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Pembrolizumab in Noncolorectal MSI-H/dMMR Solid Tumors


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As reported in the Journal of Clinical Oncology by Marabelle et al, the phase II KEYNOTE-158 trial has shown robust activity of pembrolizumab in patients with noncolorectal microsatellite instability­–high (MSI-H)/mismatch repair–deficient (dMMR) solid tumors.

Findings in the study supported the May 2017 accelerated approval of pembrolizumab for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or for patients with MSI-H or dMMR colorectal cancer that progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

Study Details

In the study, 233 patients with previously treated advanced noncolorectal disease were enrolled between February 2016 and May 2018 from 55 sites in 18 countries. Overall, patients had 27 tumor types, with the most common being endometrial cancer, gastric cancer, cholangiocarcinoma, and pancreatic cancer. Treatment consisted of pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was objective response according to RECISTv1.1 on independent central radiologic review.

Responses

Median follow up was 13.4 months. Objective response was observed in 80 patients (34.3%), including complete response (CR) in 23 (9.9%). Median time to response was 2.1 months. Median duration of response had not been reached at time of analysis (range = 2.9–31.3+ months). Response rates were 57.1% in 49 patients with endometrial cancer (CR in 8 patients), 45.8% in 24 with gastric cancer (CR in 4), 49% in 22 with cholangiocarcinoma (CR in 2), 18.2% in 22 with pancreatic cancer (CR in 1), 42.1% in 19 with small intestine cancer (CR in 3), 33.3% in 15 with ovarian cancer (CR in 3), and 0% in 13 with brain cancer.

Among all patients, median progression-free survival was 4.1 months and median overall survival was 23.5 months. Median overall survival was not reached in patients with endometrial, gastric, small intestine, or ovarian cancer, and was 24.3 months in those with cholangiocarcinoma, 5.6 months in those with brain cancer, and 4.0 months in those with pancreatic cancer.

KEY POINTS

  • Objective response was observed in 34.3% of patients, including complete response in 9.9%.
  • Median progression-free survival was 4.1 months and median overall survival was 23.5 months.

Adverse Events

Treatment-related adverse events occurred in 64.8% of patients, with the most common being fatigue (14.6%), pruritus (12.9%), diarrhea (12.0%), and asthenia (10.7%). Grade ≥ 3 treatment-related adverse events occurred in 14.6% of patients; the most common grade 3 events were increased gamma-glutamyltransferase (1.7%) and pneumonitis (1.3%). Grade 4 events occurred in three patients (Guillain-Barre syndrome in one, increased alanine aminotransferase in one, and decreased neutrophils and enterocolitis in one). Treatment-related serious adverse events occurred in 7.7% of patients, and treatment-related adverse events led to pembrolizumab discontinuation in 9.4%.

Immune-mediated adverse events or infusion reactions of any grade occurred in 23.2% of patients, with the most common being hypothyroidism, hyperthyroidism, colitis, and pneumonitis. Grade ≥ 3 events occurred in 6 of patients%; grade 3 events consisted of pneumonitis (n = 3), severe skin reactions (n = 3), hepatitis (n = 2), and hyperthyroidism, colitis, type 1 diabetes, Guillain-Barre syndrome, and pancreatitis (all n = 1). Grade 4 reactions consisted of Guillain-Barre syndrome and colitis (both n = 1). Immune-mediated adverse events led to treatment discontinuation in 5.2%. Grade 5 pneumonia occurred in one patient; no other fatal treatment-related adverse events were observed.

The investigators concluded, “Our study demonstrates the clinical benefit of…pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.”

Luis A. Diaz Jr, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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