A phase I trial of binimetinib plus hydroxychloroquine inpatients with previously treated metastatic pancreatic cancer.

Abstract

4152 Background: Combined MEK and autophagy inhibition exerts synergistic antitumor activity in preclinical models of RAS-mutant cancers. We hypothesized that blockade of autophagy with hydroxychloroquine (HCQ) can overcome therapeutic resistance to MEK inhibition with binimetinib (bini) and lead to clinical benefit in patients (pts) with previously treated, KRAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: This is an investigator-led, single-arm, open-label, phase I dose escalation/expansion study of bini + HCQ in metastatic PDAC pts. Key eligibility criteria: ECOG 0-1, adequate organ function, > 1 prior line of therapy for metastatic disease, and presence of KRAS mutation. Dose escalation followed a Bayesian optimal interval (BOIN) design. Dose level (DL) 1: bini 45 mg + HCQ 600 mg p.o. bid; DL -1: bini 45 mg + HCQ 400 mg p.o. bid; DL -2: bini 30 mg + HCQ 400 mg p.o. bid; DL -1.5: bini 30 mg + HCQ 600 mg p.o. bid. Primary endpoint was the maximum tolerated dose (MTD) of bini + HCQ. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: From December 2019 to August 2024, a total of 34 pts were enrolled in dose escalation (n = 17) and dose expansion (n = 17). Median age was 65 yrs (range: 45-79) with 56% females. Median prior lines of therapy was 2 (range: 1-4). The most prevalent KRAS mutation subtypes were G12D (35%), G12V (32%), and G12R (29%). Two dose-limiting toxicities (DLTs) occurred in 2 out 3 pts treated at DL 1: grade 3 CPK elevation with renal impairment (bini) and grade 3 QTc prolongation (HCQ). The most frequent non-hematologic AEs were rash (71%), diarrhea (71%), nausea (67%), elevated AST (67%), and elevated CPK (61%). Following dose de-escalation due to poor tolerance, the MTD was deemed to be bini 30 mg + HCQ 600 mg p.o. bid and used for dose expansion. Overall, out of 31 response-evaluable pts, 2 pts achieved a partial response (lasting 6.9 and 4.7 mos, both at DL -1.5) and 9 pts achieved stable disease (3 pts at DL -1, 6 pts at DL -1.5), consistent with ORR 6.5% and DCR 35.5%, respectively. At median follow-up of 19 mos, median PFS was 1.9 mos and median OS was 5.3 mos. Conclusions: Bini + HCQ demonstrated a challenging toxicity profile and limited clinical activity in a heavily pretreated cohort of metastatic PDAC pts. Minimal efficacy was observed in this treatment-refractory population; however, dual MEK and autophagy inhibition may warrant further study in earlier-line settings, potentially with more tolerable drug candidates and guided by biomarker selection. Clinical trial information: NCT04132505 .