LBA33 - A first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation

Background

KRAS G12D mutation is one of the most prevalent subtypes in RAS mutant cancers. However, no results of KRAS G12D inhibitors from any clinical trials have been reported yet. HRS-4642 is a highly selective KRAS G12D inhibitor. Here, we report preliminary results of the dose escalation part of a first-in-human phase 1 study of HRS-4642 in patients (pts) with advanced KRAS G12D mutant solid tumors.

Methods

Pts with histologically confirmed advanced solid tumors harboring KRAS G12D mutation who failed prior standard of care were enrolled to receive HRS-4642 i.v. at doses of 15, 50, 100, 200, and 300 mg QW in 21-day cycles. Dose escalation part allowed pts with KRAS mutation. An accelerated titration followed by a Bayesian optimal interval design is used to guide dose escalation and determine the maximum tolerated dose (MTD). The primary endpoints were safety, MTD, and recommended phase 2 dose (RP2D).

Results

At data cutoff on Aug 4, 2023, 18 pts were enrolled (lung adenocarcinoma n=10, colorectal adenocarcinoma n=5, appendiceal mucinous adenocarcinoma, ovarian cancer, and pancreatic cancer n=1 each). Pts had received a median of 3 lines of prior treatment (range 2-7). No DLTs were observed and the MTD was not reached yet. Grade ≥3 adverse events (AEs) were observed in 9 pts (50.0%). 6 pts (33.3%) had grade ≥3 treatment-related AEs (TRAEs), being hypercholesterolemia (16.7%), increased lipase (11.1%), and anemia (11.1%). No dose dependent trend was observed in the incidence of AEs. Serious TRAEs were observed in one patient (grade 2 increased ALT and grade 1 increased AST). No pts discontinued treatment or died due to TRAEs. 13 pts with baseline target lesions had at least one post-baseline assessment, and one NSCLC patient at 200 mg had partial response. 11 pts (61.1%) had stable disease and 6 (33.3%) experienced target lesion shrinkage, including lung and colorectal cancers. HRS-4642 exposure was approximately proportional to dose with a half-life of around 40 hours.

Conclusions

HRS-4642 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors harboring KRAS G12D mutation. Dose escalation is ongoing and expected to proceed to dose expansion soon.

Clinical trial identification

NCT05533463.

Editorial acknowledgement

Yanwen Wang (Jiangsu Hengrui Pharmaceuticals) provided editorial assistance in the writing of the abstract.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals.

Funding

Jiangsu Hengrui Pharmaceuticals.

Disclosure

C. Zhou: Financial Interests, Personal, Speaker’s Bureau: Amoy Diagnostics, Boehringer Ingelheim, C-Stone, Hengrui, Innovent Biologics, Lilly China, LUYE Pharma, Merck Sharp & Dohme, Qilu, Roche, Sanofi, TopAlliance Biosciences Inc.; Financial Interests, Personal, Advisory Board: Hengrui, Innovent Biologics, Qilu, TopAlliance Biosciences Inc.. R. Mao: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. C. Huang: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. X. Li: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. J. Wang: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. All other authors have declared no conflicts of interest.