Adding Thoracic Radiotherapy to Chemo-Immunotherapy Fails in SCLC

Adding concurrent thoracic radiotherapy (TRT) to first-line chemo-immunotherapy did not improve survival in patients with extensive-stage small cell lung cancer (ES-SCLC) and was associated with more adverse events and more treatment-related deaths, according to results of the phase 3 TRIPLEX trial (NCT05223647).¹

The trial was stopped early after an independent data and safety monitoring committee found no survival signal favoring radiotherapy and identified a safety concern, according to the study's lead author, Bjørn Henning Grønberg, MD, PhD, of St. Olavs Hospital in Trondheim, Norway.

Study Rationale and Design

Chemo-immunotherapy with durvalumab (Imfinzi) or atezolizumab (Tecentriq) plus platinum-etoposide chemotherapy is the current standard first-line treatment for ES-SCLC,² but the survival benefit of adding immunotherapy is modest. A previous phase 3 trial had suggested a survival benefit for consolidative TRT after chemotherapy alone in ES-SCLC, and a proposed synergistic effect between radiotherapy and immunotherapy, along with retrospective data, suggested TRT might improve survival when added to chemo-immunotherapy.

Investigators at 20 hospitals across Norway, Sweden, Estonia, Iceland, and the Netherlands enrolled patients 18 years or older with ECOG performance status 0 or 1 and stage III or IV disease (TNM 8th edition) that was ineligible for curative chemoradiotherapy.¹ Patients were randomized 1:1, stratified by presence of liver and brain metastases, to chemo-immunotherapy plus TRT or chemo-immunotherapy alone. All patients received 4 cycles of carboplatin (AUC 5), etoposide, and durvalumab 1500 mg every 3 weeks, followed by durvalumab 1500 mg every 4 weeks until progression, unacceptable toxicity, or patient wish to discontinue. In the experimental arm, TRT (30 Gy in 10 fractions) to thoracic lesions began 21 to 28 days after the first chemo-immunotherapy infusion. Prophylactic cranial irradiation was considered for responders in both arms. The primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and toxicity.

Enrollment began in January 2022 and was halted in September 2025, short of the planned 302 patients, after 228 patients had been randomized (TRT arm, n = 115; chemo-immunotherapy alone, n = 113). Baseline characteristics were well balanced between arms; median age was 68 years, half of patients were female, and roughly 40% had liver metastases and 28% had brain metastases.

Efficacy and Safety Findings

TRT did not improve OS, the trial's primary end point. Median OS was 10.0 months with TRT vs 11.8 months with chemo-immunotherapy alone (HR, 1.14; 95% CI, 0.84-1.56; P =.40). Median PFS was similar between arms (5.1 vs 5.0 months; HR, 1.10; 95% CI, 0.84-1.45; P =.49), as were overall response rates (79.1% vs 84.1%; P =.34). Subgroup analyses, including patients who completed all 4 chemo-immunotherapy cycles and those without brain or liver metastases, showed no survival benefit for TRT.

Any-grade adverse events were more common with TRT (87.8% vs 69.9%; P =.007), driven substantially by esophagitis, which occurred in 47.8% of TRT-treated patients vs less than 1% of the chemo-immunotherapy–alone arm. Rates of grade 3-4 adverse events were similar between arms (40.9% vs 33.6%; P =.26), but grade 5 adverse events were more frequent with TRT (14.7% vs 3.5%; P =.014). Deaths from causes other than SCLC were more common in the TRT arm (14.8% vs 3.5%; P =.003), a difference that was attenuated but still numerically higher after excluding deaths that occurred before TRT was scheduled to begin (9.6% vs 3.5%; P =.067).¹

Clinical Implications

The authors concluded that adding TRT after the first cycle of chemo-immunotherapy did not improve treatment outcomes in ES-SCLC and was associated with greater toxicity, including more fatal adverse events. The findings contrast with earlier data supporting consolidative radiotherapy after chemotherapy alone and challenge the hypothesis that concurrent radiotherapy and immunotherapy act synergistically in this setting.

REFERENCES

1. Grønberg BH, Dumoulin DW, Oselin K, et al. Concurrent thoracic radiotherapy (TRT), platinum/etoposide chemotherapy, and durvalumab immunotherapy in extensive-stage (ES) small cell lung cancer (SCLC): a phase III trial. J Clin Oncol. 2026;44(suppl 17):LBA8005. doi:10.1200/JCO.2026.44.17_suppl.LBA8005

2. Li M, Chen YZ, Chen DZ, Wang Y, Zhao HL. First-line treatment of extensive-stage small cell lung cancer with immune checkpoint inhibitors acting on different targets: a systematic review and network meta-analysis. Transl Cancer Res. 2025 Jul 30;14(7):3961-3972. doi: 10.21037/tcr-2025-430. Epub 2025 Jul 24. PMID: 40792152; PMCID: PMC12335701.