Akeso’s Ivonescimab Outshines Pembrolizumab on Overall Survival in Phase 3 HARMONi-2 Trial

China’s Akeso has reported another major clinical milestone for ivonescimab (AK112), its first-in-class PD-1/VEGF bispecific antibody, announcing that the drug demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit over pembrolizumab in the Phase 3 HARMONi-2 (AK112-303) trial in first-line PD-L1-positive non-small cell lung cancer (NSCLC).

According to Akeso’s announcement, a prespecified interim OS analysis conducted by the trial’s Independent Data Monitoring Committee (IDMC) met the study’s key secondary endpoint, demonstrating superiority for ivonescimab versus pembrolizumab.

The finding builds on HARMONi-2’s previously reported progression-free survival benefit and provides additional clinical validation for simultaneously targeting PD-1 and VEGF with a single bispecific antibody. (Akeso Bio)

HARMONi-2: Head-to-Head Against Pembrolizumab

HARMONi-2 (AK112-303; NCT05499390) is a randomized, double-blind, multicenter Phase 3 trial conducted in China comparing ivonescimab monotherapy with pembrolizumab monotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC whose tumors express PD-L1 at a tumor proportion score (TPS) of at least 1%.

A total of 398 patients were randomized 1:1, with 198 receiving ivonescimab at 20 mg/kg and 200 receiving pembrolizumab at 200 mg intravenously every three weeks. Randomization was stratified according to histology, clinical stage and PD-L1 expression. (PubMed)

Trial	HARMONi-2 / AK112-303
Phase	Phase 3
Patients	398
Disease	Locally advanced/metastatic NSCLC
PD-L1	TPS ≥1%
Experimental arm	Ivonescimab 20 mg/kg Q3W
Control	Pembrolizumab 200 mg Q3W
Primary endpoint	PFS
Key secondary endpoint	Overall survival
PFS HR	0.51
Interim OS result	Statistically significant benefit for ivonescimab

Importantly, Akeso has not yet disclosed the median OS, OS hazard ratio, confidence interval or maturity of the survival data. Those figures are expected to be presented at an upcoming international medical conference and subsequently published in a peer-reviewed journal. (Akeso Bio)

OS Win Follows Major PFS Advantage

The latest survival result follows the study’s earlier success on its primary endpoint.

At the prespecified PFS interim analysis, ivonescimab produced a median progression-free survival of 11.14 months compared with 5.82 months for pembrolizumab, corresponding to a hazard ratio of 0.51.

The peer-reviewed HARMONi-2 results, published in The Lancet study via PubMed in March 2025, reported an HR of 0.51 (95% CI 0.38–0.69; one-sided p<0.0001). The PFS benefit was observed across major prespecified subgroups, including both lower and higher PD-L1 expression groups. (PubMed)

Among patients with PD-L1 TPS of 1–49%, the PFS hazard ratio was 0.54, while patients with PD-L1 TPS ≥50% had an HR of 0.48. (PubMed)

The new OS finding therefore strengthens the earlier efficacy signal: the advantage seen in delaying disease progression has now translated into a statistically significant survival benefit at the prespecified interim analysis.

Why the OS Result Matters

Pembrolizumab has become one of the foundational immunotherapies in NSCLC and many other cancers. Demonstrating superiority to pembrolizumab in a randomized, double-blind Phase 3 trial therefore represents a high clinical bar.

HARMONi-2 had already attracted global attention after becoming the first randomized, double-blind Phase 3 study in this setting to demonstrate a significant positive PFS result against pembrolizumab. The newly announced OS result substantially strengthens that finding because overall survival remains one of the most clinically meaningful endpoints in oncology.

The magnitude of the OS advantage, however, cannot yet be evaluated because Akeso has not released the hazard ratio or median survival figures. The detailed presentation will therefore be critical for determining how large and durable the benefit is, as well as whether the survival advantage remains consistent across PD-L1 expression levels, histologies and other clinically relevant subgroups.

Combining PD-1 and VEGF in One Molecule

Ivonescimab represents a different approach to immunotherapy from conventional PD-1 antibodies.

Developed using Akeso’s Tetrabody technology, the bispecific antibody simultaneously blocks PD-1, an immune checkpoint exploited by tumors to suppress T-cell activity, and VEGF, a central driver of tumor angiogenesis that also contributes to an immunosuppressive tumor microenvironment.

