KEYNOTE-158 studydemonstrates the clinical benefit of anti-PD1 treatment with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR non-colorectal cancers. Toxicity was consistent with previous experience of pembrolizumab monotherapy. The study results are published as a rapid communications article on 4 November 2019 in the Journal of Clinical Oncology.
Dr Luis A. Diaz Jr of the Memorial Sloan Kettering Cancer Center, New York, NY, US and colleagues wrote in the study background that genomes of tumours that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbour hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumours are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins.
dMMR tumours represent approximately 2% to 4% of all diagnosed cancers. These tumours arise in individuals with a hereditary genetic syndrome or more often as sporadic cases. They are diagnosed with varying frequency across different cancer types: in 17% to 33% of endometrial cancers, 9% to 22% of gastric cancers, 6% to 13% of colorectal cancers, and with lower frequencies in other cancers (e.g. bladder, prostate, breast, renal cell, pancreatic, small cell lung, thyroid, sarcomas).
dMMR tumours have a unique genetic signature, harbouring 10- to 100-times more mutations than MMR proficient tumours. This signature is the result of primary biallelic defects in genes that govern DNA mismatch repair. The genes that govern mismatch repair include MLH1, MSH2, MSH6, and PMS2.
Cells from dMMR tumours can express PD-L1 on their membrane. Furthermore, these tumours have microscopic evidence of high numbers of infiltrating lymphocytes, and it is common for these immune cells to display upregulated checkpoint proteins. Immunogenic phenotype dictated by the tumour’s genotype renders these tumours susceptible to a potent reactivation of an antitumor response when treated with immune checkpoint blockade.
The KEYNOTE-158, phase II study investigated efficacy of pembrolizumab in patients with previously treated, advanced non-colorectal MSI-H/dMMR cancers. The primary endpoint was objective response rate (ORR) per RECIST v1.1, as assessed by independent central radiologic review.
Eligible patients with histologically/cytologically confirmed MSI-H/dMMR unresectable or metastatic non-colorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter.
The study enrolled 233 patients with 27 tumour types represented. The most common tumour types were endometrial, gastric, cholangiocarcinoma and pancreatic cancers.
Tumours were classified as MSI-H/dMMR when expression as detected by immunohistochemistry of at least one of four MMR proteins was absent, or when at least two allelic loci size shifts among the five analyzed microsatellite markers were detected by PCR.
Median follow-up was 13.4 months. The ORR was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached).
Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient. There were no other treatment-related fatal adverse events.
The authors concluded that study findings demonstrate durable clinical benefit of treatment with pembrolizumab in patients with metastatic or unresectable MSI-H/dMMR non-colorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumour-agnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancers.
The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ.
Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.Journal of Clinical Oncology; Published online 4 November 2019. DOI: 10.1200/JCO.19.02105.