Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Apr 30;17(9):1524.
doi: 10.3390/cancers17091524.

Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer

M Zeeshan Ozair  1 , Balazs Halmos  1 , Angelica D'Aiello  1 , Jaewon Yun  1 , Andrea R Filippi  2 , Andreas Rimner  3 , Steven H Lin  4 , Charles B Simone 2nd  5   6 , Nitin Ohri  1
Affiliations
Review

Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer

M Zeeshan Ozair et al. Cancers (Basel). .

Abstract

Background: Concurrent chemoradiotherapy (CRT) followed by immunotherapy is a standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC), yet many patients are ineligible due to treatment-related toxicity or poor functional status. Chemotherapy-free approaches using radiotherapy (RT) and immunotherapy may offer a safer and equally effective alternative in select patient populations. Methods: A comprehensive literature review was conducted using PubMed, Google Scholar, and relevant conference proceedings focusing on trials between 2000 and 2024. Studies investigating chemotherapy-free regimens combining RT and immunotherapy in LA-NSCLC were analyzed, with emphasis on clinical outcomes, biomarker use, treatment sequencing, radiation dose/fractionation, and safety. Results: Multiple Phase I/II trials reported promising efficacy with one-year progression-free survival (PFS) ranging from 39% to 76%. Toxicity was generally acceptable, though higher-grade adverse events were more frequent in older, frail populations. Trials integrating PD-L1 expression, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) showed potential for improved patient stratification. Variation in immunotherapy timing (induction, concurrent, or consolidation) and radiation schedules highlight the need for optimization. Conclusions: Chemotherapy-free regimens represent a promising treatment strategy for patients with LA-NSCLC, especially those that are ineligible for standard CRT. Biomarker-driven patient selection and the rational integration of RT and immunotherapy are critical to improving outcomes. Randomized trials are warranted to establish the efficacy and safety of these emerging approaches.

Keywords: LA-NSCLC; chemotherapy-free; immunotherapy; radiation therapy.

PubMed Disclaimer

Conflict of interest statement

M.Z.O., A.D., J.Y., and A.R. declare no conflicts of interest. B.H. received grants from Boehringer Ingelheim, Astra Zeneca, Merck, BMS, Advaxis, Amgen, AbbVie, Daiichi, Pfizer, GSK, Beigene, Janssen, Black Diamond Therapeutics, Forward Pharma, Numab, Arrivent; receipient of consulting fees from Astra Zeneca, Boehringer Ingelheim, Apollomics, Janssen, Takeda, Merck, BMS, Genentech, Pfizer, Eli Lilly, Arcus, Merus, Daiichi, Precede; and participated on the Advisory Board of BMS, TPT, Apollomics, eFECTOR, and City of Hope. A.R.F. received fees as a speaker from Astra Zeneca, MSD, Roche, Ipsen; fees for advisory role from Astra Zeneca, Roche; and research funding from Astra Zeneca and also participated in sponsored research from Astra Zeneca, Roche, and MSD. S.H.L. received grant funding from Beyond Spring Pharmaceuticals, Hitachi Chemical Diagnostics, and IntraOp Corporation and serves on the advisory board for Beyond Spring Pharmaceuticals, STCube Pharmaceuticals, and AstraZeneca; he is also a consultant for XRAD Therapeutics and is cofounder of Scenexo, Inc. C.B.S. served in a leadership or fiduciary role for the American Society for Radiation Oncology, Proton Collaborative Group, American Radium Society, and the Particle Therapy Co-Operative Group. N.O. received institutional research funding from Merck, Reflexion Medical and AstraZeneca and received consulting fees for Genentech and Merck. The funders had no role in the analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Direct and indirect cytotoxic effects induced by RT. Immunotherapy when used in a specific sequence with RT induces optimal activation of innate and humoral immunity, which promotes tumor cell death both at the primary tumor site and any secondary sites (abscopal effect). PD-L1 immunotherapy is shown as an example; however, other immune checkpoint inhibitors have a similar mechanism of action.
Figure 2
Figure 2
Ongoing and published trials of chemotherapy-free regimens for LA-NSCLC.
Figure 3
Figure 3
Considerations in design of Phase III trials for chemotherapy-free regimens for LA-NSCLC.
See this image and copyright information in PMC

References

    1. Antonia S.J., Villegas A., Daniel D., Vicente D., Murakami S., Hui R., Yokoi T., Chiappori A., Lee K.H., de Wit M., et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2017;377:1919–1929. doi: 10.1056/NEJMoa1709937. - DOI - PubMed
    1. Spigel D.R., Faivre-Finn C., Gray J.E., Vicente D., Planchard D., Paz-Ares L., Vansteenkiste J.F., Garassino M.C., Hui R., Quantin X., et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. J. Clin. Oncol. 2022;40:1301–1311. doi: 10.1200/JCO.21.01308. - DOI - PMC - PubMed
    1. Bradley J.D., Sugawara S., Lee K.H.H., Ostoros G., Demirkazik A., Zemanova M., Sriuranpong V., Gelatti A., Menezes J., Zurawski B., et al. LBA1 Durvalumab in Combination with Chemoradiotherapy for Patients with Unresectable Stage III NSCLC: Final Results from PACIFIC-2. ESMO Open. 2024;9:102986. doi: 10.1016/j.esmoop.2024.102986. - DOI
    1. Peters S., Tan D.S.W., Gerber D.E., Urbanic J., Ramalingam S.S., Yu J., Xing L., Rittmeyer A., Ciuleanu T., Menezes J., et al. CheckMate 73L: Phase 3 Study Comparing Nivolumab (N) + Concurrent Chemoradiotherapy (CCRT) Followed by N_Ipilimumab (I) v CCRT Followed by Durvalumab (D) for Previously Untreated, Locally Advanced Stage (Stg) III NSCLC. Ann. Oncol. 2024;24:100808. doi: 10.1016/j.iotech.2024.100808. - DOI
    1. Eichkorn T., Bozorgmehr F., Regnery S., Dinges L.A., Kudak A., Bougatf N., Weber D., Christopoulos P., Muley T., Kobinger S., et al. Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients with Unresectable Stage III Non-Small Cell Lung Cancer—Cross-Sectional Study of Eligibility and Administration Rates. Front. Oncol. 2020;10:586449. doi: 10.3389/fonc.2020.586449. - DOI - PMC - PubMed

LinkOut - more resources