PD-1/VEGF bispecifics and the next IO backbone

Episode Summary

Host Patrick McManus speaks with Scott E. Smith, MD, PhD, FACP, Chief Medical Officer at Kapadi, about PD-1/VEGF bispecific antibodies and their implications for immuno-oncology. The opening also considers China’s growing role in oncology innovation and the challenge of making locally generated evidence relevant to global development.

Patrick asks whether ivonescimab is a new molecular design class or a more convenient way to combine familiar targets. Scott discusses cooperative binding, HARMONi-2 and HARMONi-6, and the unanswered question of whether the bispecific format offers an advantage over two separate antibodies. The conversation then turns to programs built on pembrolizumab: what should change for new studies, trials already underway, and settings where VEGF-directed therapy is unsuitable or unproven?

Key Takeaways

• Dual PD-1 and VEGF targeting has precedents. Ivonescimab’s cooperative binding remains a mechanistic hypothesis to test against appropriate alternatives.
• A new backbone could change comparator choice, differentiation, and the relevance of studies using pembrolizumab as their default control.
• The decision depends on indication, trial maturity, the partner drug’s rationale, and whether patients can receive VEGF-directed therapy.

Featured Expert

Scott E. Smith, MD, PhD, FACP, is Chief Medical Officer at Kapadi and a physician-scientist with more than 20 years of leadership in hematology, oncology, and clinical research. As Senior Vice President and Global Head of Hematology at Parexel, he oversaw global clinical trial operations across more than 20 countries. As founder and CEO of Chemosabe Consulting, he has advised more than 15 pharmaceutical and biotechnology companies on clinical development and immunotherapy strategy, contributing to the launch of four hematology and oncology therapies.

Previously, Dr. Smith served as Associate Cancer Center Director and Section Chief of Hematology at Loyola University Medical Center, where he expanded clinical programs and led teams of more than 50 professionals. His work includes bone marrow transplantation, CAR T-cell therapy, precision medicine initiatives, and review for the FDA Orphan Products Development Program. He has authored more than 150 peer-reviewed publications and abstracts and has spoken at international meetings including ASH and ASCO. Dr. Smith earned his MD and PhD at Wayne State University and is board certified in Internal Medicine, Hematology, and Medical Oncology.

Continue the Conversation

Questions about your oncology development strategy? Contact Kapadi: https://kapadi.com/contact. Subscribe to Humaneva Insights for future episodes.

What is Humaneva Insights?

Humaneva Insights is a podcast for the business and operational leaders shaping the future of clinical research. Brought to you by Humaneva Group, a leading clinical research organization with a network of research sites, the podcast explores how to make clinical trials more efficient, overcome operational challenges, and accelerate clinical development. Hear from industry experts and thought leaders on the strategies, trends and innovations shaping the way trials are designed and delivered — and how we can ultimately get treatments to patients faster.

[00:18] PATRICK MCMANUS
Hello and welcome to the second episode of Humaneva Insights. The podcast where we explore the science, strategy, and operational realities shaping the future of drug development. My name is Patrick McManus, and I am happy to host you today. For today's episode, we are looking at what might be one of the most consequential scientific developments in immuno-oncology in 2026. The rapid rise of PD-1/VEGF bispecific antibodies, and particularly the growing attention around ivonescimab.
For much of the past decade, immuno-oncology development has followed a familiar pattern. Begin with an established checkpoint inhibitor, add another therapeutic agent, and ask whether the combination can deliver additional clinical benefit. PD-1/VEGF bispecifics introduce a potentially more disruptive idea. Rather than combine two separate therapeutic strategies, could a single engineered molecule to coordinate checkpoint inhibition and anti-angiogenic activity strongly enough to challenge established standards of care?
The recent clinical data have made that question increasingly difficult to ignore.
The scientific rationale is also compelling. VEGF is not only involved in tumor angiogenesis. It can contribute to immune suppression within the tumor microenvironment by affecting T-cell infiltration, dendritic cell function, vascular trafficking, and the accumulation of suppressive immune populations. Combining PD-1 and VEGF targeting within a single construct, therefore, has the potential to influence both the immune response and the tumor microenvironment in a highly coordinated way. But as with any emerging therapeutic class, the ultimate question will go well beyond early response rates. Overall survival, durability of benefit, safety, exposure, performance across tumor types, and comparison with rapidly evolving standards of care will ultimately determine how significant this approach becomes.
And there is another important dimension to this story. Many of the oncology assets now generating global attention are increasingly originating in China. China is no longer simply an important region for patient recruitment or clinical trial execution. It is becoming a major source of innovative molecules, translational programs, first clinical signals, and randomized evidence. That creates a new strategic challenge for global drug development. How do we translate promising China-generated evidence into a development program that remains scientifically credible, clinically relevant, and regulatorily meaningful across global markets?
Joining us to explore these developments is Dr. Scott Smith, Chief Medical Officer at Kapadi and a physician scientist with more than 20 years of leadership experience across hematology, oncology, clinical development, and translational research. Scott has led global clinical development programs across more than 20 countries, advised pharmaceutical and biotech companies on oncology and immunotherapy strategy, and contributed to the development and launch of multiple hematology and oncology therapies. He has also held senior academic leadership roles and authored more than 150 peer-reviewed publications and abstracts.
In today's episode, Scott will examine why PD-1/VEGF bispecifics may represent more than simply another new class of oncology therapy, and why their emergence, alongside China's growing role as an innovation engine, could reshape the future of global immuno-oncology development.
Welcome, Scott. Great to have you here.

