Summary: A phase 2 clinical trial of pembrolizumab has shown promising results, with 42% of patients with metastatic brain cancer benefiting from the treatment.
The trial found that pembrolizumab, an immunotherapy, was tolerated and demonstrated clinical benefit in patients with brain metastases.
The study’s authors caution that the therapy’s benefits must be balanced against toxicity risks, and further research is needed to identify patients most likely to benefit from the treatment.
- A phase 2 trial of pembrolizumab showed a 42% clinical benefit rate in patients with metastatic brain cancer.
- Five patients experienced a complete or partial response to treatment, and seven patients survived longer than two years.
- While pembrolizumab showed promise, further studies are needed to identify potential biomarkers that can predict patient response to therapy.
Source: Mass General
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).
About this immunotherapy and brain cancer research news
Original Research: Closed access.
“Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results” by Priscilla K. Brastianos et al. Nature Medicine
Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results
Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments.
Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies.
The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease.
The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31–54%).
The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5–8.7 months) across both cohorts, 6.5 months (90% CI: 4.5–18.7 months) for cohort A and 8.1 months (90% CI: 5.3–9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years.
Thirty patients (52%; 90% CI: 41–64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related.
These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance.
ClinicalTrials.gov identifier: NCT02886585