-free survival was 20.2 months in the SBRT arm and 12.5 months in the TKI-only arm (hazard ratio, 0.618; P < .001). The median overall survival was 25.5 months and 17.4 months, respectively (HR, 0.682; P < .001).

There were no grade 4/5 adverse events nor any statistically significant between-group differences in grade 3 events.
 

‘Compelling’ data with caveats

The study results suggest that “aggressive local therapy to sites at diagnosis should be explored further in large cohort phase 3 trials as a standard treatment option in this clinical scenario,” said investigator Xiao-shan Wang, MD, PhD, of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital in Chengdu.

“The data are compelling,” Dr. Wang added. “As we attempt to maximize the benefits of EGFR-directed targeted therapies, we are likely going to be moving away from a sequentially administered approach to treatment and considering combinations.”

The new findings, combined with prior phase 2 results, support “incorporation of upfront SBRT with TKI into practice for selected patients with oligometastatic disease, with the open question remaining of how many metastases are too many,” said study discussant Rachel Sanborn, MD, of Providence Cancer Institute Franz Clinic in Portland, Ore.

However, “it’s important to make note of the baseline characteristics of the patients enrolled,” she said.

Twelve percent of patients in the control arm and 4% of those in the SBRT group had EGFR exon 20 insertions. This “imbalance could have negatively impacted the outcomes in the TKI-alone arm,” Dr. Sanborn said.

Also, a higher proportion of patients in the TKI-alone arm received gefitinib, and “there was no information offered on second-line therapies in the study, which might have also affected outcomes,” Dr. Sanborn added.
 

Additional details

The study (NCT02893332) enrolled NSCLC patients with a life expectancy of at least 6 months and an Eastern Cooperative Oncology Group performance status score of 0-2. NSCLC was confirmed by pathology and EGFR mutations by gene sequencing.

The radiation dose was 25-40 Gy in five fractions. Gefitinib was used in 47% of patients in the SBRT arm and 58% of the control group. Erlotinib was used in 44% of the SBRT arm and 35% of controls. Icotinib was used by less than 10% of patients in each group.

Grade 3 skin rash occurred in 50% of patients in the SBRT arm and 62% of those in the TKI-alone arm. Grade 3 pneumonitis occurred in 30% and 15%, respectively. Grade 3 esophagitis occurred in 15% of patients in both arms.

One patient in the TKI arm had severe liver injury. One patient in the SBRT arm fractured a rib, which was considered probably related to the radiation.

Multivariate analysis revealed that, in addition to SBRT, lower baseline performance status score (0 vs. 1-2) and fewer metastases (<2 vs. ≥3) were protective for progression-free survival. Lower performance scores, fewer metastases, lower T stage (T1-2 vs. T3-4), and exon 19 versus exon 20 and 21 mutations were protective for overall survival.

The study arms were well balanced at baseline. The mean patient age was 66.9 years in the SBRT arm and 63.32 years in the TKI-only arm. In both arms, most patients were women (63% and 60%, respectively).

The study was sponsored by Sichuan Provincial People’s Hospital. The investigators and Dr. Sanborn have no relevant disclosures.

aotto@mdedge.com

SOURCE: Wang X et al. ASCO 2020, Abstract 9508.

Lillie Shockney, RN, MAS, a two-time breast cancer survivor and adjunct professor at Johns Hopkins School of Nursing in Baltimore, Maryland, mourns the many losses that her patients with advanced cancer now face in the midst of the COVID-19 pandemic. But in the void of the usual support networks and treatment plans, she sees the resurgence of something that has recently been crowded out: hospice.

The pandemic has forced patients and their physicians to reassess the risk/benefit balance of continuing or embarking on yet another cancer treatment.

“It’s one of the pearls that we will get out of this nightmare,” said Ms. Shockney, who recently retired as administrative director of the cancer survivorship programs at the Sidney Kimmel Comprehensive Cancer Center.

“Physicians have been taught to treat the disease – so as long as there’s a treatment they give another treatment,” she told Medscape Medical News during a Zoom call from her home. “But for some patients with advanced disease, those treatments were making them very sick, so they were trading longevity over quality of life.”

Of course, longevity has never been a guarantee with cancer treatment, and even less so now, with the risk of COVID-19.

“This is going to bring them to some hard discussions,” says Brenda Nevidjon, RN, MSN, chief executive officer at the Oncology Nursing Society.

“We’ve known for a long time that there are patients who are on third- and fourth-round treatment options that have very little evidence of prolonging life or quality of life,” she told Medscape Medical News. “Do we bring these people out of their home to a setting where there could be a fair number of COVID-positive patients? Do we expose them to that?”

Across the world, these dilemmas are pushing cancer specialists to initiate discussions of hospice sooner with patients who have advanced disease, and with more clarity than before.

One of the reasons such conversations have often been avoided is that the concept of hospice is generally misunderstood, said Ms. Shockney.

“Patients think ‘you’re giving up on me, you’ve abandoned me’, but hospice is all about preserving the remainder of their quality of life and letting them have time with family and time to fulfill those elements of experiencing a good and peaceful death,” she said.

Indeed, hospice is “a benefit meant for somebody with at least a 6-month horizon,” agrees Ms. Nevidjon. Yet the average length of hospice in the United States is just 5 days. “It’s at the very, very end, and yet for some of these patients the 6 months they could get in hospice might be a better quality of life than the 4 months on another whole plan of chemotherapy. I can’t imagine that on the backside of this pandemic we will not have learned and we won’t start to change practices around initiating more of these conversations.”
 

Silver lining of this pandemic?

It’s too early into the pandemic to have hard data on whether hospice uptake has increased, but “it’s encouraging to hear that hospice is being discussed and offered sooner as an alternative to that third- or fourth-round chemo,” said Lori Bishop, MHA, RN, vice president of palliative and advanced care at the National Hospice and Palliative Care Organization.

“I agree that improving informed-decision discussions and timely access to hospice is a silver lining of the pandemic,” she told Medscape Medical News.

But she points out that today’s hospice looks quite different than it did before the pandemic, with the immediate and very obvious difference being telehealth, which was not widely utilized previously.

In March, the Centers for Medicare & Medicaid Services expanded telehealth options for hospice providers, something that Ms. Bishop and other hospice providers hope will remain in place after the pandemic passes.

“Telehealth visits are offered to replace some in-home visits both to minimize risk of exposure to COVID-19 and reduce the drain on personal protective equipment,” Bishop explained.

“In-patient hospice programs are also finding unique ways to provide support and connect patients to their loved ones: visitors are allowed but limited to one or two. Music and pet therapy are being provided through the window or virtually and devices such as iPads are being used to help patients connect with loved ones,” she said.

Telehealth links patients out of loneliness, but the one thing it cannot do is provide the comfort of touch – an important part of any hospice program.

“Hand-holding ... I miss that a lot,” says Ms. Shockney, her eyes filling with tears. “When you take somebody’s hand, you don’t even have to speak; that connection, and eye contact, is all you need to help that person emotionally heal.”

This article first appeared on Medscape.com.

Lillie Shockney, RN, MAS, a two-time breast cancer survivor and adjunct professor at Johns Hopkins School of Nursing in Baltimore, Maryland, mourns the many losses that her patients with advanced cancer now face in the midst of the COVID-19 pandemic. But in the void of the usual support networks and treatment plans, she sees the resurgence of something that has recently been crowded out: hospice.

The pandemic has forced patients and their physicians to reassess the risk/benefit balance of continuing or embarking on yet another cancer treatment.

“It’s one of the pearls that we will get out of this nightmare,” said Ms. Shockney, who recently retired as administrative director of the cancer survivorship programs at the Sidney Kimmel Comprehensive Cancer Center.

“Physicians have been taught to treat the disease – so as long as there’s a treatment they give another treatment,” she told Medscape Medical News during a Zoom call from her home. “But for some patients with advanced disease, those treatments were making them very sick, so they were trading longevity over quality of life.”

Of course, longevity has never been a guarantee with cancer treatment, and even less so now, with the risk of COVID-19.

“This is going to bring them to some hard discussions,” says Brenda Nevidjon, RN, MSN, chief executive officer at the Oncology Nursing Society.

“We’ve known for a long time that there are patients who are on third- and fourth-round treatment options that have very little evidence of prolonging life or quality of life,” she told Medscape Medical News. “Do we bring these people out of their home to a setting where there could be a fair number of COVID-positive patients? Do we expose them to that?”

Across the world, these dilemmas are pushing cancer specialists to initiate discussions of hospice sooner with patients who have advanced disease, and with more clarity than before.

One of the reasons such conversations have often been avoided is that the concept of hospice is generally misunderstood, said Ms. Shockney.

“Patients think ‘you’re giving up on me, you’ve abandoned me’, but hospice is all about preserving the remainder of their quality of life and letting them have time with family and time to fulfill those elements of experiencing a good and peaceful death,” she said.

Indeed, hospice is “a benefit meant for somebody with at least a 6-month horizon,” agrees Ms. Nevidjon. Yet the average length of hospice in the United States is just 5 days. “It’s at the very, very end, and yet for some of these patients the 6 months they could get in hospice might be a better quality of life than the 4 months on another whole plan of chemotherapy. I can’t imagine that on the backside of this pandemic we will not have learned and we won’t start to change practices around initiating more of these conversations.”
 

Silver lining of this pandemic?

It’s too early into the pandemic to have hard data on whether hospice uptake has increased, but “it’s encouraging to hear that hospice is being discussed and offered sooner as an alternative to that third- or fourth-round chemo,” said Lori Bishop, MHA, RN, vice president of palliative and advanced care at the National Hospice and Palliative Care Organization.

“I agree that improving informed-decision discussions and timely access to hospice is a silver lining of the pandemic,” she told Medscape Medical News.

But she points out that today’s hospice looks quite different than it did before the pandemic, with the immediate and very obvious difference being telehealth, which was not widely utilized previously.

In March, the Centers for Medicare & Medicaid Services expanded telehealth options for hospice providers, something that Ms. Bishop and other hospice providers hope will remain in place after the pandemic passes.

“Telehealth visits are offered to replace some in-home visits both to minimize risk of exposure to COVID-19 and reduce the drain on personal protective equipment,” Bishop explained.

“In-patient hospice programs are also finding unique ways to provide support and connect patients to their loved ones: visitors are allowed but limited to one or two. Music and pet therapy are being provided through the window or virtually and devices such as iPads are being used to help patients connect with loved ones,” she said.