[03:32] SCOTT E. SMITH
Thanks, Patrick for having me here. It's a pleasure to speak to you on this episode of the podcast series.

[03:39] PATRICK MCMANUS
It is always great to have experts like you on board. So this brings me to my first question. Are PD-1/VEGF bispecifics genuinely creating a new immuno-oncology treatment class, or are they simply a more convenient way of combining checkpoint inhibition and anti-angiogenic therapy?

[03:57] SCOTT E. SMITH
That is the right first question, Patrick, because if this is only convenience, we already know how to give PD-1 antibody and an anti-VEGF antibody on the same day.
Start with what is not new. Dual pathway blockade is not a 2026 idea. IMpower150 showed that adding atezolizumab to bevacizumab plus chemotherapy improved outcomes in non-squamous lung cancer. IMbrave150 made atezolizumab plus bevacizumab a first-line standard in hepatocellular carcinoma. PD-1 or PD-L1 drugs have been paired with VEGF or VEGFR agents for years. So if the only claim is we hit PD-1 and VEGF at the same time, that is not a new class. That is new packaging of an old combination.
Convenience is real and is not trivial. One molecule, one pharmacokinetic curve, one infusion, coordinated exposure. Two separate antibodies do not occupy the same pharmacologic window. They have different half-lives, different tissue distribution, and they are dosed on independent schedules. Operational simplicity is a genuine advantage. It is not a scientific one.
The case that this is more than convenience rests on three things. First, the architecture: Ivonescimab is tetravalent. It can engage two PD-1 molecules and two VEGF molecules. VEGF is a dimer, so the antibody can form higher-order complexes. What the binding papers describe as “daisy-chain” or cluster structures. In the presence of VEGF, PD-1 binding avidity increases on the order of 10- to 18-fold, driven mainly by a slower off-rate. PD-1 engagement also tightens VEGF binding on the order of fourfold. Two separately infused monoclonal antibodies did not do that. Bevacizumab plus a PD-1 antibody is dual blockade. It is not cooperative binding. That distinction is the actual design hypothesis.
Second, the clinical pattern is not a simple replay of prior combinations. HARMONi-2 beat pembrolizumab monotherapy in first-line PD-L1-positive non-small cell lung cancer. That is a high bar. The relevant historical contrast is not IMpower150. It is LEAP-007: pembrolizumab plus lenvatinib versus pembrolizumab in a similar first-line PD-L1-positive population. The free combination did not produce an overall survival win. Toxicity went up. The study did not create a new standard. So just add anti-angiogenic therapy to a PD-1 drug has already been tried in this setting and did not automatically work. When a bispecific then beats pembrolizumab, you cannot dismiss that as two familiar drugs sharing a calendar.
Third, in squamous lung cancer, bevacizumab is contraindicated because of life-threatening pulmonary hemorrhage. Two separate antibodies were never a clean clinical option in that histology. HARMONi-6 produced an overall survival win for ivonescimab plus chemotherapy versus a PD-1 inhibitor plus chemotherapy, including in PD-L1 negative disease with grade 3 or higher hemorrhage around 3% versus 1%. That is a setting where this is only a more convenient combination is hardest to defend because the combination was not available.
Now the honest limit: no one has run the experiment that would settle this. There is no randomized trial of a PD-1/VEGF bispecific versus a PD-1 monoclonal antibody plus bevacizumab given as two drugs. Until that exists, you cannot isolate format from dual pathway blockade. You can say the molecule is a new design class. You cannot yet say the format is doing something two antibodies are biologically incapable of doing. Higher-grade 3 treatment-related events in the bispecific arms are also consistent with adding a second mechanism, not only with some unique cooperative magic.
So here is how I would put it. This is a new molecular design class with a live mechanistic hypothesis: cooperative, tumor-localized dual blockade rather than two systemic drugs co-administered.
Convenience is real. Cooperative binding is real in vitro. The phase 3 survival data are real enough that the field has to take the class seriously. What is not yet proven is that the bispecific format is biologically superior to giving the two antibodies separately. That missing head-to-head is the difference between a new treatment class and a more elegant combination. HARMONi-3, and any future study that puts the bispecific against the true dual antibody control, will decide which of these two sentences we get to keep.

