Efficacy and safety of HTMC0435 combination with temozolomide in relapsed extensive-stage small-cell lung cancer (ES-SCLC): A phase Ib/II study.

Abstract

8097 Background: Treatment options for ES-SCLC in second-line setting are limited. HTMC0435, an oral PARP inhibitor, significantly reduced the ability of PARP to repair DNA damage and inhibited tumor cell proliferation when combined with temozolomide (TMZ) in preclinical studies. We investigated the safety and activity of this regimen in relapsed SCLC. Methods: This was a phase Ⅰb/Ⅱ dose-escalation (3+3 design) and dose-expansion study. ES-SCLC patients who had progressed after first- or second-line therapy were eligible. Pts were administered with HTMC0435 6 mg or 8 mg bid on days 1-21 in combination with TMZ 75 mg/m 2 on days 1-7 of each 21-day cycle. The study objectives were to evaluate safety, pharmacokinetics and preliminary efficacy of the combination regimen. Results: From Feb-2023 to Nov-2023, 59 eligible pts were enrolled, with 7 pts in dose escalation and 52 pts in dose expansion. No dose-limiting toxicity (DLT) occurred, and HTMC0435 8mg bid combination with TMZ was selected as recommended phase 2 dose (RP2D). As of 31 October 2024, the median follow-up time was 10.3 months. 55 pts received HTMC0435 8mg bid and TMZ. Among these patients, brain and liver metastases were in 41.8% (23/55) and 23.6% (13/55) pts, respectively. 61.8% (34/55) pts had received prior platinum-based and anti–PD-(L)1 therapy as first line therapy. Among 49 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 24.5% (12/49, 95%CI: 12.0%-37.0%) and 63.3% (31/49, 95%CI: 49.3%-77.3%). The median duration of response (DoR) was 6.9 mos (95%CI: 1.22-12.58). The median progression-free survival (PFS) and overall survival (OS) were 2.8 mos (95%CI: 1.16-4.44) and 12.0 mos (95%CI: 7.85-14.75). 23 pts were platinum-resistant (chemotherapy-free interval < 90 days), with ORR of 25.0% (5/20, 95%CI: 8.7%-49.1%), DCR of 55.0% (11/20, 95%CI: 31.5%-76.9%), mDoR not reached, mPFS of 2.5 mos (95%CI: 1.38-5.03) and mOS of 12.6 mos(95%CI: 5.78-NC). Among the 29 platinum-sensitive pts (chemotherapy-free interval ≥ 90 days), ORR and DCR were 26.9% (7/26, 95%CI: 11.6%-47.8%) and 73.1% (19/26, 95%CI: 52.2%-88.4%), and the mDoR was 4.2 mos (95%CI: 4.14-NC). The mPFS and mOS were 4.2 mos (95%CI: 2.69-5.52) and 11.2 mos (95%CI: 8.38-NC). 96.6% (57/59) pts experienced treatment-related adverse events (TRAEs) and 55.9% (33/59) pts experienced grade 3-4 TRAEs. Most common TRAEs (grade 3-4) were neutropenia (35.6%), leukopenia (28.8%), thrombocytopenia (13.6%), anemia (8.5%). Six (10.2%) pts experienced TRAEs led to dose reduction of HTMC0435 and no TRAEs led to discontinuation of HTMC0435 were reported. Conclusions: This combination of HTMC0435 and TMZ showed promising anti-tumor activity and manageable safety both in platinum-sensitive and platinum-resistant SCLC patients. Clinical trial information: NCT05728619 .