A phase II study of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin for previously untreated advanced squamous non–small cell lung cancer: TORG2241(UBE-Q).

Abstract

8559 Background: Pembrolizumab plus platinum-based chemotherapy is a standard first-line treatment for previously untreated advanced squamous non-small cell lung cancer (NSCLC) based on the KEYNOTE-407 trial. Ubenimex, an oral CD13/aminopeptidase inhibitor, has immunostimulatory and antitumor activity. We conducted a phase II trial to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. Methods: This study was a prospective, multicenter, single-arm phase II trial. Eligible patients with previously untreated advanced squamous NSCLC received ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex started at level 1 (30mg/day), which was increased to levels 2 (60 mg/day) and 3 (120 mg/day) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity (DLT) rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level were analyzed. The primary efficacy endpoint was objective response rate (ORR) by independent central review, estimated descriptively with a 90% confidence interval; the ORR in the KEYNOTE-407 (62.6%) served as a reference value for study design. Results: No DLTs were observed across dose levels 1–3. Therefore, level 3 was selected as the recommended dose. From January 2024 to January 2025, 28 patients were enrolled from 18 institutions, and all patients were evaluable for efficacy and safety. Baseline characteristics were male/female 25/3; median age 72 (range, 40-86); ECOG PS 0/1 12/16. The ORR was 71.4% (90% CI, 54.3-84.9). With a median follow-up of 12.8 months, median progression-free survival (PFS) was 16.8 months (95% CI, 5.6-not reached); median overall survival (OS) was not reached. Grade 3/4 adverse events included pneumonitis (3.6%), anemia (46.4%), febrile neutropenia (10.7%). There was no treatment-related death. Conclusions: Ubenimex with 120 mg/day (60 mg twice daily) combined with pembrolizumab, nab-paclitaxel, and carboplatin was feasible and showed encouraging antitumor activity with manageable safety in previously untreated advanced squamous NSCLC, supporting further randomized evaluation. Clinical trial information: jRCT2031210707.