1L standard-of-care treatment (tx) for ES-SCLC is platinum (carboplatin or cisplatin) + etoposide. Despite high response rates, outcomes remain poor. IMpower133, a global Ph1/3, double-blind, randomized, placebo (PBO)-controlled trial evaluated efficacy and safety of adding atezolizumab (atezo; anti–PD-L1) or PBO to 1L tx (NCT02763579).
Patient (pts) without prior tx for ES-SCLC were enrolled. PD-L1 testing was not required. Randomization was 1:1 to four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) + etoposide (100 mg/m2 IV, Days 1–3) with either atezo (1200 mg IV, Day 1) or PBO, then maintenance atezo or PBO until PD, unacceptable toxicity or loss of clinical benefit. During maintenance tx, prophylactic cranial irradiation (PCI) was allowed per protocol; definitive thoracic radiation (TR) was not. Co-primary endpoints were OS and investigator-assessed PFS. Blood tumor mutation burden (bTMB) was an exploratory subgroup analysis using prespecified cutoffs (≥16 vs < 16 and ≥10 vs < 10 mutations/Mb).
Adding atezo to carboplatin + etoposide provided a significant improvement in OS and PFS in 1L ES-SCLC (Table; WCLC 2018:PL02.07). Survival benefits were consistent across key subgroups and prespecified bTMB cutoffs. 44 pts (22 in each arm) received PCI, and 7 pts (3 in atezo arm, 4 in PBO) received TR. Gr 3–4 tx-related adverse events (AE) occurred in 56.6% vs 56.1% of pts in atezo vs PBO arms, respectively; serious tx-related AEs occurred in 22.7% vs 18.9% of pts, respectively. CNS-related AE rates in patients who had PCI are shown in the table. Safety population; safety analyses conducted according to tx received (1 pt randomized to the control arm received a dose of atezo).Atezolizumab + carboplatin + etoposide n = 201 PBO + carboplatin + etoposide n = 202 Co-primary endpoints Median OS, mo 12.3 10.3 HR 0.70 [95% CI 0.54–0.91; P = 0.0069] Median PFS, mo 5.2 4.3 HR 0.77 [95% CI 0.62–0.96; P = 0.017] Secondary efficacy endpoints Investigator-assessed confirmed ORR, % 60.2 64.4 Median DoR, mo 4.2 3.9 CNS-related AEs in pts who had PCI, no. (%)a n = 23 n = 21 Fatigue 12 (52.2) 9 (42.9) Headache 8 (34.8) 3 (14.3) Asthenia 5 (21.7) 2 (9.5) Dizziness 2 (8.7) 0 Insomnia 2 (8.7) 1 (4.8) Fall 2 (8.7) 1 (4.8)
Adding atezo to carboplatin + etoposide provided a significant improvement in survival in 1L ES-SCLC in all-comers. No unexpected safety signals emerged, including in pts who had PCI or TR. Atezo + carboplatin + etoposide may represent a new standard regimen for pts with untreated ES-SCLC.
Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, Ph.D, of Health Interactions, was provided by Genentech, Inc.
NCT02763579.
F. Hoffmann-La Roche/Genentech, Inc., a member of the Roche Group.
F. Hoffmann-La Roche/Genentech, Inc., a member of the Roche Group.
T.S.K. Mok: Grants: AZ, Roche/Genentech, BMS, BI, Novartis, MSD, Pfizer, Clovis Oncology, SFJ Pharmaceuticals, Taiho, Eisai, Takeda, Xcovery; Personal fees: AZ, Roche/Genentech, Eli Lilly, BMS, BI, Novartis, MSD, Pfizer, Merck Serono, Clovis Oncology, Vertex, SFJ Pharmaceuticals, ACEA Biosciences, Oncogenex, Celgene, Ignyta Inc, Taiho, Fishawack Facilitate Ltd, Takeda, Janssen, Hutchison ChiMed, OrigiMed, Hengrui Therapeutics, Sanofi-Aventis R&D, Yuhan Corporation; Stock: Hutchison ChiMed and Sanomics; Non-financial support: geneDecode. M. Reck: Personal fees: Roche, Lilly, AZ, Abbvie, BI, BMS, Celgene, MSD, Merck, Novartis, Pfizer. L. Horn: Consultancy: AbbVie, AstraZeneca, Merck, Incyte, Xcovery, Genentech, EMD Serono. S. Lam: Employment: Genentech/Roche. D.S. Shames: Employment: Roche/Genentech; Stock: Roche; Patent pending: Genentech Inc. J. Liu: Employment: Roche (China) Holding Ltd. F. Kabbinavar: Employment: Genentech; Stock: Genentech. W. Lin, A. Sandler: Employment: Roche/Genentech; Stock: Roche. S.V. Liu: Grants: AZ, Bayer, Clovis, Corvus, Genentech, Lilly, Merck, Molecular Partners, Esanex, Pfizer, OncoMed, Blueprint, Lycera, Threshold; Personal fees: AZ, BMS, Celgene, Genentech, Lilly, Pfizer, Taiho, Takeda, Regeneron, Heron.