Telehealth links patients out of loneliness, but the one thing it cannot do is provide the comfort of touch – an important part of any hospice program.

“Hand-holding ... I miss that a lot,” says Ms. Shockney, her eyes filling with tears. “When you take somebody’s hand, you don’t even have to speak; that connection, and eye contact, is all you need to help that person emotionally heal.”

This article first appeared on Medscape.com.

Lillie Shockney, RN, MAS, a two-time breast cancer survivor and adjunct professor at Johns Hopkins School of Nursing in Baltimore, Maryland, mourns the many losses that her patients with advanced cancer now face in the midst of the COVID-19 pandemic. But in the void of the usual support networks and treatment plans, she sees the resurgence of something that has recently been crowded out: hospice.

The pandemic has forced patients and their physicians to reassess the risk/benefit balance of continuing or embarking on yet another cancer treatment.

“It’s one of the pearls that we will get out of this nightmare,” said Ms. Shockney, who recently retired as administrative director of the cancer survivorship programs at the Sidney Kimmel Comprehensive Cancer Center.

“Physicians have been taught to treat the disease – so as long as there’s a treatment they give another treatment,” she told Medscape Medical News during a Zoom call from her home. “But for some patients with advanced disease, those treatments were making them very sick, so they were trading longevity over quality of life.”

Of course, longevity has never been a guarantee with cancer treatment, and even less so now, with the risk of COVID-19.

“This is going to bring them to some hard discussions,” says Brenda Nevidjon, RN, MSN, chief executive officer at the Oncology Nursing Society.

“We’ve known for a long time that there are patients who are on third- and fourth-round treatment options that have very little evidence of prolonging life or quality of life,” she told Medscape Medical News. “Do we bring these people out of their home to a setting where there could be a fair number of COVID-positive patients? Do we expose them to that?”

Across the world, these dilemmas are pushing cancer specialists to initiate discussions of hospice sooner with patients who have advanced disease, and with more clarity than before.

One of the reasons such conversations have often been avoided is that the concept of hospice is generally misunderstood, said Ms. Shockney.

“Patients think ‘you’re giving up on me, you’ve abandoned me’, but hospice is all about preserving the remainder of their quality of life and letting them have time with family and time to fulfill those elements of experiencing a good and peaceful death,” she said.

Indeed, hospice is “a benefit meant for somebody with at least a 6-month horizon,” agrees Ms. Nevidjon. Yet the average length of hospice in the United States is just 5 days. “It’s at the very, very end, and yet for some of these patients the 6 months they could get in hospice might be a better quality of life than the 4 months on another whole plan of chemotherapy. I can’t imagine that on the backside of this pandemic we will not have learned and we won’t start to change practices around initiating more of these conversations.”
 

Silver lining of this pandemic?

It’s too early into the pandemic to have hard data on whether hospice uptake has increased, but “it’s encouraging to hear that hospice is being discussed and offered sooner as an alternative to that third- or fourth-round chemo,” said Lori Bishop, MHA, RN, vice president of palliative and advanced care at the National Hospice and Palliative Care Organization.

“I agree that improving informed-decision discussions and timely access to hospice is a silver lining of the pandemic,” she told Medscape Medical News.

But she points out that today’s hospice looks quite different than it did before the pandemic, with the immediate and very obvious difference being telehealth, which was not widely utilized previously.

In March, the Centers for Medicare & Medicaid Services expanded telehealth options for hospice providers, something that Ms. Bishop and other hospice providers hope will remain in place after the pandemic passes.

“Telehealth visits are offered to replace some in-home visits both to minimize risk of exposure to COVID-19 and reduce the drain on personal protective equipment,” Bishop explained.

“In-patient hospice programs are also finding unique ways to provide support and connect patients to their loved ones: visitors are allowed but limited to one or two. Music and pet therapy are being provided through the window or virtually and devices such as iPads are being used to help patients connect with loved ones,” she said.

Telehealth links patients out of loneliness, but the one thing it cannot do is provide the comfort of touch – an important part of any hospice program.

“Hand-holding ... I miss that a lot,” says Ms. Shockney, her eyes filling with tears. “When you take somebody’s hand, you don’t even have to speak; that connection, and eye contact, is all you need to help that person emotionally heal.”

This article first appeared on Medscape.com.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding durvalumab to first-line pemetrexed and cisplatin improved survival in patients with unresectable malignant pleural mesothelioma (MPM) in a phase 2 trial, compared with historical controls who received only pemetrexed and cisplatin.

The median overall survival was 20.4 months in patients who received durvalumab plus pemetrexed-cisplatin. This is significantly longer than the median overall survival of 12.1 months (P = .0014) observed with pemetrexed-cisplatin in a prior phase 3 study (J Clin Oncol. 2003 Jul 15;21[14]:2636-44).

The new phase 2 results are “promising,” said lead investigator Patrick Forde, MBBCh, director of the thoracic cancer clinical research program at Johns Hopkins University in Baltimore.

He presented the results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Forde noted that a phase 3 trial directly comparing pemetrexed-cisplatin plus durvalumab to pemetrexed-cisplatin will begin recruiting this year. The trial is a collaboration between U.S. investigators and Australian researchers who reported their own phase 2 results with durvalumab plus pemetrexed-cisplatin in 2018 (J Thorac Oncol. 2018 Oct;13[10]:S338-339).
 

Study details

Dr. Forde’s phase 2 study enrolled 55 patients with treatment-naive, unresectable MPM. Their median age was 68 years (range, 35-83 years), and 45 (82%) were men. All had an Eastern Cooperative Oncology Group performance status of 0-1.

Epithelioid mesothelioma was the histologic subtype in three-quarters of patients. “It was a fairly typical mesothelioma population,” Dr. Forde said.

The patients received durvalumab at 1,120 mg plus pemetrexed at 500 mg/m² and cisplatin at 75 mg/m² every 3 weeks for up to six cycles. Carboplatin was substituted when cisplatin was contraindicated or patients developed toxicities.

All but one patient had stable or responding disease on radiography and went on to durvalumab maintenance, also given at 1,120 mg every 3 weeks, for up to 1 year from study entry.
 

Results

Dr. Forde said this study had 90% power to detect a 58% improvement in median overall survival, from the 12.1 months seen in historical controls to 19 months, which was the goal of this study.

It was a positive study, he said, as the median overall survival was 20.4 months (P = .0014).

The overall survival rate was 87.2% at 6 months, 70.4% at 12 months, and 44.2% at 24 months. The progression-free survival rate was 69.1% at 6 months, 16.4% at 12 months, and 10.9% at 24 months.

The overall response rate was 56.4%, which comprised 31 partial responses. Forty percent of patients (n = 22) had stable disease. One patient had progressive disease, and one was not evaluable (1.8% each).

To help with future patient selection, the researchers looked for baseline biomarkers that predicted response. Tumor PD-L1 expression, tumor mutation burden, and other potential candidates haven’t worked out so far, but the work continues, Dr. Forde said.

He noted that many of the adverse events in this trial are those typically seen with platinum-based chemotherapy.

Grade 3/4 treatment-emergent adverse events included anemia (n = 14), fatigue (n = 4), decreased appetite (n = 1), and hypomagnesemia (n = 1).

The most common grade 1/2 adverse events of special interest were hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), AST elevation (n = 3), and hyperthyroidism (n = 3).
 

Putting the results in context

Given the role of inflammation in MPM, durvalumab is among several immunotherapies under investigation for the disease.

A phase 3 French trial showed MPM patients had a median overall survival of 18.8 months with pemetrexed-cisplatin plus bevacizumab versus 16.1 months with pemetrexed-cisplatin only (Lancet. 2016 Apr 2;387[10026]:1405-1414).

The higher overall survival in the French study’s pemetrexed-cisplatin arm, compared with the 2003 trial results, is likely due to the use of modern second-line options, said Marjorie Zauderer, MD, codirector of the mesothelioma program at Memorial Sloan Kettering Cancer Center in New York, who was the discussant for Dr. Forde’s presentation.

“I think the improvement in overall survival presented by Dr. Forde is potentially clinically meaningful,” she said, but it was “well within the 95% confidence interval” of the bevacizumab trial. Even so, “I look forward” to the phase 3 results, she said.

Dr. Zauderer also pointed out an April press release from Bristol Myers Squibb that reported improved survival over pemetrexed-cisplatin with two of the company’s immunotherapies, nivolumab and ipilimumab, not as additions but as replacement first-line therapy. However, the randomized trial data haven’t been released yet. “We are all eager to evaluate this option further,” she said.

AstraZeneca, maker of durvalumab, funded the current study. Dr. Forde is an adviser for the company and reported research funding. Dr. Zauderer reported a relationship with Roche, which markets bevacizumab through its subsidiary, Genentech. She also disclosed research funding from Bristol Myers Squibb.

aotto@mdedge.com

SOURCE: Forde PM et al. ASCO 2020, Abstract 9003.

Adding durvalumab to first-line pemetrexed and cisplatin improved survival in patients with unresectable malignant pleural mesothelioma (MPM) in a phase 2 trial, compared with historical controls who received only pemetrexed and cisplatin.

The median overall survival was 20.4 months in patients who received durvalumab plus pemetrexed-cisplatin. This is significantly longer than the median overall survival of 12.1 months (P = .0014) observed with pemetrexed-cisplatin in a prior phase 3 study (J Clin Oncol. 2003 Jul 15;21[14]:2636-44).

The new phase 2 results are “promising,” said lead investigator Patrick Forde, MBBCh, director of the thoracic cancer clinical research program at Johns Hopkins University in Baltimore.

He presented the results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Forde noted that a phase 3 trial directly comparing pemetrexed-cisplatin plus durvalumab to pemetrexed-cisplatin will begin recruiting this year. The trial is a collaboration between U.S. investigators and Australian researchers who reported their own phase 2 results with durvalumab plus pemetrexed-cisplatin in 2018 (J Thorac Oncol. 2018 Oct;13[10]:S338-339).
 

Study details

Dr. Forde’s phase 2 study enrolled 55 patients with treatment-naive, unresectable MPM. Their median age was 68 years (range, 35-83 years), and 45 (82%) were men. All had an Eastern Cooperative Oncology Group performance status of 0-1.

