Merck Withdraws Pembrolizumab Metastatic SCLC Indication in the United States

Mar 2, 2021

Merck has withdrawn pembrolizumab from the US market for the treatment of patients with metastatic small cell lung cancer who experienced disease progression on or after platinum-based chemotherapy and at least 1 previous line of treatment.

Roy Baynes, MD, PhD

Roy Baynes, MD, PhD

Merck has withdrawn pembrolizumab (Keytruda) from the US market for the treatment of patients with metastatic small cell lung cancer (SCLC) who experienced disease progression on or after platinum-based chemotherapy and at least 1 previous line of treatment, according to an announcement from the pharmaceutical company.1

The June 2019 accelerated approval of pembrolizumab had been based on findings from cohort G of the phase 2 KEYNOTE-158 trial (NCT02628067) and cohort C1 of the phase 2 KEYNOTE-028 trial (NCT02054806).2,3 Here, the PD-1 inhibitor was found to induce an overall response rate (ORR) of 19% (95% CI, 11%-29%) in this patient population, which included a complete response (CR) rate of 2% and a partial response (PR) rate of 17%.

Additionally, of the 16 responders to treatment, the majority (94%) experienced a duration of response (DOR) that was 6 months or longer, while more than half (63%) had a DOR that persisted for at least 12 months. Fifty-six percent of patients experienced a DOR that lasted for 18 months or longer. Overall, responses ranged from 4.1 months to 35.8+ months.

The continued approval of the agent was contingent on the completion of the phase 3 confirmatory KEYNOTE-604 trial (NCT03066778) to establish the superiority of pembrolizumab with regard to overall survival.

Results presented during the 2020 ASCO Virtual Scientific Program indicated that the addition of pembrolizumab to etoposide and carboplatin or cisplatin (EP) resulted in a significant improvement in progression-free survival (PFS) vs placebo/EP (hazard ratio [HR], 0.75; 95% CI, 0.61-0.91; P = .0023).4 The median PFS with the pembrolizumab regimen was 4.5 months (95% CI, 4.3-5.4) vs 4.3 months (95% CI, 4.2-4.4) with placebo. At 6 months, the PFS rates in the investigative and control arms were 34.1% vs 23.8%, respectively; at 12 months, these rates were 13.6% vs 3.1%, respectively.

Although the HR for OS favored pembrolizumab/EP, the significance threshold was missed (HR, 0.80; 95% CI, 0.64-0.98; P = .0164). The median OS in the investigative arm was 10.8 months (95% CI, 9.2-12.9) vs 9.7 months (95% CI, 8.6-10.7) in the control arm. At 12 months, the OS rates in the pembrolizumab/EP and placebo/EP arms were 45.1% vs 39.6%, respectively, while at 24 months, these rates were 22.5% and 11.2%, respectively.

Following a consultation with the FDA, the pharmaceutical company decided to withdraw the SCLC indication from the US market. This action was done in accordance with the regulatory agency’s standard procedures for assessing accelerated approvals that have not met their post-marketing requirements and as part of a bigger industry-wide evaluation.

“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 [patients with] cancer [who have] advanced disease, including SCLC, access new treatments,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, as well as chief medical officer of Merk Research Laboratories, stated in a press release. “[Pembrolizumab] remains a foundational treatment for certain patients with metastatic non–small cell lung cancer. We will continue to rigorously evaluate the benefits of [pembrolizumab] in SCLC and other types of cancer, in pursuit of Merck’s mission to save and improve lives.”

In KEYNOTE-604, investigators enrolled patients with stage IV SCLC who did not receive previous systemic therapy and had an ECOG performance status of either 0 or 1. To be eligible for enrollment, patients had to have acceptable organ function and a life expectancy of 3 months or longer. Patients could not have unstable brain metastases.

In the trial, participants were randomized 1:1 to receive either pembrolizumab at 200 mg on day 1 plus etoposide at 100 mg/m2 on days 1 through 3, and carboplatin area under the curve 5 on day 1 or cisplatin 75 mg/m2 on day 1 for 4 every-3-week cycles (n = 228), or placebo plus the same dosing and schedule of chemotherapy (n = 225).

The co-primary end point was PFS per RECIST v1.1 criteria by blinded independent central review (BICR) and OS, while secondary end points comprised ORR and DOR per RECIST v1.1 criteria by BICR and safety.

At baseline, the median age of participants was 64.5 years, 64.9% of patients were male, and 74.4% had an ECOG performance status of 1. Additionally, the majority of patients were former or current smokers, more than half had lactate dehydrogenase that was above the upper limit of normal, 12.15% had brain metastases and 41.3% had liver metastases.

Regarding safety, all patients on the pembrolizumab arm experience all-grade adverse effects (AEs) versus 99.6% of those who received the placebo; 76.7% and 74.9%, respectively, were grade 3 or higher in severity. Additionally, 6.3% of patients on the experimental arm had grade 5 toxicity vs 5.4% of those on the control arm.

Approximately 15% of patients on the pembrolizumab arm experienced toxicities that led to discontinuation of any treatment vs 6.3% of patients on the placebo arm; 4.0% and 3.6% of patients, respectively, discontinued all treatment due to toxicity.


  1. Merck provides update on KEYTRUDA (pembrolizumab) indication in metastatic small cell lung cancer in the US. News release. March 1, 2021. Accessed March 2, 2021.
  2. Chung HC, Lopez-Martin J, Kao S, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer: KEYNOTE-158. J Clin Oncol. 2018;36(suppl 15):8506. doi:10.1200/JCO.2018.36.15_suppl.8506
  3. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34):3823-3829. doi:10.1200/JCO.2017.72.5069
  4. 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
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