Summit Therapeutics' bispecific antibody ivonescimab (Idafang) has achieved another significant milestone in its campaign to challenge established immunotherapies in the treatment of non-small cell lung cancer (NSCLC). The company recently announced positive results from the Phase III HARMONi-6 trial, where ivonescimab plus chemotherapy demonstrated superior progression-free survival (PFS) compared to BeiGene's PD-1 inhibitor tislelizumab plus chemotherapy in patients with squamous NSCLC.
This latest success follows previous positive data from the HARMONi-2 trial, where ivonescimab showed a 49% reduction in the risk of disease progression or death compared to Merck's blockbuster Keytruda (pembrolizumab) in first-line NSCLC treatment. These results have positioned ivonescimab as a potential disruptor in the lucrative cancer immunotherapy market, which Summit values at more than $90 billion.
The Dual-Targeting Approach
Ivonescimab's mechanism of action targets both PD-1 and VEGF pathways simultaneously through a bispecific antibody design. This dual-targeting approach aims to enhance anti-tumor activity by combining immune checkpoint inhibition with anti-angiogenic effects, potentially offering advantages over single-target therapies like Keytruda.
Dr. Jack West, vice president of clinical development at Summit, highlighted the differentiated safety profile of ivonescimab compared to competitors. "The combination of efficacy with toxicity liabilities looks very different from what other therapies offer," West stated, adding that clinicians see "a great need for alternatives that have a very different and potentially less challenging toxicity profile."
In the HARMONi-6 trial, which enrolled 532 patients across 66 sites in China, ivonescimab demonstrated clinically meaningful PFS benefits in both PD-L1-positive and PD-L1-negative populations. Approximately 63% of enrolled patients had centrally located squamous cell carcinoma, representing a distribution consistent with real-world patient populations.
Regulatory Progress and Market Potential
Ivonescimab has already gained regulatory approval in China. In May 2024, Chinese authorities approved the bispecific for use in NSCLC patients who have progressed after tyrosine kinase inhibitor (TKI) therapy. Akeso, Summit's Chinese partner, secured a broader label expansion last month, covering first-line NSCLC patients.
The global regulatory pathway is now a key focus for Summit. Results from a global Phase III trial testing ivonescimab in NSCLC patients who progressed on a TKI are expected in mid-2025. This readout will provide crucial insights into whether Summit can replicate the results of Akeso's Chinese trials in a global population.
Summit's stock rose 21.49% following the announcement of the HARMONi-6 results, while Akeso's stock increased by 13.12%, reflecting investor optimism about the drug's potential.
Competitive Landscape and Challenges
Despite the promising data, questions remain about ivonescimab's overall survival (OS) benefit. Akeso recently published interim OS data showing a 22.3% reduction in the risk of death compared to Keytruda, but this difference fell short of statistical significance, sparking debate among analysts about the long-term competitive position of the drug.
The competitive landscape is also intensifying. BioNTech entered the race by acquiring its PD-L1xVEGF bispecific partner Biotheus for $800 million and has initiated a Phase II/III trial of its candidate BNT327 in first-line NSCLC. Merck has licensed LM-299 from LaNova Medicines for $588 million, signaling its intent to defend its dominant position in the market.
"Should PD-1xVEGF show that OS benefit, we have an advantage of having unique portfolio agents that have clear potential for combinability," said Dean Li, president of Merck Research Laboratories, highlighting the company's strategy to potentially leapfrog competitors through combination approaches.
Strategic Partnerships and Future Directions
Summit has formed strategic partnerships to enhance ivonescimab's potential. The company is collaborating with Pfizer to investigate combinations with several of Pfizer's antibody-drug conjugates (ADCs). This approach aligns with the broader industry trend toward combination therapies to improve efficacy and address resistance mechanisms.
The companies are also expanding their clinical program globally. The multi-regional Phase III HARMONi-3 trial is ongoing, and the HARMONi-7 trial is being established to generate data that could support regulatory approvals in the US, Europe, and other major markets.
Market Implications
GlobalData predicts that Keytruda sales will peak in 2027 at $36.1 billion, likely due to patent expiration in 2028. Meanwhile, ivonescimab is projected to reach blockbuster status in 2029, with 2030 sales estimated at $1.62 billion.
Summit's ability to establish ivonescimab as a preferred treatment option will depend on several factors, including the strength of overall survival data from ongoing trials, safety profile in larger patient populations, and competitive pricing strategies, particularly as Keytruda biosimilars enter the market after 2028.
The upcoming readouts from global Phase III trials will be critical in determining whether ivonescimab can truly challenge Keytruda's dominance and reshape the treatment landscape for NSCLC patients worldwide.
