Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan)

9064 Background: Development of targeted therapy for SCLC based on a large-scale genomic screening is an innovative challenge. Gedatolisib is a highly potent dual inhibitor of PI3K/mTOR and is expected to have an effect for tumors with PI3K/AKT/mTOR pathway alterations. SCLC harboring this pathway alterations is rare. Thus, we conducted a phase II study based on a nationwide genomic screening network in Japan (LC-SCRUM-Japan) to develop novel targeted therapies. Methods: SCLC pts with targetable genetic alterations were screened at 154 institutions in Japan. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of gedatolisib in advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The primary endpoint was objective response rate (ORR). The planned sample size was 19 (threshold and expected ORR of 20% and 50%, one-sided alpha of 5%, and power of 80%). Results: 930 SCLC pts were screened from July 2015 to January 2020. Targetable genetic alterations were identified in 148 pts (16%), including 53 PI3K/AKT/mTOR (6%), 81 MYC family (9%), 10 EGFR (1%) and 15 KRAS (2%). A total of 12 pts with genetic alterations in the PI3K/AKT/mTOR pathway (5 PIK3CA, 6 PTEN, and 1 AKT1 mutation) were enrolled in the phase II study. The median age was 67 years (range 58-79), 7 pts were male and 5 pts received 2 or more prior chemotherapy (range 1-4). The ORR was 0% and disease control rate was 25%. The median progression-free survival (PFS) was 0.9 months (95% CI, 0.4 to 3.0). The median overall survival was 5.8 months (95% CI, 1.1 to NR). Treatment-related G3 adverse events (hypertension, hypoalbuminemia, oral mucositis, ALT increased and creatinine increased) were observed in 4 pts. One patient with PTEN I8fs mutation had a long duration of stable disease (PFS; 6.7 months). Conclusions: This Large-scale nationwide genomic screening network was effective to identify rare targetable genetic alterations and had a potential role to develop targeted therapies in SCLC. This phase II study didn’t show promising clinical benefit of gedatolisib for advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The safety profile of gedatolisib was similar to that reported previously. Clinical trial information: UMIN000020585.