A randomized phase II/ III trial of nivolumab versus nivolumab plus docetaxel for previously treated advanced or recurrent non-small cell lung cancer: TORG1630.

9030 Background: Immuno-checkpoint inhibitor (ICI) monotherapy is a standard second-line treatment for non-small-cell lung cancer (NSCLC). Addition of a cytotoxic agent to ICI may enhance the benefits. Methods: This multi-institutional open-label randomized phase II/III study compared the arm A consisting of nivolumab (NIV) monotherapy and arm B consisting of NIV + docetaxel (DTX) for patients with previously treated ICI-naïve NSCLC, prestratified by PS/histological types/sex/driver-mutations. The primary endpoint was superiority of arm B in OS in the phase III part. Assuming a HR of 0.75 for OS with the estimated mOS of arm A/B as 10.5/14.0 mo, a total 350 patients would be required to provide 80% power at a one-sided α of significance being 0.05. It was started at Nov. 2017, however, the patients’ accrual was discontinued due to the approval of ICI in the first-line setting in late 2018. Eventually, a total of 131 patients were enrolled for analysis. Results: 128 patients (64 in each arm) were eligible and included in full analysis set (FAS), and the patients’ demographics were well-balanced in each arm. The mOS was 14.7 mo (95%CI, 11.4-18.7) in arm A, and 23.1 mo (95%CI, 16.7-NR) in arm B. The HR of OS was 0.63 (90%CI, 0.42-0.95; p = 0.0310). The mPFS was 3.1 mo (95%CI, 2.0-3.9) and 6.7 mo (95%CI, 3.8-9.4) in arm A and B, respectively. The HR for PFS was 0.58 (95%CI, 0.39-0.88; p = 0.0095). The ORR was 14.0% (95%CI, 6.3-25.8) in arm A, and 41.8% (95%CI, 28.7-55.9) in arm B, with a statistical significance (p = 0.0014). Subgroup analyses for OS disclosed that the HRs favored arm B over arm A across all prespecified subgroups. The mOS of EGFR-mutant subgroup also showed better tendency in arm B than A (11.0 mo in arm A; 95%CI, 3.5-14.0; vs 20.6 mo in B; 95%CI, 5.8-NR; HR 0.45; 95%CI, 0.17-1.17). The hematological toxicity and gastrointestinal adverse events were more common in arm B than in A. Six (9.4%) in arm A and 25 patients (39.1%) in arm B discontinued protocol treatment due to adverse events. Overall, two treatment-related deaths were observed; one from pneumonitis in arm A, and one from myocarditis in arm B. Conclusions: Although the resulting statistical power was limited because of reduced sample size, the addition of DTX to NIV in the second-line NSCLC therapy significantly improved OS, PFS, and ORR, despite slightly elevated risk of toxicity. This is the first randomized clinical trial that confirmed significant survival benefit of ICI + chemotherapy over ICI alone in any cancer type. Clinical trial information: UMIN000021813.