Consolidation nivolumab and ipilimumab versus observation in limited-disease small cell lung cancer after chemo-radiotherapy - Results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

ABSTRACT Background Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25-33%. Methods STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab (1 mg/kg, every three weeks (Q3W)) plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. Results Of the 222 patients enrolled, 153 were randomised (78:experimental;75:observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% PS 0/1. Up to 25/May/2020 (median follow-up 22.4months), 40 PFS events were observed in the experimental arm, with median PFS 10.7months (95%CI 7.0-Not Estimable(NE)) versus 42 events and median 14.5months (8.2-NE) in the observation, HR=1.02 (0.66-1.58), 2-sided p=0.93. With updated follow-up (03/June/2021; median: 35months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR=0.95 (0.59-1.52), p=0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. Grade≥3 adverse events were experienced by 62% pts in experimental and 25% in observation arm, with 4 and 1 fatal, respectively. Conclusions The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.