Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non–Small Cell Lung Cancer: A Nonrandomized Controlled Trial
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Importance: Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy. Objective: To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC. Design, Setting, and Participants: This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019. Interventions: Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment. Main Outcomes and Measures: Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates. Results: Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months. Conclusions and Relevance: These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT02621398.
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α-PD-1/PD-L1 plus chemoradiotherapy was tolerable in advanced NSCLC, HNSCC, and SCLC patients, with promising clinical outcomes, in phase 1/2 studies.
“Moreover, the results of some phase 1/2 studies (NCT02621398, NCT02434081, NCT02586207, NCT02383212, and NCT02402920) showed that α-PD-1/PD-L1 plus chemoradiotherapy was tolerable in advanced NSCLC, head and neck squamous cell carcinoma (HNSCC), and SCLC patients, with promising clinical outcomes [78–82].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [78]
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- Authors
- Jabbour, S. K., Berman, A. T., Decker, R. H., Lin, Y., Feigenberg, S. J., Gettinger, S. N., Aggarwal, C., Langer, C. J., Simone, C. B., Bradley, J. D., Aisner, J., & Malhotra, J.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Abramson Cancer Center (US)
- Yale University (US)
- New York Proton Center (US)
- Emory University (US)
- Corresponding author
- Jabbour, Salma K.
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2020-06-01
- Volume
- 6
- Issue
- 6
- Pages
- 848
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC7042914
- OpenAlex
- W3008012565
- Cited by
- 125
- References
- 27
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 24 · 2023: 25 · 2022: 21 · 2021: 25 · 2020: 14
- FWCI
- 11.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- pembrolizumab, anti-PD-1 therapy, non-small cell lung cancer, stage III NSCLC, locally advanced unresectable lung cancer, chemoradiotherapy, concurrent immunotherapy, carboplatin, paclitaxel, radiotherapy, pneumonitis, immune-related adverse events, dose-limiting toxicity, maximum tolerated dose, safety and tolerability, consolidation immunotherapy
- MeSH terms
- Antineoplastic Agents, Immunological, Immune Checkpoint Inhibitors, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Carboplatin, Treatment Outcome, Paclitaxel, Chemoradiotherapy, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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