Safety and efficacy of lurbinectedin plus atezolizumab as second-line treatment for advanced small-cell lung cancer: Results of the 2SMALL phase 1/2 study (NCT04253145).

8013 Background: Small-cell lung cancer (SCLC) is an aggressive malignancy, accounting for 13% of all lung cancers, with a 5-year survival rate below 12%. Relapsed SCLC remains a major therapeutic challenge, underscoring the need for innovative second-line treatments. The combination of lurbinectedin (LUR) plus atezolizumab (ATZ) has shown synergy in immunocompetent models, and clinical feasibility in a phase I trial. Here we evaluate the efficacy and safety of the regimen as second line treatment for SCLC patients. Methods: This prospective, open-label, multicenter study enrolled patients with ECOG PS 0-1, measurable disease by RECIST 1.1, and progression after one prior platinum-based chemotherapy alone (cohort 1 - C1) or combined with PD-1/ PD-L1 blockade (cohort 2 - C2). Key inclusion criteria included a chemotherapy-free interval (CTFI) of ≥30 days, adequate organ function. Treated brain metastases previously managed with radiotherapy were permitted. Patients received LUR (3.2 mg/m² i.v. 1 hour infusion) following ATZ (1200 mg i.v. 30–60 minutes infusion) on day 1, every 3 weeks. Primary G-CSF prophylaxis was administered for 5 days. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Between June 2022 and March 2024, 218 patients were screened, and 151 were enrolled: 68 in C1 and 83 in C2. The median age was 64 years (range: 45–79), with 58% being male. Most patients (73%) had an ECOG 1, and 60.92% had a CTFI of ≥90 days. Efficacy results are summarized in Table 1. The combination was well-tolerated, with no unexpected safety signals. Treatment-emergent adverse events (TEAEs) were reported in 91% of patients. Grade ≥3 hematological toxicities included neutropenia (C1: 16.18%; C2: 7.23%), febrile neutropenia (C1: 2.94%; C2: 2.41%) and thrombocytopenia (C1: 8.82%; C2: 1.20%). Treatment- emergent deaths occurred in 7 patients (C1: 4; C2: 3). Conclusions: The combination of LUR and ATZ showed promising efficacy in patients with relapsed SCLC regardless of prior exposure to immunotherapy, including those with resistance to platinum. The associated safety profile is manageable. The regimen is being evaluated in a phase III trial in the maintenance setting (IMforte trial NCT05091567). Clinical trial information: NCT04253145 . Cohort 1 (n=68) Cohort 2 (n=83) CTFI<90 (n=59) CTFI≥90 (n=92) Overall Response,% (95% CI) 44.12 (32.27-56.63) 37.35 (27.18-48.7) 35.59 (23.87-49.20) 43.48 (33.30-54.20) CR, n (%) 3 (4.41%) 1 (1.20%) 0 (0.00%) 4 (4.35%) PR, n (%) 27 (39.71%) 30 (36.14%) 21 (35.59%) 36 (39.13%) SD, n (%) 21 (30.88%) 25 (30.12%) 20 (33.90%) 26 (28.26%) Median PFS (months), n (95%CI) 4.90 (3.87-7.27) 4.43 (3.27-5.17) 4.77 (3.27-5.90) 4.63 (3.60-6.13) Median OS (months), n (95%CI) 11 (9.37-15.07) 9.53 (7.90-12.87) 10.10 (8.17-11.97) 11 (8.67-15.07)