PD-(L)1×VEGF bispecifics have emerged as a closely watched new class in immuno-oncology, with multiple candidates advancing through trials in lung cancer. But the potential of these drugs may be highest in cancers where angiogenesis and immune escape are tightly intertwined.
The next wave of immuno-oncology innovation may not come from entirely new mechanisms but from smarter combinations engineered into a single molecule. A case in point: PD-(L)1×VEGF bispecific antibodies. Once viewed as gradual extensions of existing checkpoint and anti-angiogenic therapies, these assets have rapidly become one of the hottest platforms in biopharma, resulting in significant deal-making.
High-value deals such as Akeso’s out-licensing of ivonescimab to Summit Therapeutics (up to $5 billion), Bristol Myers Squibb’s $11.1 billion partnership with BioNTech for pumitamig (BNT327), Pfizer’s multi-billion-dollar deal for SSGJ-707 and Merck’s early bet on LaNova’s LM-229 (MK-2010) collectively signal that this class of bispecifics is being treated as a potential next-generation immuno-oncology platform.
As consultants at Lifescience Dynamics who work closely with clients in biopharma, we believe that while the lion’s share of clinical trials on these candidates have so far explored their use in lung cancer, other cancers may be more fruitful indications for this class. These antibodies target both immune checkpoints and angiogenesis—the formation of new blood vessels to provide nutrients and oxygen to cancer cells, enabling their growth and spread. Thus, in cancers where these processes are intertwined, such as hepatocellular carcinoma, PD-(L)1×VEGF bispecifics could be a one-two punch that knocks down these hard-to-treat malignancies.
A nuanced success story
Lung cancer has emerged as the frontrunner indication for the most advanced PD-(L)1×VEGF bispecifics. Early-stage studies, particularly those reported in China, have yielded high response rates and encouraging progression-free survival data. However, as larger, late-stage trials read out, the picture is proving more nuanced than investment trends alone might suggest.
In first-line squamous non-small cell lung cancer (NSCLC), the China-only Phase 3 HARMONi-6 study reported a clear progression-free survival advantage for ivonescimab plus chemotherapy (11.1 months) compared with the anti-PD-1 tislelizumab plus chemotherapy (6.9 months), with improvements seen across PD-L1 subgroups. Safety was broadly comparable between arms, and the relatively low rate of severe bleeding events (1.9%) is notable given the hemorrhage concerns associated with anti-VEGF therapies in this patient population.
These findings, alongside the progression-free survival (PFS) benefit seen in the HARMONi-2 study of ivonescimab vs. pembrolizumab (anti-PD-1) in first-line PD-L1-positive NSCLC, suggest a degree of consistency for these agents in delivering PFS gains. Based on the positive data, China’s National Medical Products Administration has accepted the supplemental NDA for the ivonescimab regimen, having already approved the HARMONi-2 regimen. However, global regulators, including the FDA and the European Medicines Agency, typically look for a more robust overall survival benefit before considering approval.
For now, the absence of a clear statistically significant overall survival signal from HARMONi-6 introduces an element of caution. A similar pattern has emerged in the global Phase 3 HARMONi trial in previously-treated patients with EGFR-mutant NSCLC where ivonescimab plus chemotherapy delivered a strong PFS improvement versus chemotherapy alone, yet overall survival results have been harder to interpret. That said, in January, Summit announced that the FDA has accepted its Biologics License Application (BLA) for ivonescimab plus chemotherapy, with an action date of November 14.
More recently, Summit’s’ disclosure that ivonescimab failed to reach a statistical bar for PFS in the Phase 3 HARMONi-3 trial in first-line NSCLC at an early interim analysis was met with some disappointment from analysts, with the company’s shares trading nearly 26% down at market close on Friday, May 1. Meanwhile, Merck’s PD-1 x VEGF bispecific, MK-2010, generated an unconfirmed ORR of 55% as a first-line treatment for NSCLC, which some analysts appeared to interpret as competitive but undifferentiated from the data already seen with ivonescimab.
Taken together, the results to date suggest that while PD-(L)1×VEGF bispecifics may deliver robust PFS gains and deeper responses in lung cancer, a clean globally consistent overall survival win has not yet been demonstrated. In the competitive lung cancer landscape, which is saturated with immuno-oncology, chemotherapy and antibody-drug conjugate (ADC) combinations, incremental PFS benefits without an unambiguous overall survival advantage may not reshape standards of care in the clinic.
Normalizing vasculature could be a differentiator
So why are many companies and investors still writing multibillion-dollar checks for this asset class? Mechanistically, colocalizing checkpoint blockade and VEGF inhibition in a single molecule has the potential to normalize tumor vasculature, relieve VEGF-driven immunosuppression and potentially use lower systemic VEGF exposure more effectively than separate anti-PD-(L)1 plus bevacizumab (anti-VEGF) combinations.
While lung cancers may have been the lead indications for PD(L)-1×VEGF bispecifics initially, several companies are starting to investigate the class in Phase 3 studies in other indications, both within and outside of China. PD(L)-1×VEGF antibodies are now being investigated in Phase 3 studies in first-line colorectal, biliary tract, pancreatic and triple-negative breast cancers in China. Elsewhere, Pfizer and BioNTech/BMS appear to have the most advanced programs for PF-08634404 and pumitamig, respectively, with three currently listed non-lung Phase 3 trials for each. In addition, Pfizer’s PF-08634404 is currently being investigated in a Phase 1/2 study in hepatocellular carcinoma, an angiogenesis-heavy tumor.
Notably, as of publication, none of the key assets in this class are in Phase 3 clinical development for hepatocellular carcinoma. The success of atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) as a frontline standard in unresectable hepatocellular carcinoma established a clear mechanistic precedent supporting PD-(L)1×VEGF bispecifics in this indication and offers one of the most derisked paths forward for this asset class outside of lung cancer.
For R&D leaders and investors, the implications are straightforward. While lung cancer may still be treated as a validation arena, the performance of PD(L)-1×VEGF bispecific antibodies in this space should not be viewed as the sole value driver. Displacing entrenched regimens of chemotherapy plus immuno-oncology in lung cancers will likely require a decisive global overall survival win in a head-to-head study against standard of care. Indication selection should therefore be more biology-led, prioritizing highly VEGF-dependent tumors where angiogenesis and immune escape are tightly intertwined. Moreover, China-origin data, while invaluable, must be confirmed in multi-regional populations before being assumed to translate into global practice-changing impact.
The emerging potential of this asset class may therefore be more nuanced than what the headline deal news flow would suggest. While PD-(L)1×VEGF bispecifics may still potentially secure their first approvals in lung cancer, their highest value could lie in tumors where immune and vascular biology are inseparable and where the bar set by first-generation immuno-oncology combinations is eminently beatable.
