A phase II, open-label, combination therapy of durvalumab and ceralasertib in relapsed and refractory small cell lung cancer (SUKSES-N4).

8104 Background: In extensive stage small-cell lung cancer (SCLC), the standard first-line treatment is an immune checkpoint inhibitor (ICI) combined with chemotherapy. However, in the relapsed or refractory setting, the benefits of ICI-based combinations are modest, regardless of prior ICI exposure. Ceralasertib, a selective ATR inhibitor, not only enhances DNA damage, inducing apoptosis, but also affects immune and inflammatory pathways. This study assesses the safety and efficacy of combining durvalumab with ceralasertib in SCLC patients. Methods: This open-label, phase II, multi-cohort umbrella trial recruited relapsed and refractory SCLC patients independent of biomarker status. Initially, patients received 1500mg of durvalumab on day 1, followed by 240mg of ceralasertib twice daily from day 15 to 28 of a 28-day cycle (Dose A). An amendment aligned the dosing regimen to other studies to 240mg of ceralasertib twice daily from day 1 to 7, with 1500mg of durvalumab administered on day 8 (Dose B). The primary endpoint was the objective response rate (ORR), with a target enrollment of 40 evaluable patients. Results: Between June 2022 and May 2023, forty-two patients were recruited (Dose A: 27; Dose B: 15). The median age was 67 (range: 43-83), with a predominance of males (n = 36) and smokers (n = 40). ECOG PS scores were 0 (n = 1) or 1 (n = 41), and nearly half (n = 20, 47.6%) had prior ICI exposure. The ORR per RECIST was 9.5%, with a disease control rate of 26.2%, including 4 partial responses (PR) and 7 cases of stable disease (SD). Median progression-free survival (PFS) was 1.64 months (95% CI: 1.61-1.97), and overall survival was 7.16 months (95% CI: 6.07-13.9). The duration of responses was notable, showing PFS of 4.8, 17.0, and 18.3 months in ICI-naïve PR patients and 14.1 months in ICI-exposed patient currently still ongoing on treatment. A sustained clinical benefit of up to 10.7 months was observed in an ICI-naïve patient with SD. Hematologic adverse events (AEs) included thrombocytopenia as grade 4 (n = 9) and grade 3 (n = 3), anemia as grade 3 (n = 3), and neutropenia as grade 4 (n = 3) and grade 3 (n = 1). Other AEs were mostly grades 1 or 2 and manageable. Exploratory biomarker analysis is in progress and will be presented. Conclusions: Ceralasertib and durvalumab combination therapy have demonstrated durable responses in select patients with manageable hematologic toxicity. Biomarker research is ongoing to identify patients most likely to benefit from this treatment strategy. Clinical trial information: NCT04361825 .