Scott J. Antonia, MD, PhD

In an analysis reported in The Lancet Oncology, Scott J. Antonia, MD, PhD, of Duke Cancer Institute, and colleagues identified long-term survival rates with nivolumab therapy in patients with previously treated advanced non–small cell lung cancer (NSCLC), including comparative outcomes vs docetaxel and findings on the effect of response status on subsequent survival.¹ Overall, 4-year survival rates were 14% among all patients receiving nivolumab and 53% among those with complete or partial response to treatment.

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 to identify survival outcomes according to response, disease control, or progressive disease; 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. In 572 patients (86%), the nivolumab dose was 3 mg/kg every 2 weeks; 33 patients (5%) received 1 mg/kg every 2 weeks; and 59 (9%) received 10 mg/kg every 2 weeks. The minimum follow-up for all four studies was 51.6 months.

Overall Survival in All Patients

For the pooled studies, the median overall survival in all patients treated with nivolumab was 10.3 months. In the two comparative trials vs docetaxel, the 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% (95% CI = 11%–17%), with rates of 19% (95% CI = 15%–24%) in patients with programmed cell death ligand 1 (PD-L1) expression ≥ 1% and 11% (95% CI = 7%–16%) 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 an Eastern Cooperative Oncology Group performance status of 0, PD-L1 expression ≥ 1% or ≥ 10%, and less likely to have liver metastases.

In CheckMate 017 and 057, the 4-year overall survival was 14% (95% CI = 11%–18%) in patients who received nivolumab vs 5% (95% CI = 3%–7%) in those treated with docetaxel.

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 patients, 103 (84%) had a response at 6 months. Among these 103 patients, the overall survival at 4 years after the landmark analysis was 56% (95% CI = 45%–65%); 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% (95% CI = 12%–27%; HR vs progressive disease = 0.49, 95% CI = 0.38–0.64); among 227 patients with progressive disease at 6 months, the 4-year rate was 4% (95% CI = 2%–7%).

Outomes After Best Response to Treatment

Among all 122 patients with a best response of complete or partial response to nivolumab, the median duration of response was 19.1 months (95% CI = 14.7–29.9 months), the median overall survival from the time of response was 63.2 months (95% CI = 29.8 months to not reached), and the estimated 4-year overall survival was 53% (95% CI = 44%–61%). The estimated median overall survival after disease progression in all patients who experienced disease progression was 6.6 months (95% CI = 5.7–7.7 months), with a 3-year overall survival from the time of disease progression of 8% (95% CI = 6%–11%). Among patients who experienced disease progression after a best overall response of complete or partial response, the 3-year overall survival rate after disease progression was 29% (95% CI = 18%–41%), compared with 12% (95% CI = 7%–18%) among those who disease progression after a best response of stable disease and 3% (95% CI = 1%–5%) after a best response of progressive disease.

The estimated median durations of response among all patients with a partial or complete response in the combined CheckMate 017 and 057 trials were 23.8 months (95% CI = 11.4–36.1 months) in patients receiving nivolumab and 5.6 months (95% CI = 4.4–7.0 months) in those receiving docetaxel. The 4-year overall survival from the time of response was 54% (95% CI = 42%–64%) vs 13% (95% CI = 5%–23%).

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 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 (51.3/100 person-years of exposure).

Among other potentially immune-related adverse events, the rates per 100 person-years of exposure were 20.7 (26.4 during the 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 reactions, and 4.6 (6.8) for renal events.Death considered related to treatment occurred in six patients receiving nivolumab.

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.” ■

DISCLOSURE: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.

REFERENCE

1. Antonia SJ, Borghaei H, Ramalingam SS, et al: Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: A pooled analysis. Lancet Oncol 20:1395-1408, 2019.