Maintenance immunotherapy fails to improve survival in extensive small cell lung cancer
Maintenance treatment with combination nivolumab/ipilimumab or nivolumab alone did not improve OS compared with placebo in patients with extensive-stage small cell lung cancer, according to results from the phase 3 CheckMate 451 study presented at European Lung Cancer Congress.
“This appears to be the end of the story for maintenance immunotherapy in unselected [patients with] small cell lung cancer,” Pilar Garrido, MD, co-chair of European Lung Cancer Congress and head of the thoracic tumor section of the medical oncology department at Ramón y Cajal University Hospital in Madrid, said in a press release. “A previous smaller study was also negative. Although the PFS results seem positive, the design of the study means they cannot be considered because the primary endpoint was negative. On top of that, there’s concern about deaths and stopping treatment because of toxicity.”
Approximately 60% to 70% of patients with small cell lung cancer have extensive disease at diagnosis. First-line, platinum-based chemotherapy confers high rates of response, but the responses generally are brief and the cancer often grows within a short period of time.
The usual approach after chemotherapy is to wait until the tumor grows before initiating further treatment.
The current global, double-blind, phase 3 study sought to determine whether earlier intervention with maintenance immunotherapy would prolong OS. The study included 834 patients with extensive-stage small cell lung cancer, an ECOG performance status of 1 or less, and stable disease or response after four cycles of first-line platinum-based chemotherapy.
Researchers randomly assigned patients to one of the following: 1 mg/kg IV nivolumab (Opdivo, Birstol-Myers Squibb) plus 3 mg/kg ipilimumab (Yervoy, Bristol-Myers Squibb) every 3 weeks, with four doses followed by 240 mg nivolumab every 2 weeks (n = 279); 240 mg IV nivolumab every 2 weeks (n = 280); or placebo (n =275).
The three groups had similar baseline characteristics.
Patients started the regimens between 3 and 9 weeks after the last dose of chemotherapy or 3 and 11 weeks after prophylactic cranial irradiation.
The researchers stratified patients by performance status, sex and previous prophylactic cranial irradiation. Treatment continued for up to 2 years or until disease progression or intolerable toxicity.
OS for combination nivolumab/ipilimumab vs. placebo served as the primary endpoint. OS for nivolumab vs. placebo and PFS according to blinded independent central review for both comparisons served as secondary endpoints.
Minimum follow-up was 9 months.
Compared with placebo, nivolumab/ipilimumab did not significantly prolong OS (HR = 0.92; 95% CI, 0.75-1.12), nor did nivolumab monotherapy (HR = 0.84; 95% CI, 0.69-1.02), although the latter was not formally analyzed because of statistical hierarchy.
HRs for PFS compared with placebo were 0.72 (95% CI, 0.6-0.87) for nivolumab plus ipilimumab and 0.67 (95% CI, 0.56-0.81) for nivolumab monotherapy.
Treatment-related adverse events occurred at the following rates: 86% (grade 3 to grade 4, 52%) with nivolumab plus ipilimumab; 61% (12%) with nivolumab monotherapy; and 50% (8%) with placebo. Rates of discontinuation due to treatment-related toxicity were 31% with nivolumab/ipilimumab, 9% with nivolumab, and less than 1% with placebo.
Seven patients assigned the immunotherapy combination, one patient assigned nivolumab alone and one patient assigned placebo died as a result of treatment.
Study author Taofeek Owonikoko, MD, PhD, co-chair of the clinical and translational review committee at Winship Cancer Institute of Emory University, referred to the findings as “a big disappointment.”
However, Owonikoko noted that there was some indication that cancer progressed more slowly in patients receiving nivolumab/ipilimumab or nivolumab monotherapy.
“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,” Owonikoko said in the release “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.” – by Jennifer Byrne
Owonikoko T, et al. Abstract LBA-1. Presented at: European Lung Cancer Congress; April 10-13, 2019; Geneva.
Disclosures: Owonikoko reports research support from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bristol-Myers Squibb, Corvus, G1 Therapeutics, Novartis, Pfizer and Regeneron/Sanofi; advisory board roles with AbbVie, AmGen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly/Armo, PharmaMar and Xcovery; independent review committee/data and safety monitoring Bboard roles with EMD Serono and Roche/Genentech; and is founder of Cambium Oncology. Please see the abstract for all other authors’ relevant financial disclosures. HemOnc Today could not confirm relevant financial disclosures for Garrido at the time of reporting.