The rationale is to combine checkpoint inhibition and anti-angiogenesis within a single molecule, potentially increasing antitumor activity in the tumor microenvironment.

Akeso describes ivonescimab as a first-in-class PD-1/VEGF bispecific antibody. In Summit Therapeutics’ licensed territories, including the United States, Europe, Canada and Japan, the molecule is also known as SMT112. (Akeso Bio)

China Approval Already Secured

The HARMONi-2 PFS results previously supported regulatory approval in China for ivonescimab monotherapy in first-line PD-L1-positive advanced NSCLC.

According to Akeso, the indication received Chinese regulatory approval in 2025, establishing a chemotherapy-free treatment option for these patients. (Akeso Bio)

The new OS result could further strengthen ivonescimab’s clinical positioning in China, although the implications outside China require additional consideration because HARMONi-2 was conducted entirely in China.

That distinction is particularly relevant to global regulatory development.

Summit and Akeso Push Ivonescimab Globally

Akeso entered a major licensing agreement with Summit Therapeutics in December 2022 covering ivonescimab in the United States, Canada, Europe and Japan.

Under the original agreement, Akeso received $500 million upfront and is eligible for regulatory and commercial milestone payments that could bring the total transaction value to $5 billion, in addition to low-double-digit royalties on net sales. Akeso retained rights in China and other territories. (Akeso Bio)

Because HARMONi-2 is a China-only study, Summit is conducting separate international Phase 3 programs intended to support development and potential regulatory submissions in its licensed markets.

Of particular relevance is HARMONi-7 (AK112-3007), an international multicenter Phase 3 study comparing ivonescimab monotherapy directly with pembrolizumab in first-line NSCLC patients with high PD-L1 expression. Akeso confirmed that HARMONi-7 remains ongoing. (Akeso Bio)

The HARMONi-2 OS result consequently provides important validation for the therapeutic hypothesis underlying HARMONi-7, although the global trial will need to establish efficacy and safety independently in its broader international population.

Ivonescimab Raises the Stakes in the PD-1/VEGF Race

The result also has implications beyond Akeso and Summit.

PD-1/VEGF bispecific antibodies have emerged as one of the most closely watched new classes in oncology, with multiple pharmaceutical and biotechnology companies pursuing approaches designed to combine immune-checkpoint blockade with VEGF inhibition.

Ivonescimab has been the clinical frontrunner in this field. A statistically significant OS advantage over pembrolizumab adds another level of validation to the underlying PD-(L)1/VEGF strategy and could intensify competition around next-generation checkpoint inhibitors.

For Akeso, the announcement also marks another milestone for a drug that has become one of the most prominent examples of a China-originated oncology asset moving toward global development.

Akeso CEO Dr. Yu Xia said the latest result means that a fourth Phase 3 study involving an ivonescimab-based regimen has now demonstrated statistically significant benefit in both OS and PFS. The company believes the growing clinical dataset supports further development of the molecule across lung cancer and other solid tumors. (Akeso Bio)

What to Watch Next

The most important next event will be disclosure of the full HARMONi-2 OS dataset.

Investors, physicians and competitors will be watching particularly closely for the OS hazard ratio, median OS in each treatment arm, survival-curve separation and maturity, subgroup outcomes by PD-L1 expression and histology, and updated safety results.

Those numbers will ultimately determine the magnitude of ivonescimab’s survival advantage over pembrolizumab.

Nevertheless, the topline finding represents an important milestone. After previously cutting the risk of progression or death by approximately half versus pembrolizumab in the primary PFS analysis, ivonescimab has now demonstrated that its benefit extends to overall survival.

If international studies reproduce the results seen in HARMONi-2, ivonescimab could potentially challenge the established PD-1 monotherapy paradigm in first-line PD-L1-positive NSCLC and further establish PD-1/VEGF bispecific antibodies as an important new class of cancer immunotherapy.

References

1. Akeso — Ivonescimab Meets Overall Survival Key Secondary Endpoint in Phase III HARMONi-2
2. Akeso / PR Newswire — HARMONi-2 Overall Survival Announcement
3. Summit Therapeutics — HARMONi-2 Overall Survival Update
4. The Lancet HARMONi-2 Publication — PubMed
5. Akeso — HARMONi-2 Phase III Results Published in The Lancet
6. Akeso — Summit Therapeutics Ivonescimab Global Licensing Agreement
7. U.S. SEC — Summit Therapeutics HARMONi-2 OS Disclosure