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FDA Grants Pembrolizumab Priority Review for Advanced SCLC

Gina Columbus @ginacolumbusonc
Published: Wednesday, Feb 20, 2019

Jonathan Cheng, MD

Jonathan Cheng, MD

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) as a treatment for patients with advanced small cell lung cancer (SCLC) whose disease has progressed following ≥2 prior lines of therapy.1

The application is based on findings from cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 studies, in which pembrolizumab elicited 19% and 33% overall response rates (ORRs) in patients with advanced and extensive-stage SCLC, respectively.2,3 Under the Prescription Drug User Fee Act, the FDA will make a decision on the sBLA on or before June 17, 2019.

“There is a significant need for new treatment options for small cell lung cancer, which has a 5-year survival rate of only 6% overall,” said Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories, the developer of the PD-1 inhibitor. “Keytruda has already been established as an important treatment option for many patients with advanced non–small cell lung cancer and this acceptance provides an opportunity to potentially benefit even more patients.”

In the phase II KEYNOTE-158 basket study (NCT02628067), patients with 10 tumor types plus microsatellite instability–high (MSI-H) cancers, including advanced SCLC, were enrolled regardless of biomarker status. Patients were treated with pembrolizumab at 200 mg intravenously (IV) every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or study withdrawal. Patients were followed up for survival. The primary endpoint was centrally-reviewed ORR by RECIST v1.1 criteria; secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Efficacy in biomarker subgroups was an exploratory endpoint.

To be eligible for enrollment in the SCLC cohort, patients had unresectable and/or metastatic disease, progression on or intolerance to standard therapy, an ECOG performance status of 0 or 1, ≥1 measurable lesion, evaluable tumor sample for biomarker assessments, and no autoimmune disease or noninfectious pneumonitis.

In the SCLC cohort (n = 107), the median age was 63 years (range, 24-84) and 75 patients were male. Thirty-five percent (n = 37) and 65% of patients had an ECOG performance status of 0 and 1, respectively. Fifteen percent (n = 16) of patients had brain metastases. Regarding histology, 1% (n = 1) had carcinoid tumors, 7% (n = 7) had neuroendocrine tumors, and 93% (n = 99) had small cell carcinoma. One patient had previously received neoadjuvant/adjuvant therapy, 45 (n = 42) received 1, 34% (n = 36) received 2, and 23% (n = 25) received ≥3 prior treatments.

Additionally, 39% (n = 42) of tumors were PD-L1 positive, 47% (n = 50) were PD-L1 negative, and 14% of patients were nonevaluable. Ninety-one percent of tumors were not MSI-H, and 9% were nonevaluable.  

At a median follow-up of 9.3 months (range, 0.5-22.3) of the 107 patients, results showed that the ORR was 18.7% (95% CI, 11.8-27.4); this included 3 complete responses (CRs), 17 partial responses (PRs), and 12 cases of stable disease. Sixty-two patients had progressive disease; the disease control rate was 30%. The median duration of response was not reached (range, 2.1+ to 18.7+).

The median PFS was 2.0 months (95% CI, 1.9-2.1) and the median OS was 8.7 months (95% CI, 5.6-12.0).

The responses were higher in the PD-L1–positive population, with a 35.7% ORR (95% CI, 21.6-52.0) compared with a 6.0% ORR (95% CI, 1.3-16.5) in the PD-L1–negative group. Median PFS was comparable in both arms with 2.1 months (95% CI, 2.0-8.1) and 1.9 months (95% CI, 1.6-2.0) in the PD-L1–positive and –negative groups, respectively. However, the median OS was higher in the PD-L1–positive subset (14.9 months; 95% CI, 5.6-NR) versus those who were PD-L1 negative (5.9 months; 95% CI, 3.3-10.1).

Regarding safety, all-grade adverse events (AEs) occurred in 60% of patients, with AEs occurring in ≥10% of patients being fatigue (14%), pruritis (12%), hypothyroidism (12%), decreased appetite (10%), and nausea (10%). Twelve percent of patients experienced grade 3/4 AEs; grade 3/4 pancreatitis occurred in 2% of patients. Additionally, 2 fatal treatment-related AEs, pneumonia and encephalopathy, occurred during the safety follow-up.

All-grade immune-mediated AEs and infusion reactions included hypothyroidism (12%), hyperthyroidism (7%), severe skin reactions (3%), adrenal insufficiency (2%), nephritis (2%), pancreatitis (2%), pneumonitis (2%), colitis (1%), infusion reactions (1%), and thyroiditis (1%). Grade 3 immune-mediated AEs that occurred at 1% were severe skin reactions, adrenal insufficiency, pneumonitis, and colitis; grade 3 immune-mediated pancreatitis occurred in 2% of patients.

In the international, nonrandomized, multi-arm, phase Ib KEYNOTE-028 basket trial (NCT02054806), investigators evaluated the safety and efficacy of pembrolizumab in patients with advanced solid tumors.


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Year in Review™: Reflecting on Recent Evidence With an Eye to the Future of Lung Cancer ManagementMar 30, 20191.5
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