550O - Safety and efficacy of D-1553 in combination with cetuximab in KRAS G12C mutated colorectal cancer (CRC): A phase II study

Background

As a highly selective and potent KRAS^G12C inhibitor, D-1553 has shown encouraging antitumor activity in patients (pts) with KRAS G12C mutated CRC. Targeting KRAS and EGFR pathways at the same time may enhance the antitumor activity of D-1553. An ongoing multi-country phase II study (NCT04585035) is evaluating the safety and efficacy of D-1553 combined with cetuximab, an EGFR antibody, in KRAS G12C mutated CRC.

Methods

Pts with metastatic CRC progressed after standard treatment were enrolled. Pts were required to have KRAS G12C mutations, and no prior KRAS G12C directed treatment. Enrolled pts received D-1553 600 mg BID combined with cetuximab (standard dose). Study endpoints included efficacy (RECIST, v1.1), safety, and pharmacokinetics (PK).

Results

As of April 17, 2023, 29 pts (37.9% female, median age 56.0 [range 32-76] years, 65.5% with ≥3 prior therapies [median 3; range 1-6], 100% stage IV disease at baseline, and 24.1%/75.9% ECOG PS 0/1) were enrolled. At data cutoff, 20 (69.0%) pts remained on treatment. The median treatment duration was 5.95 (range 1.35-9.13) months with a median follow-up of 6.24 (range 2.33-9.13) months. A preliminary overall response rate of 51.7% (15/29) was observed and 9 out of 15 responders had confirmed response, with 5 still on treatment and their responses to be confirmed. The disease control rate was 93.1% (27/29). Median progression-free survival (PFS) was 7.56 months (95% CI: 5.49, NA). Treatment-related adverse events (TRAEs) of any grade occurred in 29 (100%) pts, with the most common (≥ 20%) being rash, increased AST, increased ALT, and paronychia, predominantly ≤ grade 2. Grade 3-4 TRAEs occurred in 3 (10.3%) pts, all of which were related to cetuximab. No grade 5 TRAEs were reported. TRAEs led to D-1553 dose interruption in 2/29 (6.9%) pts, to cetuximab dose reduction and interruption in 1/29 (3.4%) and 5/29 (17.2%) pts respectively, and cetuximab discontinuation in 1/29 (3.4%) pt.

Conclusions

Combination of D-1553 and cetuximab showed an acceptable safety profile and achieved a higher response rate than D-1553 monotherapy and a promising PFS in heavily pretreated pts with KRAS G12C mutated CRC. More data will be presented at the meeting.

Clinical trial identification

NCT04585035.

Editorial acknowledgement

Medical writing support was provided by Yihong Zhang and Xinying Liu (InventisBio Co., Ltd).

Legal entity responsible for the study

InventisBio Co., Ltd.

Funding

InventisBio Co., Ltd.

Disclosure

R. Xu: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, MSD; Financial Interests, Personal, Advisory Board: Henrui, BeiGene, Astalas, Merck, Junshi. C.R. Underhill: Financial Interests, Institutional, Principal Investigator, To his institution for conducting clinical trial: InventisBio. K. Lee: Financial Interests, Institutional, Principal Investigator, To his institution for conducting clinical trial: InventisBio. X. Xie: Financial Interests, Personal, Full or part-time Employment: InventisBio. Z. Xiang, Z. Shi, L. Zhang: Financial Interests, Personal, Full or part-time Employment: InventisBio; Financial Interests, Personal, Stocks/Shares: InventisBio. All other authors have declared no conflicts of interest.