medwireNews: ETOP/IFCT 4-12 STIMULI findings do not support the use of consolidation nivolumab plus ipilimumab for limited-stage small-cell lung cancer (SCLC) patients who have completed chemoradiotherapy (CRT) and prophylactic cranial irradiation (PCI).
Presenting the results at the ESMO Virtual Congress 2020, Solange Peters, from CHUV Lausanne in Switzerland, reported that the phase 2 study did not meet the primary endpoint of improved progression-free survival (PFS) with dual immune checkpoint inhibitor therapy compared with observation alone.
The stage I–IIIB SCLC patients had completed four cycles of cisplatin or carboplatin plus etoposide chemotherapy with concurrent radiotherapy, followed by PCI, and all had a good ECOG performance status (PS) of 0–2. Two-thirds of the patients had received one radiotherapy fraction per day and had an ECOG PS of 1.
After a median 22.7 months of follow-up, median PFS was 10.7 months for the 78 participants randomly assigned to receive four cycles of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg at 21-day intervals, followed by nivolumab 240 mg every 2 weeks for up to 12 months.
This did not significantly differ from the median 14.5 months for the 75 patients who received no further treatment. The survival curves crossed over multiple times, with the p value for the test for nonproportionality indicating that “there is no clear signal for a benefit in terms of PFS of nivo-ipi over time”, Peters commented.
Subgroup analysis suggested that patients with an ECOG PS of 1 (significant) and those who had received two radiotherapy fractions per day may have derived a greater PFS benefit.
Median overall survival (OS) was comparable for the combination regimen and observation arms, at unreached and 31.6 months, respectively.
But Peters noted again that because the survival curves for the two treatment arms crossed, the assumption of proportional hazard rates was violated and the test for nonproportionality had a p value of 0.059. Exploratory analysis at 36 months favored nivolumab plus ipilimumab with a hazard ratio (HR) of 0.25, with 53.9% of patients alive at this time point versus 40.7% of controls, although the p value was not significant.
Subgroup analysis found that median OS favored nivolumab plus ipilimumab given twice-daily fractions (unreached vs 25.6 months, HR=0.41), whereas no significant difference in median OS was found for those given once-daily fractions.
Similarly, median OS was significantly poorer with nivolumab plus ipilimumab among patients with a ECOG performance status of 0 (17.4 vs unreached months, HR=4.62) but the reverse was true for those with a PS of 1 (unreached vs 29.9 months, HR=0.44)
“Exploratory translation work is ongoing to identify biomarker-defined subgroups that could benefit from the consolidation immunotherapy treatment”, Peters commented.
As expected, safety analysis showed a higher rate of any-cause grade 3–5 adverse events for the combination arm versus controls (62 vs 25%), with nivolumab plus ipilimumab resulting in treatment-related adverse events that lead to discontinuation in 49% of patients.
Indeed, Peters noted that patients assigned to receive nivolumab plus ipilimumab discontinued treatment after a median 1.7 months, with 6- and 12-month rates of 25.6% and 15.6%, respectively, although she emphasized that treatment failure was due to toxicity in 36 of the 65 cases in the combination arm versus disease progression in 35 of the 44 controls.
“A short period on active treatment observed in the study related to toxicity and treatment discontinuation has certainly impacted efficacy results,” the presenter commented.
“A longer follow-up of the study will allow exploration of possible late effect of immunotherapy consolidation on survival, which is already apparent at the current short follow-up,” she concluded.
Session discussant Corinne Faivre-Finn (Manchester University, UK) described the 36-month OS result as “favorable” but she noted that the study participants had a good ECOG PS and had responded to CRT.
Furthermore, recognizing that slow accrual meant only half the expected patients were enrolled to the STIMULI trial, she emphasized that phase 2 studies with less than 200 patients “cannot be considered definitive and practice changing.”
While waiting for more information on radiotherapy and biomarker data for this population, Faivre-Finn concluded that new immunotherapy–CRT trials are now recruiting, and encouraged delegates to “watch this space.”
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