Concomitant radiotherapy, tremelimumab, and durvalumab for advanced NSCLC patients progressing on first-line immunotherapy: A phase 2 study (CORAL-Lung).

8583 Background: The optimal treatment for advanced NSCLC that developed resistance to immune checkpoint inhibitors (CPIs) remains undefined. We hypothesized that combining anti-PD-L1, anti-CTLA-4 (at an effective dose) and radiotherapy could be effective against CPI-resistant tumors. Methods: This open-label, single-arm, phase 2a trial evaluated two CPIs plus radiotherapy in patients with advanced/metastatic NSCLC who progressed on/after 1L CPI given alone or in combination with chemotherapy. Co-Primary endpoints were safety and response rate (RR; by RECIST 1.1). Secondary endpoints were to evaluate progression free survival (PFS) and overall survival (OS). The study included a safety run-in cohort and a Simon two-step design expansion. RR ≥ 20% in non-irradiated lesions was required to advance from the initial efficacy to expansion cohort. Patients with prior anti-CTLA-4 treatment were excluded. At least one measurable non-irradiated lesion was required. Treatment included tremelimumab at a fixed dose of 300 mg at D1 and 12 weeks later and 1500 mg Durvalumab q4w (starting from D1). This dosing was based on PK and pharmacodyamic data from study D4190C00006, suggesting tremelimumab of dose greater than 1 mg/kg with a higher peak exposure may be associated with a higher pharmacodynamic effect. On D21, patients began radiotherapy: 11 fractions of 3 Gy (total of 33 Gy), selected based on our real-world database analysis (Onn et al, Cancers 2021, 13(11), 2800). The study was sponsored by Sheba MC and funded by AstraZeneca Pharmaceuticals. NIH trials registry identifier: NCT05000710. Results: Ten patients were enrolled, median age was 71 (range 51-82); 50% males; all stage IV; 50% adenocarcinoma; 50% with PD-L1 < 1%; 80% past/current smokers; none had actionable driver mutations. Previous treatment lines were 1/2 in 80%/20% respectively; all patients received prior pembrolizumab and platinum-based doublet. Median (range) durvalumab and tremelimumab cycles administered were 2 (1-7), 1(1-3). Median radiotherapy dose was 33 Gy, in 78% targeting lung lesions. Nine patients were included in the safety run-in, three experienced treatment-related toxicities leading to treatment discontinuation (all grade 3 diarrhea), remaining below the predefined 40% threshold and permitting continuation. All other treatment-related toxicities were grade 2 or lower. The initial efficacy cohort (n = 10) RR was 10%, leading to the study closure. Median PFS was 2.2 months, median OS was 13.9 months. The study was terminated on Dec 31, 2024. Conclusions: In unselected patients with advanced CPI-resistant NSCLC, the combination of anti-PD-L1, anti-CTLA4 at a high dose and radiotherapy did not demonstrate a meaningful response rate. Toxicity of a high dose of anti-CTLA-4 is not negligible. Better patient selection might lead to higher efficacy and lower toxicity. Clinical trial information: NCT05000710 .