Ivonescimab Results: The Study That Launched a Thousand Ships

Dr. John Heymach from MD Anderson Cancer Center discussed the ivonescimab data from HARMONi-2 at the World Congress of Lung Cancer Meeting in 2024.

He recently joined the Uromigos podcast to provide more color commentary on the results of the trial and the impact on the Lung Cancer research community. He also discussed the potential to see similar efficacy benefits in Kidney Cancer with Dr. Brian Rini and Dr. Tom Powles.

"This has shaken the field..."

"I would say this has shaken the field and up more so than any study presented in the last several years maybe in memory in terms of outperforming expectations."

The HARMONi-2 trial comparing ivonescimab (PD1-VEGF bispecific) to pembrolizumab in lung cancer certainly made waves. While the hazard ratio of 0.51 is impressive, skeptics note this China-only trial hasn't yet shown overall survival benefits - the true gold standard in NSCLC.

"Absolutely shocking"

"Really what was absolutely shocking to us was the magnitude of benefit for ivonescimabessimab versus pembrolizumab PFS hazard ratio 0.51."

Dr. Heymach didn't hide his surprise at seeing PFS double from 5.8 to 11 months. The dramatic improvement stands in stark contrast to previous VEGF-targeted approaches in combination with immunotherapies. 

"Doubled PFS"

"I would have expected maybe a month or two improvement in PFS, but it basically doubled the PFS from 5.8 months to 11 months."

Doubling progression-free survival is undeniably noteworthy. However, the comparison against pembrolizumab monotherapy (rather than chemo+PD1) in a PDL1<50% population differs from typical US/European practice, potentially limiting real-world applicability.

"Hand waving"

"I don't know, I'd be, I'd be hand waving here. I mean, what I can say in terms of the phenomena here is they do appear to have a better than expected toxicity profile and dramatically greater activity than we'd seen for any combination of PD1 and VEGF or VEGFR 2 inhibition.

Dr. Heymach candidly acknowledged the speculative nature of explaining why this VEGF-targeting approach succeeded where others failed. The proposed "oligomerization" mechanism offers a plausible theory but remains unproven - refreshing scientific humility amid the excitement.

"1100..1200 hundred ships"

"Based on the number of different drugs we've heard about in the past couple of months that are coming along, I think it's probably about 1100...1200 ships, not just 1000 ships."

This colorful exaggeration captures the industry buzz, with competitors already developing similar bispecifics. The enthusiasm has sparked considerable investment despite lingering questions about generalizability beyond Chinese patients and the conspicuous absence of survival data.

"Too good to be true?"

"You know, I think this is everybody's first thought that this may be just Pembro had a bad day or Ivo had a good day."

The hosts' direct question received an interesting response - Heymach acknowledged initial skepticism but suggested accumulating evidence across multiple trials supports ivonescimab's efficacy. 

The field eagerly awaits phase 3 results in Western populations that could confirm these promising findings.