In the Journals

Pembrolizumab after radiotherapy appears safe, induces encouraging responses in lung cancer subset

Joshua M. Bauml, MD
Joshua M. Bauml

Combining radiotherapy and pembrolizumab appeared safe and induced promising responses among patients with advanced non-small cell lung cancer, according to results of two separate phase 2 studies published in JAMA Oncology.

“The theoretical reason why radiation could enhance the efficacy of immunotherapy is built on the concept of neoantigens,” Joshua M. Bauml, MD, assistant professor of medicine at University of Pennsylvania, told HemOnc Today. “The immune system can identify these as ‘other’ and eradicate abnormal cells. In the case of cancer, the immune system is unable to identify these abnormal cells as problematic, so a tumor can grow. One of the goals of immunotherapy is to reverse this immune evasion. By lysing cancer cells with radiation, it allows the immune system to see different parts of proteins that may be overexpressed in the cancer. The goal is to identify novel neoantigens that may amplify the response to immunotherapy.”

However, because previous studies were conducted prior to the advent of immunotherapy, whether the combination of radiotherapy with checkpoint inhibition improved outcomes for these patients had been unknown.

Pembrolizumab after SBRT

In the phase 2 PEMBRO-RT trial, Willemijn S.M.E. Theelen, MD, of the department of thoracic oncology at Netherlands Cancer Institute, and colleagues randomly assigned 76 patients with advanced NSCLC (median age, 62 years; range, 35-78; 58% men) to 200 mg IV pembrolizumab (Keytruda, Merck) every 3 weeks alone (control group; n = 40) or after three doses of 8 Gy stereotactic body radiotherapy (experimental group; n = 36) to a single tumor site. Treatment continued until confirmed radiographic progression, unacceptable toxicity, patient withdrawal, or for a maximum of 24 months.

Overall response rate at 12 weeks following randomization served as the study’s primary endpoint. Researchers also assessed PFS, OS and disease control rate at 12 weeks.

Median follow-up was 23.6 months (range, 0.1-34.4).

Results showed an ORR of 18% (95% CI, 7-33) in the control group and 36% (95% CI, 21-54) in the experimental group. The study failed to meet its primary endpoint because the ORR improvement at 12 weeks did not increase from 20% in the control group to 50% in the experimental group.

Compared with the control group, patients in the experimental group demonstrated longer median PFS (6.6 months vs. 1.9 months; HR = 0.71; 95% CI, 0.42-1.18) and median OS (15.9 months vs. 7.6 months; HR = 0.66; 95% CI, 0.37-1.18). These differences did not reach statistical significance, although in a subgroup of patients with PD-L1-negative tumors, researchers observed significant benefits of SBRT in terms of PFS (HR = 0.49; P = .03) and OS (HR = 0.48; P = .046).

The most common adverse events among all patients included fatigue (39%), flulike symptoms (32%) and cough (28%). Researchers observed no increase in treatment-related toxicity in the experimental group.

Pembrolizumab after locally ablative therapy

In a separate single-arm phase 2 trial, Bauml and colleagues assigned 45 patients with oligometastatic NSCLC (median age, 64 years; range, 46-82; 53% men) to pembrolizumab from 4 to 12 weeks after completing locally ablative therapy. Patients received 200 mg IV pembrolizumab every 21 days for eight cycles. Those without disease progression could extend treatment to 16 cycles.

PFS from the start of locally ablative therapy and PFS from the start of pembrolizumab therapy served as the study’s primary endpoints. OS, safety and quality of life served as secondary endpoints.

Median follow-up was 25 months.

Results showed median PFS of 19.1 months (95% CI, 9.4-28.7) from the start of locally ablative therapy, which was significantly greater than the historical median PFS of 6.6 months (P = .005).

Median PFS from the start of pembrolizumab was 18.7 months (95% CI, 10.1-27.1).

Results also showed an OS rate of 90.9% at 12 months and 77.5% at 24 months.

Researchers did not observe new safety signals nor a decline in quality of life for patients after receiving pembrolizumab following local ablative therapy.

“There have now been two randomized studies, including one previously published, documenting an improved OS with locally ablative therapy for patients with oligometastatic cancer,” Bauml said. “Although they are not definitive and require confirmation in larger studies, many physicians are excited about these data and have been using local ablative therapy in this setting based on the exciting results these studies showed. As a result, we have the potential opportunity to randomly assign patients with oligometastatic NSCLC to local ablative therapy alone or local ablative therapy followed by pembrolizumab.”

An early body of evidence

The results of these studies provide early evidence that radical local therapy could improve overall outcomes compared with the standard of care for patients with metastatic lung cancer, Joshua Walker, MD, PhD, assistant professor of cell, developmental and cancer biology and of radiation at Oregon Health and Science University, and Billy W. Loo Jr., MD, PhD, professor of radiation at Stanford University, wrote in an accompanying editorial.

However, questions remain regarding the significance of metastatic disease burden, the use of biomarkers and the sequencing of treatment, they noted.

“At this stage of early excitement, it is all the more important to approach these questions through systematic clinical and translational research to maximize the promise that radiotherapy will throw its beams further toward cure through synergy with immunotherapy,” Walker and Loo wrote. – by John DeRosier

Disclosures: Theelen reports research funding from Merck Sharp & Dohme. Bauml reports research funding from Amgen, AstraZeneca, Bayer, Carevive Systems, Incyte, Janssen Pharmaceuticals, Merck, Novartis International and Takeda, as well as consultant/advisory roles with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Janssen Pharmaceuticals, Merck, Regeneron and Takeda. Please see the studies for all other authors’ relevant financial disclosures. Loo reports serving on the board of TibaRay Inc. and research funding from Varian Medical Systems. Walker reports no relevant financial disclosures.

