Nivo-Ipi Consolidation Fails to Demonstrate Long-Term Survival Advantage Over Placebo in SCLC

The immunotherapeutic combination of nivolumab and ipilimumab did not prolong progression-free survival in patients with small cell lung cancer compared to placebo.

According to the results of the STIMULI trial published in Annals of Oncology.

Immune checkpoint inhibitors have been shown to be clinically beneficial in patients with SCLC. Thirty percent of SCLC patients have limited disease. Even with a curative-intent treatment strategy, the results of LD-SCLC remain poor, with a median survival of 1 to 24 months and a 5-year survival of 25% to 33%. Adding the combination of nivolumab and ipilimumab may help improve survival.

STIMULI was a phase 2 trial (NCT02046733) that randomized patients 1:1 to receive consolidation or observational immunotherapy after chemoradiotherapy. The study had an actual enrollment of 174 participants and primary endpoints of overall survival (OS) and progression-free survival (PFS). Secondary endpoints include objective response, time to treatment failure, and adverse events.

The combined arm recruited 78 participants, 8 of whom completed treatment. Five patients remain on treatment and 65 treatments have failed. Reasons for failure included toxicity (36), progression (15), patient decision (7), investigator decision (4), and death (3).

The observation group recruited 75 patients. Thirty-three completed ‘treatment visits’ and 4 were considered to be in ‘treatment’. Forty-four patients were considered “treatment failures”. Reasons for “failure” included progression (35), patient decision (1), death (1), and others (1).

The median age of patients in the combined group was 61.1 years (range, 37.7-83.2 years) and 64.1% were male. Sixty-five percent of patients were former smokers and 34.6% were current smokers. Additionally, 64.1% had an ECOG performance status of 1. Stages included IB (2.6%), IIA (3.8%), IIB (7.7%), IIIA (33.3%) and IIIB (51.3%). Most patients, 83.3% of patients, had a partial response to chemo-radiotherapy. Complete responses were observed in 11.5% of patients and stable disease in 5.2% of patients.

In the observation group, the median age was 61.9 years (range: 38.6-77.3) and 56% were male. Sixty-five percent of patients were former smokers and 33.3% were current smokers. Sixty-eight percent of patients had an ECOG performance status of 1. Stages included IA (2.7%), IB (1.3%), IIA (6.7%), IIB (2.7%) , IIIA (36%) and IIIB (48%). Eighty percent of patients had a partial response to chemo-radiotherapy and 14.7% had a complete response. Stable disease was observed in 4% of patients.

The ORR in the experimental arm was 38% (95% CI, 26% to 50%) and 47% in the observation arm. The duration of response over 12 months was 63% (95% CI, 40.5% to 79%) in the experimental arm and 73.2% in the observation arm (95% CI, 53.4 % to 86.0%). Median PFS in the nivolumab arm was 10.7 months (range, 7-NE) and median OS was not reached (24.1-NE). In the observation group, PFS was 14.5 months (8.2-NE) and OS was 32.1 months (26.1-NE).

Adverse events of any grade occurred in 98.7% of patients in the combined group, with adverse events of grade 3 or higher occurring in 61.5% of patients. Adverse events led to treatment discontinuation in 55.1% of patients in this arm. Adverse events resulted in the death of 5.1% of patients in this group. In the observation group, adverse events of any grade occurred in 86.7% of patients, with adverse events of grade 3 or higher occurring in 25.3% of patients. Adverse events occurred in 1.3% of patients in the observation group.

Common adverse events occurring in the combination arm and observation arm include fatigue (48.7% vs 28%), anorexia (32.1% vs 16%) and diarrhea (28.2% vs 8 %). Grade 3 events in the combined arm included fatigue (3%), anorexia (6.4%) and diarrhea (9%). Grade 3 events observed in the observation group included pneumonitis (1.3%), hyperthyroidism (1.3%) and anemia (1.3%).

“The short active treatment period, with a median time to discontinuation of nivolumab and ipilimumab of 1.7 months, certainly affected efficacy. Similar observations were made in the Checkmate-451 trial, with ipilimumab-nivolumab maintained on the same schedule, where only a median of two treatment cycles could be administered,” the authors wrote. study.


Peters S, Pujol J, Dani U, et al. Nivolumab and ipilimumab consolidation versus observation in disease-limited small cell lung cancer after chemo-radiotherapy – results from the randomized phase II ETOP/IFCT 4-12 STIMULI trial. Anne Oncol. 2022;33(1):67-79. doi: 10.1016/j.annonc.2021.09.011.

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