Epithelioid mesothelioma was the histologic subtype in three-quarters of patients. “It was a fairly typical mesothelioma population,” Dr. Forde said.

The patients received durvalumab at 1,120 mg plus pemetrexed at 500 mg/m² and cisplatin at 75 mg/m² every 3 weeks for up to six cycles. Carboplatin was substituted when cisplatin was contraindicated or patients developed toxicities.

All but one patient had stable or responding disease on radiography and went on to durvalumab maintenance, also given at 1,120 mg every 3 weeks, for up to 1 year from study entry.
 

Results

Dr. Forde said this study had 90% power to detect a 58% improvement in median overall survival, from the 12.1 months seen in historical controls to 19 months, which was the goal of this study.

It was a positive study, he said, as the median overall survival was 20.4 months (P = .0014).

The overall survival rate was 87.2% at 6 months, 70.4% at 12 months, and 44.2% at 24 months. The progression-free survival rate was 69.1% at 6 months, 16.4% at 12 months, and 10.9% at 24 months.

The overall response rate was 56.4%, which comprised 31 partial responses. Forty percent of patients (n = 22) had stable disease. One patient had progressive disease, and one was not evaluable (1.8% each).

To help with future patient selection, the researchers looked for baseline biomarkers that predicted response. Tumor PD-L1 expression, tumor mutation burden, and other potential candidates haven’t worked out so far, but the work continues, Dr. Forde said.

He noted that many of the adverse events in this trial are those typically seen with platinum-based chemotherapy.

Grade 3/4 treatment-emergent adverse events included anemia (n = 14), fatigue (n = 4), decreased appetite (n = 1), and hypomagnesemia (n = 1).

The most common grade 1/2 adverse events of special interest were hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), AST elevation (n = 3), and hyperthyroidism (n = 3).
 

Putting the results in context

Given the role of inflammation in MPM, durvalumab is among several immunotherapies under investigation for the disease.

A phase 3 French trial showed MPM patients had a median overall survival of 18.8 months with pemetrexed-cisplatin plus bevacizumab versus 16.1 months with pemetrexed-cisplatin only (Lancet. 2016 Apr 2;387[10026]:1405-1414).

The higher overall survival in the French study’s pemetrexed-cisplatin arm, compared with the 2003 trial results, is likely due to the use of modern second-line options, said Marjorie Zauderer, MD, codirector of the mesothelioma program at Memorial Sloan Kettering Cancer Center in New York, who was the discussant for Dr. Forde’s presentation.

“I think the improvement in overall survival presented by Dr. Forde is potentially clinically meaningful,” she said, but it was “well within the 95% confidence interval” of the bevacizumab trial. Even so, “I look forward” to the phase 3 results, she said.

Dr. Zauderer also pointed out an April press release from Bristol Myers Squibb that reported improved survival over pemetrexed-cisplatin with two of the company’s immunotherapies, nivolumab and ipilimumab, not as additions but as replacement first-line therapy. However, the randomized trial data haven’t been released yet. “We are all eager to evaluate this option further,” she said.

AstraZeneca, maker of durvalumab, funded the current study. Dr. Forde is an adviser for the company and reported research funding. Dr. Zauderer reported a relationship with Roche, which markets bevacizumab through its subsidiary, Genentech. She also disclosed research funding from Bristol Myers Squibb.

aotto@mdedge.com

SOURCE: Forde PM et al. ASCO 2020, Abstract 9003.

Adding durvalumab to first-line pemetrexed and cisplatin improved survival in patients with unresectable malignant pleural mesothelioma (MPM) in a phase 2 trial, compared with historical controls who received only pemetrexed and cisplatin.

The median overall survival was 20.4 months in patients who received durvalumab plus pemetrexed-cisplatin. This is significantly longer than the median overall survival of 12.1 months (P = .0014) observed with pemetrexed-cisplatin in a prior phase 3 study (J Clin Oncol. 2003 Jul 15;21[14]:2636-44).

The new phase 2 results are “promising,” said lead investigator Patrick Forde, MBBCh, director of the thoracic cancer clinical research program at Johns Hopkins University in Baltimore.

He presented the results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Forde noted that a phase 3 trial directly comparing pemetrexed-cisplatin plus durvalumab to pemetrexed-cisplatin will begin recruiting this year. The trial is a collaboration between U.S. investigators and Australian researchers who reported their own phase 2 results with durvalumab plus pemetrexed-cisplatin in 2018 (J Thorac Oncol. 2018 Oct;13[10]:S338-339).
 

Study details

Dr. Forde’s phase 2 study enrolled 55 patients with treatment-naive, unresectable MPM. Their median age was 68 years (range, 35-83 years), and 45 (82%) were men. All had an Eastern Cooperative Oncology Group performance status of 0-1.

Epithelioid mesothelioma was the histologic subtype in three-quarters of patients. “It was a fairly typical mesothelioma population,” Dr. Forde said.

The patients received durvalumab at 1,120 mg plus pemetrexed at 500 mg/m² and cisplatin at 75 mg/m² every 3 weeks for up to six cycles. Carboplatin was substituted when cisplatin was contraindicated or patients developed toxicities.

All but one patient had stable or responding disease on radiography and went on to durvalumab maintenance, also given at 1,120 mg every 3 weeks, for up to 1 year from study entry.
 

Results

Dr. Forde said this study had 90% power to detect a 58% improvement in median overall survival, from the 12.1 months seen in historical controls to 19 months, which was the goal of this study.

It was a positive study, he said, as the median overall survival was 20.4 months (P = .0014).

The overall survival rate was 87.2% at 6 months, 70.4% at 12 months, and 44.2% at 24 months. The progression-free survival rate was 69.1% at 6 months, 16.4% at 12 months, and 10.9% at 24 months.

The overall response rate was 56.4%, which comprised 31 partial responses. Forty percent of patients (n = 22) had stable disease. One patient had progressive disease, and one was not evaluable (1.8% each).

To help with future patient selection, the researchers looked for baseline biomarkers that predicted response. Tumor PD-L1 expression, tumor mutation burden, and other potential candidates haven’t worked out so far, but the work continues, Dr. Forde said.

He noted that many of the adverse events in this trial are those typically seen with platinum-based chemotherapy.

Grade 3/4 treatment-emergent adverse events included anemia (n = 14), fatigue (n = 4), decreased appetite (n = 1), and hypomagnesemia (n = 1).

The most common grade 1/2 adverse events of special interest were hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), AST elevation (n = 3), and hyperthyroidism (n = 3).
 

Putting the results in context

Given the role of inflammation in MPM, durvalumab is among several immunotherapies under investigation for the disease.

A phase 3 French trial showed MPM patients had a median overall survival of 18.8 months with pemetrexed-cisplatin plus bevacizumab versus 16.1 months with pemetrexed-cisplatin only (Lancet. 2016 Apr 2;387[10026]:1405-1414).

The higher overall survival in the French study’s pemetrexed-cisplatin arm, compared with the 2003 trial results, is likely due to the use of modern second-line options, said Marjorie Zauderer, MD, codirector of the mesothelioma program at Memorial Sloan Kettering Cancer Center in New York, who was the discussant for Dr. Forde’s presentation.

“I think the improvement in overall survival presented by Dr. Forde is potentially clinically meaningful,” she said, but it was “well within the 95% confidence interval” of the bevacizumab trial. Even so, “I look forward” to the phase 3 results, she said.

Dr. Zauderer also pointed out an April press release from Bristol Myers Squibb that reported improved survival over pemetrexed-cisplatin with two of the company’s immunotherapies, nivolumab and ipilimumab, not as additions but as replacement first-line therapy. However, the randomized trial data haven’t been released yet. “We are all eager to evaluate this option further,” she said.

AstraZeneca, maker of durvalumab, funded the current study. Dr. Forde is an adviser for the company and reported research funding. Dr. Zauderer reported a relationship with Roche, which markets bevacizumab through its subsidiary, Genentech. She also disclosed research funding from Bristol Myers Squibb.

aotto@mdedge.com

SOURCE: Forde PM et al. ASCO 2020, Abstract 9003.

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind.

The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.

This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.

“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.

“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.

Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.

Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.

“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.

An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
 

Implications in cancer treatment

For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.

“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”

A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.

BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.

The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).

Therapeutic action

For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.

Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.

Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.

For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.

Looking ahead

The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”

Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”

It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?

“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”

An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.

The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.

This article first appeared on Medscape.com.

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind.

The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.

This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.

“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.

“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.

Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.

Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.

“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.

An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
 

Implications in cancer treatment

For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.

“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”

A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.

BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.

The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).

Therapeutic action

For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.

Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.

Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.

For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.

Looking ahead

The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”

Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”

It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?

“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”

An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.

The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.

This article first appeared on Medscape.com.

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind.

The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.

This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.

“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.

“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.

Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.

Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.

“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.

An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
 

Implications in cancer treatment

For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.

“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”

A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.

BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.

The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).

Therapeutic action

For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.

Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.

Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.

For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.

Looking ahead

The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”

Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”

It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?

“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”

An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.

The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.

This article first appeared on Medscape.com.

Poziotinib, a pan-EGFR inhibitor, shrank tumors in a majority of patients with previously treated non–small cell lung cancer and EGFR exon 20 insertion mutations, but most of these patients did not achieve a response in the ongoing phase 2 ZENITH20 study.

The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.

The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.

Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.

Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.

Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.

The median progression-free survival was 4.2 months.
 

Patients, treatment, and safety

The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.

Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).

AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.

Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.

Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.

Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
 

Implications

The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.

“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.

The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.

Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.

In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.

The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.

“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”

“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
 

Next steps

Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.

Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.

Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.

“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”

ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.

sworcester@mdedge.com

SOURCE: Le X et al. AACR 2020, Abstract CT081.

Poziotinib, a pan-EGFR inhibitor, shrank tumors in a majority of patients with previously treated non–small cell lung cancer and EGFR exon 20 insertion mutations, but most of these patients did not achieve a response in the ongoing phase 2 ZENITH20 study.

The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.

The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.

Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.

Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.

Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.

The median progression-free survival was 4.2 months.
 

Patients, treatment, and safety

The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.

Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).

AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.

Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.

Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.

Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
 

Implications

The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.

“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.

The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.

Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.

In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.

The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.

“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”

“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
 

Next steps

Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.

Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.

Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.

“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”

ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.

sworcester@mdedge.com

SOURCE: Le X et al. AACR 2020, Abstract CT081.