[09:00] PATRICK MCMANUS
That really raises the question of whether we are looking at just another treatment option or a potential shift in the foundation of immuno-oncology development. So Scott, if PD-1/VEGF bispecifics outperform established checkpoint regimens, what happens to the large number of IO programs currently using pembrolizumab or another PD-1 inhibitor as their development backbone?

[09:25] SCOTT E. SMITH
They do not all disappear. They get sorted. Pembrolizumab is still the most validated checkpoint inhibitor in oncology. It has overall survival data across a long list of tumors, global approvals, payer coverage, and a generation of physicians who know how to use it. A bispecific winning in first-line lung cancer does not erase that. What it does is change the default assumption that PD-1 plus X is the only way to build an immuno-oncology program.
Think in three buckets. Bucket 1: New starts in settings where the bispecific has already beaten a PD-1 regimen. First-line non-small cell lung cancer is the obvious example if HARMONi-3 confirms what HARMONi-2 and HARMONi-6 have suggested. If you are opening a new phase 3 in that space in 2027, using pembrolizumab as the backbone because that is what everyone used in 2019 is no longer a neutral choice. It is a strategic bet that yesterday's standard will still be the standard when you read out. Regulators and payers will ask why the control was not the emerging standard. Partners will ask why the combination was built on a backbone that may already be losing share. New programs in those indications should treat the backbone as a decision not a default.
Bucket 2: Trials already in flight. This is the uncomfortable group. There are a large number of phase 2 and phase 3 studies designed as novel agent plus pembrolizumab versus pembrolizumab, or novel agent plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy. If those trials are near readout, you finish them. A positive study against the then standard still has scientific value. It may not have the same commercial or practice-changing value if the field has moved. If they are early, sponsors have a real amendment question, stay the course and risk comparator obsolescence, or rebuild around the new backbone and accept delay, new toxicity, and a different statistical plan. There is no free option. The hidden cost of the last decade's PD-1-plus-everything model is that hundreds of protocols assumed the backbone was immortal.
Bucket 3: Settings where the bispecific has not earned the right to replace PD-1. That is most of oncology today, adjuvant and perioperative disease. Most non-lung tumors, patients who cannot take VEGF-directed therapy, recent surgery, high bleeding risk, certain squamous anatomies, uncontrolled hypertension. Those programs should not be stampeded into a backbone swap on the basis of lung data. That would be the same error in reverse, treating one molecule as universal because it won in one histology.
The deeper issue is not pembrolizumab. It is the development model. For 10 years, the industry treated a PD-1 antibody as infrastructure, the thing you build on, the way you used to build platinum. Bispecifics compete in that infrastructure layer, not only as another add-on. That is new. Merck's Keytruda plus X strategy and every me-too version of it now has to answer a different question. Is X still additive when the backbone itself is a dual-mechanism drug with VEGF-class toxicity and a different pharmacokinetic profile? Some combinations will still make sense. Some will become scientifically incoherent. Some will become operationally too toxic.
If I were sitting on a development committee tomorrow, I would ask four questions of every PD-1 backbone program in the portfolio. One: Is the indication one where a PD-1/VEGF bispecific already has or will soon have phase 3 overall survival data against a PD-1 regimen? Two: Is the trial early enough to change the backbone or late enough that the only honest move is to finish and interpret it as a trial against a prior standard? Three: Does the partnered mechanism still have a rationale on top of dual PD-1/VEGF blockade, or was it designed to fix a gap that the bispecific may already close? And four: Can the patients you intend to enroll actually receive VEGF-directed therapy? Programs that survive those four questions stay. Programs that cannot should be redesigned or stopped before they consume another three years and a few hundred million dollars, proving something the field will no longer need.
So the short version, pembrolizumab does not vanish. The unexamined habit of using it as the universal development backbone does. That is part of the immuno-oncology enterprise that actually gets redefined.

[14:18] PATRICK MCMANUS
Thank you, Scott, this has been incredibly insightful. And I think you've given us a lot to think about as we look at where immuno-oncology development may be heading next.
One of the big takeaways from our conversation is that PD-1/VEGF bispecifics may represent much more than another incremental addition to the treatment landscape. If the emerging clinical results continue to hold up, they could begin to redefine what we think of as the standard immuno-oncology backbone, and that has important implications for the many development programs currently built around pembrolizumab and other PD-1 inhibitors. For sponsors, the question may increasingly become not simply whether those programs still work, but whether their scientific rationale, positioning, comparator strategy, and level of differentiation remain competitive in a rapidly changing landscape. Scott, thank you again for joining us and for sharing your perspective.
And to everyone listening, thank you for joining us for this episode of Humaneva Insights. If you enjoyed the conversation, make sure to subscribe to the podcast so you don't miss any of our upcoming episodes. And if today's discussion raised questions about what these changes could mean for your own oncology development strategy, we'll be happy to continue the conversation. You'll find the contact information in the show notes. Thanks for listening, and we'll see you next time on Humaneva Insights.