1504TiP - HARMONi: Randomized, double-blind, multi-center, phase III clinical study of ivonescimab or placebo combined with pemetrexed and carboplatin in patients with EGFR-mutant locally advanced or metastatic non-squamous NSCLC who have progression following EGFR-TKI treatment

Background

For patients (pts) with EGFR-mutant NSCLC, upfront treatment with tyrosine kinase inhibitors is standard. Drug resistance remains a challenge and an effective therapy after progression is needed. Ivonescimab (SMT112/AK112) is a novel bispecific antibody that provides dual blockade of PD-1 and VEGF activity. And coengagement of these 2 targets increases affinity to PD-1 by more than 10 fold. Given the correlation between VEGF-A and PD-1 expression in the tumor microenvironment, simultaneous blockade of these 2 targets by ivonescimab may produce enhanced antitumor activity, with an improved safety profile, compared to co-administration of individual anti-PD-(L)1 and an anti-VEGF agents. Phase 2 trial data reported that in 19 pts with EGFR mutated NSCLC who progressed following TKI therapy, the response rate to ivonescimab plus pemetrexed and carboplatin was of 68.4% (13/19) and a tolerable safety profile in the total population (N=83) treated with ivonescimab plus chemotherapy.

Trial design

HARMONi is a randomized, double-blind, multiregional phase 3 trial of ivonescimab or placebo in combination with pemetrexed and carboplatin in pts with locally advanced or metastatic EGFR-mutant NSCLC. 470 pts will be randomized 1:1 and to receive ivonescimab/placebo plus pemetrexed and carboplatin (Q3W, 4 cycles, 21 days per cycle) followed by ivonescimab/placebo plus pemetrexed for maintenance therapy for up to 2 yrs until progression or unacceptable toxicity. The co-primary endpoints are overall survival and progression-free survival assessed by IRC per RECIST v1.1. Secondary endpoints include overall response rate, incidence/severity of adverse events and immunogenicity of ivonescimab. Key eligibility criteria include advanced or metastatic NSq- NSCLC with an activating EGFR mutation, Eastern Cooperative Oncology Group Performance Status 0 or 1 and progression on/following third generation EGFR-TKI. The study will be a multi-national study including United States, Cana, Euroadpe and China.

Clinical trial identification

NCT05184712.

Editorial acknowledgement

Legal entity responsible for the study

Summit Therapeutics and Akeso Biopharma.

Funding

Summit Therapeutics and Akeso Biopharma.

Disclosure

F. Cappuzzo: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Mirati, Novocure, Ose, and MSD; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Mirati, PharmaMar, Novocure, Ose, Galecto and MSD. J.W. Goldman: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech, Eli Lilly, Janssen, AbbVie, Gritstone; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Eli Lilly; Financial Interests, Institutional, Local PI: Genentech, Janssen, BMS, AbbVie. J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, MSD, Boehringer Ingelheim; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca, Ose Immunotherapeutics, BMS, Janssen, Takeda, Sanofi; Financial Interests, Institutional, Invited Speaker: Merck Portugal; Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD; Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525): AstraZeneca; Non-Financial Interests, Member, Secretary of the Lung Cancer Group at the EORTC: EORTC. W. Li, M. Xia: Financial Interests, Personal, Full or part-time Employment: Akeso. J. Li, D. James, L. Styles: Financial Interests, Personal, Full or part-time Employment: Summit Therapeutics; Financial Interests, Personal, Stocks/Shares: Summit Therapeutics. H.L. West: Financial Interests, Personal, Advisory Role: Summit Therapeutics. L. Zhang: Financial Interests, Institutional, Research Grant, research grant & Trial Chair: AZ; Financial Interests, Institutional, Research Grant: BMS, Roche; Financial Interests, Institutional, Trial Chair: QiLu pharm, Henrui Pharm, Novartis, Hansoh Pharma, China Shiyao Pharma, Kelun Pharm. All other authors have declared no conflicts of interest.