Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆

Abstract

Background: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.Patients and methods: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). Results: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P ¼ 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score !1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. Conclusion: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Pembrolizumab Plus Amrubicin in Patients With Relapsed SCLC: Multi-Institutional, Single-Arm Phase 2 Study

“…Prospective trials revealed that CPS score did not predict PFS with Pembro or nivolumab. 9,13 In this study, patients with CPS greater than or equal to 1% or TIL 3þ tended to have slightly better outcomes, but not statistically significant. Gay et al 15 recently proposed four subtypes of SCLC on the basis of transcription factors and the inflamed subtype revealed higher sensitivity to ICI plus chemotherapy.…”

Toxicities of Immunotherapy for Small Cell Lung Cancer

“…There were five treatment-related death, two with nivolumab and three with chemotherapy. The incidences of irAEs (all grade) of endocrine, skin, gastrointestinal, liver, lung and kidney were 12, 11, 7, 5, 1 and <1% respectively (32). In study CheckMate-032, skin toxicity (any grade, 21.1%) was the most common.…”

“…In IFCT-1603 study, atezolizumab monotherapy was compared with topotecan or re-induction of initial chemotherapy (31). A phase III trial CHECKMATE-331 investigated the efficacy and safety of nivolumab monotherapy in the second line of therapy (32). Both trials demonstrated no superiority of immunotherapy over traditional chemotherapy.…”

Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆

“…73,74 In addition, the phase III RCT, CheckMate 331, comparing nivolumab to topotecan (or amrubicin) as second-line treatment in unselected (platinum-sensitive and -resistant) patients with stage IV SCLC and a PS of 0-1 failed to demonstrate an improvement in OS, PFS or ORR for nivolumab versus ChT. 75 Limited efficacy was also seen in the phase II French Cooperative Thoracic Intergroup 16-03 trial evaluating atezolizumab in relapsed SCLC (N Q14 ¼ 73); the disappointing ORR (2.3%) and median PFS (1.4 months) following immunotherapy precluded activation of the phase III part of the study. 76 The combination of cytotoxic T-lymphocyte-associated protein 4 and PD-L1 blockade is being evaluated in several ongoing trials.…”