Pembrolizumab Combo Hits PFS, But Not OS Endpoint in Frontline Small Cell Lung Cancer

Roy Baynes, MD, PhD

The combination of pembrolizumab (Keytruda) and chemotherapy improved progression-free survival (PFS) compared with chemotherapy alone as a first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC), meeting 1 of 2 primary endpoints of the phase III KEYNOTE-604 trial (NCT03066778).¹ However, the regimen did not show a statistically significant improvement in overall survival (OS).

Results of a prior interim analysis showed that combining the PD-1 inhibitor with etoposide and carboplatin or cisplatin led to a 25% reduction in the risk of disease progression or death versus chemotherapy alone, which was statistically significant (HR, 0.75; 95% CI, 0.61-0.91).

However, at the final analysis, the OS results were not found to be statistically significant as per a prespecified statistical plan (HR, 0.80; 95% CI, 0.64-0.98), missing the second primary endpoint of the study.

The safety profile with the PD-1 inhibitor was consistent with what has been observed in prior studies. Full findings of the trial will be presented at an upcoming medical meeting, and will also be shared with regulatory authorities, Merck (MSD), the developer of pembrolizumab, stated in a press release.

“Results of KEYNOTE-604 demonstrated the potential of Keytruda, in combination with chemotherapy, to improve outcomes for patients newly diagnosed with extensive stage small cell lung cancer, a highly aggressive malignancy,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, and chief medical officer of Merck Research Laboratories, stated in the press release. “We sincerely thank the patients and investigators for their participation in this study and are committed to helping patients who face difficult-to-treat types of lung cancer.”

In the double-blind, placebo-controlled, phase III KEYNOTE-604 trial, 453 patients with newly diagnosed ES-SCLC were randomized to receive pembrolizumab in combination with chemotherapy or placebo plus chemotherapy alone. Pembrolizumab was administered at a fixed dose of 200 mg on day 1 of each 21-day cycle; etoposide was given at 100 mg/m² on days 1, 2, and 3. Investigator’s choice of chemotherapy consisted of carboplatin titrated to area under the curve 5 on day 1 or cisplatin at 75 mg/m² on day 1.

To be eligible for enrollment, patients must have had a documented new diagnosis of SCLC by histology or cytology, have extensive-stage disease, have ≥1 measurable lesion, provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion that was not previously irradiated, an ECOG performance status of 0 or 1, a life expectancy of ≥3 months, and had adequate organ function.

Those who had received prior systemic therapy, were expected to require any other form of antineoplastic therapy while on study, had known central nervous system metastases, completed treatment ≥14 days prior to the first dose of study treatment, had a known history of interstitial lung disease or pneumonitis that required steroids, HIV infection, or hepatitis B or C infection were excluded from enrolling on the trial.

The dual primary endpoints were OS and PFS; secondary endpoints included objective response rate (ORR), duration of response (DOR), safety, and quality of life.

In June 2019, the FDA granted an accelerated approval to single-agent pembrolizumab for the treatment of patients with SCLC who have disease progression on or after platinum-based chemotherapy and ≥1 other prior line of therapy.

The decision was based on pooled results from cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 trials, which demonstrated that the PD-1 inhibitor elicited a 19% ORR (95% CI, 11%-29%) in patients with SCLC who had disease progression on or after platinum-based chemotherapy and ≥1 other prior line of therapy.² The ORR comprised a 2% complete response rate and a 17% partial response rate. Moreover, among the 16 responding patients, 94% had a DOR of ≥6 months, 63% had a DOR of ≥12 months, and 56% of patients had a DOR of ≥18 months. The responses ranged from 4.1 to 35.8+ months.

References

1. Merck’s KEYTRUDA^® (pembrolizumab) in combination with chemotherapy significantly improved progression-free survival compared to chemotherapy alone as first-line treatment for extensive stage small cell lung cancer [news release]. Merck. Published January 6, 2020. https://bit.ly/2SYbh70. Accessed January 7, 2020.
2. FDA approves Merck’s KEYTRUDA^® (pembrolizumab) as monotherapy 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 [news release]. Merck. Published June 18, 2019. https://bit.ly/2Kn2Tur. Accessed June 18, 2019.