Safety, efficacy, and biomarker analysis of HTMC0435 plus temozolomide in relapsed extensive-stage small-cell lung cancer: A phase Ib/II trial

Second-line treatment options for extensive-stage small cell lung cancer (ES-SCLC) are limited. This study investigated HTMC0435, an oral Poly-ADP-ribose polymerase (PARP) inhibitor, combined with temozolomide in patients with relapsed ES-SCLC. In this phase Ⅰb/II trial (NCT05728619), patients with relapsed ES-SCLC who had been treated with one or two lines of previous therapy received HTMC0435 plus temozolomide until disease progression or intolerable toxicity. The recommended phase II dose (RP2D) of HTMC0435 was determined per results from the phase Ib part with a “3 + 3” dose-escalation design, while temozolomide was given at a fixed dose of 75 mg/m 2 on days 1–7 of each 21-day cycle. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), RP2D, and adverse events. From February 2023 to November 2023, a total of 59 patients were enrolled. As no DLT occurred in the phase Ib part, the MTD could not be determined in this study. Fifty-five patients (three in phase Ib and 52 in phase II) received HTMC0435 at RP2D (8 mg twice daily). Grade 3–4 treatment-related adverse events occurred in 33 (55.9%) of 59 patients, with the most common being neutropenia (23 [39.0%]) and leukopenia (18 [30.5%]). No treatment-related deaths occurred. Efficacy was evaluable in 48 patients, with an objective response rate of 25.0% (12/48; 95% CI: 13.6–39.6). Median overall survival in all the 55 patients was 11.2 months (95% CI: 8.97–13.14). Similar benefit trends were observed between platinum-sensitive (chemotherapy-free interval ≥ 90 days) and platinum-resistant (chemotherapy-free interval < 90 days) patients. HTMC0435 plus temozolomide showed a manageable safety profile and initial indications of anti-tumor activity in patients with recurrent ES-SCLC, but further validation is needed in randomized controlled trials.