Ivonescimab Beats Pembrolizumab in Phase 3, But China-Only Data Leaves FDA Path Unresolved

Ivonescimab Outperforms Keytruda in China NSCLC Trial

Summit Therapeutics and Akeso's PD-1/VEGF bispecific antibody, ivonescimab, demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to Merck's Keytruda in the Phase 3 HARMONi-2 trial. The study, conducted in China, involved patients with first-line non-small cell lung cancer (NSCLC) expressing PD-L1. Ivonescimab achieved a PFS of 11.14 months versus Keytruda's 5.82 months. While the drug is already approved in China for this indication, Summit needs to replicate these results in Western patients to secure FDA approval, with a global Phase 3 HARMONi-3 trial underway. An FDA decision for ivonescimab in EGFR-mutated NSCLC is expected in November.

• Superior Efficacy in HARMONi-2 Trial: Ivonescimab, a PD-1/VEGF bispecific antibody developed by Summit Therapeutics and Akeso, achieved both overall survival (OS) and progression-free survival (PFS) superiority over Merck's Keytruda in the Phase 3 HARMONi-2 trial. This trial focused on first-line non-small cell lung cancer (NSCLC) patients in China whose tumors expressed PD-L1.
• Significant PFS Benefit: The interim results from the HARMONi-2 trial showed a substantial improvement in progression-free survival for ivonescimab, reaching 11.14 months. This was nearly double the PFS observed with Keytruda, which was 5.82 months, highlighting a clinically meaningful benefit for patients in this specific population.
• Global Regulatory Pathway and Future Trials: Despite the strong results from the Chinese HARMONi-2 trial, Summit Therapeutics faces the challenge of replicating these findings in Western patient populations to gain FDA approval. The global Phase 3 HARMONi-3 trial is currently evaluating ivonescimab with chemotherapy against Keytruda in metastatic NSCLC, with data expected this half to support broader regulatory filings.
• Existing Approvals and Upcoming Decisions: Ivonescimab is already approved in China for the first-line NSCLC indication and two others. In the U.S., Summit is awaiting an FDA decision in November for the therapy specifically for NSCLC patients with epidermal growth factor receptor (EGFR) mutations, indicating a separate regulatory path for different patient subpopulations.

Ivonescimab's HARMONi-2 Data: Outperforming Keytruda in Chinese NSCLC

Several recent clinical trials in non-small cell lung cancer (NSCLC) have evaluated immunotherapy-based regimens with notable safety and efficacy findings. The Lung-MAP S1400I phase 3 randomized clinical trial assessed nivolumab plus ipilimumab versus nivolumab alone in patients with advanced, pretreated, immunotherapy-naive squamous NSCLC. The study was closed for futility at a planned interim analysis: overall survival was not significantly different between groups (hazard ratio 0.87; 95% CI, 0.66–1.16; P = .34), with median survival of 10 months in the nivolumab/ipilimumab group versus 11 months in the nivolumab group. Grade 3 or higher treatment-related adverse events occurred in 39.5% of patients receiving nivolumab/ipilimumab versus 33.3% receiving nivolumab alone, and toxic effects led to discontinuation in 25% versus 15% of patients, respectively.

A phase 1 nonrandomized controlled trial evaluated pembrolizumab administered concurrently with chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation) for locally advanced, unresectable stage III NSCLC. No dose-limiting toxic effects were observed in any cohort, though one case of grade 5 pneumonitis occurred in the safety expansion cohort. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median progression-free survival (PFS) for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 months (95% CI, 11.8–29.4 months), with 12-month PFS of 69.7% (95% CI, 49.3%–90.2%). These findings suggested that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS outcomes.

The PACIFIC post hoc subgroup analysis examined durvalumab (10 mg/kg intravenously every 2 weeks, for up to 1 year) as consolidation therapy after chemoradiotherapy in patients with unresectable stage III EGFR-mutant (EGFRm) NSCLC. Among 35 patients with locally confirmed EGFRm NSCLC (durvalumab, n = 24; placebo, n = 11), median PFS was 11.2 months (95% CI: 7.3–20.7) with durvalumab versus 10.9 months (95% CI: 1.9–not evaluable) with placebo (hazard ratio = 0.91; 95% CI: 0.39–2.13). Median overall survival was 46.8 months (95% CI: 29.9–not evaluable) with durvalumab versus 43.0 months (95% CI: 14.9–not evaluable) with placebo (hazard ratio = 1.02; 95% CI: 0.39–2.63). The authors noted these statistical analyses were post hoc and exploratory, and results should be interpreted with caution owing to small patient numbers.

