Ivonescimab: Another "Head-to-Head" Victory.

Ivonescimab, the highly anticipated drug, has for the first time reached the overall survival (OS) endpoint in a major indication beyond lung cancer.

On August 26, Akeso Biopharma announced that this PD-1/VEGF bispecific antibody achieved positive overall survival (OS) results in first-line biliary tract cancer. Specific data were not disclosed; Akeso plans to release more information at the ESMO conference in October.

"This is significant," Akeso founder Xia Yu told industry media Endpoints News. "Since we started developing ivonescimab, we believed it would not be limited to lung cancer but would cover a broader range of indications. This is the first achievement beyond the lung cancer field."

For a drug that has long been at the center of the "head-to-head" storm, the positive biliary tract cancer result not only expands its indication boundaries but also once again places ivonescimab under the scrutiny of the strongest comparators.

Over the past few years — from challenging pembrolizumab (Keytruda) in lung cancer, to challenging durvalumab (Imfinzi) in biliary tract cancer, to the potential combination with targeted therapies in pancreatic cancer — every step of ivonescimab has been accompanied by high expectations, high controversy, and high attention. Xia Yu does not shy away from this: it's a good thing, but it also brings pressure.

Chapter 1: Challenging the Gold Standard Under the "Difficult-to-Treat" Label

Biliary tract cancer is a gastrointestinal malignancy with an extremely poor prognosis, long treated with gemcitabine plus cisplatin chemotherapy as the backbone. The addition of immune checkpoint inhibitors has changed the treatment landscape, but the improvement has been modest.

In the TOPAZ-1 study, Imfinzi plus chemotherapy reduced the risk of death by 20% (OS HR = 0.80); in the Keynote-966 study, Keytruda plus chemotherapy had an OS HR of 0.83. In other words, even the current standard of care offers only "modest" survival benefits.

Earlier, Roche had attempted to combine its PD-L1 inhibitor Tecentriq with its VEGF inhibitor Avastin for first-line biliary tract cancer, but the combination failed to show significant OS benefit. That failure cast a shadow over the feasibility of "PD-(L)1 + VEGF" in biliary tract cancer, and made Akeso's ivonescimab data in this indication even more critical.

Xia Yu emphasized that ivonescimab's tetravalent bispecific antibody structure is fundamentally different from simple combination therapy.

"Our bispecific antibody, especially its tetravalent structure, has a mechanism of action that differs from those combination studies. Ivonescimab is not a simple combination, nor is it just any type of bispecific play," Xia added.

In the Phase III biliary tract cancer study HARMONi-GI1, Akeso chose Imfinzi plus chemotherapy as the comparator — not Keytruda. Xia explained that the former's data are more robust. Another reason: Imfinzi is a PD-L1 molecule, and "we really wanted to try it out and play another interesting game."

This choice continues Akeso's strategy in lung cancer of "only challenging the strongest competitor," and sets a higher bar of credibility for ivonescimab's biliary tract cancer data.

Regarding whether Chinese data can be extrapolated to global populations, Xia expressed cautious optimism. She believes that Summit's U.S. lung cancer studies have already shown consistency with Chinese data, providing preliminary evidence for cross-regional extrapolation.

Additionally, Keytruda and Imfinzi have shown similar efficacy data in Asian patients compared to the overall population, and both TOPAZ-1 and Keynote-966 trials included a substantial proportion of Asian patients — especially Chinese patients — which further supports the推测 that ivonescimab may have similar efficacy in Western patients. However, she also emphasized that more data are still needed to confirm this inference.

Currently, Summit has not independently initiated a biliary tract cancer study, but ECOG-ACRIN (one of the world's leading cancer clinical trial research organizations) is about to launch a Phase II/III trial that may provide more evidence.

Chapter 2: Only Challenging the Strongest Opponent

One of ivonescimab's most prominent labels is its direct challenge to Keytruda in the lung cancer field.

In PD-L1-positive first-line non-small cell lung cancer, Akeso conducted a Phase III study of ivonescimab monotherapy versus Keytruda. Xia recalled the decision-making logic at the time: "We believed Keytruda is a blockbuster drug in this field and occupies a large share of the global lung cancer indication."

In biliary tract cancer, Akeso once again chose one of the current gold-standard therapies with the strongest data — Imfinzi. Akeso did not frame the "head-to-head" approach as a gamble, but rather as an active strategic choice: either don't do it, or compete against the strongest opponent. The logic is straightforward: to prove ivonescimab's clinical value, it should be placed against the global standard of care, rather than circumventing competition.

