Ivonescimab Beats Pembrolizumab on Overall Survival in First-Line PD-L1-Positive NSCLC: HARMONi-2 Data at WCLC 2026
核心洞察
Akeso's Phase III HARMONi-2 trial met its overall survival endpoint, with ivonescimab monotherapy cutting the risk of death by 27% versus pembrolizumab in first-line PD-L1-positive advanced NSCLC.
Median overall survival reached 30.8 months with ivonescimab versus 22.6 months with pembrolizumab (HR=0.73; 95% CI 0.57-0.95; P=0.009) at 36 months of median follow-up.
Benefit was most pronounced in PD-L1-high patients (TPS >=50%), where the hazard ratio was 0.58, corresponding to a 42% reduction in the risk of death.
Akeso, Inc. reported positive overall survival (OS) results from the randomized, double-blind, multicenter, registrational Phase III HARMONi-2 study (AK112-303), showing that first-line ivonescimab monotherapy significantly prolonged survival compared with pembrolizumab in patients with PD-L1-positive (PD-L1 TPS >=1%) locally advanced or metastatic non-small cell lung cancer (搜索) (NSCLC). The data were presented at the 2026 World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer (IASLC), and were selected as a Late-Breaking Abstract for oral presentation and included in the official WCLC press program.
According to the company, HARMONi-2 is the first randomized, double-blind, controlled Phase III clinical study to demonstrate statistically significant positive OS and PFS results versus pembrolizumab.
Overall Survival in the Intention-to-Treat Population
As of the data cutoff on August 20, 2026, median follow-up was 36 months and 234 overall survival events had occurred. The OS analysis used a prespecified O'Brien-Fleming spending function with a one-sided alpha of 0.0141.
In the intention-to-treat (ITT) population, ivonescimab monotherapy significantly prolonged OS versus pembrolizumab, with median OS of 30.8 months versus 22.6 months (HR=0.73; 95% CI: 0.57-0.95; P=0.009), corresponding to a 27% reduction in the risk of death. The finding met the prespecified statistical significance threshold. Summit Therapeutics, Akeso's development partner, characterized the result as an improvement in median overall survival of 8.2 months.
The overall survival benefit was generally consistent across prespecified subgroups, with particularly pronounced benefit observed in the PD-L1-high population.
Subgroup Analyses
In the PD-L1 TPS >=50% subgroup, OS HR was 0.58 (95% CI: 0.38-0.89), corresponding to a 42% reduction in the risk of death (n=168). In the PD-L1 TPS 1-49% subgroup, OS HR was 0.85 (95% CI: 0.61-1.18), a 15% relative reduction in the risk of death (n=230).
By histology, the squamous cell carcinoma subgroup showed an OS HR of 0.65 (95% CI: 0.45-0.95), a 35% reduction in the risk of death (n=181), while the non-squamous subgroup showed an OS HR of 0.79 (95% CI: 0.55-1.14), a 21% reduction (n=217). Summit noted that the subgroup analyses were descriptive and not formally powered.
Squamous Patients and Anti-VEGF Contraindications
Squamous NSCLC patients accounted for 45.5% of the HARMONi-2 population and non-squamous patients for 54.5%. Among squamous patients treated with ivonescimab, 72.2% had central tumors, 10.0% had tumor cavitation or necrosis, and 6.7% had tumors encasing major vessels. These populations are traditionally considered contraindicated or high-risk for anti-VEGF (搜索) therapies and have long lacked effective treatment options, according to the company. However, no apparent increase in bleeding risk was observed with ivonescimab, and these patients showed favorable benefit.
Safety and Prior Progression-Free Survival Data
Ivonescimab continued to demonstrate an acceptable and manageable safety profile consistent with previous Phase III studies of the agent, with no additional safety signals noted in the current data cut, which involved longer treatment duration (median of 14 cycles of ivonescimab versus 10 cycles of pembrolizumab) compared with the previous data cut. Safety characteristics were generally consistent between arms.
