Humaneva Insights

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.

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Episode Summary

In the inaugural episode of Humaneva Insights, host Patrick McManus speaks with Dr. Brandon Fletcher, Head of Medical Affairs and Cell & Gene Therapy at Kapadi, about when a single adequate and well-controlled clinical trial may be sufficient to support an FDA regulatory decision in oncology.

A one-trial pathway is not a shortcut to a lower evidentiary standard. In immuno-oncology, the study still needs to produce evidence that is interpretable, attributable, internally credible, and clinically meaningful. Patrick and Brandon discuss when an exceptional response signal may speak for itself, why uncertainty around causality and contribution of components can still require randomization, and how early design choices determine whether a promising program reaches the application stage with evidence regulators can confidently assess.

Key Takeaways

• One pivotal trial may be sufficient, but it should not be interpreted as less evidence.
• When one study carries the weight of an entire development program, the control arm, population definition, response assessment, missing-data strategy, and endpoint attribution must be defensible from the outset.
• Regulatory strategy, estimand definition, biomarker strategy, imaging methodology, and confirmatory planning should be integrated early rather than treated as downstream activities.
• A very large and durable response may sometimes support accelerated approval in a refractory population with a well-characterized natural history and limited treatment options.
• Combination regimens, heterogeneous post-immunotherapy populations, delayed immune effects, retreatment, and investigator interpretation can make clinically impressive results difficult to attribute.
• Randomized expansion cohorts can establish the contribution of treatment components, reduce dependence on historical controls, and close evidentiary gaps before a traditional phase 3 program.

Featured Expert

Dr. Brandon Fletcher is Head of Medical Affairs and Cell & Gene Therapy at Kapadi. She brings more than three decades of drug development experience, with a deep focus on immuno-oncology and cell and gene therapies. Her work spans clinical development strategy, protocol design, scientific and medical oversight, investigator engagement, and translating complex biology into executable clinical programs. She was an original collaborator with the NCI’s origination of cancer cell and gene therapeutics and has continued in the field of immuno-oncology and genetically modified cell therapeutics since. She co-founded a global philanthropic organization that supports and trains investigators in underserved countries.