A phase II study, the first histology-agnostic trial dedicated specifically for the population of patients with brain metastases, met its primary endpoint, demonstrating a 42.1% intracranial benefit rate of pembrolizumab, but the intracranial response rate was only 8.8%. Combined with extracranial efficacy observed in diverse histologies, the findings provide additional evidence that immune checkpoint inhibitors (ICIs) deserve further investigation as first-line treatment paradigms for brain metastases.
However, the high toxicity rate of ICI underscores the importance of identifying predictive biomarkers of response. The findings are reported at 2023 ASCO Annual Meeting on 2 June in Chicago, IL, US along with a simultaneous publication in the Nature Medicine by Dr. Priscilla Kaliopi Brastianos of the Massachusetts General Hospital Cancer Center, Harvard Medical School in Boston, MA, US, and colleagues; drs. Priscilla Kaliopi Brastianos and Albert Eusik Kim contributed equally.
The authors wrote in the background that due to expanded screening for brain metastases, an increasing number of patients present with intracranial lesions that are relatively small and minimally symptomatic. Other patients have brain metastases in an inoperable location. Many systemic therapies have demonstrated limited intracranial efficacy. The difficulty in treating brain metastases is due, in part, to distinct mutational and transcriptional differences between brain metastases and extracranial metastases.
Recent work suggests that tumor microenvironment (TME) of brain metastases is more immunosuppressive compared to that of primary tumours or extracranial metastases and a logical therapeutic strategy for brain metastases is to evaluate immune-based strategies that augment T cell cytotoxicity within brain metastases. Recent studies have demonstrated considerable promise for ICIs in brain metastases, but the investigations of ICI for brain metastases of non-melanoma or lung histologies in prospective clinical studies have been limited.
This clinical scenario is of increasing importance, given the rising incidence of brain metastases for histologies that do not classically have a high central nervous system (CNS) tropism. While ICI-based paradigms have shown durable efficacy for many solid tumours, most studies historically excluded patients with brain metastases. Based on translational work suggesting that the immunosuppressive TME of brain metastases drives treatment resistance, the study team hypothesized that pembrolizumab would result in antitumour activity within the CNS.
The investigators designed a prospective, single-arm, open-label, phase II study evaluating pembrolizumab in 9 patients with treatment-naïve (cohort A) and 48 patients with recurrent and progressive brain metastases (cohort B) of diverse histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response (CR), partial response (PR), or stable disease by Response Assessment in Neuro-Oncology criteria. Secondary endpoints included overall survival (OS), extracranial response defined by RECIST v1.1, time to intracranial progression (TTPCNS), time to extracranial progression (TTPextracranial) and toxicity.
The median time between initial cancer diagnosis and study enrolment was 23 months for cohort A and 38 months for cohort B; 50 patients (87.7%) received systemic therapies before enrolment, 25 patients (43.9%) received CNS-specific systemic therapies following the initial diagnosis of brain metastases and before study enrolment. The median number of prior CNS-specific systemic therapies was 2 (range: 1–15); 41 patients (71.9%) received prior intracranial radiation and 45 patients (78.9%) underwent prior brain surgery. Patients were allowed to receive additional antitumour-directed therapy after stopping protocol treatment.
Among enroled patients with breast cancer, 16 patients had HER2-positive disease, 17 patients had hormone receptor-positive disease and 11 patients had the triple-negative subtype. Among 7 patients with non-small cell lung cancer (NSCLC), 2 had EGFR mutations and 1 had an ALK rearrangement. Among 2 patients with melanoma, 1 had an activating BRAF mutation.
The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval [CI] 31–54%). Intracranial efficacy was observed for diverse histologies, including breast, ovarian, pituitary, and alveolar sarcoma. In particular, 37% of patients with breast cancer and 43% of patients with NSCLC had intracranial benefit. All breast cancer subtypes that have been enroled derived efficacy from pembrolizumab. No patient with NSCLC and a known oncogenic driver had an intracranial response; however, the study enroled only 3 patients meeting these criteria.
However, only 5 patients (8.8%) had an intracranial response as defined by either PR or CR. The primary tumour histologies for these 5 patients were NSCLC in 2 cases, melanoma, alveolar sarcoma, and prostate cancer.
The median OS, 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; 7 patients (12.3%), encompassing breast, melanoma, and sarcoma histologies, had OS greater than 2 years. The median TTPCNS was 1.6 months in cohort A and 2.2 months in cohort B. The median TTPextracranial was 4.5 months for cohort A and 4.6 months for cohort B.
In total, 30 patients (52%) had one or more grade 3 or higher adverse events that were at least possibly treatment related and 2 patients had grade 4 adverse events (cerebral oedema) that were deemed at least possibly treatment related.
The authors concluded that pembrolizumab showed promising activity in a subset of these tumours and results in improved outcomes compared to historical controls. These results, combined with prior studies, illustrate a potential paradigm shift in integrating immune-based therapies for brain metastases treatment regimens, which have traditionally been centred around surgical resection and radiotherapy. However, this promising efficacy will need to be carefully balanced with the risk of toxicity.
Besides the study met its primary endpoint, additional studies regarding molecular or TME facets of brain metastases are needed to identify biomarkers of response or mechanisms of resistance. Those studies can be applied to enhance the therapeutic benefit of PD1 blockade in rationally designed combinatorial regimens.
Funding for this study was provided by Merck Sharp & Dohme, a subsidiary of Merck & Co. to Massachusetts General Hospital, Damon Runyon Cancer Research Foundation, Ben and Catherine Ivy Foundation.
References
Brastianos PK, Kim AE, Giobbie-Hurder A, et al. Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results. Nature Medicine; Published online 2 June 2023. DOI: https://doi.org/10.1038/s41591-023-02392-7
Brastianos PK, Kim AE, Giobbie-Hurder A, et al. Phase II trial of pembrolizumab in patients with brain metastases. J Clin Oncol 41, 2023 (suppl 16; abstr 2006).
