Maintenance immunotherapy fails in SCLC

MDedge News

Maintenance immunotherapy offers no added survival benefit in patients with extensive disease small cell lung cancer (ED-SCLC), according to results from the CheckMate 451 trial.

The phase 3 results showed that neither a combination of nivolumab and ipilimumab, nor nivolumab alone could beat placebo, reported Taofeek Owonikoko, MD, PhD, of the Winship Cancer Institute of Emory University in Atlanta.

During his presentation at the European Lung Cancer Conference, Dr. Owonikoko described the existing practice gap that prompted the trial.

Taofeek Owonikoko, MD, PhD

“We all recognize the fact that patients with extensive disease small cell lung cancer respond very well to front-line, platinum-based chemotherapy,” Dr. Owonikoko said at the meeting, presented by the European Society for Medical Oncology. “ However, prognosis remains very poor for these patients, because the efficacy in the front-line is not durable.” He highlighted that, to date, no maintenance strategy has been shown to extend the benefit of front-line chemotherapy.

The CheckMate 451 trial involved 834 patients with ED-SCLC who had an Eastern Cooperative Oncology Group (ECOG) performance status no greater than 1 and responded or achieved stable disease with four cycles of standard front-line chemotherapy. Patients were randomized equally into three groups: nivolumab + ipilimumab (nivo+ipi), nivolumab alone (nivo alone), or placebo. Treatment started from 3 to 9 weeks after finishing chemotherapy, or up to 11 weeks later for patients who underwent prophylactic cranial irradiation. Treatment was given for up to 2 years, or until toxicity or disease progression. The primary endpoint compared median overall survival of nivo+ipi with placebo. Secondary endpoints included a survival comparison of nivo alone with placebo, and progression-free survival rates for all treatment groups.

After a minimum follow-up period of 9 months, data analysis revealed that nivo+ipi did not improve median overall survival, compared with placebo

After a minimum follow-up period of 9 months, data analysis revealed that nivo+ipi did not improve median overall survival, compared with placebo (hazard ratio 0.92; P = .3693). Nivo alone did not beat placebo, but it demonstrated a numerically better hazard ratio, at 0.84, which Dr. Owonikoko cautioned was not formally tested due to statistical hierarchy. Progression-free survival (PFS) rates followed a similar pattern, with nivo+ipi showing a hazard ratio of 0.72, compared with nivo alone, at 0.67; these figures also lack statistical significance, due to the negative primary endpoint.

No new safety signals emerged during treatment, Dr. Owonikoko said, and toxicity patterns were generally as anticipated, with more patients discontinuing treatment when given novo+ipi than nivo alone (31% vs 9%). Treatment-related deaths were also higher in the combination group than the monotherapy group (2.5% vs less than 1%).

In a press release, Dr. Owonikoko called the survival results “a big disappointment.”

In a press release, Dr. Owonikoko called the survival results “a big disappointment.” However, he said that the findings may direct future studies, suggesting that focused patient selection might improve outcomes. “There was some indication that compared to placebo, it took longer for the cancer to progress in patients who received either combination immunotherapy or nivolumab alone,” he said. “This was not the primary endpoint of the study so we cannot make definitive conclusions, but it shows that this strategy could be promising, especially in patients who are responsive to immunotherapy. The challenge will be how to select and identify those patients since patients who began maintenance therapy sooner after completion of chemotherapy did appear to derive greater benefit.”

Invited discussant Luis Paz-Ares, MD, PhD, of the Hospital Universitario 12 de Octubre in Madrid, said that the findings of the study were not surprising, considering recent data. Echoing Dr. Owonikoko, Dr. Paz-Ares suggested that refined patient selection might improve outcomes in this treatment setting.

“Looking at the data, the very initial months are terrible in this trial … if any, it could be those in the later part of the [survival] curve who could benefit,” Dr. Paz-Ares said; however, he pointed out that existing data do not yet reveal which patient factors might predict treatment responses. Looking to the future, he suggested that PD-L1 expression level was one such factor worth investigating. “Some more biomarkers are needed,” he concluded.

In the press release, Pilar Garrido, MD, cochair of the ELCC Congress, called this “the end of the story for maintenance immunotherapy in unselected SCLC patients.”

The study was funded by Bristol-Myers Squibb. The investigators reported financial relationships with Lilly, Merck, MSD, Novartis, Pfizer, Roche, and others.

Luis Paz-Ares, MD, PhD

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