In May 2024, a prespecified interim analysis of progression-free survival (PFS) assessed by the Independent Data Monitoring Committee confirmed that HARMONi-2 met its primary PFS endpoint with statistically significant and clinically meaningful results. Median PFS was 11.14 months with ivonescimab versus 5.82 months with pembrolizumab (HR=0.51, P<0.0001). In the study's primary analysis, PFS by Independent Radiologic Review Committee showed an HR of 0.51 (95% CI: 0.38-0.69; p<0.0001). Akeso received marketing authorization for ivonescimab from China's National Medical Products Administration based on the HARMONi-2 results in April 2025.
Development Program and Global Expansion
"HARMONi-2 is the fourth Phase III study of ivonescimab to demonstrate statistically significant improvements for both overall survival and progression-free survival in head-to-head comparisons against standard-of-care regimens," said Robert W. Duggan, Chairman and Co-Chief Executive Officer of Summit Therapeutics. "Demonstrating a survival benefit against pembrolizumab monotherapy in this setting further strengthens our conviction that ivonescimab has the potential to advance treatment beyond PD-1 (搜索) blockade alone and define what a next-generation immuno-oncology therapy can deliver for patients with lung cancer."
"Positive overall survival results in HARMONi-2 mark a pivotal moment for ivonescimab and underscore the promise of its differentiated PD-1 (搜索) / VEGF (搜索) bispecific approach," said Dr. Maky Zanganeh, President and Co-Chief Executive Officer of Summit Therapeutics. "These data build on the study's previously reported progression-free survival benefit, while further informing our confidence in the broader ivonescimab development program, including HARMONi-7, our ongoing global Phase III study evaluating ivonescimab monotherapy against pembrolizumab monotherapy in patients with PD-L1 high-expressing metastatic non-small cell lung cancer (搜索)."
HARMONi-2 was a single-region, multicenter Phase III study conducted in China and sponsored by Akeso, with all relevant data generated, managed, and analyzed by Akeso. The trial results will be presented by Professor Caicun Zhou, Principal Investigator of HARMONi-2 and President of IASLC, on September 15, 2026.
An international multicenter Phase III study evaluating ivonescimab monotherapy versus pembrolizumab as first-line treatment for PD-L1-high NSCLC (HARMONi-7/AK112-3007; NCT06767514) is currently recruiting, with a target enrollment of 780 patients globally and co-primary endpoints of PFS and OS. Summit initiated the study in early 2025.
Ivonescimab, known as SMT112 in Summit's license territories and as AK112 outside them, is a novel, potential first-in-class investigational bispecific antibody combining immunotherapy via blockade of PD-1 (搜索) with anti-angiogenesis effects associated with blocking VEGF (搜索) into a single molecule. By design, it displays cooperative binding to each of its intended targets with multifold higher affinity to PD-1 in the presence of VEGF. Its tetravalent structure (four binding sites) is intended to enable higher avidity in the tumor microenvironment, with a half-life of 6 to 7 days after the first dose, increasing to approximately 10 days at steady-state dosing.
To date, ivonescimab has consistently achieved dual-positive OS and PFS results across multiple Phase III head-to-head trials against PD-1 (搜索)/L1 therapies and continues to expand into major solid tumors beyond lung cancer. Five Phase III ivonescimab clinical trials have read out to date, all with positive data; four are in NSCLC and one is in biliary tract cancer (搜索). There are currently 16 Phase III clinical studies announced, ongoing, or completed studying ivonescimab, five of which are Summit-sponsored global studies. Over 4,000 patients have been treated with ivonescimab in clinical studies globally, and over 70,000 patients when considering those treated in a commercial setting in China, as noted by Akeso.
Ivonescimab remains investigational and is not approved by any regulatory authority in Summit's license territories, including the United States and Europe. In the United States, a Biologics License Application for ivonescimab combined with chemotherapy in EGFR-mutated, locally advanced or metastatic non-squamous NSCLC previously treated with a third-generation EGFR TKI was accepted for filing by the FDA in January 2026, with a goal PDUFA date of November 14, 2026.