ENDOLUNG trial, part II. A phase II study of the Akt/mTOR inhibitor and autophagy inducer ibrilatazar (ABTL0812) in combination with paclitaxel/carboplatin in patients with squamous non-small cell lung cancer

Background: Advanced squamous non-small cell lung cancer (sq-NSCLC) has long relied on chemotherapy and, more recently, on its combination with PD-1 immunotherapy. Ibrilatazar (ABTL0812) is an innovative oral agent that induces cytotoxic autophagy selectively in cancer cells. In the ENDOLUNG trial we have evaluated the efficacy and safety of ibrilatazar combined with chemotherapy in sq-NSCLC patients. Methods: Patients with stage III/IV sq-NSCLC received ibrilatazar (1300 mg tid) alongside paclitaxel (175 mg/m2) and carboplatin (AUC 5) every 3 weeks for up to 8 cycles, followed by ibrilatazar maintenance until progression or toxicity. Primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: 40 patients were enrolled constituting the intention-to-treat (ITT) population (90 % male, median age 66, ECOG 0–1). The efficacy analysis (FA) subset included 25 patients, excluding 15 patients without a measurement of the primary variable. For ITT and FA populations, the ORR was 32.5 % (95 % Confidence Interval (CI) 21.3–50.1) vs 52.0 % (95 % CI 34.2–65.9), the disease control rate (DCR) was 52.5 % (95 % CI: 36.1–68.5) vs 84.0 % (95 % CI: 63.9–95.5), the PFS was identical (6.2 months; 95 % CI: 4.4–8.8) and the OS was 18.4 months (95 % CI: 9.5-NC) and 22.5 months (95 % CI: 10.4-NC), respectively. Most common adverse events included asthenia (62.5 %), diarrhea (45.0 %), nausea (37.5 %), anemia (32.5 %) and neutropenia (27.5 %). Pharmacokinetic and pharmacodynamic data confirmed ibrilatazar activity. Conclusions: Ibrilatazar combined with paclitaxel and carboplatin shows promising efficacy and safety in sq-NSCLC, warranting further clinical development.