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Comparative Study
. 2019 Oct;20(10):1395-1408.
doi: 10.1016/S1470-2045(19)30407-3. Epub 2019 Aug 14.

Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis

Scott J Antonia  1 , Hossein Borghaei  2 , Suresh S Ramalingam  3 , Leora Horn  4 , Javier De Castro Carpeño  5 , Adam Pluzanski  6 , Marco A Burgio  7 , Marina Garassino  8 , Laura Q M Chow  9 , Scott Gettinger  10 , Lucio Crinò  7 , David Planchard  11 , Charles Butts  12 , Alexander Drilon  13 , Joanna Wojcik-Tomaszewska  14 , Gregory A Otterson  15 , Shruti Agrawal  16 , Ang Li  16 , John R Penrod  16 , Julie Brahmer  17
Affiliations
Comparative Study

Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis

Scott J Antonia et al. Lancet Oncol. 2019 Oct.

Abstract

Background: Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival.

Methods: We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab.

Findings: Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11-17) for all patients (n=664), 19% (15-24) for those with at least 1% PD-L1 expression, and 11% (7-16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11-18) in patients treated with nivolumab, compared with 5% (3-7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12-0·27) for nivolumab and 0·43 (0·29-0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37-0·71) for nivolumab and 0·80 (0·61-1·04) for docetaxel. Long-term data did not show any new safety signals.

Interpretation: Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage.

Funding: Bristol-Myers Squibb.

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Conflict of interest statement

Declaration of interests

SJA is on the advisory board or scientific advisory board of Bristol-Myers Squibb, Novartis, Merck, CBMG, Boehringer Ingelheim, AstraZeneca/MedImmune, Memgen, FLX Bio, Nektar, and Veen; has done contracted research for Novartis; was previously employed by H Lee Moffitt Cancer Center & Research Institute (Tampa, FL, USA); and is currently employed by Duke Cancer Institute (Durham, NC, USA). HB reports grants from Bristol-Myers Squibb, Celgene, Lilly, Merck, and Millennium; personal fees for consultancy or advisory board services (or both) from Bristol-Myers Squibb, Celgene, Genentech, Lilly, EMD-Serono, Merck, Millennium, Pfizer, Boehringer Ingelheim, AstraZeneca, Genmab, Novartis, Regeneron, BioNTech, Cantargia AB, Amgen, and Axiom; has provided educational services for AbbVie and Axiom; and has served on a Data and Safety Monitoring Board for Takeda. SSR reports grants from AstraZeneca, Merck and Tesaro, and personal fees for consultant or advisory board services from Amgen, AbbVie, Bristol-Myers Squibb, Lilly, Genentech, Takeda, and Luxo. LH reports grants from Boehringer Ingelheim and Xcovery; non-financial support from Xcovery; and personal fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck, Genentech, Incyte, EMD Serono, and Tesaro. JDCC reports personal fees from Bristol-Myers Squibb, AstraZeneca, MSD, and Roche. AP reports personal fees from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, and Roche, and non-financial support from Bristol-Myers Squibb, Boehringer Ingelheim, and Roche. MG reports personal fees from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka Pharma, Celgene, Roche, Pfizer, Incyte, Inivata, and Takeda, and has served as principal investigator or conducted patient enrolment in clinical trials (or both) for Bristol-Myers Squibb, AstraZeneca, Eli Lilly, MSD, Novartis, Otsuka Pharma, Celgene, Roche, Pfizer, Tiziana Sciences, Clovis, Merck Serono, and Bayer. LQMC reports grants from Bristol-Myers Squibb, AstraZeneca/MedImmune, Genentech, Novartis, Merck, Lilly/ImClone, Incyte, Pfizer, VentiRx, Seattle Genetics and Dynavax; and personal fees from Bristol-Myers Squibb, Amgen, AstraZeneca/MedImmune, Genentech, Novartis, Merck, Pfizer, Sanofi-Genzyme, Seattle Genetics, Synthorx, Takeda, and Dynavax. SG served as a consultant or advisor (or both) to Bristol-Myers Squibb and NEKTAR; reports research funding from Bristol-Myers Squibb; and reports financial support to his institution from Iovance, Takeda/ARIAD and Genentech for clinical trials. DP reports honoraria from Bristol-Myers Squibb, AstraZeneca, Boehringer, Celgene, Novartis, Pfizer, MSD, Roche, prIME Oncology, and peer CME for services as a consultant, advisor, or lecturer; travel expenses from AstraZeneca, Roche, Novartis, prIME Oncology, and Pfizer, and financial support to his institution from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo for clinical trials. CB reports honoraria from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Merck, and Pfizer. AD reports honoraria from Medscape, Onclive, PeerVoice, Physicians Education Resources, Tyra Biosciences, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, Peerview, AstraZeneca, Genentech and Bayer, and has served as a consultant or advisor to Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, BluePrint Medicines, Genentech, Takeda, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, and Bayer. GAO reports grants from Bristol-Myers Squibb, AstraZeneca, Merck, Genentech, and Pfizer, and consultant fees for his institution from Merck, Novartis, Pfizer and Takeda. SA and JRP are employed by and own stocks in Bristol-Myers Squibb. AL is employed by Bristol-Myers Squibb. JB reports grants and travel expenses from Bristol-Myers Squibb and personal fees from AstraZeneca, Genentech, and Merck. MAB, LC, and JW-T declare no competing interests.