Reshaping First-Line NSCLC: Ivonescimab's Competitive Edge Against Keytruda

Published clinical studies across multiple treatment modalities in NSCLC reveal a nuanced landscape in which investigational and approved targeted therapies, immunotherapies, and chemotherapy combinations each demonstrate distinct efficacy and safety profiles relative to established standards of care. In ROS1 fusion-positive NSCLC, entrectinib — evaluated across the ALKA-372-001, STARTRK-1, and STARTRK-2 trials in 168 ROS1 TKI-naïve patients — achieved a confirmed objective response rate of 68% (95% CI: 60.2–74.8), a median duration of response of 20.5 months, a median progression-free survival of 15.7 months, and a median overall survival of 47.8 months. In patients with measurable baseline CNS metastases, the intracranial objective response rate reached 80% (95% CI: 59.3–93.2). In the perioperative setting, adjuvant osimertinib has been established as the standard of care for resected EGFR-mutant NSCLC following the ADAURA study, building on earlier work with adjuvant gefitinib in the CTONG1104 trial. The PACE-LUNG trial is evaluating a biomarker-driven escalation strategy in which patients with persisting ctDNA EGFR mutations at weeks 3–4 after first-line osimertinib receive additional chemotherapy (4 cycles of cisplatin/pemetrexed or carboplatin/pemetrexed), with progression-free survival as the primary endpoint.

In the immunotherapy space, atezolizumab combined with chemotherapy demonstrated significant improvement in progression-free survival and overall survival in IMpower 130 and 150 (non-squamous NSCLC) and IMpower 133 (SCLC), with an acceptable safety profile. The most common immune-related adverse events were rash (18–28%), hypothyroidism (8–15%), hepatitis (5–17%), pneumonitis (2–7%), and colitis (1.5–2.3%). A systematic review of 24 randomized controlled trials involving 14,256 patients confirmed that ICI therapy was associated with a significantly lower frequency of grade 3–5 treatment-related adverse events compared with chemotherapy (RR: 0.65; 95% CI: 0.51–0.82; P<0.001), with anti-PD-1 inhibitors showing a lower risk of treatment-related adverse events than anti-PD-L1 or anti-CTLA-4 agents. For first-line pembrolizumab in PS 2 patients with PD-L1 TPS ≥50%, the GOIRC-2018-01 study reported a median PFS of 2.4 months and median OS of 3.0 months overall, though patients with PS 2 driven by comorbidities (n=41) had substantially better outcomes — median PFS 5.6 months and OS 11.8 months — compared with those with disease burden-induced PS 2 (median PFS 1.8 months, OS 2.8 months).

In elderly or unselected populations, a randomized phase II trial in patients aged ≥70 years with stage IIIB/IV NSCLC found that erlotinib (150 mg daily) and the combination of gemcitabine plus erlotinib did not improve outcomes over single-agent gemcitabine, with 6-month progression-free survival rates of 24%, 25%, and 22% and median overall survival of 5.8, 5.6, and 6.8 months across the erlotinib, combination, and gemcitabine arms, respectively, leading to the conclusion that erlotinib or erlotinib plus gemcitabine do not warrant further investigation in an unselected elderly population. An analysis of years of life lost across driver mutation subtypes further contextualized the relative benefit of targeted therapies: while ROS1-targeted therapy ameliorated 44.3% of estimated years of life lost, ALK-targeted therapy ameliorated 20.5%, and EGFR-targeted therapy ameliorated 28.2%, underscoring that despite meaningful survival gains, a substantial gap in years of life lost persists across all targetable mutation subtypes relative to older patients without driver mutations.

Navigating Global Approval: Ivonescimab's Path Beyond China

Several key trials across the NSCLC landscape have evaluated a range of therapeutic strategies — from neoadjuvant immunochemotherapy to chemoradiotherapy and targeted agents — each with distinct design parameters and endpoints. The table below summarizes the study design and endpoint data from the trials represented in the available literature.

Challenging Keytruda: Ivonescimab's Global Ambition in NSCLC

The recent announcement regarding ivonescimab's performance in the HARMONi-2 trial against Keytruda represents a pivotal moment in the treatment landscape for non-small cell lung cancer (NSCLC). Demonstrating significantly improved progression-free survival (PFS) and overall survival (OS) in a head-to-head comparison with a leading immune checkpoint inhibitor is a rare and impactful achievement. This bispecific antibody, targeting both PD-1 and VEGF-A, offers a novel mechanism that research indicates can effectively remodel the tumor microenvironment, enhancing anti-tumor responses.

For Summit Therapeutics and Akeso, these results underscore a robust strategic pathway. The drug is already approved in China for first-line PD-L1+ NSCLC and EGFR-mutated NSCLC post-TKI therapy, providing a strong foundation. The ongoing global HARMONi-3 trial is critical for translating this success to Western markets, where the competitive landscape is fierce. An upcoming FDA decision for EGFR-mutated NSCLC further highlights the immediate potential for market entry.

However, the path forward is not without considerations. While efficacy is compelling, studies indicate a higher incidence of Grade 3 or higher treatment-related adverse events with ivonescimab compared to pembrolizumab. Clinicians will need to be mindful of specific toxicities, including hypertension and potential for hemorrhage, which are associated with VEGF inhibition. Furthermore, rare but severe immune-mediated events, such as endocrine dysfunctions like arginine vasopressin deficiency, have been observed, necessitating careful patient selection and monitoring. The successful replication of these impressive Chinese trial results in a broader, global patient population will be paramount for widespread adoption and market penetration. If successful, ivonescimab could redefine the standard of care, offering a powerful new option for patients with advanced NSCLC.