Akeso has data showing ivonescimab can extend the lives of patients with previously treated EGFR-mutated non-small cell lung cancer (NSCLC), results that can give the red-hot PD-(L)1xVEGF bispecific class a boost.
The addition of ivonescimab to chemotherapy significantly reduced the risk of death by 26% in patients with EGFR-mutated nonsquamous NSCLC who had tried an EGFR inhibitor, according to the final analysis of the China-only phase 3 HARMONi-A trial. The data were presented Friday at the 2025 Society for Immunotherapy of Cancer annual meeting.
With a data cutoff in April 2025 and a median follow-up of 32.5 months, patients who got ivonescimab on top of chemotherapy lived a median 16.8 months, whereas those who received chemo and a placebo lived 14.1 months.
The results marked the first time a phase 3 trial of a drug in the hot PD-(L)1xVEGF bispecific class has met the gold-standard overall survival (OS) endpoint.
The statistically significant OS showing is an important win for ivonescimab and reads positive for the bispecific class, according to an Oct. 31 preview of the readout from Leerink Partners analysts led by Daina Graybosch, Ph.D.
The 26% death risk reduction was an improvement from the 20% posted at a median follow-up of 17.6 months back in December 2023. At that time, with OS data maturity at 52%, the median OS was 17.1 months for the experimental arm and 14.5 months for control.
A graphic visualizing the number of deaths shows that starting around 28 months, the roughly 30% remaining patients in the ivonescimab arm experienced relatively stable survival status, with very few new deaths.
A flat tail of the OS curve would be “particularly meaningful” because it would suggest an immune mechanism contributed to the bispecific’s clinical benefit, Graybosch’s team said in the note late last month. Because EGFR-mutant NSCLC is relatively insensitive to immunotherapy, the analysts said the regimen being able to mount a benefit here would increase their confidence that the PD-(L)1xVEGF bispecifics can replace anti-PD-1 inhibitors like Merck & Co.’s Keytruda.
As the likes of Keytruda have never been able to crack into EGFR NSCLC, ivonescimab’s success shows that its bispecific construct is more than just a simple combination of PD-1 and VEGF inhibition, Akeso CEO Michele Xia, Ph.D., said in an interview with Fierce Pharma.
But while the OS win serves as another validation for the closely watched drug class in the broader cancer landscape, ivonescimab may not ultimately win out in this particular indication.
A few days ago, China’s Kelun-Biotech unveiled phase 3 data for its Merck-partnered sacituzumab tirumotecan (sac-TMT) showing the TROP2 antibody-drug conjugate lowered the risk of death by 40% versus chemotherapy in Chinese patients with pretreated EGFR-mutant NSCLC. The ADC achieved that result by itself, unlike ivonescimab, which was added to chemo.
The median OS was not reached by the time of the interim analysis of the OptiTROP-Lung04 trial, versus the median result of 17.4 months for chemo.
In this study, 85.5% of patients in the chemotherapy arm received a subsequent treatment, including 19.6% who got an ADC. For the sac-TMT arm, the numbers were 72.3% and 1.4%, respectively.
In HARMONi-A, 62.7% of patients in the ivonescimab arm and 72% in the control group received subsequent therapies. These include 50.3% and 54% on targeted therapies such as another EGFR inhibitor, 5.6% and 5% on an investigational antitumor drug, and 0% and 1.9% on an ADC.
However, Xia argued that looking more broadly, PD-1xVEGF and TROP2 ADCs could create treatment synergies rather than competition.
The two drug classes approach cancer from two directions. With ivonescimab, Akeso is trying to replace existing PD-1 inhibitors, whereas TROP2 ADCs offer more precise delivery of chemo, Xia noted. That’s why the Akeso CEO suggested that combinations of ivonescimab and ADCs could hold potential in multiple tumor types.
Akeso envisions setting ivonescimab as “the choice of combo with all different types of ADCs to work on all different types of tumor indications,” Xia said.
The company has an internal ADC platform and will report some initial data next year, she added.
A boost for ivonescimab’s profile would be good news for Summit Therapeutics, which holds rights to the drug in the U.S., Europe, Canada and Japan. But as Graybosch noted in her team’s preview, that paradoxically may not entirely be the case here because better outcomes in HARMONi-A would translate into worse performance of the Western subgroup in Summit’s global HARMONi trial.
Recently, Summit’s global HARMONi trial, which had a large portion of its participants from the Chinese HARMONi-A trial, failed on its OS endpoint. Because Western patients were enrolled slower than expected, the HARMONi study reached its preplanned OS analysis threshold while data from the Western portion were still immature. The global trial had a similar design in that it measured the performance of ivonescimab and chemo versus chemo and placebo in previously treated EGFR-mutated NSCLC.
After a longer follow-up of the Western population, Summit recorded what it called a consistent OS showing between Chinese and Western patients. With a median follow-up of 13.7 months, a 16% death risk reduction was observed for ivonescimab in the U.S. and EU, with median OS of 17 months and 14 months for the two trial arms. That’s compared with a 24% improvement, and 16.7 months and 14 months of median OS, respectively, after a median follow-up of 32.7 months in the Chinese subgroup.
The Chinese portion of the HARMONi data appeared to have used the same April 2025 data cutoff as HARMONi-A. The two data sets are slightly different because HARMONi only included about 86% of the HARMONi-A subjects who had tried a third-generation EGFR inhibitor.
Despite the similar OS numbers, Graybosch’s team at that time remained skeptical because Summit didn’t provide Western-specific OS curves, arguing that the Western data, which will be critical for an FDA review, were still immature to support Summit’s regional consistency claim.
A rough comparison of the OS curves between the two trials appears to show a similar pattern, although the onset of ivonescimab’s advantage seems earlier in HARMONi-A, starting at around five months, compared with HARMONi’s separation occurring after 10 months.
As Graybosch pointed out in her Oct. 31 note, it would also be important to understand ivonescimab’s longer-term effects, as well as whether the survival difference between the two treatment arms would narrow among Western patients once they receive powerful subsequent treatments.
At least for now, the two trials’ OS curves don’t indicate any negative pullback from the Western population in HARMONi beyond the first few months. But, again, the follow-up time for the Western population was relatively short.
Despite the lack of a statistically significant OS showing as requested by the FDA, Summit has decided to take a risk and file ivonescimab for approval this year.
As Jefferies analyst Clara Dong, Ph.D., said in a September note, second-line EGFR-mutated NSCLC represents a relatively small market compared with the broader NSCLC opportunity. Summit has recently tweaked the design of its global HARMONi-3 trial that’s pitting ivonescimab against Keytruda in their respective combinations with chemo in first-line NSCLC. The new design will evaluate patients with nonsquamous and squamous cancers separately rather than lumping them together.
“After I saw this long-term final analysis of overall survival of ivonescimab [in HARMONi-A], it really boosted my confidence on the other non-small cell lung cancer results,” Xia said.