Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer
Simple Summary
Abstract
1. Introduction
2. Mechanism of Synergy Between Immunotherapy and Radiation
3. Chemotherapy-Free Treatment Regimens for Advanced/Metastatic NSCLC
4. Completed Clinical Trials Exploring Chemotherapy-Free Regimens in LA-NSCLC
Registration #, Trial Name | Sample Size | Phase | Primary Endpoint | Immunotherapy Schedule and Timing | RT Schedule | Patient/Biomarker Selection | Key Findings |
---|---|---|---|---|---|---|---|
jRCT2080224763 DOLPHIN [20] | 35 | II | 1-year PFS rate | Durvalumab, every two weeks for one year, starting concurrent with RT | 60 Gy in 30 fractions | PD-L1 TPS ≥ 1% | 1-year PFS = 72% 1-year OS = 94% |
NCT04249362 DUART [21,22] (Cohort A) | 53 | II | Safety | Durvalumab, every four weeks for one year, starting after RT | 60 Gy (+/−10%) | Ineligible for chemotherapy | 7 Grade 3–5 adverse events related to study therapy 1-year PFS = 47% 1-year OS = 64% |
JMA-IIA00434 (jRCT) SPIRAL-RT [17,18] | 33 | II | 1-year PFS rate | Durvalumab, every two weeks for one year, starting after RT | 54 to 66 Gy in 27 to 33 fractions | Ineligible for concurrent chemo-radiotherapy | 1-year PFS = 39% 1-year OS = 72% |
NCT03523702 SPRINT [19] | 25 | II | 1-year PFS rate | Pembrolizumab, every three weeks, before RT (3 cycles) and after RT (12 cycles) | 48 or 55 Gy in 20 fractions (risk-adapted) | PD-L1 TPS ≥ 50% | 1-year PFS = 76% 1-year OS = 92% |
NCT03999710 DART [26] | 27 | II | 2-year PFS rate | Durvalumab, every four weeks for one year, starting concurrent with RT | 54–66 Gy in 27–33 fractions | Ineligible for concurrent chemo-radiotherapy | 1-year PFS = 42% 1-year OS = 75% |
NCT04003246 [27] | 10 | II | PFS rate | Durvalumab, every four weeks for one year, starting concurrently with RT. | 54–66 Gy in 27–33 fractions | Medically inoperable disease or unwilling to undergo surgery PD-L1 TPS (any) | 1-year PFS = 20% |
NCT03801902 NRG-LU004 [28] | 24 | I | Safety | Durvalumab, every four weeks for one year, starting 0–2 weeks before RT start | Cohort 1: 60 Gy in 30 fractions Cohort 2: 60 Gy in 15 fractions | PD-L1 TPS ≥ 50% | No DLTs related to study therapy |
5. Ongoing Chemotherapy-Free Clinical Trials in LA-NSCLC Patients
6. Considerations for Future Studies of Chemotherapy-Free Treatment of LA-NSCLC
6.1. Patient Selection
- (1)
- Patients who are deemed to be ineligible for standard chemoradiotherapy
- (2)
- Patients for whom chemotherapy-free treatment is expected to yield superior outcomes compared to standard chemoradiotherapy.
6.2. Identification of LA-NSCLC Patients Most Likely to Benefit from Immunotherapy
6.3. Radiation Type and Dose
6.4. Safety and Toxicity
6.5. Type and Order of Immunotherapy
7. Future Directions
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Trial Name | Phase | Primary Endpoint(s) | Immunotherapy Schedule and Timing | RT Schedule | Patient/Biomarker Selection | Status |
---|---|---|---|---|---|---|
NCT04013542 | I | Safety and feasibility | Nivolumab, every three weeks for up to 8 cycles, and ipilimumab every six weeks for up to 4 cycles, both starting with RT. | 60 Gy in 30 fractions | Ineligible for concurrent chemoradiotherapy | Active, not recruiting |
NCT03818776 (PARTICLE-D) | I | Safety | Durvalumab, every four weeks for one year, starting one week before RT | Arm 1: 60–69 CGyE in 30 fractions (proton radiotherapy) | Ineligible for concurrent chemoradiotherapy | Terminated |
NCT05451173 | I/II | Safety, PFS | Durvalumab, every four weeks for one year, starting concurrently with RT. | 3.5–4.0 Gy × 15 fractions | PD-L1 TPS ≥ 1% (“preferred”) | Not yet recruiting |
NCT04577638(AIRING) | II | DCR * | Nivolumab, every two weeks for six months, starting concurrently with RT. | 66 Gy in 24 fractions | ≥1 of several “fragility criteria”, which include ECOG performance status 2 and age > 74 | Recruiting |
NCT04310020(SWOG S1933) | II | PFS | Atezolizumab, every three weeks for one year, starting after RT | 60 Gy in 15 fractions | Ineligible for concurrent chemoradiotherapy | Recruiting |
NCT04351256(Trade-HYPO) | II | Safety and feasibility | Durvalumab, every four weeks for one year, starting concurrently with RT. | 55 Gy in 20 fractions | Ineligible for concurrent chemoradiotherapy | Recruitiing |
NCT06865339 | II | ORR † to induction immuno-therapy | Cemiplimab and Fianlimab, every three weeks, before RT (3 cycles) and after RT (13 cycles) | Risk-adapted conventional fractionation | Low PD-L1 TPS (<50%) | Recruiting |
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Ozair, M.Z.; Halmos, B.; D’Aiello, A.; Yun, J.; Filippi, A.R.; Rimner, A.; Lin, S.H.; Simone, C.B., II; Ohri, N. Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer. Cancers 2025, 17, 1524. https://doi.org/10.3390/cancers17091524
Ozair MZ, Halmos B, D’Aiello A, Yun J, Filippi AR, Rimner A, Lin SH, Simone CB II, Ohri N. Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer. Cancers. 2025; 17(9):1524. https://doi.org/10.3390/cancers17091524
Chicago/Turabian StyleOzair, M. Zeeshan, Balazs Halmos, Angelica D’Aiello, Jaewon Yun, Andrea R. Filippi, Andreas Rimner, Steven H. Lin, Charles B. Simone, II, and Nitin Ohri. 2025. "Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer" Cancers 17, no. 9: 1524. https://doi.org/10.3390/cancers17091524
APA StyleOzair, M. Z., Halmos, B., D’Aiello, A., Yun, J., Filippi, A. R., Rimner, A., Lin, S. H., Simone, C. B., II, & Ohri, N. (2025). Chemotherapy-Free Treatment with Radiotherapy and Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer. Cancers, 17(9), 1524. https://doi.org/10.3390/cancers17091524