Pooled Analysis of 4-Year Survival With Nivolumab Therapy in Patients With Previously Treated Advanced NSCLC
In an analysis reported in The Lancet Oncology, Antonia et al identified long-term survival rates with nivolumab therapy in patients with previously treated advanced non–small cell lung cancer (NSCLC).
The pooled analysis included data from the CheckMate 017, 057, 063, and 003 trials, each of which had at least 4 years of follow-up. Comparisons of nivolumab vs docetaxel therapy included all patients from the phase III CheckMate 017 and 057 trials. Landmark analyses were performed according to response status at 6 months; patients without radiographic evaluation at 6 months were excluded from these analyses.
Across all four studies, 664 patients received nivolumab, including 129 in CheckMate 003, 117 in CheckMate 063, 131 in CheckMate 017, and 287 in CheckMate 057. In CheckMate 017 and 057 combined, 427 patients received nivolumab and 427 patients received docetaxel. Minimum follow-up time for all 4 studies was 51.6 months.
Overall Survival in All Patients
For the pooled studies, median overall survival in all patients treated with nivolumab was 10.3 months. In the two comparative trials that compared nivolumab to docetaxel, median overall survival was 11.1 vs 8.1 months (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.59–0.79).
Estimated 4-year overall survival in all patients receiving nivolumab was 14%, with rates of 19% in patients with programmed cell death ligand 1 (PD-L1) expression ≥ 1%, and 11% among those with PD-L1 expression < 1%. Survival at 4 years was similar for patients with squamous vs nonsquamous tumor histology.
Patients surviving at least 4 years were more likely to have Eastern Cooperative Oncology Group performance status of 0, PD-L1 expression of at least 1%, and PD-L1 expression of at least 10%. They were less likely to have liver metastases.
In CheckMate 017 and 057, 4-year overall survival was 14% in patients treated with nivolumab vs 5% in those treated with docetaxel.
Response Status at 6 Months
A total of 480 patients were included in the landmark analysis of overall survival. Of the 234 patients excluded, 228 had died before 6 months.
Among the 664 patients treated with nivolumab, 122 (18%) had a complete or partial response; of these, 103 (84%) had response at 6 months. Among these 103 patients, overall survival at 4 years postlandmark was 56% (HR vs progressive disease = 0.18, 95% CI = 0.13–0.25). Among 100 patients with stable disease at 6 months, the 4-year rate was 19% (HR vs progressive disease = 0.49, 95% CI = 0.38–0.64); among 227 with progressive disease at 6 months, the rate was 4%.
In landmark analysis of patients in the pooled comparative trials vs docetaxel based on response status at 6 months, hazard ratios for overall survival were 0.18 (95% CI = 0.12–0.27) for nivolumab and 0.43 (95% CI = 0.29–0.65) for docetaxel for complete or partial response vs progressive disease and 0.52 (95% CI = 0.37–0.71) for nivolumab and 0.80 (95% CI = 0.61–1.04) for docetaxel for stable disease vs progressive disease.
Response Duration and Survival After Best Response
Among all 122 patients with best response of complete or partial response to nivolumab, median duration of response was 19.1 months; median overall survival from time of response was 63.2 months; and estimated 4-year overall survival was 53%. Estimated median overall survival after disease progression in all patients with progression was 6.6 months, with 3-year overall survival from time of progression of 8%. Among patients with disease progression after a best overall response of complete or partial response, 3-year overall survival after progression was 29%, compared with 12% among those with progression after best response of stable disease and 3% after best response of progressive disease.
Estimated median duration of response among all patients with partial or complete response in the combined CheckMate 017 and 057 trials was 23.8 months in patients receiving nivolumab and 5.6 months in those receiving docetaxel. Four-year overall survival from time of response was 54% vs 13%.
Safety Profile
According to the investigators, the pooled long-term safety data did not reveal any new safety signals. Overall, treatment-related grade 3 or 4 adverse events occurred in 13% of patients treated with nivolumab; serious treatment-related adverse events occurred in 10%, with the most common being pneumonitis in 3%.
The most common treatment-related potentially immune-related adverse events were skin reactions; the overall exposure-adjusted incidence rate was 38.6 per 100 person-years, with the highest rate during the first year of treatment (51.3 per 100 person-years of exposure). Among other potentially immune-related adverse events, rates per 100 person-years of exposure were 20.7 (26.4 during first year) for gastrointestinal events, 13.6 (16.4) for hepatic events, 12.4 (18.8) for endocrine events, 9.4 (11.0) for pulmonary events, 5.9 (8.2) for hypersensitivity/infusion reaction, and 4.6 (6.8) for renal events.
Death considered related to treatment occurred in six patients receiving nivolumab, with causes consisting of pneumonitis in two, sepsis in one, ischemic stroke in one, hypoxic pneumonia after rapid tumor progression in one, and encephalitis in one.
The investigators concluded, “In summary, our analyses provide evidence that response and disease control with nivolumab strongly benefit long-term survival, even after progression. A smaller overall survival benefit was associated with stable disease vs progressive disease at 6 months in the landmark analysis. Although response to docetaxel also favored longer-term survival, the association between response and survival was less pronounced than with nivolumab. Additional analyses assessing the effect of various factors on long-term survival with immunotherapy vs chemotherapy are planned.”
Scott J. Antonia, MD, PhD, of Duke Cancer Institute, Durham, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
