This is a moment of truth for Akeso’s ivonescimab, and for many, a make-or-break test for China’s burgeoning biotech industry. And the first-in-class PD-1xVEGF bispecific did not disappoint, at least when it came to the headline message of overall survival.
Ivonecimab and chemotherapy resulted in a statistically significant 34% improvement in overall survival (OS), making it the first regimen to exceed the established standard of PD-1 inhibitors and chemotherapy in patients with previously untreated advanced squamous non-small cell lung cancer.
The latest overall survival data was generated from an interim analysis of the Phase 3 Harmoni-6 trial conducted in China, and marks the first time that a China-only dataset has been selected for presentation at the prestigious plenary session of the American Society of Clinical Oncology (ASCO) Annual Meeting.
This 34% number exceeded the expectations of many industry watchers, who typically consider a 30% improvement to be a significant accomplishment. Before this revelation, groups within the oncology community were skeptical that Harmoni-6 would meet statistical significance. The p-value was 0.0017, meeting the prespecified statistical significance boundary of 0.0049.
Dr. David Spiegel, president and chief medical officer of the Sarah Cannon Institute and a lung cancer expert at ASCO, said in a press conference that the results are “certainly very encouraging.” The study “offers an important new path forward for patients with difficult-to-treat cancers for whom treatment options are limited,” he said in an ASCO release.
good news
Ever since ivoencimab made headlines in 2024 when it beat Merck & Co.’s Keytruda in progression-free survival (PFS) in a Chinese head-to-head trial in first-line PD-L1-positive NSCLC, questions have been swirling whether bispecific drugs can improve overall survival when compared with PD-1 and chemotherapy in a clinically more appropriate approach.
The original Harmoni-2 trial, which previously showed a 22.3% reduction in mortality risk with ivonecicimab alone versus the single-agent Keytruda, was unimpressive, albeit from an unplanned interim analysis with a very high statistical significance bar.
Furthermore, single VEGF inhibitors have historically proven difficult to deliver overall survival benefit in first-line NSCLC, despite being associated with promising PFS outcomes.
In the latest Harmoni-6 trial, ivonecicimab and chemotherapy increased median overall survival by 4.2 months compared to BeOne Medicines’ Tevinbra and chemotherapy, reaching 27.9 months after a median follow-up of 21.4 months.
The drug’s efficacy appeared to be consistent between PD-L1-negative and PD-L1-positive patients, with OS improvements of 36% and 32%, respectively.
As shown in the phase 3 Rationale-307 trial conducted in China, the median OS of 23.7 months in the control arm was consistent with the historical performance of the Tevinbra chemotherapy regimen of 22.8 months. Additionally, as Spigel pointed out, in the squamous cell subgroup of the Empower-Lung3 trial, Regeneron’s PD-1 drug Libtayo in combination with chemotherapy resulted in a median OS of 21.9 months.
Regarding Keytruda, the median OS for the Keytruda chemotherapy arm in the China expansion portion of the Phase 3 Keynote-407 trial reached 30.1 months, which was widely considered to be an outlier because it was significantly higher than the 17.1 months observed in the global trial.
All things considered, past experience with combining PD-1 and chemotherapy suggests that the survival benefits of ivonecicimab are not driven by poor-performing comparators.
Julie Brammer, M.D., director of the thoracic oncology program at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, who was invited by ASCO to discuss Hamoni-6, also said she was not aware that less intensive subsequent treatments were skewing the overall survival results.
“I’ve had quite a bit of treatment since then, so I’m not really worried about that,” she said in an interview with Fierce. “There was a significant amount of continuous IO.”
Prior to the development of ibonecimab, free-standing VEGF inhibitors such as bevacizumab were strictly prohibited in squamous NSCLC due to the potential for life-threatening bleeding risks.
The PD-1xVEGF bispecific approach now allows squamous NSCLC patients to benefit from anti-VEGF mechanisms.
“PD-1 and chemotherapy aren’t very effective in this patient population, so it’s great to have another option,” Brammer said.
But Brammer’s praises for Harmoni-6 end there.