Poziotinib, a pan-EGFR inhibitor, shrank tumors in a majority of patients with previously treated non–small cell lung cancer and EGFR exon 20 insertion mutations, but most of these patients did not achieve a response in the ongoing phase 2 ZENITH20 study.

The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.

The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.

Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.

Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.

Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.

The median progression-free survival was 4.2 months.
 

Patients, treatment, and safety

The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.

Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).

AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.

Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.

Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.

Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
 

Implications

The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.

“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.

The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.

Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.

In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.

The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.

“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”

“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
 

Next steps

Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.

Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.

Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.

“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”

ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.

sworcester@mdedge.com

SOURCE: Le X et al. AACR 2020, Abstract CT081.

The Food and Drug Administration has approved ramucirumab (Cyramza) in combination with erlotinib for the first-line treatment of metastatic non–small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 mutations.

The approval was supported by results from the phase 3 RELAY trial (Lancet Oncol. 2019 Dec;20[12]:1655-69). The trial enrolled 449 patients with previously untreated, EGFR-mutated, metastatic NSCLC.



Patients received either ramucirumab at 10 mg/kg or placebo every 2 weeks as an intravenous infusion in combination with erlotinib at 150 mg orally once daily. Patients continued treatment until they progressed or developed unacceptable toxicity. The median progression-free survival was 19.4 months in the ramucirumab-erlotinib arm, compared with 12.4 months in the placebo-erlotinib arm (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P < .0001). The overall response rate was 76% in the ramucirumab arm and 75% in the placebo arm. The median duration of response was 18.0 months and 11.1 months, respectively. Overall survival data were not mature at the final analysis.

Adverse events that were more common in the ramucirumab arm were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. Full prescribing information is available on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved ramucirumab (Cyramza) in combination with erlotinib for the first-line treatment of metastatic non–small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 mutations.

The approval was supported by results from the phase 3 RELAY trial (Lancet Oncol. 2019 Dec;20[12]:1655-69). The trial enrolled 449 patients with previously untreated, EGFR-mutated, metastatic NSCLC.



Patients received either ramucirumab at 10 mg/kg or placebo every 2 weeks as an intravenous infusion in combination with erlotinib at 150 mg orally once daily. Patients continued treatment until they progressed or developed unacceptable toxicity. The median progression-free survival was 19.4 months in the ramucirumab-erlotinib arm, compared with 12.4 months in the placebo-erlotinib arm (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P < .0001). The overall response rate was 76% in the ramucirumab arm and 75% in the placebo arm. The median duration of response was 18.0 months and 11.1 months, respectively. Overall survival data were not mature at the final analysis.

Adverse events that were more common in the ramucirumab arm were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. Full prescribing information is available on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved ramucirumab (Cyramza) in combination with erlotinib for the first-line treatment of metastatic non–small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 mutations.

The approval was supported by results from the phase 3 RELAY trial (Lancet Oncol. 2019 Dec;20[12]:1655-69). The trial enrolled 449 patients with previously untreated, EGFR-mutated, metastatic NSCLC.



Patients received either ramucirumab at 10 mg/kg or placebo every 2 weeks as an intravenous infusion in combination with erlotinib at 150 mg orally once daily. Patients continued treatment until they progressed or developed unacceptable toxicity. The median progression-free survival was 19.4 months in the ramucirumab-erlotinib arm, compared with 12.4 months in the placebo-erlotinib arm (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P < .0001). The overall response rate was 76% in the ramucirumab arm and 75% in the placebo arm. The median duration of response was 18.0 months and 11.1 months, respectively. Overall survival data were not mature at the final analysis.

Adverse events that were more common in the ramucirumab arm were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. Full prescribing information is available on the FDA website.

lfranki@mdedge.com

Among patients with HER2-mutated non–small cell lung cancer (NSCLC) in an ongoing phase 2 trial, treatment with trastuzumab deruxtecan (T-DXd) has yielded a high response rate, and the median duration of response has not yet been reached, an investigator reported.

The overall response rate (ORR) exceeded 60% among these heavily pretreated patients, with an estimated median progression-free survival (PFS) of 14 months, according to Egbert F. Smit, MD, PhD, of the Netherlands Cancer Institute.

Interstitial lung disease is an identified risk associated with T-DXd treatment, though the events in the DESTINY-Lung01 trial have been low-grade and have not resulted in any deaths, Dr. Smit said when presenting results from the trial as part of the American Society of Clinical Oncology virtual scientific program.

“These data demonstrate the potential of T-DXd as a new treatment option for patients with HER2-mutated non–small-cell lung cancer,” Dr. Smit said.
 

‘A good targeted therapy’

The findings are a “nice early confirmation” of the initial results seen with T-DXd in an earlier, smaller, phase 1 population, said invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“Trastuzumab-DXd showed clinical outcomes that meet the standards of what we expect a good targeted therapy should have in terms of overall response rate and progression free survival,” Dr. Dy said.

She noted that the ORR in DESTINY-Lung01 exceeds a 23% ORR seen among NSCLC patients treated with dual HER2-targeted therapy – trastuzumab plus pertuzumab – in a basket trial (J Clin Oncol. 2018 Feb 20;36[6]:536-42). Moreover, the response and PFS data “far surpass” results seen to date with oral tyrosine kinase inhibitors, including pyrotinib, poziotinib, neratinib, and afatinib.

The T-DXd results also look favorable in comparison to another antibody-drug conjugate, ado trastuzumab emtansine, Dr. Dy added, referencing another basket trial in which investigators reported an ORR of 44% and a median PFS of 5 months among 18 patients with advanced HER2-mutant lung adenocarcinomas (J Clin Oncol. 2018 Aug 20;36[24]:2532-7).

“Although T-DM1 [ado trastuzumab emtansine] demonstrated some degree of activity, its lower dosing, which was limited by the payload, lower drug-antibody ratio, and shorter half-life likely explain why results were better with T-DXd,” Dr. Dy said.

T-DXd was, in fact, designed to deliver an optimal antitumor effect, according to Dr. Smit.

The treatment incorporates a humanized anti-HER2 IgG1 monoclonal antibody that has the same amino acid sequence as trastuzumab. The antibody is attached via a cleavable, tumor-selective linker to a payload of deruxtecan, a topoisomerase I inhibitor.

The resulting antibody-drug conjugate has a high drug-to-antibody ratio, with 8 DXd molecules per monoclonal antibody, according to Dr. Smit.

Study details

The DESTINY-Lung01 trial included 42 patients with HER2-mutated NSCLC who received T-DXd at a dose of 6.4 mg/kg every 3 weeks. The patients’ median age was 63 years, and about 64% were female. Eastern Cooperative Oncology Group performance status was 0 in about one-quarter of the patients, and 1 in the remainder.

Patients had received up to six prior lines of treatment, including platinum-based chemotherapy in about 91%, a PD-1 or PD-L1 inhibitor in 55%, and docetaxel in 19%.

The confirmed ORR by independent central review was 61.9% (26/42). That included a single complete response (2.4%) and 25 partial responses (59.5%).

The duration of response was not reached (95% CI, 5.3 months to not estimable), and the median PFS was 14.0 months (95% CI, 6.4-14.0 months).

All patients experienced a treatment-related adverse event. Treatment-related events of grade 3 or greater were seen in 22 patients (52%). These mainly included decreased neutrophil count, anemia, nausea, vomiting, and fatigue.

There were five cases of interstitial lung disease, all of which were grade 2. In four cases, T-DXd was withdrawn. In one case, the drug was interrupted. All patients were treated with steroids.

“Two [patients] recovered, one recovered with sequelae, one was recovering, and one had not recovered by data cutoff,” Dr. Smit said.

DESTINY-Lung01 also includes a cohort of patients with HER2-expressing NSCLC not reported at the meeting. Enrollment in the HER2-mutated cohort that was reported has been expanded with another 50 patients to “better characterize the risk-benefit ratio,” Dr. Smit said.

The DESTINY-Lung01 study is sponsored by Daiichi Sankyo Inc. Dr. Smit reported relationships with Daiichi Sankyo and many other companies. Dr. Dy reported disclosures related to Amgen, AstraZeneca/Medimmune, GlaxoSmithKline, Takeda, and Tesaro.

SOURCE: Smit EF et al. ASCO 2020, Abstract 9504.

Among patients with HER2-mutated non–small cell lung cancer (NSCLC) in an ongoing phase 2 trial, treatment with trastuzumab deruxtecan (T-DXd) has yielded a high response rate, and the median duration of response has not yet been reached, an investigator reported.

The overall response rate (ORR) exceeded 60% among these heavily pretreated patients, with an estimated median progression-free survival (PFS) of 14 months, according to Egbert F. Smit, MD, PhD, of the Netherlands Cancer Institute.

Interstitial lung disease is an identified risk associated with T-DXd treatment, though the events in the DESTINY-Lung01 trial have been low-grade and have not resulted in any deaths, Dr. Smit said when presenting results from the trial as part of the American Society of Clinical Oncology virtual scientific program.

“These data demonstrate the potential of T-DXd as a new treatment option for patients with HER2-mutated non–small-cell lung cancer,” Dr. Smit said.
 

‘A good targeted therapy’

The findings are a “nice early confirmation” of the initial results seen with T-DXd in an earlier, smaller, phase 1 population, said invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“Trastuzumab-DXd showed clinical outcomes that meet the standards of what we expect a good targeted therapy should have in terms of overall response rate and progression free survival,” Dr. Dy said.

She noted that the ORR in DESTINY-Lung01 exceeds a 23% ORR seen among NSCLC patients treated with dual HER2-targeted therapy – trastuzumab plus pertuzumab – in a basket trial (J Clin Oncol. 2018 Feb 20;36[6]:536-42). Moreover, the response and PFS data “far surpass” results seen to date with oral tyrosine kinase inhibitors, including pyrotinib, poziotinib, neratinib, and afatinib.

The T-DXd results also look favorable in comparison to another antibody-drug conjugate, ado trastuzumab emtansine, Dr. Dy added, referencing another basket trial in which investigators reported an ORR of 44% and a median PFS of 5 months among 18 patients with advanced HER2-mutant lung adenocarcinomas (J Clin Oncol. 2018 Aug 20;36[24]:2532-7).

“Although T-DM1 [ado trastuzumab emtansine] demonstrated some degree of activity, its lower dosing, which was limited by the payload, lower drug-antibody ratio, and shorter half-life likely explain why results were better with T-DXd,” Dr. Dy said.

