Concurrent thoracic radiotherapy (TRT), platinum/etoposide chemotherapy, and durvalumab immunotherapy in extensive-stage (ES) small cell lung cancer (SCLC): A phase III trial.

LBA8005 Background: A phase III trial indicated a survival benefit of TRT after chemotherapy in ES SCLC. A synergistic effect of concurrent radiotherapy and immunotherapy has been proposed and retrospective studies suggest that TRT improves survival in ES SCLC patients receiving chemoimmunotherapy (chemo-ICI). The main aim of this phase III trial was to investigate whether adding TRT to chemo-ICI improves overall survival (OS) in ES SCLC. Methods: Eligible patients were ≥18 years, had ECOG performance status (PS) 0-1 and disease stage III-IV (TNM 8) ineligible for curative chemoradiotherapy and were randomized 1:1 to chemo-ICI plus TRT («TRT») or chemo-ICI alone («C-I»), stratified by presence of liver and brain metastases. Patients received 4 courses of carboplatin (AUC 5), etoposide (100 mg/m 2 iv day 1-3 or 100 mg/m 2 iv day 1 plus 200 mg/m 2 po days 2-4) and durvalumab 1500 mg q3w, followed by durvalumab 1500 mg q4w until progression, unacceptable toxicity or patients wished to discontinue. TRT of 30 Gy/10 fractions to thoracic lesions started 21-28 days after day 1 of the 1st chemo-ICI cycle. Prophylactic cranial irradiation of 25-30 Gy/10-15 fractions was considered for those responding to chemo-ICI. Primary endpoint was OS, secondary endpoints include overall response rates (ORR), progression free survival (PFS) and toxicity. To show an increase in 1-year survival rates from 53% to 66% with a 2-tailed α of 0.05 and a β of 0.20, 128 patients were required in each group. Results: Enrolment started in January 2022 and was prematurely discontinued in September 2025 according to recommendations by the independent Data and Safety Monitoring Committee due to more serious adverse events (AE) in the TRT group and futility. By then, 228 patients from 20 European hospitals were randomized (TRT: n =115, C-I: n =113). Median age was 68 (range 39-84), 50.4% were female, 37.7% had PS 0, 96.1% stage IV disease, 39.9% metastases to the liver and 28.1% to the brain. Treatment groups were well balanced. Mean number of chemo-ICI courses was 3.6, mean number of total durvalumab courses 7.5 (range 1-30) and 91.3% in the TRT group received TRT. TRT did not improve OS (median 10.0 [TRT] vs. 11.1 months, HR 1.12, 95% CI 0.82-1.54, p=0.47), ORR (TRT: 88.5%, C-I: 89.6%, p=0.79) or PFS (median 5.1 [TRT] vs. 5.1 months, HR 1.09, 95% CI 0.83-1.44, p=0.53). Overall, there were more AEs in the TRT group (87.8% vs. 69.9%, p=0.006), but not more grade 3-4 AEs (TRT: 21.1%, C-I: 17.5%, p=0.33). Esophagitis occurred in 47.8% and grade 3-4 esophagitis in 10.4% of the TRT group. There were more deaths from other causes than SCLC in the TRT group (14.8% vs. 3.5%, p=0.003), though not significantly more when excluding deaths occuring before TRT commenced (9.6% vs. 3.5%, p=0.067). Conclusion: The addition of TRT after the first cycle of chemo-ICI did not improve treatment outcomes in ES SCLC. Clinical trial information: NCT05223647 .