Figures

Figure 1:
Figure 1:. Overall survival in all patients treated with nivolumab (A) and in the combined CheckMate 017 and 057 population (B)
(A) Data are for all patients treated with nivolumab in CheckMate 017, 057, 063, and 003; 566 (85%) of 664 patients had an event. (B) Data are for all patients in the intention-to-treat populations of CheckMate 017 and 057; 364 (85%) of 427 in the nivolumab group and 410 (96%) of 427 patients in the docetaxel group had an event.
Figure 2:
Figure 2:. Overall survival landmark analysis by response category at 6 months in the pooled CheckMate population of patients treated with nivolumab
Overall survival is shown from the time of the landmark response assessment at 6 months. Patients with no response assessment at 6 months owing to death or loss to follow-up were excluded. 46 (45%) of 103 patients with CR or PR, 81 (81%) of 100 patients with SD, and 211 (93%) of 227 patients with PD at 6 months had an event. CR=complete response. NR=not reached. PD=progressive disease. PR=partial response. SD=stable disease.
Figure 3:
Figure 3:. Overall survival landmark analysis by response category at 6 months in the combined CheckMate 017 and 057 population
Overall survival is shown from the time of the landmark response assessment at 6 months. Patients with no response assessment at 6 months owing to death or loss to follow-up were excluded. In the nivolumab group, 29 (41%) of 70 patients with CR or PR, 53 (80%) of 66 patients with SD, and 135 (94%) of 144 patients with PD at 6 months had an event. In the docetaxel group, 30 (88%) of 34 patients with CR or PR, 98 (96%) of 102 patients with SD, and 122 (95%) of 128 patients with SD at 6 months had an event. CR=complete response. NR=not reached. PD=progressive disease. PR=partial response. SD=stable disease.
Figure 4:
Figure 4:. Overall survival post-response in the combined CheckMate 017 and 057 population of patients who achieved a CR or PR
Overall survival was calculated from the time of response of each patient. In the nivolumab group, 38 (46%) of 83 patients had an event; in the docetaxel group, 44 (92%) of 48 patients had an event. CR=complete response. NR=not reached. PR=partial response.
Figure 5:
Figure 5:. Overall survival post-progression in the combined CheckMate 017 and 057 population by best overall response
Data are for all patients who had a best overall response of PD or disease progression after a best overall response of CR or PR or SD. In the nivolumab group, 273 (92%) of 297 patients had an event, including 27 (66%) of 41 with CR or PR, 74 (89%) of 83 patients with SD, and 172 (99%) of 173 patients with PD as best overall response. In the docetaxel group, 273 (96%) of 285 patients had an event, including 35 (92%) of 38 patients with CR or PR, 115 (96%) of 120 patients with SD, and 123 (97%) of 127 patients with PD as best overall response. Patients who died without previous radiographic evidence of disease progression (56 treated with nivolumab and 86 treated with docetaxel) were excluded. CR=complete response. PD=progressive disease. PR=partial response. SD=stable disease.
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