 

Joshua M. Bauml, MD
Joshua M. Bauml

Combining radiotherapy and pembrolizumab appeared safe and induced promising responses among patients with advanced non-small cell lung cancer, according to results of two separate phase 2 studies published in JAMA Oncology.

“The theoretical reason why radiation could enhance the efficacy of immunotherapy is built on the concept of neoantigens,” Joshua M. Bauml, MD, assistant professor of medicine at University of Pennsylvania, told HemOnc Today. “The immune system can identify these as ‘other’ and eradicate abnormal cells. In the case of cancer, the immune system is unable to identify these abnormal cells as problematic, so a tumor can grow. One of the goals of immunotherapy is to reverse this immune evasion. By lysing cancer cells with radiation, it allows the immune system to see different parts of proteins that may be overexpressed in the cancer. The goal is to identify novel neoantigens that may amplify the response to immunotherapy.”

However, because previous studies were conducted prior to the advent of immunotherapy, whether the combination of radiotherapy with checkpoint inhibition improved outcomes for these patients had been unknown.

Pembrolizumab after SBRT

In the phase 2 PEMBRO-RT trial, Willemijn S.M.E. Theelen, MD, of the department of thoracic oncology at Netherlands Cancer Institute, and colleagues randomly assigned 76 patients with advanced NSCLC (median age, 62 years; range, 35-78; 58% men) to 200 mg IV pembrolizumab (Keytruda, Merck) every 3 weeks alone (control group; n = 40) or after three doses of 8 Gy stereotactic body radiotherapy (experimental group; n = 36) to a single tumor site. Treatment continued until confirmed radiographic progression, unacceptable toxicity, patient withdrawal, or for a maximum of 24 months.

Overall response rate at 12 weeks following randomization served as the study’s primary endpoint. Researchers also assessed PFS, OS and disease control rate at 12 weeks.

Median follow-up was 23.6 months (range, 0.1-34.4).

Results showed an ORR of 18% (95% CI, 7-33) in the control group and 36% (95% CI, 21-54) in the experimental group. The study failed to meet its primary endpoint because the ORR improvement at 12 weeks did not increase from 20% in the control group to 50% in the experimental group.

Compared with the control group, patients in the experimental group demonstrated longer median PFS (6.6 months vs. 1.9 months; HR = 0.71; 95% CI, 0.42-1.18) and median OS (15.9 months vs. 7.6 months; HR = 0.66; 95% CI, 0.37-1.18). These differences did not reach statistical significance, although in a subgroup of patients with PD-L1-negative tumors, researchers observed significant benefits of SBRT in terms of PFS (HR = 0.49; P = .03) and OS (HR = 0.48; P = .046).

The most common adverse events among all patients included fatigue (39%), flulike symptoms (32%) and cough (28%). Researchers observed no increase in treatment-related toxicity in the experimental group.

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Pembrolizumab after locally ablative therapy

In a separate single-arm phase 2 trial, Bauml and colleagues assigned 45 patients with oligometastatic NSCLC (median age, 64 years; range, 46-82; 53% men) to pembrolizumab from 4 to 12 weeks after completing locally ablative therapy. Patients received 200 mg IV pembrolizumab every 21 days for eight cycles. Those without disease progression could extend treatment to 16 cycles.

PFS from the start of locally ablative therapy and PFS from the start of pembrolizumab therapy served as the study’s primary endpoints. OS, safety and quality of life served as secondary endpoints.

Median follow-up was 25 months.

Results showed median PFS of 19.1 months (95% CI, 9.4-28.7) from the start of locally ablative therapy, which was significantly greater than the historical median PFS of 6.6 months (P = .005).

Median PFS from the start of pembrolizumab was 18.7 months (95% CI, 10.1-27.1).

Results also showed an OS rate of 90.9% at 12 months and 77.5% at 24 months.

Researchers did not observe new safety signals nor a decline in quality of life for patients after receiving pembrolizumab following local ablative therapy.

“There have now been two randomized studies, including one previously published, documenting an improved OS with locally ablative therapy for patients with oligometastatic cancer,” Bauml said. “Although they are not definitive and require confirmation in larger studies, many physicians are excited about these data and have been using local ablative therapy in this setting based on the exciting results these studies showed. As a result, we have the potential opportunity to randomly assign patients with oligometastatic NSCLC to local ablative therapy alone or local ablative therapy followed by pembrolizumab.”

An early body of evidence

The results of these studies provide early evidence that radical local therapy could improve overall outcomes compared with the standard of care for patients with metastatic lung cancer, Joshua Walker, MD, PhD, assistant professor of cell, developmental and cancer biology and of radiation at Oregon Health and Science University, and Billy W. Loo Jr., MD, PhD, professor of radiation at Stanford University, wrote in an accompanying editorial.

However, questions remain regarding the significance of metastatic disease burden, the use of biomarkers and the sequencing of treatment, they noted.

“At this stage of early excitement, it is all the more important to approach these questions through systematic clinical and translational research to maximize the promise that radiotherapy will throw its beams further toward cure through synergy with immunotherapy,” Walker and Loo wrote. – by John DeRosier

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Disclosures: Theelen reports research funding from Merck Sharp & Dohme. Bauml reports research funding from Amgen, AstraZeneca, Bayer, Carevive Systems, Incyte, Janssen Pharmaceuticals, Merck, Novartis International and Takeda, as well as consultant/advisory roles with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Janssen Pharmaceuticals, Merck, Regeneron and Takeda. Please see the studies for all other authors’ relevant financial disclosures. Loo reports serving on the board of TibaRay Inc. and research funding from Varian Medical Systems. Walker reports no relevant financial disclosures.

 

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