乌鸦传媒

Consolidation therapy with nivolumab (Opdivo) plus ipilimumab (Yervoy) after chemoradiotherapy did not lead to better survival outcomes for patients with limited-disease small cell lung cancer (SCLC), the randomized phase II STIMULI trial found.

With a median follow-up of 22.4 months, progression-free survival (PFS) was 10.7 months in patients receiving the combined immunotherapy compared with 14.5 months in those under observation after standard treatment (HR 1.02, 95% CI 0.66-1.58, 2-sided P=0.93), reported Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and colleagues.

Additionally, in an updated follow-up (median of 35 months), there was no improvement in median overall survival (OS) with the combination regimen compared with observation (not reached vs 32.1 months, HR 0.95, 95% CI 0.59-1.52, P=0.82), they noted in .

Furthermore, substantial toxicity was observed in the immunotherapy group, with grade ≥3 adverse events reported in 61.5% of patients (vs 25.3% of patients in the observation arm). Over half (55.1%) of patients in this arm experienced adverse events resulting in treatment discontinuation, with a median time-to-treatment-discontinuation of just 1.7 months.

"The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemoradiotherapy," Peters and colleagues wrote. "A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results."

As noted by the authors, concurrent chemotherapy and thoracic radiotherapy (RT), followed by prophylactic cranial irradiation (PCI) is the standard treatment for limited-disease SCLC. However, 5-year survival rates range from only 25% to 33%. The STIMULI trial was the first to compare the immunotherapy combination with observation after standard treatment in this patient population.

"Unfortunately, this large study did not pave the way for immunotherapy in limited-disease SCLC," Fred Hirsch, MD, PhD, of the Tisch Cancer Institute at Mount Sinai in New York City, told 乌鸦传媒. "However, the role of immunotherapy in this disease setting in the future should not be ruled out."

"Clinical studies should still explore immunotherapy options for patients with limited-disease SCLC -- a patient category where treatment progress still is needed," added Hirsch, who was not involved in the study.

The study enrolled 222 patients with stage I-IIIB histologically or cytologically confirmed limited-disease SCLC, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, renal, lung, and pulmonary function.

All patients received 4 cycles of platinum chemotherapy, plus etoposide, along with concurrent RT, followed by PCI. Among the enrolled patients, 77 did not meet the criteria for randomization at the end of the chemoradiotherapy phase, leaving a total of 153 patients (median age 62, 60% men) who were randomized to the nivolumab/ipilimumab arm (n=78) or the observation arm (n=75). Patients in the immunotherapy arm first received 4 cycles of induction nivolumab plus ipilimumab every 3 weeks, followed by nivolumab maintenance every 2 weeks for a maximum of 12 months.

While the study showed no significant difference in PFS between the groups, there did appear to be a difference in treatment effect for ECOG performance status and radiotherapy schedule.

Patients with an ECOG status of 1 did better on immunotherapy, as did patients who were treated with two RT fractions per day (interaction P=0.022 and P=0.096, respectively).

A differential OS benefit was also seen between different RT schedules, with a higher benefit of combined immunotherapy in patients receiving twice-daily RT (interaction P=0.010), as well as in patients with an ECOG status of 1 (interaction P<0.001).

"Our finding of a differential OS benefit between the RT schedules, with statistically significant benefit for the nivolumab-ipilimumab combination in patients on a twice-daily RT schedule, underlines the need to further investigate the optimal RT schedule for the combination with immunotherapy, in order to promote potential synergistic effects," wrote Peters and colleagues.

As for toxicity, the most frequent adverse event of any grade in the nivolumab/ipilimumab arm was fatigue (48.7%), followed by anorexia (32.1%), diarrhea (28.2%), pneumonitis (28.2%), hyperthyroidism (28.2%), vomiting (26.9%), cough (25.6%), and nausea (24.4%).

Treatment-related deaths occurred in four patients in the combination arm and one patient in the observation arm.

"New immunological treatment paradigms are needed in SCLC," concluded Peters and colleagues. "In the future, such clinical attempts will hopefully rely on strong translational research data obtained from current trials, reflecting the unique biology and natural history of SCLC and offer acceptable tolerability in these fragile and comorbid patients."

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