PD-1/VEGF Inhibitors: The Next Frontier in Cancer Immunotherapy

A new class of cancer drugs targeting both PD-1 and VEGF pathways has emerged as a potential successor to Merck's blockbuster immunotherapy Keytruda, sparking a wave of research and investment across the pharmaceutical industry. These bispecific antibodies aim to combine the benefits of checkpoint inhibition and anti-angiogenesis in a single molecule, potentially offering improved efficacy and broader applicability in cancer treatment.

Ivonescimab Takes Center Stage

Summit Therapeutics and Akeso's ivonescimab has become the poster child for this new approach, with striking Phase 3 results in non-small cell lung cancer. The drug demonstrated a significant advantage over Keytruda, reducing the risk of disease progression by half and extending progression-free survival by nearly six months.

"This really was a 'black swan' event," said Allen Yang, Summit's chief medical officer. "It's clearly what everybody's been looking for."

However, questions remain about ivonescimab's overall survival benefit and its performance against the current standard of care combining Keytruda with chemotherapy. Crucial data expected later this year and in 2025 could validate the drug's potential as a new cornerstone of cancer therapy.

A Crowded Field of Contenders

In the wake of ivonescimab's success, more than a dozen companies have entered the PD-1/VEGF inhibitor race. Notable players include:

• BioNTech, with BNT327 in Phase 3 trials for lung cancer and Phase 2 for triple-negative breast cancer
• Merck, which recently acquired rights to LaNova Medicines' MK-2010/LM-299
• Ottimo Pharma, a startup led by industry veteran David Epstein, developing jankistomig
• Crescent Biopharma, with its candidate CR-001 expected to enter clinical trials in late 2025

Each company touts unique features of their molecules, from improved binding affinities to enhanced stability and manufacturability. The sheer number of entrants, however, has led some experts to question how many will ultimately succeed in this competitive landscape.

Mechanism of Action and Potential Advantages

PD-1/VEGF inhibitors aim to simultaneously unleash the immune system against cancer cells and cut off the tumor's blood supply. This dual mechanism could potentially overcome limitations of current therapies, particularly in "cold" tumors that don't respond well to existing immunotherapies.

Proponents argue that combining these functions in a single molecule may offer synergistic benefits beyond what's achievable with separate drugs. "We believe that those two features make ivonescimab, and the whole class of PD-1/VEGFs, unique," said Yang.

However, safety concerns persist, particularly regarding the management of VEGF-related side effects when the entire drug must be discontinued. The true extent of these drugs' efficacy and safety profiles will only become clear with more extensive clinical testing.

As the pharmaceutical industry eagerly awaits further data, the potential of PD-1/VEGF inhibitors to reshape cancer treatment remains a topic of intense interest and debate. The coming years will reveal whether these drugs can truly dethrone established therapies and usher in a new era of cancer immunotherapy.