Despite the positive topline readout and historic overall survival victory, Dr. Brammer pulled out the latest ivonecicimab data in a critical evaluation of patient selection, toxicity, and applicability to the global population.
“Just the fact that the data was positive made me think it was a breakthrough, especially for squamous epithelium,” Brammer said. “But when you look at the details, you can say it’s provocative.”
not so good news
First, on a less negative note, Brammer said he would like to see a long-term follow-up from Harmoni-6.
Typically, in oncology clinical trials, achieving statistical significance early is a commendable feat. Because it shows the power of the drug in just a few events. However, given the experience with VEGF inhibitors in which early positive signals of OS often disappear later, longer follow-up may be more reassuring for physicians considering a PD-1xVEGF approach.
At this interim analysis, median follow-up was less than 2 years, which was shorter than the median OS in both groups.
Dr. Daina Graybosch, an analyst at Leerink Partners, made a similar point in a preview interview with Fierce before looking at the Harmoni-6 data. Assuming a median follow-up of about 19 to 20 months, Graybosch said, “I just happen to think that Harmoni-6 is very immature, so it’s at the tail end of the curve, so we don’t have a lot of data, so I don’t know if we can draw any conclusions.”
At least for now, Harmoni-6’s OS curves recorded deaths in the two treatment groups, which were clearly separated and showed no signs of recovery, according to slides shared by study lead author Xun Lu, MD, PhD, of Shanghai Chest Hospital, School of Medicine, Jiaotong University, during a press conference. This suggests that the benefits for the ivonecicimab and control groups are improving over time, and Brammer said he expects the curve to continue to widen.
Harmoni-6 interim OS, median follow-up 21.4 months. (Shun Lu et al/ASCO 2026)
Brahmer is also less than impressed with the VEGF-related safety profile of the ivonescimab regimen. Bispecificity clearly resolved the bleeding limitations associated with distinct VEGF inhibition, as grade 3 or higher bleeding occurred in only 2.6% of patients in the ivonecicimab chemotherapy group compared with 0.8% of patients in the Tevinbra chemotherapy group. However, overall, Brammer said, there were no significant differences in VEGF-specific adverse events between ivonecicimab therapy and historical independent anti-VEGF agents.
Professor Brammer also criticized the eligibility criteria for Harmoni-6, saying these created uncertainty for clinical oncologists.
Harmoni-6 excluded patients whose tumors significantly invaded, surrounded, or engulfed major blood vessels or who had a history of severe hemoptysis, both of which put them at increased risk of bleeding, Brammer noted. However, this study also found some mild cases with these risk factors.
“Fortunately, some of them were included, so we didn’t see any major safety signals,” she said. “But on the flip side, how do we decide who to put it on and who not to put it on? How do we know that in the clinic, especially in the case of squamous epithelium, because squamous epithelium is more likely to be central (part of the lung), more likely to develop a cavity, more likely to develop hemoptysis?”
Brammer added that while Harmoni-6 was conducted almost exclusively in men, squamous cell trials are generally expected to enroll at least 20% women.
Exclusion based on age also became a major issue for her. The median age of patients in Harmoni-6 was similar to global experience, although the Chinese study uniquely excluded patients over 75 years of age.
The median age of lung cancer patients in the United States is much higher than that of patients in China, Brammer noted, approaching 70 years. For individuals over 65 years of age, the combination of ivonecicimab and chemotherapy had a hazard ratio of nearly 1 relative to the control group, so patients “failed to benefit,” he said. Fierce had not received the complete dataset at the time of publication and was unable to independently verify this data point.
Dr. Brahmer compared this to the landmark ECOG 4599 trial, which tested adding bevacizumab to chemotherapy for NSCLC, but also found no benefit in older patients.
In that trial, researchers found higher rates of toxicity in older patients. This led Brammer to believe that the same phenomenon may have occurred with Harmoni-6, but he does not have that information at this time.
All of this made Brahmer question whether the findings of the Harmoni-6 OS could be applied to people around the world.
“At this point, I would say no. That doesn’t apply to the global patient population,” she said. “We really need the next wave of Harmoni research.”
