Keytruda Shows Benefit in Small Cell Lung Cancer

Patrick Ott, M.D., Ph.D.

The immunotherapy agent Keytruda (pembrolizumab) had an overall response rate (ORR) of 33 percent in a recent trial including patients with extensive-stage small cell lung cancer (SCLC). Findings of the phase 1b KEYNOTE-028 trial were published in the Journal of Clinical Oncology.

One patient (4.2 percent) experienced a complete response, seven (29.2 percent) had partial responses and one (4.2 percent) had stable disease for less than six months. Thirteen patients (54.2 percent) experienced disease progression as the best overall response.

“This study is, to our knowledge, the first report to evaluate the immune checkpoint inhibitor pembrolizumab in patients with heavily pretreated (87.5 percent with 2 or more lines of prior therapy; 37.5 percent with 3 or more) extensive-stage SCLC,” first author Patrick A. Ott, M.D., Ph.D., clinical director, Center for Immuno-Oncology, Dana-Farber Cancer Institute, and coinvestigators wrote. “Pembrolizumab showed clinically meaningful antitumor activity and overall was well tolerated; the safety was consistent with the reported safety profile in other tumor types.”

The international, nonrandomized, multi-arm, phase 1b KEYNOTE-028 trial (NCT02054806) explored the safety and activity of Keytruda in patients with advanced solid tumors. For the SCLC cohort, 163 patients were screened for enrollment from March 2014 to May 2015. Of those patients, 145 had biopsy samples for PD-L1 evaluation.

Expression of PD-L1 (a protein that prevents the body from recognizing and attacking cancer cells) was assessed by immunohistochemistry, and PD-L1—positive patients had membranous PD-L1 expression in at least 1 percent of tumor and associated inflammatory cells or positive staining in stroma. Forty-six patients (31.7 percent) tested positive for PD-L1 expression, but 15 did not meet inclusion criteria. Ultimately, 24 patients were treated.

The median age of the treated patients was 60.5 years (range, 41-80). Fourteen (58.3 percent) of 24 patients were men. Median follow-up duration was 9.8 months (range, 0.5-24.4). All patients had received prior chemotherapy for SCLC, and 87.5 percent had received two or more prior lines of therapy. All patients had received prior platinum plus etoposide as first-line treatment. Eleven patients (45.8 percent) received second-line treatment with either topotecan or irinotecan.

Patients received 10 mg/kg of Keytruda every two weeks for 24 months or until progression, intolerable toxicity, physician decision to discontinue or withdrawal of consent occurred.

Median time to response was two months (range, 1.7-3.7) and median duration of response was 19.4 months (range, 3.6 to 20). Investigators said the responses were durable, with three patients remaining on-treatment at the time of data cutoff.

Median progression-free survival (PFS) was 1.9 months. Estimated six-month PFS was 28.6 percent and estimated 12-month PFS was 23.8 percent. The median overall survival (OS) was 9.7 months. Estimated six- and 12-month OS rates were 66 percent and 37.7 percent, respectively.

All patients experienced adverse events (AEs). The most common all-grade AEs were asthenia (seven patients), fatigue (seven patients), cough (six patients), arthralgia (five patients), diarrhea (five patients), insomnia (five patients) and rash (five patients).

Sixteen patients (66.7 percent) experienced treatment-related AEs, the most common of which were arthralgia, asthenia, and rash (four patients each), as well as diarrhea and fatigue (three patients each). Eight patients (33.3 percent) had grade 3 or higher AEs, two of whom had AEs that were determined to be related to treatment. One patient experienced grade 3 bilirubin elevation, and another experienced grade 3 asthenia and grade 5 colitis/intestinal ischemia.

One other patient experienced grade 2 autoimmune thyroiditis. Another had a grade 1 infusion-related reaction that occurred during cycle 2 and resolved upon interruption of Keytruda. The reaction recurred during cycle 3 and again resolved with Keytruda interruption. That patient subsequently discontinued treatment because of progression.

Pembrolizumab has FDA approved indications in melanoma, non—small cell lung cancer, head and neck cancer, Hodgkin lymphoma, urothelial carcinoma and microsatellite instability-high cancer.