Pembrolizumab Plus Etoposide Continues to Show Survival Benefit in Untreated ES-SCLC

Pembrolizumab and etoposide continues to demonstrate improvements in survival outcomes compared with placebo and etoposide in patients with previously untreated extensive stage-small cell lung cancer.

Pembrolizumab (Keytruda) in combination with etoposide has continued to demonstrate positive survival outcomes compared with placebo and etoposide alone in patients with previously untreated extensive stage-small cell lung cancer (SCLC), according to long-term follow-up data from the phase 3 KEYNOTE-604 trial (NCT03066778) that were presented at the 2022 World Conference on Lung Cancer.1

The 36-month overall survival (OS) rate in the pembrolizumab arm was 15.5% compared with 5.9% (HR, 0.76; 95% CI, 0.63-0.93) in the placebo arm, reducing the risk for death by 24%. Moreover, median OS was 10.8 months (95% CI, 9.2-12.9) with pembrolizumab, compared with 9.7 months (95% CI, 8.6-10.7) with placebo.

Additionally, the 36-month progression-free survival (PFS) rate was 6.9% in the pembrolizumab arm vs 0.5% in the placebo arm (HR, 0.70; 95% CI, 0.57-0.85). The median PFS was 4.8 months (95% CI, 4.3-5.4) with pembrolizumab, compared with 4.3 months (95% CI, 4.2-4.5) with placebo.

“[With 3.5] years of follow up now, the patients who are on pembrolizumab continue to show clinically meaningful improvements, in particular PFS as well as OS,” Charles Rudin, MD, PhD, chief of thoracic oncology service, co-director of Druckenmiller Center for Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center, said during a presentation on the findings. “There's about a tripling of the 3-year OS rate, [and] about a 20-fold improvement in 2-year PFS. Those patients who have completed [the] full 2 years of pembrolizumab and have durable responses, with the majority, remaining alive now with about 4 years of follow up after randomization. We need to continue to explore the benefits of immunotherapy in this patient population and see if we can build the tail of the curve to raise it up to 5 or more [years of survival].”

The study included patients with stage IV SCLC who had not previously been treated with a systemic therapy and had an ECOG performance status of 0 or 1. Patients needed to also have a sample available for biomarker analysis. Those who enrolled could not have unstable brain metastases and were required to have adequate organ function and a life expectancy of 3 months or more. Stratification factors included type of cisplatin agent, ECOG performance status, and lactate dehydrogenase level.

A total of 453 patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg on day 1, plus 100 mg/m2 of etoposide on days 1 to 3, and carboplatin or 75 mg/m2 of cisplatin every 3 weeks for 4 cycles (n = 228); or the chemotherapy backbone plus placebo (n = 225). Those in the placebo arm went on to receive maintenance pembrolizumab on day 1 every 3 weeks for up to 31 cycles.

The dual primary end points were progression-free survival (PFS) and OS, with key secondary end points including overall response rate (ORR), duration of response (DOR), and safety.

In the experimental arm, a total of 18 patients completed 35 cycles of treatment with pembrolizumab and 122 went on to receive a subsequent therapy. Fifteen patients received treatment with a subsequent immune checkpoint inhibitor. In the placebo group, 2 patients completed treatment and 220 discontinued due to progressive disease (n = 196), adverse events (AEs; n = 13), consent withdrawal (n = 7), physician decision (n = 3), and protocol violation (n = 1). The median time from randomization to cutoff was 43.3 months.

The median age in the pembrolizumab group was 64.0 years vs 65.0 years in the placebo group, and the majority of patients in both arms were men. Most patients in both the pembrolizumab and placebo cohorts had an ECOG performance status of 1 (73.7% vs 75.1%, respectively) and were current or former smokers (96.5% vs 96.4%). Additionally, 70.6% and 69.3% of patients in both respective cohorts had received treatment with carboplatin.

The overall response rate in the pembrolizumab arm was 70.6% (95% CI, 64.2%-76.4%) vs 61.8% (95% CI, 55.1%-68.2%) in the placebo cohort. Among those in the experimental arm, 2.2% experienced a complete response (CR), 68.4% achieved a partial response, 17.5% had stable disease, and 3.5% had progressive disease. Additionally, the DOR rates at 12, 24, 36, and 42 months or more were 20.7%, 14.6%, 11.5%, and 10.1%, respectively. In the placebo arm, the CR rate was 0.9%, the PR rate was 60.9%, the stable disease rate was 24.9%, and the progressive disease rate was 5.3% The DOR rates at 12, 24, 36, and 42 months or more were 3.3%, 0.8%, 0.8%, and 0.8%, respectively.

All patients in the pembrolizumab arm experienced any-grade of AE and 78.9% experienced grade 3 to 5 AEs. Additionally, 15.7% of patients had AEs that led to discontinuation of any treatment, 4.0% had AEs that led to discontinuation of all treatment, and 6.3% had AEs that led to death. Immune-mediated AEs occurred in 27.4% of patients within this group, 8.1% of which were grade 3 to 5. Additionally, 0.4% of patients in this cohort had grade 3/4 infusion reactions.

In the placebo cohort, 99.6% of patients had any-grade AEs and 77.1% had grade 3 to 5 AEs. In this population, 6.3% of patients had AEs that led to discontinuation of any treatment, 3.6% had AEs that led to discontinuation of all treatments, and 5.4% had AEs that led to death. Immune-mediated AEs were reported in 12.1% of patients, 1.3% of which were grade 3 to 5.

Previous findings from the study indicated that the 12- and 24-month OS rates for patients in the pembrolizumab arm were 45.1% and 23.0%, respectively, compared with 39.6% and 12.7% in the placebo arm. The PFS rate at 12 months and 24 months in the pembrolizumab arm was 17.1% and 11.1%, respectively, vs 5.0% and 0.5% in the placebo arm.

Reference
Rudin CM, Kim HR, Navarro A, et al. First-line pembrolizumab or placebo combined with etoposide and platinum for ES-SCLC: KEYNOTE-604 long-term follow-up results. Presented at the 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract 1849.