The FDA has accepted a biologics license application (BLA) seeking the approval of ivonescimab (AK112; SMT112) in combination with platinum-doublet chemotherapy for the treatment of patients with EGFR-mutated, locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) whose disease has progressed after third-generation TKI therapy.1
The BLA submission is supported by results of the phase 3 HARMONi trial (NCT06396065), which evaluated ivonescimab plus chemotherapy vs placebo plus chemotherapy in adult patients with EGFR-mutant, locally advanced or metastatic nonsquamous NSCLC who had progressed on a third-generation EGFR TKI, such as osimertinib (Tagrisso).1,2
According to findings from the trial presented at the IASLC 2025 World Conference on Lung Cancer, ivonescimab plus platinum-based chemotherapy (n = 172) generated a statistically significant and clinically meaningful progression-free survival (PFS) benefit as assessed by independent radiology review committee (IRRC) vs placebo plus chemotherapy (n = 173). The median PFS was 6.8 months vs 4.4 months in these respective arms (HR, 0.52; 95% CI, 0.41-0.66; P < .0001).2 Of note, this PFS benefit was consistent across predefined patient subgroups. PFS by investigators also demonstrated a consistent benefit with ivonescimab (HR, 0.58; 95% CI, 0.45-0.73).
The Prescription Drug User Fee Act goal date for the review of this application is November 14, 2026. 1
HARMONi Trial: Fast Facts
- Ivonescimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy, reaching a median PFS of 6.8 months vs 4.4 months in these respective arms (HR, 0.52; 95% CI, 0.41-0.66; P < .0001).
- The final OS analysis demonstrated a trend favoring the ivonescimab arm (HR, 0.79; 95% CI, 0.62-1.01; P = .0570); this benefit was sustained longer-term follow-up data from Western patients were included (HR, 0.78; 95% CI, 0.62-0.98; P =.0332).
- The efficacy of the ivonescimab-based combination was consistent across patient subgroups, including a pronounced PFS benefit for patients with brain metastases (HR, 0.34; 95% CI, 0.20-0.57). The investigational combination also maintained a manageable safety profile, with serious TRAEs reported in 28.0% of patients in the ivonescimab arm.
What is the mechanism of action of ivonescimab?
Ivonescimab is a bispecific antibody engineered to target both the PD-1 and VEGF pathways simultaneously. By co-blocking immune checkpoint signaling and angiogenesis, the therapy is designed to enhance antitumor immune responses and mitigate VEGF-mediated immunosuppression within the tumor microenvironment.
The drug’s tetravalent structure purportedly enables cooperative binding to both targets, potentially increasing its activity relative to separate single-target antibodies. Preclinical models indicate that this dual engagement fosters greater PD-1 blockade in the presence of VEGF, though clinical data validating this mechanism in NSCLC remain limited to early and intermediate clinical trial data.
What was the design of the HARMONi trial?
The multicenter, global, double-blind, placebo-controlled HARMONi trial enrolled patients with locally advanced or metastatic NSCLC harboring an EGFR sensitizing mutation who had progressed on a third-generation EGFR TKI.2 Patients needed to have an ECOG performance status of 0 or 1 and could have any PD-L1 expression level.
A total of 438 patients were randomly assigned 1:1 to receive ivonescimab at 20 mg/kg every 3 weeks plus chemotherapy (carboplatin at area under the curve of 5 every 3 weeks for 4 21-day cycles plus pemetrexed at 500 mg/m2 every 3 weeks), or placebo plus chemotherapy at the same dose and schedule.
PFS by IRRC and overall survival (OS) served as the study’s coprimary end points. Secondary end points included overall response rate (ORR), duration of response (DOR), and safety and tolerability.
What additional efficacy findings were seen in HARMONi?
An OS trend favoring the ivonescimab arm (n = 219) was observed, with a median OS of 16.8 months vs 14.0 months with placebo (n = 219; HR, 0.79; 95% CI, 0.62-1.01; P = .0570). Notably, OS data derived from a time point at which the North American and European Union (EU) follow-up data were not yet mature. The overall median follow-up was 29.7 months, while the median follow-up in North American and the EU was 9.2 months.
When OS was assessed using longer-term Western data, the benefit with ivonescimab was sustained. The median OS was 16.8 months in the ivonescimab arm vs 14.0 months in the placebo arm (HR, 0.78; 95% CI, 0.62-0.98; P = .0332).
The ORR was 45% in the ivonescimab arm vs 34% in the placebo arm. The median DORs in these respective arms were 7.6 months (95% CI, 5.5-10.6) and 4.2 months (95% CI, 2.9-4.7).
What is the safety profile of ivonescimab?
In HARMONi, any-grade treatment-related adverse effects (TRAEs) occurred in 95.0% of evaluable patients in the ivonescimab arm (n = 218). In total, 50.0% of patients in this arm experienced grade 3 or higher TRAEs. The most common any-grade immune-related TRAEs reported in this arm included hypothyroidism (8.3%), hyperthyroidism (4.1%), increased alanine aminotransferase levels (2.8%), increased aspartate aminotransferase levels (3.2%), rash (2.8%), and stomatitis (2.8%). The most common any-grade VEGF-related TRAEs were proteinuria (13.8%), hypertension (13.3%), and hemorrhage (10.6%).
References
- Summit Therapeutics announces U.S. FDA acceptance of biologics license application (BLA) seeking approval for ivonescimab in combination with chemotherapy in treatment of patients with EGFRm NSCLC post-TKI therapy. News release. Summit Therapeutics Inc. January 29, 2026. Accessed January 29, 2026. https://www.smmttx.com/news/press-releases/news-details/2026/Summit-Therapeutics-Announces-U-S--FDA-Acceptance-of-Biologics-License-Application-BLA-Seeking-Approval-for-Ivonescimab-in-Combination-with-Chemotherapy-in-Treatment-of-Patients-with-EGFRm-NSCLC-Post-TKI-Therapy/default.aspx
- Goldman JW, Passaro A, Laskin J, et al. Ivonescimab vs placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi. Presented at: IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4808.
