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

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. 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. NCT05184712. Summit Therapeutics and Akeso Biopharma. Summit Therapeutics and Akeso Biopharma.