Debio 0123, a highly selective WEE1 inhibitor, in combination with carboplatin (C) and etoposide (E), in patients (pts) with recurrent small cell lung cancer (SCLC): Determination of recommended dose (RD) from a phase 1 escalation.

Abstract

8098 Background: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, allowing mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Debio 0123 is in clinical development in solid tumors, as monotherapy and in combination with different therapeutic agents. Debio 0123 has shown manageable safety profile and initial signals of antitumor activity. SCLC is an aggressive disease that carries a high mutational burden and genomic instability . Debio 0123 has shown to significantly improve the antitumor activity of DNA damaging agents, C + E, in preclinical SCLC models . Methods: This Phase 1 study (NCT05815160) is evaluating Debio 0123 in combination with C + E in pts with recurrent SCLC after first line of platinum-based chemotherapy. Of note, pts with stable brain metastasis were eligible. In the dose escalation, pts who had a chemotherapy-free interval (CFI)>45 days since the last dose of platinum chemotherapy, received escalating doses of Debio 0123 (D1–3 and D8–10) in combination with standard C (AUC5) on D1 and E (100 mg/m2) on D1-3 in 21-day cycles. Results: Dose escalation data (cut-off date Oct 24th, 2024) are presented. Overall, 16 pts were treated (44% female, mean age 63.3 years). Using a Bayesian Logistic model-guided dose escalation, tested doses of Debio 0123 ranged from 200-400 mg. The RD was selected at 200 mg. At this dose level, 3/10 pts experienced a dose-limiting toxicity. The treatment was considered well tolerated with a manageable overall safety profile, in line with that expected for the chemotherapy combination. Most frequent Debio 0123 -related toxicities are shown in Table 1. PK data showed Debio 0123 plasma levels increasing proportionally with the dose. Debio 0123 CSF/plasma ratio was ~40%, suggesting that Debio 0123 crosses the blood brain barrier. At 200 mg, confirmed partial responses (PR) occurred in 4/9 evaluable pts overall, and in 4/7 pts in the subgroup with CFI>90 days, including pt with intracranial response; 4 pts had SD of which 2 had tumor shrinkage of > 20 %. mPFS at the RD (n=10) was 7.2 months. Conclusions: Debio 0123 combined with C + E is well tolerated, with a manageable safety profile, up to 200 mg; this combination led to promising antitumor activity in pts with recurrent SCLC after prior platinum-based therapy with CFI > 45 days. Further investigation of Debio 0123 at 200 mg in pts with a CFI > 90 days is ongoing. Clinical trial information: NCT05815160 . Summary of treatment-emergent adverse events (TEAEs) related to Debio 0123 in ≥ 2 pts at the RD (200 mg). TEAE Any grade(N=10)n (%) Grade ≥3(N=10)n (%) Neutropenia/neutrophil count decreased 4 (40) 3 (30) Nausea 3 (30) 0 Diarrhea 2 (20) 1 (10) Thrombocytopenia/platelet count decreased 2 (20) 1 (10)