Patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab (Opdivo) lived significantly longer when they continued treatment instead of stopping after 1 year, according to the first randomized data on the issue.
Continuous treatment was associated with a median progression-free survival (PFS) of 24.7 months versus 9.4 months for patients who stopped after a year. Median overall survival (OS) improved by almost 40% with continuous therapy.
No new safety issues arose among patients who continued treatment beyond a year, David M. Waterhouse, MD, of US Oncology in Cincinnati, and coauthors reported in the Journal of Clinical Oncology.
“To our knowledge, CheckMate 153 is the first randomized study in NSCLC to evaluate fixed-duration versus continuous treatment with a therapy that targets the PD-1 pathway,” the authors stated. “Findings indicated that continuing nivolumab provided a clinically meaningful benefit versus stopping treatment at one year in patients with previously treated NSCLC. After random assignment, median PFS and OS were longer with continuous treatment.”
“Interestingly, the trend in OS benefit with continuous versus one-year fixed-duration treatment was similar in the ITT [intention-to-treat] and PFS populations,” they continued. “Furthermore, in the PFS population, patients with CR/PR [complete/partial response] at random assignment seemed to derive greater benefit with continuous versus one-year fixed-duration treatment. In contrast, patients with SD [stable disease] at random assignment seemed to derive similar benefit in both arms.”
Patients treated beyond progression also appeared to live longer with continuous therapy, the authors added. However, the results should be interpreted cautiously because of the small number of patients.
The trial’s primary objective was to assess toxicity and grade ≥3 treatment-related adverse events. The evaluation of longer-duration treatment represented an exploratory analysis that resulted from an amendment to the original protocol, authors of an accompanying editorial noted.
“Although promising, we agree with the authors that these data are preliminary and have inherent limitations,” Marina Chiara Garassino, MD, of the National Institute of Cancer in Milan, Italy, and coauthors wrote. “For instance, the sample size for the randomization part of the study was not planned in advance … but was based on a convenience sample, and the estimates of results remain imprecise, particularly for subgroup analyses.”
“CheckMate 153 does not allow us to definitively answer the question on the optimal duration of treatment yet,” Garassino and colleagues added. “For the time being, in the absence of clear data, the integration of patients’ preferences could help, especially in decisions in which uncertainty is highly likely in this case.”
The exploratory analysis involved 1,428 patients with previously treated advanced NSCLC treated with nivolumab monotherapy. Patients still on treatment after a year (n=252) were randomized to continue nivolumab or to stop treatment with the option for retreatment at disease progression. The randomized portion of the study included 174 patients who remained progress free and 76 patients perceived to benefit from nivolumab despite radiographic progression.
The ITT analysis comprised all patients still on treatment at 1 year, and investigators performed a separate analysis of patients who remained progression-free at 1 year. Both PFS and OS were based on the time from randomization. Median follow-up from randomization for all patients was 13.5 months.
The PFS analysis showed that continuous treatment with nivolumab was associated with a marked reduction in rate of progression or death (HR 0.56, 95% CI 0.37-0.84). The 1-year PFS was 64.6% with continuous treatment and 44.0% with fixed-duration therapy, and the 2-year PFS was 51.9% and 30.7% for the continuous and fixed-duration groups, respectively.
Patients who had an objective response (complete or partial response) at randomization had a median PFS of 31.0 months with continuous therapy and 10.6 months with fixed-duration treatment, for a hazard ratio of 0.46 (95% CI 0.27-0.77).
Median OS had yet to be reached among patients on continuous therapy as compared with a median of 32.5 months with fixed-duration therapy (HR 0.61, 95% CI 0.37-0.99). OS at 1 and 2 years was 86.1% and 73.4%, respectively, with continuous therapy and 82.0% and 60.9% with fixed-duration nivolumab. Patients who had objective responses (complete or partial) at randomization had significantly prolonged OS with continuous therapy (not reached vs 33.5 months, HR 0.50, 95% CI 0.26-0.97).
In the ITT population, median OS had yet to be reached in the continuous-treatment arm versus 28.8 months with fixed-duration nivolumab (HR 0.62, 95% CI 0.42-0.92). The 1-year OS was similar (82.9% vs 81.7%) but favored continuous treatment at 2 years (70.4% vs 56.8%).
With 39 patients retreated with nivolumab at disease progression following randomization, four remained on treatment and 14 were still alive at data lock (minimum 1-year follow-up from randomization).
The CheckMate 153 trial was supported by Bristol Myers Squibb and Ono Pharmaceuticals.
Waterhouse reported relationships with Bristol Myers Squibb, AZ Therapeutics, AbbVie, Amgen, Celgene, McGivney Global, CTI, Janssen Oncology, and Seattle Genetics.
Garassino reported relationships with MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers Squibb, Novartis, Roche, Tiziana Life Sciences, Sanofi-Aventis, Celgene, Daiichi Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Eli Lilly, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, Janssen, Otsuka, Genentech, Spectrum Pharmaceuticals, Ipsen, Turning Point Therapeutics, and Exelixis.