77MO - A first-in-human, open-label, dose-escalation study of ERK1/2 inhibitor HMPL-295 in patients with advanced solid tumors

Background

HMPL-295 (’295), a small molecule inhibitor of extracellular signal-regulated kinase 1 and 2 (ERK1/2), showed potent inhibition of MAPK/ERK signaling pathway activated due to upstream signaling molecule mutations (RAS, RAF) in non-clinical studies. This is a first-in-human, dose-escalation study of ’295 in patients (pts) with advanced solid tumors. Here, we report the results of the continuous-administration dose-escalation stage.

Methods

Pts with advanced solid tumors who have failed standard therapy were enrolled to receive ’295 once daily (QD) in 28-day cycles. The mTPI-2 design was used for dose escalation, having explored from 5 to 75 mg in 6 cohorts. The study aims to determine the maximum tolerated dose (MTD) /recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics /pharmacodynamics (PK/PD), preliminary efficacy (best of response, BOR). The intermittent administration dose escalation will be explored after continuous regimen finding.

Results

As of May 22, 2023, 22 pts with advanced solid tumors were enrolled (n=1, 1, 3, 6, 5, 6 in 5, 10, 20, 40, 75, 50 mg QD cohorts, respectively), with a median age of 56 years, 9 (40.9%) male pts. During the dose escalation from 5 to 75 mg QD cohort, 1 pt given 40 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 dermatitis acneiform and 2 pts given 75 mg QD experienced DLTs of grade 3 rash and acute kidney injury. After single-dose oral administration, ’295 plasma concentrations reach peak at 1.0-1.5 hours post dose and the exposure (C_max and AUC) displayed dose dependent increase. For PMA-stimulated RSK phosphorylation, a downstream signaling molecule regulated by ERK1/2, ’295 displayed dose dependent inhibition. The BOR was partial response each in 1 pt with duodenal adenocarcinoma in 40 mg QD cohort and 1 pt with endometrial cancer in 50 mg QD cohort. Ten (45.5%) pts reported grade ≥3 TRAEs, most commonly (≥10.0%) rash (18.2%), acneiform dermatitis (13.6%), and anemia (13.6%).

Conclusions

Combining safety, tolerability, PK/PD and preliminary efficacy results, the continuous-administration MTD was determined to be 50 mg QD. Intermittent-administration dose-escalation is currently ongoing.

Clinical trial identification

NCT04908046.

Editorial acknowledgement

Medical writing assistance was provided by Shan Lian of HUTCHMED Limited.

Legal entity responsible for the study

HUTCHMED Limited.

Funding

HUTCHMED Limited.

Disclosure

W. Su, M. Shi, S. Fan, B. Zhang, B. Pan, Y. Ren, J. Wang, C. Zhong, L. Ma: Financial Interests, Personal, Full or part-time Employment: HUTCHMED (China) Limited. All other authors have declared no conflicts of interest.