1630P - Phase I/Ib study of SHP2-ERK inhibition in KRASm pancreatic cancer (SHERPA trial) and preclinical identification of potential resistance markers

Background

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of < 5%. Therapy options are limited. KRAS is mutated in >85% of PDAC and could be a key target. Preclinical studies have shown that SHP2 and ERK inhibition in KRAS mutant (KRASm) PDAC models results in inhibition of proliferation. The aim of this phase I/Ib trial is to assess safety and efficacy of treatment with SHP2 inhibitor RMC-4630 and ERK inhibitor LY3214996 in KRASm PDAC, non-small cell lung carcinoma (NSCLC) and colorectal carcinoma (CRC) patients. In the expansion phase, only PDAC patients will be included. In preclinical setting, potential resistance markers will be investigated to anticipate patient response.

Methods

In the dose escalation phase, patients with KRASm PDAC, NSCLC or CRC were treated in a 28-day cycle with RMC-4630 on day 1 and 2 every week and LY3214996 daily. The main objective was to determine the Recommended Phase II Dose (RP2D). Other objectives included safety and tolerability assessed by the incidence of adverse events, efficacy determined by objective response rate (ORR) according to RECIST 1.1, pharmacokinetics (PK), and pharmacodynamics assessed by MAPK downstream protein expression levels. Resistance markers were explored by CRISPR.

Results

Eleven patients were enrolled in 2 cohorts: Cohort 1a 140 mg RMC-4630 and 100 mg LY3214996; cohort 1b 100 mg RMC-4630 and 200 mg LY3214996. Eight patients were evaluable for dose limiting toxicity (DLT). In cohort 1a, 2 out of 5 patients developed a DLT: grade 3 thrombocytopenia and renal insufficiency. No DLTs occurred in cohort 1b. PK analysis showed high interpatient variability. The exposure of LY3214966 was dose proportional. The ORR in both cohorts was 0%. In KRASm tumor cell lines, PTEN downregulation, c-JUN hyperactivation and increased PI3K/AKT/mTOR pathways activation were identified as mechanisms of resistance.

Conclusions

Two DLTs out of 5 patients limited the tolerability of the combination in cohort 1a, no DLTs were identified in cohort 1b. Patient enrolment is ongoing in the next dose level. The RP2D has not been determined yet. Alterations in the PI3K/AKT/mTOR and the c-JUN pathways could be markers for drug resistance, which data are pending.

Clinical trial identification

NCT04916236.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Lustgarten Foundation – Pancreatic Cancer Collective, New York, USA Stand Up To Cancer (SU2C), USA.

Disclosure

E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate, to charity: Biogeneration Ventures; Financial Interests, Institutional, Advisory Board, Hourly rate, no compensation in 2019-2020: InteRNA; Financial Interests, Personal, Member of Board of Directors, independent, non-executive director and share holder: Sanofi; Financial Interests, Personal, Other, Founder, strategic adviser and share holder: Mosaic Therapeutics; Financial Interests, Personal, Ownership Interest, Mandatory shares as part of board membership: Sanofi; Financial Interests, Personal, Ownership Interest, Start-up company with shares: Mosaic Therapeutics; Financial Interests, Institutional, Coordinating PI, DRUP trial: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Clovis Oncology, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Coordinating PI, DRUP trial drug Access Protocol: Bayer, Roche; Financial Interests, Institutional, Coordinating PI, Drug Access Protocol: Sanofi; Non-Financial Interests, Other, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: JAMA Oncology; Non-Financial Interests, Leadership Role, Board of Directors: Cancer Core Europe. F. Opdam: Non-Financial Interests, Principal Investigator: GSK, Int1B3, AstraZeneca, Cytovation, Relay, Taiho, Roche, Merus, Boehringer Ingelheim, Crescendo, Pierre Fabre, Lilly, RevMed, Incyte. All other authors have declared no conflicts of interest.