T-DXd was, in fact, designed to deliver an optimal antitumor effect, according to Dr. Smit.

The treatment incorporates a humanized anti-HER2 IgG1 monoclonal antibody that has the same amino acid sequence as trastuzumab. The antibody is attached via a cleavable, tumor-selective linker to a payload of deruxtecan, a topoisomerase I inhibitor.

The resulting antibody-drug conjugate has a high drug-to-antibody ratio, with 8 DXd molecules per monoclonal antibody, according to Dr. Smit.

Study details

The DESTINY-Lung01 trial included 42 patients with HER2-mutated NSCLC who received T-DXd at a dose of 6.4 mg/kg every 3 weeks. The patients’ median age was 63 years, and about 64% were female. Eastern Cooperative Oncology Group performance status was 0 in about one-quarter of the patients, and 1 in the remainder.

Patients had received up to six prior lines of treatment, including platinum-based chemotherapy in about 91%, a PD-1 or PD-L1 inhibitor in 55%, and docetaxel in 19%.

The confirmed ORR by independent central review was 61.9% (26/42). That included a single complete response (2.4%) and 25 partial responses (59.5%).

The duration of response was not reached (95% CI, 5.3 months to not estimable), and the median PFS was 14.0 months (95% CI, 6.4-14.0 months).

All patients experienced a treatment-related adverse event. Treatment-related events of grade 3 or greater were seen in 22 patients (52%). These mainly included decreased neutrophil count, anemia, nausea, vomiting, and fatigue.

There were five cases of interstitial lung disease, all of which were grade 2. In four cases, T-DXd was withdrawn. In one case, the drug was interrupted. All patients were treated with steroids.

“Two [patients] recovered, one recovered with sequelae, one was recovering, and one had not recovered by data cutoff,” Dr. Smit said.

DESTINY-Lung01 also includes a cohort of patients with HER2-expressing NSCLC not reported at the meeting. Enrollment in the HER2-mutated cohort that was reported has been expanded with another 50 patients to “better characterize the risk-benefit ratio,” Dr. Smit said.

The DESTINY-Lung01 study is sponsored by Daiichi Sankyo Inc. Dr. Smit reported relationships with Daiichi Sankyo and many other companies. Dr. Dy reported disclosures related to Amgen, AstraZeneca/Medimmune, GlaxoSmithKline, Takeda, and Tesaro.

SOURCE: Smit EF et al. ASCO 2020, Abstract 9504.

Among patients with HER2-mutated non–small cell lung cancer (NSCLC) in an ongoing phase 2 trial, treatment with trastuzumab deruxtecan (T-DXd) has yielded a high response rate, and the median duration of response has not yet been reached, an investigator reported.

The overall response rate (ORR) exceeded 60% among these heavily pretreated patients, with an estimated median progression-free survival (PFS) of 14 months, according to Egbert F. Smit, MD, PhD, of the Netherlands Cancer Institute.

Interstitial lung disease is an identified risk associated with T-DXd treatment, though the events in the DESTINY-Lung01 trial have been low-grade and have not resulted in any deaths, Dr. Smit said when presenting results from the trial as part of the American Society of Clinical Oncology virtual scientific program.

“These data demonstrate the potential of T-DXd as a new treatment option for patients with HER2-mutated non–small-cell lung cancer,” Dr. Smit said.
 

‘A good targeted therapy’

The findings are a “nice early confirmation” of the initial results seen with T-DXd in an earlier, smaller, phase 1 population, said invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“Trastuzumab-DXd showed clinical outcomes that meet the standards of what we expect a good targeted therapy should have in terms of overall response rate and progression free survival,” Dr. Dy said.

She noted that the ORR in DESTINY-Lung01 exceeds a 23% ORR seen among NSCLC patients treated with dual HER2-targeted therapy – trastuzumab plus pertuzumab – in a basket trial (J Clin Oncol. 2018 Feb 20;36[6]:536-42). Moreover, the response and PFS data “far surpass” results seen to date with oral tyrosine kinase inhibitors, including pyrotinib, poziotinib, neratinib, and afatinib.

The T-DXd results also look favorable in comparison to another antibody-drug conjugate, ado trastuzumab emtansine, Dr. Dy added, referencing another basket trial in which investigators reported an ORR of 44% and a median PFS of 5 months among 18 patients with advanced HER2-mutant lung adenocarcinomas (J Clin Oncol. 2018 Aug 20;36[24]:2532-7).

“Although T-DM1 [ado trastuzumab emtansine] demonstrated some degree of activity, its lower dosing, which was limited by the payload, lower drug-antibody ratio, and shorter half-life likely explain why results were better with T-DXd,” Dr. Dy said.

T-DXd was, in fact, designed to deliver an optimal antitumor effect, according to Dr. Smit.

The treatment incorporates a humanized anti-HER2 IgG1 monoclonal antibody that has the same amino acid sequence as trastuzumab. The antibody is attached via a cleavable, tumor-selective linker to a payload of deruxtecan, a topoisomerase I inhibitor.

The resulting antibody-drug conjugate has a high drug-to-antibody ratio, with 8 DXd molecules per monoclonal antibody, according to Dr. Smit.

Study details

The DESTINY-Lung01 trial included 42 patients with HER2-mutated NSCLC who received T-DXd at a dose of 6.4 mg/kg every 3 weeks. The patients’ median age was 63 years, and about 64% were female. Eastern Cooperative Oncology Group performance status was 0 in about one-quarter of the patients, and 1 in the remainder.

Patients had received up to six prior lines of treatment, including platinum-based chemotherapy in about 91%, a PD-1 or PD-L1 inhibitor in 55%, and docetaxel in 19%.

The confirmed ORR by independent central review was 61.9% (26/42). That included a single complete response (2.4%) and 25 partial responses (59.5%).

The duration of response was not reached (95% CI, 5.3 months to not estimable), and the median PFS was 14.0 months (95% CI, 6.4-14.0 months).

All patients experienced a treatment-related adverse event. Treatment-related events of grade 3 or greater were seen in 22 patients (52%). These mainly included decreased neutrophil count, anemia, nausea, vomiting, and fatigue.

There were five cases of interstitial lung disease, all of which were grade 2. In four cases, T-DXd was withdrawn. In one case, the drug was interrupted. All patients were treated with steroids.

“Two [patients] recovered, one recovered with sequelae, one was recovering, and one had not recovered by data cutoff,” Dr. Smit said.

DESTINY-Lung01 also includes a cohort of patients with HER2-expressing NSCLC not reported at the meeting. Enrollment in the HER2-mutated cohort that was reported has been expanded with another 50 patients to “better characterize the risk-benefit ratio,” Dr. Smit said.

The DESTINY-Lung01 study is sponsored by Daiichi Sankyo Inc. Dr. Smit reported relationships with Daiichi Sankyo and many other companies. Dr. Dy reported disclosures related to Amgen, AstraZeneca/Medimmune, GlaxoSmithKline, Takeda, and Tesaro.

SOURCE: Smit EF et al. ASCO 2020, Abstract 9504.

While nivolumab plus doublet chemotherapy was effective in extensive-stage small-cell lung cancer (ES-SCLC) in a recent randomized trial, the results might not be sufficient to change current clinical practice, in which two first-line chemo-immunotherapies are already approved and recommended, sources said.

Nivolumab added to platinum/etoposide doublet chemotherapy was well tolerated and significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone, according to results of ECOG-ACRIN EA5161, a randomized, phase 2 trial including 160 patients with ES-SCLC.

Risks of progression and death were reduced by 32% and 27%, respectively, when the immune checkpoint inhibitor was given along with chemotherapy, according to data presented by investigator Ticiana A. Leal, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“Our study, EA5161, confirms the efficacy of nivolumab in extensive-stage small cell lung cancer,” Dr. Leal said in a presentation she gave as part of the American Society of Clinical Oncology virtual scientific program.

Nivolumab did demonstrate a clear PFS advantage in EA5161, but “more surprisingly for a small trial” it also showed a clear OS advantage, said Taofeek K. Owonikoko, MD, PhD, in a commentary on the study.

“While the study as currently reported is insufficient to change practice, it does however provide very strong data to make the combination of nivolumab and platinum doublet acceptable as a platform for future clinical trials,” he said in the commentary, which was also included in the virtual ASCO proceedings.

Going forward, it would be difficult to justify another nondefinitive randomized phase 2 chemo-immunotherapy trial, especially if there are no “immediate plans” for a confirmatory phase 3 trial, added Dr. Owonikoko, who is director of thoracic oncology at Winship Cancer Institute of Emory University in Atlanta.

Nivolumab wasn’t the only immune checkpoint with new first-line data in ES-SCLC at ASCO. In the randomized, double-blind, phase 3 KEYNOTE-604 trial, pembrolizumab added to etoposide and platinum significantly prolonged PFS and showed a trend toward improved OS. However, the significance threshold for OS was missed, according to the report.

While these pembrolizumab data are also insufficient to change today’s practice standards, results for both the pembrolizumab- and nivolumab-containing regimens are nevertheless compelling to support their use as a platform for new treatment strategies, according to Dr. Owonikoko.

With these new ASCO data, there are now randomized data confirming a benefit of immune checkpoint inhibitor–based regimens in ES-SCLC, according to Lauren A. Byers, MD, from the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

Immune checkpoint inhibitors that are approved by the Food and Drug Administration for first-line treatment of ES-SCLC include atezolizumab (in combination with carboplatin and etoposide) and durvalumab (in combination with either carboplatin or cisplatin plus etoposide). In current National Comprehensive Cancer Network (NCCN) guidelines, both are described as “preferred” regimens for primary or adjuvant therapy.

“A lot of times in oncology we have trials with similar drugs, and you get somewhat different answers in terms of the outcome of the trials, so we’re kind of trying to tease them apart,” Dr. Byers said in an interview.

“I think in this situation, we’ve got four studies, and they essentially are extremely similar in terms of the result, which just gives us even more confidence that there is benefit, at least for a subset of patients.”

The EA5161 study was developed to evaluate the role of nivolumab in ES-SCLC, Dr. Leal said in her virtual ASCO presentation.

Of the 160 patients enrolled and randomized, 145 were eligible and treated, including 75 in the nivolumab plus chemotherapy arm and 70 in the chemotherapy arm. Participants were evenly split between performance status 0 and 1, and little more than half of patients were women, and a median of five treatment cycles were delivered in each arm.

