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Clinical Trial
. 2022 Nov;28(11):2374-2380.
doi: 10.1038/s41591-022-01977-y. Epub 2022 Aug 25.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial

Miranda Gogishvili  1 , Tamar Melkadze  2 , Tamta Makharadze  3 , Davit Giorgadze  4 , Mikhail Dvorkin  5 , Konstantin Penkov  6 , Konstantin Laktionov  7 , Gia Nemsadze  8 , Marina Nechaeva  9 , Irina Rozhkova  10 , Ewa Kalinka  11 , Christian Gessner  12   13 , Brizio Moreno-Jaime  14 , Rodolfo Passalacqua  15 , Siyu Li  16 , Kristina McGuire  16 , Manika Kaul  16 , Anne Paccaly  16 , Ruben G W Quek  16 , Bo Gao  16 , Frank Seebach  16 , David M Weinreich  16 , George D Yancopoulos  16 , Israel Lowy  16 , Giuseppe Gullo  16 , Petra Rietschel  16
Affiliations
Clinical Trial

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial

Miranda Gogishvili et al. Nat Med. 2022 Nov.

Abstract

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.

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Conflict of interest statement

M.G., T. Melkadze, T. Makharadze, D.G., M.D., K.L., G.N., M.N., I.R. and B.M.-J. report no conflicts of interest. K.P. reports honoraria from AstraZeneca, Merck Sharp & Dohme, Nektar, Pfizer, Regeneron Pharmaceuticals and Roche and a consulting or advisory role with Nektar. E.K. reports honoraria from Merck Sharp & Dohme, Bristol Myers Squibb, Nektar, Pfizer, Roche, AstraZeneca, Amgen and Regeneron Pharmaceuticals. C.G. reports advisory board fees or honoraria from GlaxoSmithKline, Pfizer, AstraZeneca, Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Berlin-Chemie, Chiesi, Boehringer Ingelheim and Sanofi. R.P. reports advisory board or speaker roles for Astellas, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme, Roche and Sanofi-Aventis and institutional funding for research projects from Amgen, AstraZeneca, Novartis and Pierre-Fabre. S.L., K.M., A.P., R.G.W.Q., B.G., F.S., D.M.W., G.D.Y., I.L., G.G. and P.R. are employees and shareholders of Regeneron Pharmaceuticals.

Figures

Fig. 1
Fig. 1. CONSORT diagram of EMPOWER-Lung 3 part two.
All randomized patients were included in the efficacy analyses, and all patients who received treatment were included in the safety analyses.
Fig. 2
Fig. 2. Survival data for the cemiplimab plus chemotherapy and placebo plus chemotherapy arms.
a, Kaplan–Meier OS curves of all patients. b, Forest plots of OS by subgroups. c, Kaplan–Meier PFS curves of all patients. d, Forest plots of PFS by subgroups. Median OS and PFS and corresponding two-sided 95% CIs were estimated by the Kaplan–Meier method. HRs and corresponding two-sided 95% CIs for OS and PFS were calculated using a stratified Cox proportional hazard model with Efron’s method of tie handling. Cemi, cemiplimab; chemo, chemotherapy; met, metastasis; PBO, placebo.
Fig. 3
Fig. 3. Tumor response data for the cemiplimab plus chemotherapy and placebo plus chemotherapy arms.
a, Kaplan–Meier curves of DOR in all patients. The median DOR and corresponding two-sided 95% CI were estimated by the Kaplan–Meier method. b, Forest plots of objective response in pre-specified subgroups. Odds ratios and corresponding two-sided 95% CIs were calculated using the Cochran–Mantel–Haenszel method. c, ORR in correlation with baseline PD-L1 levels. ORR and the corresponding two-sided 95% CI were calculated using the Clopper–Pearson method. d, Tumor response in correlation with baseline PD-L1 levels. Median percent change in tumor size over time was calculated descriptively (LOCF). Cemi, cemiplimab; chemo, chemotherapy; LOCF, last observation carried forward; met, metastasis; PBO, placebo.
Extended Data Fig. 1
Extended Data Fig. 1. Clinical activity of tumor response in patients with evaluable post-baseline tumor assessment per RECIST 1.1 by independent review committee.
a, Waterfall plot of tumor response in patients who received cemiplimab plus chemotherapy (n = 312). b, Waterfall plot of tumor response in patients who received placebo plus chemotherapy (n = 154). PD, progressive disease; SD, stable disease.
Extended Data Fig. 2
Extended Data Fig. 2. Time to definitive clinically meaningful deterioration in a, GHS/QoL and b, pain symptoms.
Median time to clinically meaningful deterioration in GHS/QoL and pain symptoms, and corresponding two-sided 95% CIs for each, were estimated using the Kaplan–Meier method. Hazard ratios and corresponding two-sided 95% CIs for time to definitive clinically meaningful deterioration were calculated using a stratified Cox proportional hazard model with Efron’s method of tie handling. Cemi, cemiplimab; chemo, chemotherapy; NYR, not yet reached; PBO, placebo.
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References

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