First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer
Open accessAbstract
BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).
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Many of the studies used ICIs as monotherapy in a heavily pretreated population, whereas current standard first-line therapy often includes combination ICIs or ICI with chemotherapy for multiple tumor types.
“Third, many of these studies utilized ICIs as monotherapy in a heavily pretreated population whereas current standard first-line therapy often includes a combination of ICIs or ICI with chemotherapy for multiple tumor types (35–40).”
From A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors (2021) · cites this paper as [38]
Maintenance immune checkpoint therapy provides clinical benefit in non-small cell lung cancer, extensive-stage small cell lung cancer, and bladder cancer, leading to FDA approvals.
“Clinical benefi t with maintenance ICT in specifi c settings was demonstrated in patients with nonsmall cell lung cancer (NSCLC; ref.50 ), extensive-stage small cell lung cancer ( 51,52 ), and bladder cancer ( 53 ), leading to FDA approvals in these tumor types.”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [51]
Atezolizumab combined with chemotherapy is FDA-approved for squamous and nonsquamous NSCLC, small cell lung cancer, and PD-L1-positive triple-negative breast cancer.
“to date, atezolizumab, in combination with chemotherapy, has been approved by the FDA for the treatment of squamous and nonsquamous NSCLC, small cell lung cancer, and PD-L1-positive triple-negative breast cancer (66)(67)(68)(69).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [68]
Pharmacologic blockade of immune checkpoints can result in anti-tumor immunity and autoinflammation at other sites, which clinically manifests as immune-related adverse events.
“Pharmacologic blockade, therefore, can result in not only anti-tumor immunity, but autoinflammation at other sites, which clinically manifest as immune related adverse events.16”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [16]
Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, STING agonist, FMT, epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity.
“Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, stimulator of interferon genes (STING) agonist, fecal microbiota transplantation (FMT), epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity [22–31].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [23]
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- Authors
- Horn, L., Mansfield, A. S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M. J., Huemer, F., Losonczy, G., Johnson, M. L., Nishio, M., Reck, M., Mok, T., Lam, S., Shames, D. S., Liu, J., Ding, B., Lopez-Chavez, A., Kabbinavar, F., Lin, W., Sandler, A., & Liu, S. V.
- Affiliations
- Mayo Clinic (US)
- From Vanderbilt University Medical Center (L. Horn) and Sarah Cannon Research Institute–Tennessee Oncology (M.L.J.), Nashville; Mayo Clinic, Rochester, MN (A.S.M.); Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy, Otwock (A. Szczęsna), and Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie, Warsaw (M.K.) — both in Poland; Thomayerova Nemocnice, Pneumologická Klinika 1.LF UK, Prague, Czech Republic (L. Havel); the Department of Respiratory and Critical Care Medicine (M.J.H.) and...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-12-06
- Volume
- 379
- Issue
- 23
- Pages
- 2220-2229
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2893960509
- Cited by
- 3,586
- References
- 26
- Citations by year
- 2026: 376 · 2025: 482 · 2024: 481 · 2023: 473 · 2022: 497 · 2021: 545 · 2020: 477 · 2019: 229 · 2018: 18 · 2017: 2
- FWCI
- 119.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- F. Hoffmann-La Roche / Genentech
- Topics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- atezolizumab, extensive-stage small cell lung cancer, first-line therapy, PD-L1 blockade, PD-1/PD-L1 blockade, carboplatin, etoposide, combination chemotherapy, overall survival, progression-free survival, maintenance therapy, immune checkpoint inhibitors, IMpower133, safety and tolerability, treatment-related adverse events
- MeSH terms
- Progression-Free Survival, Aged, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Etoposide, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Carboplatin, Kaplan-Meier Estimate, Small Cell Lung Carcinoma, Antibodies, Monoclonal, Humanized
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