Pembrolizumab Indication for Treatment of Metastatic SCLC Withdrawn

Pembrolizumab has been withdrawn from the United States market as a treatment option for patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

An indication for pembrolizumab (Keytruda) has been withdrawn from the United States market as a treatment option for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy, according to a press release from Merck.1

Withdrawal from this indication for pembrolizumab was executed based on a consultation with the FDA. This process will reportedly continue through the weeks to come. The company noted, however, that other indications for pembrolizumab are not impacted by this action.

“The accelerated pathways created by the FDA have been integral to the remarkable progress in oncology care over the past 5 years and have helped many cancer patients with advanced disease, including small cell lung cancer, access new treatments,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories.”

The FDA first granted approval to pembrolizumab for the treatment of patients with metastatic SCLC in 2019 based on data from cohort G of the KEYNOTE-158 clinical trial (NCT02628067) and cohort C1 from the KEYNOTE-028 (NCT02054806) clinical trial.2 In both studies, pembrolizumab demonstrated favorable overall survival (OS), but continued FDA approval was contingent on the demonstration of statistically significant OS improvement in a phase 3 confirmatory trial.

The phase 3 KEYNOTE-604, randomized, double-blind, placebo-controlled trial was launched to confirm the efficacy and safety observed with pembrolizumab in the prior KEYNOTE-158 and KEYNOTE-028 trials. KEYNOTE-604 showed significant improvement in OS when pembrolizumab was added to etoposide and cisplatin of carboplatin chemotherapy compared with etoposide and platinum-based chemotherapy (EP) alone in patients with extensive-stage SCLC.

In the intent-to-treat population of 445 patients, the median OS observed with the pembrolizumab combination was 10.8 months compared with 9.7 months with EP alone (HR, 0.80; 95% CI, 0.64-0.98; P = .0164). The addition of pembrolizumab to EP also showed improvement in progression-free survival (PFS) compared with EP only at a median PFS of 4.5 versus 4.3 months, respectively (HR, 0.75; 95% CI, 0.61-0.91; P = .0023). But the study prespecified that with the pembrolizumab combination there should be a one-sided P = .0048 for PFS and = .0128 for OS, and therefore, KEYNOTE-604 missed its primary end point.3

Notably, pembrolizumab did show good responses in the study with an objective response rate of 70.6% (95% CI, 64.2%-76.4%) for pembrolizumab/EP compared with 62% (95% CI, 55.1%-68.2%) with EP/placebo. The median duration of response in the pembrolizumab combination arm was 4.2 months (range, 1.0+ to 26.0+) compared with 3.7 months (range, 1.4+ to 25.8+) in the EP alone arm.

The safety profile observed with pembrolizumab in the KEYNOTE-604 study was manageable. Adverse events (AEs) of any grade were seen in 100% of the pembrolizumab combination arm compared with 99.6% of the EP alone arm. Grade 3 AEs occurred in 76.7% of the pembrolizumab/EP arm compared with 74.9% in the EP-only arm. There were also grade 5 AEs in the study, which were observed in 6.3% of patients who received pembrolizumab/EP versus 5.4% of those who received EP alone.

The most common AEs of any grade occurring in the pembrolizumab-containing arm versus the EP-only arm were neutropenia, respectively were neutropenia (57.0% vs 53.4%), anemia (48.4% vs 46.6%), and nausea (38.6% vs 37.7%). Any-grade immune-mediated AEs were seen in 24.7% of the pembrolizumab-treated population compared with 10.3% of the EP alone arm and grade 3 immune-mediated AEs occurred in 7.2% versus 1.3%, respectively. The most common immune-mediated AEs in the pembrolizumab/EP arm versus the EP only arm, respectively were hypothyroidism (10.3% vs 2.2%), hyperthyroidism (6.7% vs 2.7%), and pneumonitis (4.0% vs 2.2%).

Regardless of the positive response and safety data, the KEYNOTE-604 ultimately did not meet the post-marketing requirements for pembrolizumab as treatment of patients with metastatic SCLC. Providers prescribing pembrolizumab to their patients with this disease are being informed by Merck about the withdrawal.

“Keytruda remains a foundational treatment for certain patients with metastatic non–small cell lung cancer. We will continue to rigorously evaluate the benefits of Keytruda in small cell lung cancer and other types of cancer, in pursuit of Merck’s mission to save and improve lives,” stated Baynes, in the press release.


1. Merck provides update on Keytruda® (pembrolizumab) Indication in metastatic small cell lung cancer in the US. News release. Merck. March 1, 2021. Accessed March 2, 2021.

2. FDA approves pembrolizumab for metastatic small cell lung cancer. FDA. Updated June 18, 2019. Accessed March 2, 2021.

3. Rudin CM, Awad MM, Navarro A, et al. KEYNOTE-604: Pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC). J Clin Oncol. 2020;38(suppl 15):9001. doi:10.1200/JCO.2020.38.15_suppl.9001