Jun 2, 2023

ws clinical benefit In a phase 2 trial of patients with brain cancer that metastasized from a wide range of primary tumors, Mass General Cancer Center researchers found that the immune checkpoint inhibitor pembrolizumab had a durable, antitumor effect in a subset of patients Mass General Brigham In a phase 2 clinical trial of the immune checkpoint inhibitor pembrolizumab, investigators found that 42 percent of patients with metastatic brain cancer benefited from the therapy, with seven patients in the trial surviving longer than two years. The authors caution that these benefits must be weighed against risk of toxicity, but, overall, the study shows promising results that warrant larger studies and efforts to identify patients most likely to benefit from this treatment. Their findings are published in Nature Medicine and presented simultaneously at the 2023 ASCO Annual Meeting on June 2. “There are very few effective treatments for patients with brain metastases. Our overarching objective is to find improved therapies for this patient population,” said corresponding author Priscilla K. Brastianos, MD , of the Mass General Cancer Center . “With this trial, we investigated pembrolizumab, which is an immunotherapy for patients with brain metastases. We showed that pembrolizumab was tolerated and showed clinical benefit in the brain in 42 percent of patients, which is promising for this patient population.” The single-arm, open-label, phase 2 trial, funded in part by Merck Sharp & Dohme, a subsidiary of Merck & Co, the manufacturer of pembrolizumab, included nine patients with previously untreated, asymptomatic brain metastases (cohort A) and 48 patients with recurrent and progressive disease after prior therapy (cohort B). Participants were enrolled in the trial between Oct. 6, 2016 and Oct. 16, 2018. The primary endpoint of the study was response rate, including complete response, partial response, or stable disease. Patients in the trial had primary tumor diagnoses that included breast, melanoma, non-small cell lung, small-cell lung, pituitary, and other cancers. The research team found that 24 of the 57 patients had an intracranial benefit, with five patients experiencing a complete or partial response to treatment. This included three patients in cohort A and 21 in cohort B, meaning the study achieved its primary endpoint. The team also reported that median overall survival for participants was 8 months. While the study did not have a control arm, previous studies have estimated overall survival for patients with brain metastases to be 4-6 months. Seven patients in the study experienced prolonged overall survival of two or more years, including five patients with primary breast cancer, one patient with primary melanoma and one patient with primary sarcoma. The team also examined safety and tolerability. Five patients discontinued treatment due to toxicity, and 50 of the 57 patients had one more adverse event. The most frequent adverse events were fatigue, nausea, headache, vomiting and transaminitis (elevated levels of liver enzymes in the blood). As next steps, the research team recommends investigating biomarkers of response, especially among the study’s “exceptional responders,” that may help to predict which patients are most likely to respond to therapy. The authors note that additional studies will be needed to identify specific facets to those patients’ tumors or tumor microenvironments that led to such a favorable response. “Our study illustrates the promise of checkpoint inhibitors for future therapeutic strategies for brain metastases,” said Brastianos. “And our work suggests that the decision to give a checkpoint inhibitor should not be based solely on the primary tumor’s origin—it is likely that there are yet-to-be determined factors that may predict response. Future studies to identify these factors may help guide, inform, and personalize treatment for patients with brain metastases.” Disclosures: Brastianos consulted for Tesaro, Angiochem, Genentech-Roche, ElevateBio, Eli Lilly, SK Life Sciences, Pfizer, Voyager Therapeutics, Sintetica, MPM, Advise Connect Inspire, Kazia and Dantari, received institutional research funding (to MGH) from Merck, Mirati, Eli Lilly, Kinnate, BMS and Pfizer and has received honoraria from Merck, Medscape, Pfizer, and Genentech-Roche. Additional disclosures for co-authors can be found in the Nature Medicine paper. Funding: Funding for this trial was provided by Merck Sharp & Dohme, a subsidiary of Merck & Co., Damon Runyon Cancer Research Foundation, Ben and Catherine Ivy Foundation. Brastianos also receives support from Breast Cancer Research Foundation, Hellenic Women’s Club Demetra Fund, Terry and Jean de Gunzburg MGH Research Scholar Fund and the National Institutes of Health (1R01CA227156-01 and 1R01CA244975-01). Additional support from American Brain Tumor Association Basic Research Fellowship In Honor of P. Fabbri, the William G. Kaelin, Jr., Physician-Scientist Award of the Damon Runyon Cancer Research Foundation, American Association for Cancer Research Breast Cancer Research Fellowship and the American Society of Clinical Oncology Young Investigator Award and the National Cancer Institute (R01CA211238 and R01CA244975). Paper cited: Brastianos, Priscilla et al. “Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results” Nature Medicine DOI: 10.1038/s41591-023-02392-7 ### About Mass General Brigham Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org. Journal COI Statement P.K.B. consulted for Tesaro, Angiochem, Genentech-Roche,ElevateBio, Eli Lilly, SK Life Sciences, Pfizer, Voyager Therapeutics,Sintetica, MPM, Advise Connect Inspire, Kazia and Dantari, receivedinstitutional research funding (to MGH) from Merck, Mirati, Eli Lilly, Kinnate, BMS and Pfizer and has received honoraria from Merck,Medscape, Pfizer, and Genentech-Roche. B.O. has received clinicaltrial support from Incyte and Eisai. J.D. has served as a consultantfor Amgen, Blue Earth Diagnostics and Unum Therapeutics andreceived research support (to MGH) from Novartis and Eli Lilly. R.S.H.consulted for AbbVie, Daichii Sankyo, EMD Serono, Lilly, Novartis,Regeneron, and Sanofi; and received institutional research funding(to MGH) from Abbvie, Agios, Corvus, Daichii Sankyo, Erasca, Exelixis,Lilly, Mirati, Novartis and Turning Point. P.Y.W. received institutionalresearch funding (to DF/HCC) from AstraZeneca/Medimmune,Beigene, Celgene, Chimerix, Eli Lilly, Erasca, Genentech/Roche,Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Puma, Servier,Vascular Biogenics and VBI Vaccines, and has served on the scientificadvisory board for AstraZeneca, Bayer, Black Diamond, Celularity,Chimerix, Day One Bio, Genenta, Mundipharma, Novartis, Novocure,Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet,Vascular Biogenics and VBI Vaccines. H.A.S. has served on thescientific advisory board for Advanced Accelerator Applications, andreceived institutional research funding (to MGH) from AbbVie. R.J.S.consulted for Novartis, BMS and Pfizer, and received institutionalresearch funding (to MGH) from Merck. The remaining authorsdeclare no competing interests. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system. Media Contact