Median PFS, the primary end point of the trial, was 5.5 months for nivolumab plus chemotherapy versus 4.7 months for chemotherapy alone for all eligible and treated patients (hazard ratio, 0.68; 95% confidence interval, 0.48-1.00; P = .047). In the intent-to-treat population, median PFS was 5.5 and 4.6 months in the respective arms (HR, 0.65; 95% CI, 0.46-0.91; P = .012).

Median overall survival was 11.3 months and 9.3 months for the nivolumab plus chemotherapy and chemotherapy-only arms, respectively, for all eligible and treated patients (HR, 0.73; 95% CI, 0.49-1.1), and in the intent-to-treat population, median OS was 11.3 and 8.5 months for the respective arms (HR, 0.67; 95% CI, 0.46-0.98; P = .038).

The overall response rate was 52% for nivolumab plus chemotherapy and 47% for chemotherapy alone, with a median duration of response of 5.6 and 3.3 months, respectively, Dr. Leal reported.

Treatment was generally well tolerated in both arms, according to the investigator, with no safety signals observed. Toxicities resulting in death occurred in nine patients in the nivolumab plus chemotherapy arm and seven in the chemotherapy-only arm. “Most of the events were related to progression of disease,” Dr. Leal said.

While nivolumab and pembrolizumab’s use in the first-line setting may be uncertain, it is currently approved for metastatic SCLC that has progressed following platinum-based chemotherapy and at least one more line of therapy, according to the drug’s package insert.

The EA5161 study was sponsored by the National Cancer Institute. Dr. Leal provided disclosures related to AbbVie, AstraZeneca, Bayer, BeyondSpring, Bristol-Myers Squibb, Genentech, InvisionFirst Lung, Merck, Mirati, Novocure, and Takeda.

Dr. Owonikoko provided disclosures related to Bristol-Myers Squibb, Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, and Takeda, among others. Dr. Byers reported disclosures related to Bristol-Myers Squibb, AstraZeneca, AbbVie, GenMab, PharmaMar, and Sierra Oncology, Tolero, Alethia, Merck, Jazz Pharmaceuticals, and Pfizer.

SOURCE: Leal TA et al. ASCO 2020, Abstract 9000.

While nivolumab plus doublet chemotherapy was effective in extensive-stage small-cell lung cancer (ES-SCLC) in a recent randomized trial, the results might not be sufficient to change current clinical practice, in which two first-line chemo-immunotherapies are already approved and recommended, sources said.

Nivolumab added to platinum/etoposide doublet chemotherapy was well tolerated and significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone, according to results of ECOG-ACRIN EA5161, a randomized, phase 2 trial including 160 patients with ES-SCLC.

Risks of progression and death were reduced by 32% and 27%, respectively, when the immune checkpoint inhibitor was given along with chemotherapy, according to data presented by investigator Ticiana A. Leal, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“Our study, EA5161, confirms the efficacy of nivolumab in extensive-stage small cell lung cancer,” Dr. Leal said in a presentation she gave as part of the American Society of Clinical Oncology virtual scientific program.

Nivolumab did demonstrate a clear PFS advantage in EA5161, but “more surprisingly for a small trial” it also showed a clear OS advantage, said Taofeek K. Owonikoko, MD, PhD, in a commentary on the study.

“While the study as currently reported is insufficient to change practice, it does however provide very strong data to make the combination of nivolumab and platinum doublet acceptable as a platform for future clinical trials,” he said in the commentary, which was also included in the virtual ASCO proceedings.

Going forward, it would be difficult to justify another nondefinitive randomized phase 2 chemo-immunotherapy trial, especially if there are no “immediate plans” for a confirmatory phase 3 trial, added Dr. Owonikoko, who is director of thoracic oncology at Winship Cancer Institute of Emory University in Atlanta.

Nivolumab wasn’t the only immune checkpoint with new first-line data in ES-SCLC at ASCO. In the randomized, double-blind, phase 3 KEYNOTE-604 trial, pembrolizumab added to etoposide and platinum significantly prolonged PFS and showed a trend toward improved OS. However, the significance threshold for OS was missed, according to the report.

While these pembrolizumab data are also insufficient to change today’s practice standards, results for both the pembrolizumab- and nivolumab-containing regimens are nevertheless compelling to support their use as a platform for new treatment strategies, according to Dr. Owonikoko.

With these new ASCO data, there are now randomized data confirming a benefit of immune checkpoint inhibitor–based regimens in ES-SCLC, according to Lauren A. Byers, MD, from the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

Immune checkpoint inhibitors that are approved by the Food and Drug Administration for first-line treatment of ES-SCLC include atezolizumab (in combination with carboplatin and etoposide) and durvalumab (in combination with either carboplatin or cisplatin plus etoposide). In current National Comprehensive Cancer Network (NCCN) guidelines, both are described as “preferred” regimens for primary or adjuvant therapy.

“A lot of times in oncology we have trials with similar drugs, and you get somewhat different answers in terms of the outcome of the trials, so we’re kind of trying to tease them apart,” Dr. Byers said in an interview.

“I think in this situation, we’ve got four studies, and they essentially are extremely similar in terms of the result, which just gives us even more confidence that there is benefit, at least for a subset of patients.”

The EA5161 study was developed to evaluate the role of nivolumab in ES-SCLC, Dr. Leal said in her virtual ASCO presentation.

Of the 160 patients enrolled and randomized, 145 were eligible and treated, including 75 in the nivolumab plus chemotherapy arm and 70 in the chemotherapy arm. Participants were evenly split between performance status 0 and 1, and little more than half of patients were women, and a median of five treatment cycles were delivered in each arm.

Median PFS, the primary end point of the trial, was 5.5 months for nivolumab plus chemotherapy versus 4.7 months for chemotherapy alone for all eligible and treated patients (hazard ratio, 0.68; 95% confidence interval, 0.48-1.00; P = .047). In the intent-to-treat population, median PFS was 5.5 and 4.6 months in the respective arms (HR, 0.65; 95% CI, 0.46-0.91; P = .012).

Median overall survival was 11.3 months and 9.3 months for the nivolumab plus chemotherapy and chemotherapy-only arms, respectively, for all eligible and treated patients (HR, 0.73; 95% CI, 0.49-1.1), and in the intent-to-treat population, median OS was 11.3 and 8.5 months for the respective arms (HR, 0.67; 95% CI, 0.46-0.98; P = .038).

The overall response rate was 52% for nivolumab plus chemotherapy and 47% for chemotherapy alone, with a median duration of response of 5.6 and 3.3 months, respectively, Dr. Leal reported.

Treatment was generally well tolerated in both arms, according to the investigator, with no safety signals observed. Toxicities resulting in death occurred in nine patients in the nivolumab plus chemotherapy arm and seven in the chemotherapy-only arm. “Most of the events were related to progression of disease,” Dr. Leal said.

While nivolumab and pembrolizumab’s use in the first-line setting may be uncertain, it is currently approved for metastatic SCLC that has progressed following platinum-based chemotherapy and at least one more line of therapy, according to the drug’s package insert.

The EA5161 study was sponsored by the National Cancer Institute. Dr. Leal provided disclosures related to AbbVie, AstraZeneca, Bayer, BeyondSpring, Bristol-Myers Squibb, Genentech, InvisionFirst Lung, Merck, Mirati, Novocure, and Takeda.

Dr. Owonikoko provided disclosures related to Bristol-Myers Squibb, Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, and Takeda, among others. Dr. Byers reported disclosures related to Bristol-Myers Squibb, AstraZeneca, AbbVie, GenMab, PharmaMar, and Sierra Oncology, Tolero, Alethia, Merck, Jazz Pharmaceuticals, and Pfizer.

SOURCE: Leal TA et al. ASCO 2020, Abstract 9000.

While nivolumab plus doublet chemotherapy was effective in extensive-stage small-cell lung cancer (ES-SCLC) in a recent randomized trial, the results might not be sufficient to change current clinical practice, in which two first-line chemo-immunotherapies are already approved and recommended, sources said.

Nivolumab added to platinum/etoposide doublet chemotherapy was well tolerated and significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone, according to results of ECOG-ACRIN EA5161, a randomized, phase 2 trial including 160 patients with ES-SCLC.

Risks of progression and death were reduced by 32% and 27%, respectively, when the immune checkpoint inhibitor was given along with chemotherapy, according to data presented by investigator Ticiana A. Leal, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“Our study, EA5161, confirms the efficacy of nivolumab in extensive-stage small cell lung cancer,” Dr. Leal said in a presentation she gave as part of the American Society of Clinical Oncology virtual scientific program.

Nivolumab did demonstrate a clear PFS advantage in EA5161, but “more surprisingly for a small trial” it also showed a clear OS advantage, said Taofeek K. Owonikoko, MD, PhD, in a commentary on the study.

“While the study as currently reported is insufficient to change practice, it does however provide very strong data to make the combination of nivolumab and platinum doublet acceptable as a platform for future clinical trials,” he said in the commentary, which was also included in the virtual ASCO proceedings.

Going forward, it would be difficult to justify another nondefinitive randomized phase 2 chemo-immunotherapy trial, especially if there are no “immediate plans” for a confirmatory phase 3 trial, added Dr. Owonikoko, who is director of thoracic oncology at Winship Cancer Institute of Emory University in Atlanta.

Nivolumab wasn’t the only immune checkpoint with new first-line data in ES-SCLC at ASCO. In the randomized, double-blind, phase 3 KEYNOTE-604 trial, pembrolizumab added to etoposide and platinum significantly prolonged PFS and showed a trend toward improved OS. However, the significance threshold for OS was missed, according to the report.

While these pembrolizumab data are also insufficient to change today’s practice standards, results for both the pembrolizumab- and nivolumab-containing regimens are nevertheless compelling to support their use as a platform for new treatment strategies, according to Dr. Owonikoko.

With these new ASCO data, there are now randomized data confirming a benefit of immune checkpoint inhibitor–based regimens in ES-SCLC, according to Lauren A. Byers, MD, from the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

Immune checkpoint inhibitors that are approved by the Food and Drug Administration for first-line treatment of ES-SCLC include atezolizumab (in combination with carboplatin and etoposide) and durvalumab (in combination with either carboplatin or cisplatin plus etoposide). In current National Comprehensive Cancer Network (NCCN) guidelines, both are described as “preferred” regimens for primary or adjuvant therapy.

