EMPOWER-Lung 3

Background

Phase III, double-blind, placebo-controlled RCT (EMPOWER-Lung 3). N=466 with stage IV or recurrent NSCLC (squamous and non-squamous), any PD-L1 level, no EGFR/ALK/ROS1 alterations, no prior systemic therapy. First-line all-comer IO + chemotherapy. Stratified by histology, region, ECOG PS.

Interventions and follow up

Arm A: Cemiplimab 350 mg IV q3wk + platinum-based chemotherapy × 4 cycles, then cemiplimab maintenance (N=312)
Arm B: Placebo + same chemotherapy × 4 cycles, then placebo maintenance (N=154)
Primary endpoint: Overall survival
mFollow up: 21 months

Results

OS: 21.9 vs 13.0 mo, HR 0.71 (95% CI 0.53–0.93), P=.014
PFS: 8.0 vs 5.0 mo, HR 0.56 (0.44–0.70), P<.001
ORR: 43% vs 23%
OS (PD-L1 ≥50%): HR 0.51

Adverse events

Overall (grade ≥3): 61.9% (cemiplimab+chemo) vs 52.3% (chemo)
Immune-related (grade ≥3): 11.5% vs 0.7%
Pulmonary: pneumonitis 3.8%
Discontinuation (cemiplimab): 9.6%

Conclusions

Cemiplimab + chemotherapy improved OS vs chemotherapy alone in 1L NSCLC regardless of PD-L1 level (HR 0.71), establishing an all-comer first-line option. Benefit was greater in PD-L1 ≥50% (HR 0.51), consistent with IO class effects.

Key Limitations

Smaller trial (N=466) vs KEYNOTE-189 (N=616) with less power for subgroup analyses. 2:1 randomization limits comparative power. OS benefit modest in PD-L1 <1% subgroup. No active IO + chemo comparator. Heterogeneous chemotherapy backbone between histologies. Histology subgroups not individually powered.

Clinical Context

FDA-approved (2022) and EMA-approved all-comer 1L IO + chemo regimen, alongside pembrolizumab+chemo (KEYNOTE-189/407), atezolizumab+chemo (IMpower150), durvalumab+chemo (POSEIDON). ESMO-MCBS 3. Cemiplimab is an alternative where other agents are less accessible.

References