First-line pembrolizumab plus platinum-etoposide for extensive-stage small-cell lung cancer

Long-term follow-up of the Keynote-604 study in patients with extensive-stage small cell lung cancer (ES-SCLC) who were given pembrolizumab and etoposide/platinum (EP) versus placebo + EP as first-line therapy continued to show a clinically meaningful improvement in survival with a manageable safety profile. These results support the continued exploration of pembrolizumab-based combinations for patients with small cell lung cancer.

Previously, single-agent pembrolizumab demonstrated durable antitumour activity and manageable toxicity in previously treated, recurrent or metastatic small-cell lung cancer (SCLC) in the Keynote-028 and Keynote-158 trials. In the phase III Keynote-604 study, pembrolizumab plus etoposide/platinum (EP) significantly improved progression-free survival (PFS) versus placebo plus EP in patients with previously untreated extensive-stage SCLC (HR[95%CI]: 0.75[0.61-0.91], p= 0.0023). Although the hazard ratio for overall survival (OS) favoured pembrolizumab plus EP, the significance threshold was not met. At WCLC 2022, updated results with approximately 3.5 years of follow-up and outcomes in patients who completed 35 cycles of pembrolizumab were presented.

Study design

In Keynote-604, eligible patients with previously untreated stage IV SCLC were randomised 1:1 to pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus 4 cycles of standard-dose EP. Dual primary endpoints were OS and PFS (RECISTv1.1, blinded central review) in the intent-to-treat (ITT) population. No alpha was allocated for this updated analysis.

Results

Among the 453 randomised patients in the ITT population (pembrolizumab + EP, N= 228; placebo + EP, N= 225), median (range) time from randomisation to data cut-off  was 43.3 (37.8-52.3) months. In total, 54.7% of patients in the pembrolizumab + EP group and 66.8% in the placebo + EP group received subsequent therapy (11.2% vs. 22.1% received subsequent immune checkpoint inhibitor). Efficacy outcomes, including OS and PFS, were improved with pembrolizumab + EP. The three-years OS was almost three times higher among patients treated with pembrolizumab + EP as compared to those treated with placebo + EP (15.5% vs. 5.9%, respectively). Median OS was 10.8 months in the pembrolizumab arm vs. 9.7 months in the placebo arm (HR[95%CI]: 0.76[0.63-0.93]). The three-years PFS was 6.9% among patients treated with pembrolizumab + EP vs. 0.5% in those treated with placebo + EP. Median PFS was 4.8 months in the pembrolizumab arm vs. 4.3 months in the placebo arm (HR[95%CI]: 0.70[0.57-0.85]). The OS and PFS benefit of pembrolizumab was consistent across all subgroups, with the exception of patients with baseline brain metastases. The objective response rate (ORR) was 70.6% for pembrolizumab + EP and 61.8% for placebo + EP, with two complete responses (CR) in each arm. In the pembrolizumab arm, 10.1% of the patients had a median duration of response of at least 42 months (vs. 0.8% in the placebo arm).

Among the as-treated population, grade 3-5 AEs occurred in 78.9% of patients in the pembrolizumab + EP group and 77.1% of  patients in the placebo + EP group. Eighteen patients completed 35 cycles of pembrolizumab (median [range] time from randomisation to database cut-off, 42.5 [38.2-49.5] months). Of them, 14 patients were alive as of the last assessment before data cut-off. The objective response rate among these patients was 100%, including two complete responses, and the median duration of response was not reached.  From the time of completing 35 cycles (~2 years), median OS was not reached (95% CI, 16.6 months to not reached). Two-year OS rate from the time of completing 35 cycles of pembrolizumab was 72.2%.

Conclusion

With approximately 3.5 years of follow-up, pembrolizumab + EP continued to show a clinically meaningful improved in OS and PFS versus placebo +  EP in patients with previously untreated ES-SCLC. In addition, the safety profile of pembrolizumab + EP was as expected and generally manageable. Patients who completed 35 cycles of pembrolizumab had durable responses, and a majority were alive two years after completing treatment. As such, these results support the continued exploration of pembrolizumab-based combinations for the treatment of ES-SCLC.

Reference

Rudin C, 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 IASLC WCLC 2022; Abstract OA12.06.