“A lot of times in oncology we have trials with similar drugs, and you get somewhat different answers in terms of the outcome of the trials, so we’re kind of trying to tease them apart,” Dr. Byers said in an interview.

“I think in this situation, we’ve got four studies, and they essentially are extremely similar in terms of the result, which just gives us even more confidence that there is benefit, at least for a subset of patients.”

The EA5161 study was developed to evaluate the role of nivolumab in ES-SCLC, Dr. Leal said in her virtual ASCO presentation.

Of the 160 patients enrolled and randomized, 145 were eligible and treated, including 75 in the nivolumab plus chemotherapy arm and 70 in the chemotherapy arm. Participants were evenly split between performance status 0 and 1, and little more than half of patients were women, and a median of five treatment cycles were delivered in each arm.

Median PFS, the primary end point of the trial, was 5.5 months for nivolumab plus chemotherapy versus 4.7 months for chemotherapy alone for all eligible and treated patients (hazard ratio, 0.68; 95% confidence interval, 0.48-1.00; P = .047). In the intent-to-treat population, median PFS was 5.5 and 4.6 months in the respective arms (HR, 0.65; 95% CI, 0.46-0.91; P = .012).

Median overall survival was 11.3 months and 9.3 months for the nivolumab plus chemotherapy and chemotherapy-only arms, respectively, for all eligible and treated patients (HR, 0.73; 95% CI, 0.49-1.1), and in the intent-to-treat population, median OS was 11.3 and 8.5 months for the respective arms (HR, 0.67; 95% CI, 0.46-0.98; P = .038).

The overall response rate was 52% for nivolumab plus chemotherapy and 47% for chemotherapy alone, with a median duration of response of 5.6 and 3.3 months, respectively, Dr. Leal reported.

Treatment was generally well tolerated in both arms, according to the investigator, with no safety signals observed. Toxicities resulting in death occurred in nine patients in the nivolumab plus chemotherapy arm and seven in the chemotherapy-only arm. “Most of the events were related to progression of disease,” Dr. Leal said.

While nivolumab and pembrolizumab’s use in the first-line setting may be uncertain, it is currently approved for metastatic SCLC that has progressed following platinum-based chemotherapy and at least one more line of therapy, according to the drug’s package insert.

The EA5161 study was sponsored by the National Cancer Institute. Dr. Leal provided disclosures related to AbbVie, AstraZeneca, Bayer, BeyondSpring, Bristol-Myers Squibb, Genentech, InvisionFirst Lung, Merck, Mirati, Novocure, and Takeda.

Dr. Owonikoko provided disclosures related to Bristol-Myers Squibb, Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, and Takeda, among others. Dr. Byers reported disclosures related to Bristol-Myers Squibb, AstraZeneca, AbbVie, GenMab, PharmaMar, and Sierra Oncology, Tolero, Alethia, Merck, Jazz Pharmaceuticals, and Pfizer.

SOURCE: Leal TA et al. ASCO 2020, Abstract 9000.

An international survey sent to clinicians who treat non–small cell lung cancer (NSCLC) has found that one-third were unaware of evidence-based guidelines that recommend targeted therapies when a driver mutation is identified.

Moreover, the majority of these clinicians believe that fewer than 50% of patients in their country undergo molecular testing, the same survey showed.

The survey was conducted by the International Association for the Study of Lung Cancer (IASLC); 2537 questionnaires from 102 countries were returned and analyzed.

It was published online May 20 in the Journal of Thoracic Oncology.

The results are concerning because “the risk of death for patients with NSCLC is substantially reduced when a gene alteration is identified and the available targeted therapy is administered,” the authors emphasize.

“Specific protocols to initiate reflex testing for guideline-recommended molecular markers would help providers consider molecular testing earlier and optimize tissue,” they suggest.
 

Surprised that clinicians were unaware of guidelines

“I was not surprised that we found suboptimal testing rates based on other research that has demonstrated the need to improve the quality of lung cancer in some areas,” corresponding author Matthew Smeltzer, PhD, University of Memphis, Tennessee, told Medscape Medical News in an email.

“However, I was surprised that so many respondents were unaware of guidelines,” he said.

The College of American Pathologists, IASLC, and Association for Molecular Pathology established evidence-based standards for the selection of NSCLC patients for molecular testing in 2013, and these guidelines were subsequently endorsed by the American Society of Clinical Oncology.

“We suspect that the level of access a provider has to targeted therapies does affect molecular testing rates,” Smeltzer acknowledged.
 

Molecular testing survey

“The survey included a seven-question introduction for all respondents and then divided respondents into one of three tracks,” the authors explain.

These tracks included respondents who requested tests and who treated patients (medical oncologists), those who analyzed and interpreted assays (pathologists), and those who acquired tissue samples (surgeons, pulmonologists, radiologists).

Countries were also grouped into five geographic regions — Asia, Europe, Latin America, United States, and Canada — and the rest of the world (ROW).

“Overall, respondents reported that molecular testing rates were lower than we would like but they were not satisfied with the current state of testing, and they reported higher testing rates in their own clinics,” Smeltzer noted.

However, when tests were ordered, “we found 99% of respondents in the requesting/treating track ordered tests for EGFR, 95% for ALK, 79% for ROS1, and < 50% ordered other tests,” the authors observe.

Indeed, EGFR, ALK, and ROS1 were the top three tests ordered across all regions, though less frequently so in the ROW, they add.

More than half of requesting/treating track respondents also order multiplex assays, although Latin America and the ROW did this less frequently than other regions.

Over 90% of respondents who perform or interpret assays indicated that they perform EGFR testing, while 83% of the same group do ALK testing; 69% tested for KRAS; 68% for BRAF, 64% for ROS1, and 56% for HER2. Fewer than half of them performed other tests.

Survey results also showed that EGFR, ALK, and KRAS are the top three tests performed across all regions, with no regional differences.

“Respondents also reported on the acquisition and testing of liquid biopsies,” survey authors point out.

Here, 87% of requesting/treating track respondents indicated that they “sometimes” request molecular testing on liquid biopsies, but the proportions of those who sometimes use liquid biopsy varied by region and were lowest in Latin America and the ROW.

A lower proportion of those who perform and interpret assays, at 69%, also offer tests on liquid biopsies, but this percentage, too, varied significantly by region, being the least frequently done in the United States and Canada, as well as in the ROW.

All the above tests are for genetic mutations or alterations that guide clinicians on use of targeted therapy directed at particular mutations, for example, drugs like erlotinib for EGFR and crizotinib for ALK.

However, immunotherapy with checkpoint inhibitors has also made a big impact on the treatment of NSCLC, and the use of these agents is sometimes guided by testing for programmed cell-death ligand (PD-L1).

PD-L1 is not a molecular marker per se, the authors note.

Nevertheless, “we found that 84% of respondents in the requesting/treating track ordered PD-L1 and 68% of respondents who perform or interpret assays report PD-L1 is offered in their own lab,” the authors observe.

Smeltzer commented that both approaches — targeted therapies and immunotherapy — have made inroads into the treatment of NSCLC, in some cases replacing chemotherapy.

He emphasized that “it is important to know if a specific oncogene driver is present before initiating immunotherapy treatment,” and noted that when tissue is sent out for both types of testing, the results for PD-L1 are usually available before the results for the full molecular testing panel are back.
 

Barriers to testing

“The most frequent barrier to molecular testing in every region was cost,” the survey authors note.

Insufficient amount of tumor cells was the main reason for molecular testing failures along with inadequate tissue quality.

The majority of respondents who order tests and treat patients were sure that the laboratories they use perform appropriate validation of molecular tests, while almost all of those who perform or interpret assays said they perform validation tests in their labs.

Only 30% of respondents who request tests and treat patients have access to molecular testing labs within their own institutions; the remaining respondents have to outsource testing completely or partially.

Most respondents who test and treat patients also have multidisciplinary tumor boards to discuss patients with NSCLC, but almost one quarter of the same group indicated their board met less than once a month.

“Turnaround time is a barrier to molecular testing across the world,” the authors continue, with 29% of those who request tests and treat patients reporting that it typically takes 10 days or more to receive molecular testing results.

Interestingly, the highest percentage of respondents who reported this long turnaround time were in North America.

Perhaps encouragingly, 41% of respondents who perform or interpret assays indicated they were dissatisfied with the condition of molecular testing in their country, although in this regard, the United States and Canada had the lowest rates of dissatisfaction.

In fact, 39% of those who request tests and treat patients ranked the conditions of molecular testing in their country as “average or below,” while 42% of respondents in the tissue acquisition track ranked the conditions of molecular testing as average or below, the worst rankings coming from Latin America and the ROW.

Low quality of tissue samples was another reason respondents expressed dissatisfaction with the current state of molecular testing in their country.

Smeltzer is a research consultant for the Association of Community Cancer Centers.

This article first appeared on Medscape.com.

An international survey sent to clinicians who treat non–small cell lung cancer (NSCLC) has found that one-third were unaware of evidence-based guidelines that recommend targeted therapies when a driver mutation is identified.

Moreover, the majority of these clinicians believe that fewer than 50% of patients in their country undergo molecular testing, the same survey showed.

The survey was conducted by the International Association for the Study of Lung Cancer (IASLC); 2537 questionnaires from 102 countries were returned and analyzed.

It was published online May 20 in the Journal of Thoracic Oncology.

The results are concerning because “the risk of death for patients with NSCLC is substantially reduced when a gene alteration is identified and the available targeted therapy is administered,” the authors emphasize.

“Specific protocols to initiate reflex testing for guideline-recommended molecular markers would help providers consider molecular testing earlier and optimize tissue,” they suggest.
 

Surprised that clinicians were unaware of guidelines

“I was not surprised that we found suboptimal testing rates based on other research that has demonstrated the need to improve the quality of lung cancer in some areas,” corresponding author Matthew Smeltzer, PhD, University of Memphis, Tennessee, told Medscape Medical News in an email.

“However, I was surprised that so many respondents were unaware of guidelines,” he said.

The College of American Pathologists, IASLC, and Association for Molecular Pathology established evidence-based standards for the selection of NSCLC patients for molecular testing in 2013, and these guidelines were subsequently endorsed by the American Society of Clinical Oncology.

“We suspect that the level of access a provider has to targeted therapies does affect molecular testing rates,” Smeltzer acknowledged.
 

