Abstract C030: HARMONi-3: A randomized, controlled, multiregional Phase 3 study of ivonescimab combined with chemotherapy versus pembrolizumab combined with chemotherapy for the first-line treatment of metastatic squamous non-small cell lung cancer

Abstract BACKGROUND In the first-line metastatic squamous non-small cell lung cancer (NSCLC) setting, treatment with the combination of a PD-1 checkpoint inhibitor plus platinum doublet chemotherapy has become standard of care1,2. The addition of antiangiogenic agents to immunotherapy has emerged as a promising strategy for cancer treatment3,4,5. Therefore, a combined anti-angiogenesis and PD-1 blockade strategy with a bispecific PD-1 and VEGF antibody may improve clinical outcomes. Ivonescimab (SMT112/AK112) is a novel tetravalent bispecific antibody (2 binding sites for PD-1 and 2 binding sites for VEGF) with an engineered Fc-null region and a half-life of 6-7 days. In the presence of VEGF, binding affinity to PD-1 increases more than 10-fold6. Given the correlation between VEGF and PD-1 expression in the tumor microenvironment6,7,8, simultaneous blockade of these 2 targets by ivonescimab drives antitumor activity9,10. Additionally, the engineered Fc-null region and shorter half-life could potentially lead to reduced adverse events​, compared to co-administration of individual anti-PD-(L)1 and anti-VEGF agents7,8,10. At ASCO 2023, Zhang L, et al. (abstract# 9087) reported Phase 2 trial data, which included 63 first-line advanced or metastatic squamous NSCLC patients without EGFR/ALK alterations treated with ivonescimab plus paclitaxel and carboplatin. These patients had an objective response rate of 67%, a median duration of response of 15 months, 9-month overall survival (OS) estimate of 93% (median OS not reached). Furthermore, ivonescimab was well tolerated in combination with platinum doublet chemotherapy with a treatment emergent adverse event discontinuation rate of 11%. TRIAL DESIGN HARMONi-3 is a randomized, blinded, controlled, multiregional Phase 3 study of ivonescimab combined with chemotherapy versus pembrolizumab combined with chemotherapy for the first-line treatment of metastatic squamous NSCLC. Approximately 400 patients will be randomized 1:1 to receive ivonescimab (dual blockade of PD-1/VEGF) or pembrolizumab plus carboplatin-paclitaxel/nab-paclitaxel (Q3W, 4 cycles, 21 days per cycle) followed by single-agent ivonescimab or pembrolizumab maintenance therapy for up to 2 years, or until progression, or unacceptable toxicity. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate and duration of response (RECIST v1.1), as well as incidence/severity of adverse events. Key eligibility criteria include treatment naïve metastatic squamous NSCLC, ECOG PS 0 or 1 and exclusion of patients with major blood vessel invasion or encasement by cancer or intratumor cavitation. Citation Format: Jonathan Riess, Shun Lu, Jarushka Naidoo, Sara Kuruvilla, Annie Hung, Ahmed Khaled, Deborah Doroshow. HARMONi-3: A randomized, controlled, multiregional Phase 3 study of ivonescimab combined with chemotherapy versus pembrolizumab combined with chemotherapy for the first-line treatment of metastatic squamous non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C030.