This "strongest comparator" logic is uncommon in the industry.

Most Chinese innovative drugs choose chemotherapy or placebo as the comparator in early confirmatory studies to reduce the risk of failure. Akeso's choice carries both risk and reward: once successful, it means ivonescimab has the data foundation to challenge global standard of care; but at the same time, any data fluctuation will be magnified by market interpretation.

And indeed, that's what happened. Previously, shares of Akeso's partner Summit Therapeutics fluctuated due to changes in the progression-free survival (PFS) hazard ratio (HR) in the HARMONi-6 study.

In the final analysis of that study, the PFS HR rose from 0.60 in the interim data to 0.72, raising market concerns: was ivonescimab's efficacy "shrinking"?

Xia proactively addressed this controversy in the interview: "We had previously submitted an NDA to Chinese regulators with interim PFS data, and later were asked to provide OS data. Regulators also requested the final PFS analysis. So for the final PFS, the HR (0.72) is slightly higher than the initial HR (0.60) — this is very normal for a Phase III trial. Not every trial does this, but a considerable number do."

Using Keynote-407 and IMpower150 as examples: in the Keytruda trial, the OS HR changed from 0.64 to 0.71; in the Tecentriq study, OS benefit went from "significant" to "numerical."

An increase in HR can be interpreted as a narrowing of the difference between the two arms, but it remains a statistically significant trial. The trend in ivonescimab's trial is similar to that of other trials and cannot be simplistically characterized as "worsening efficacy."

Chapter 3: Pan-Tumor Expansion

Biliary tract cancer is just the starting point for ivonescimab in gastrointestinal tumors. It is understood that Akeso is studying ivonescimab's potential in colorectal cancer and pancreatic cancer, with the latter being particularly promising.

In first-line pancreatic ductal adenocarcinoma (PDAC), immunotherapy has generally been ineffective, but based on ivonescimab's Phase II data, Akeso believes it has a strong opportunity in the overall first-line PDAC population. Akeso has already initiated a Phase III clinical study in first-line metastatic PDAC in China, planning to enroll 999 patients, with 50% already enrolled.

Even more值得关注的 is the potential synergy between ivonescimab and Revolution Medicines.

Recently, Revolution Medicines achieved approval for a RAS-targeted drug in pancreatic cancer, breaking the years of silence in the field with no targeted therapy breakthroughs. The company's precision therapies targeting the RAS pathway have shifted pancreatic cancer treatment from "no drugs available" to "treatment by subtype," reigniting industry enthusiasm for pancreatic cancer drug development.

Xia believes that targeted therapy and immunotherapy may be complementary in pancreatic cancer. "One could imagine that these PDAC patients could benefit not only from Revolution Medicines' targeted drugs, but also from PD-1/VEGF immuno-oncology drugs like those from Akeso."

In fact, combination studies have already begun. Revolution Medicines and Akeso's overseas partner Summit Therapeutics are conducting a combination study in the U.S. to explore ivonescimab in combination with RAS-targeted drugs; Akeso is advancing Phase III trials of ivonescimab as monotherapy or in combination regimens in PDAC in China. If the data support it, ivonescimab could become the "icebreaker" for first-line immunotherapy in pancreatic cancer.

The story of ivonescimab is a缩影 of Chinese innovative drug companies daring to go "head-to-head" against global standard of care. From lung cancer to biliary tract cancer, from monotherapy challenging Keytruda to combining against Imfinzi, and then to potential synergy with Revolution Medicines in pancreatic cancer — Akeso is attempting to use successive head-to-head data to prove that bispecific antibodies are not just "1+1," but may reshape the competitive landscape of tumor immunotherapy.

But the flip side of the coin is: the stronger the opponent and the higher the expectations, the greater the pressure of interpretation. The biliary tract cancer data at the ESMO conference will be the next critical juncture in whether ivonescimab can prove itself once again amidst the "bloody storm."

References:

1. Statistically significant positive OS results versus international gold standard! Ivonescimab plus chemotherapy meets primary endpoint in Phase III first-line biliary tract cancer trial; Akeso Biopharma

2. Q&A: Akeso CEO spells out why she thinks its biliary tract cancer data are a big deal; Endpoints News