Molecular testing survey

“The survey included a seven-question introduction for all respondents and then divided respondents into one of three tracks,” the authors explain.

These tracks included respondents who requested tests and who treated patients (medical oncologists), those who analyzed and interpreted assays (pathologists), and those who acquired tissue samples (surgeons, pulmonologists, radiologists).

Countries were also grouped into five geographic regions — Asia, Europe, Latin America, United States, and Canada — and the rest of the world (ROW).

“Overall, respondents reported that molecular testing rates were lower than we would like but they were not satisfied with the current state of testing, and they reported higher testing rates in their own clinics,” Smeltzer noted.

However, when tests were ordered, “we found 99% of respondents in the requesting/treating track ordered tests for EGFR, 95% for ALK, 79% for ROS1, and < 50% ordered other tests,” the authors observe.

Indeed, EGFR, ALK, and ROS1 were the top three tests ordered across all regions, though less frequently so in the ROW, they add.

More than half of requesting/treating track respondents also order multiplex assays, although Latin America and the ROW did this less frequently than other regions.

Over 90% of respondents who perform or interpret assays indicated that they perform EGFR testing, while 83% of the same group do ALK testing; 69% tested for KRAS; 68% for BRAF, 64% for ROS1, and 56% for HER2. Fewer than half of them performed other tests.

Survey results also showed that EGFR, ALK, and KRAS are the top three tests performed across all regions, with no regional differences.

“Respondents also reported on the acquisition and testing of liquid biopsies,” survey authors point out.

Here, 87% of requesting/treating track respondents indicated that they “sometimes” request molecular testing on liquid biopsies, but the proportions of those who sometimes use liquid biopsy varied by region and were lowest in Latin America and the ROW.

A lower proportion of those who perform and interpret assays, at 69%, also offer tests on liquid biopsies, but this percentage, too, varied significantly by region, being the least frequently done in the United States and Canada, as well as in the ROW.

All the above tests are for genetic mutations or alterations that guide clinicians on use of targeted therapy directed at particular mutations, for example, drugs like erlotinib for EGFR and crizotinib for ALK.

However, immunotherapy with checkpoint inhibitors has also made a big impact on the treatment of NSCLC, and the use of these agents is sometimes guided by testing for programmed cell-death ligand (PD-L1).

PD-L1 is not a molecular marker per se, the authors note.

Nevertheless, “we found that 84% of respondents in the requesting/treating track ordered PD-L1 and 68% of respondents who perform or interpret assays report PD-L1 is offered in their own lab,” the authors observe.

Smeltzer commented that both approaches — targeted therapies and immunotherapy — have made inroads into the treatment of NSCLC, in some cases replacing chemotherapy.

He emphasized that “it is important to know if a specific oncogene driver is present before initiating immunotherapy treatment,” and noted that when tissue is sent out for both types of testing, the results for PD-L1 are usually available before the results for the full molecular testing panel are back.
 

Barriers to testing

“The most frequent barrier to molecular testing in every region was cost,” the survey authors note.

Insufficient amount of tumor cells was the main reason for molecular testing failures along with inadequate tissue quality.

The majority of respondents who order tests and treat patients were sure that the laboratories they use perform appropriate validation of molecular tests, while almost all of those who perform or interpret assays said they perform validation tests in their labs.

Only 30% of respondents who request tests and treat patients have access to molecular testing labs within their own institutions; the remaining respondents have to outsource testing completely or partially.

Most respondents who test and treat patients also have multidisciplinary tumor boards to discuss patients with NSCLC, but almost one quarter of the same group indicated their board met less than once a month.

“Turnaround time is a barrier to molecular testing across the world,” the authors continue, with 29% of those who request tests and treat patients reporting that it typically takes 10 days or more to receive molecular testing results.

Interestingly, the highest percentage of respondents who reported this long turnaround time were in North America.

Perhaps encouragingly, 41% of respondents who perform or interpret assays indicated they were dissatisfied with the condition of molecular testing in their country, although in this regard, the United States and Canada had the lowest rates of dissatisfaction.

In fact, 39% of those who request tests and treat patients ranked the conditions of molecular testing in their country as “average or below,” while 42% of respondents in the tissue acquisition track ranked the conditions of molecular testing as average or below, the worst rankings coming from Latin America and the ROW.

Low quality of tissue samples was another reason respondents expressed dissatisfaction with the current state of molecular testing in their country.

Smeltzer is a research consultant for the Association of Community Cancer Centers.

This article first appeared on Medscape.com.

An international survey sent to clinicians who treat non–small cell lung cancer (NSCLC) has found that one-third were unaware of evidence-based guidelines that recommend targeted therapies when a driver mutation is identified.

Moreover, the majority of these clinicians believe that fewer than 50% of patients in their country undergo molecular testing, the same survey showed.

The survey was conducted by the International Association for the Study of Lung Cancer (IASLC); 2537 questionnaires from 102 countries were returned and analyzed.

It was published online May 20 in the Journal of Thoracic Oncology.

The results are concerning because “the risk of death for patients with NSCLC is substantially reduced when a gene alteration is identified and the available targeted therapy is administered,” the authors emphasize.

“Specific protocols to initiate reflex testing for guideline-recommended molecular markers would help providers consider molecular testing earlier and optimize tissue,” they suggest.
 

Surprised that clinicians were unaware of guidelines

“I was not surprised that we found suboptimal testing rates based on other research that has demonstrated the need to improve the quality of lung cancer in some areas,” corresponding author Matthew Smeltzer, PhD, University of Memphis, Tennessee, told Medscape Medical News in an email.

“However, I was surprised that so many respondents were unaware of guidelines,” he said.

The College of American Pathologists, IASLC, and Association for Molecular Pathology established evidence-based standards for the selection of NSCLC patients for molecular testing in 2013, and these guidelines were subsequently endorsed by the American Society of Clinical Oncology.

“We suspect that the level of access a provider has to targeted therapies does affect molecular testing rates,” Smeltzer acknowledged.
 

Molecular testing survey

“The survey included a seven-question introduction for all respondents and then divided respondents into one of three tracks,” the authors explain.

These tracks included respondents who requested tests and who treated patients (medical oncologists), those who analyzed and interpreted assays (pathologists), and those who acquired tissue samples (surgeons, pulmonologists, radiologists).

Countries were also grouped into five geographic regions — Asia, Europe, Latin America, United States, and Canada — and the rest of the world (ROW).

“Overall, respondents reported that molecular testing rates were lower than we would like but they were not satisfied with the current state of testing, and they reported higher testing rates in their own clinics,” Smeltzer noted.

However, when tests were ordered, “we found 99% of respondents in the requesting/treating track ordered tests for EGFR, 95% for ALK, 79% for ROS1, and < 50% ordered other tests,” the authors observe.

Indeed, EGFR, ALK, and ROS1 were the top three tests ordered across all regions, though less frequently so in the ROW, they add.

More than half of requesting/treating track respondents also order multiplex assays, although Latin America and the ROW did this less frequently than other regions.

Over 90% of respondents who perform or interpret assays indicated that they perform EGFR testing, while 83% of the same group do ALK testing; 69% tested for KRAS; 68% for BRAF, 64% for ROS1, and 56% for HER2. Fewer than half of them performed other tests.

Survey results also showed that EGFR, ALK, and KRAS are the top three tests performed across all regions, with no regional differences.

“Respondents also reported on the acquisition and testing of liquid biopsies,” survey authors point out.

Here, 87% of requesting/treating track respondents indicated that they “sometimes” request molecular testing on liquid biopsies, but the proportions of those who sometimes use liquid biopsy varied by region and were lowest in Latin America and the ROW.

A lower proportion of those who perform and interpret assays, at 69%, also offer tests on liquid biopsies, but this percentage, too, varied significantly by region, being the least frequently done in the United States and Canada, as well as in the ROW.

All the above tests are for genetic mutations or alterations that guide clinicians on use of targeted therapy directed at particular mutations, for example, drugs like erlotinib for EGFR and crizotinib for ALK.

However, immunotherapy with checkpoint inhibitors has also made a big impact on the treatment of NSCLC, and the use of these agents is sometimes guided by testing for programmed cell-death ligand (PD-L1).

PD-L1 is not a molecular marker per se, the authors note.

Nevertheless, “we found that 84% of respondents in the requesting/treating track ordered PD-L1 and 68% of respondents who perform or interpret assays report PD-L1 is offered in their own lab,” the authors observe.

Smeltzer commented that both approaches — targeted therapies and immunotherapy — have made inroads into the treatment of NSCLC, in some cases replacing chemotherapy.

He emphasized that “it is important to know if a specific oncogene driver is present before initiating immunotherapy treatment,” and noted that when tissue is sent out for both types of testing, the results for PD-L1 are usually available before the results for the full molecular testing panel are back.
 

Barriers to testing

“The most frequent barrier to molecular testing in every region was cost,” the survey authors note.

Insufficient amount of tumor cells was the main reason for molecular testing failures along with inadequate tissue quality.

The majority of respondents who order tests and treat patients were sure that the laboratories they use perform appropriate validation of molecular tests, while almost all of those who perform or interpret assays said they perform validation tests in their labs.

Only 30% of respondents who request tests and treat patients have access to molecular testing labs within their own institutions; the remaining respondents have to outsource testing completely or partially.

Most respondents who test and treat patients also have multidisciplinary tumor boards to discuss patients with NSCLC, but almost one quarter of the same group indicated their board met less than once a month.

“Turnaround time is a barrier to molecular testing across the world,” the authors continue, with 29% of those who request tests and treat patients reporting that it typically takes 10 days or more to receive molecular testing results.

Interestingly, the highest percentage of respondents who reported this long turnaround time were in North America.

Perhaps encouragingly, 41% of respondents who perform or interpret assays indicated they were dissatisfied with the condition of molecular testing in their country, although in this regard, the United States and Canada had the lowest rates of dissatisfaction.

In fact, 39% of those who request tests and treat patients ranked the conditions of molecular testing in their country as “average or below,” while 42% of respondents in the tissue acquisition track ranked the conditions of molecular testing as average or below, the worst rankings coming from Latin America and the ROW.

Low quality of tissue samples was another reason respondents expressed dissatisfaction with the current state of molecular testing in their country.

Smeltzer is a research consultant for the Association of Community Cancer Centers.

This article first appeared on Medscape.com.