658MO - Phase I study of SHR-A2009, a HER3-targeted ADC, in advanced solid tumors

Background

HER3 is widely expressed in solid tumors and associated with tumor growth/spread, drug resistance and poor prognosis. SHR-A2009 is a novel ADC composed of a fully human anti-HER3 IgG1 mAb, cleavable peptide linker and DNA topoisomerase I inhibitor. We report preliminary results from the first-in-human, multinational phase 1 trial of SHR-A2009 in patients (pts) with advanced solid tumors refractory to standard therapy.

Methods

SHR-A2009 was given at doses of 1.5-10.5 mg/kg (Q3W, iv) in an i3+3 dose escalation scheme, followed by cohort expansion at selected doses. The primary endpoints were MTD/MAD, RP2D and safety.

Results

At data cutoff (Apr 24, 2023), 42 pts were enrolled (ECOG 1, 83.3%; stage IV, 100%; NSCLC, 85.7%; brain metastasis, 31.0%); median prior lines of systemic therapy was 3 (range, 1-11). Among 36 NSCLC pts, 34 (94.4%) had EGFR mutations; all were resistant to EGFR-TKI, with 85.3% (29/34) previously treated with 3^rd generation agents. Up to 10.5 mg/kg, no DLT was observed; dose-escalation is ongoing. Grade≥3 TRAEs were reported in 13 (31.0%) pts, with all occurring in ≥5% being hematotoxicities. TRAEs led to drug discontinuation in 3 (7.1%) pts. Interstitial lung disease occurred in 2 (4.8%) pts. In evaluable pts, ORR was 25.0% (9/36; 95% CI 12.1-42.2) across all tumor types and 30.0% (9/30; 95% CI 14.7-49.4) in NSCLC; median DoR was 7.0 mo (range, 2.8-8.5) in both pt sets. Tumor response by dose is shown in the table. 1. 6-mo PFS rate was 46.4% (95% CI 27.0-63.8) across all tumors and 49.8% (95% CI 28.8-67.8) in NSCLC. Systemic exposure of SHR-A2009, total antibody and free toxin increased approximately dose proportionally after single/multiple doses at 1.5-9.0 mg/kg; plasma toxin exposure was low across all levels (data not available for 10.5 mg/kg). Table: 658MO

Tumor response by dose

Analyzed in pts with post-baseline assessment. ^∗Including unconfirmed response. ^† EGFR-WT, n=2 (PR, n=1; SD, n=1). NE, not evaluable.

Conclusions

SHR-A2009 showed a tolerable safety profile and encouraging anti-tumor activity in pts with heavily pretreated advanced solid tumors. The trial is ongoing to assess SHR-A2009 at higher doses and in selected cancer types (NSCLC and other solid tumors).

Clinical trial identification

NCT05114759.

Editorial acknowledgement

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

Y. Wu: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol Myers Squibb, Hengrui; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Roche, Boehringer Ingelheim, Takeda; Financial Interests, Personal, Research Funding: Boehringer Ingelheim, Roche, Pfizer, Bristol Myers Squibb. Y. Kuboki: Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Taiho, ONO, Bayer, Sanofi; Non-Financial Interests, Personal, Principal Investigator: Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GSK, Genmab, Astellas; Financial Interests, Personal, Advisory Role: Takeda, Boehringer Ingelheim, Taiho. N. Yamamoto: Financial Interests, Institutional, Research Grant: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, Rakuten Medical; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai, MERCK, Healios; Financial Interests, Personal, Speaker, Consultant, Advisor: ONO, Chugai, Daiichi Sankyo, Eisai. Z. Zhu, J. Shuang, F. Qiu, W. Shi: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.