The approval of checkpoint inhibitor drugs targeting the PD-1 pathway marked a significant milestone in oncology more than a decade ago, spawning a multi-billion-dollar franchise for Merck & Co. with its drug Keytruda.
While Keytruda has seen runaway success, it only benefits an estimated 20% to 30% of patients when used as a monotherapy, leaving a large number in need of better options, said Denny Lanfear, president and CEO of Coherus Oncology. Coherus is among the companies working to solve that problem by shifting away from a silver bullet approach and moving toward combinations that simultaneously target multiple aspects of tumor biology or boost the effects of checkpoint inhibitors.
Monotherapy trials have become less common. In 2007, approximately 70% of cancer trials were testing a single drug, but by 2021, that number had dropped below 30%. Moderna, Merck and AbbVie are among the biopharma giants testing approaches involving two or more drugs.
These approaches have yielded some success, including Gilead Sciences’ Trodelvy and Keytruda duo, which appears to significantly slow progression in patients with aggressive triple-negative breast cancer compared with standard chemotherapy. Another combination, Moderna’s personalized neoantigen mRNA vaccine, intismeran autogene, and Keytruda, saw favorable results in a recent phase 2 trial in high-risk melanoma. The dual approach reduced the risk of recurrence or death by nearly half compared with Keytruda alone.
“PD-1s work as monotherapy, [but] their biggest success ... has been in combinations that potentiate the immune system,” said Theresa LaVallee, chief scientific and development officer at Coherus.
The risk/benefit ratio
Coherus is building its pipeline around this combination approach.
The biotech recently signed a deal that allows Johnson & Johnson to use its early-stage drug tagmokitug alongside the pharma giant’s pasritamig in a phase 1 prostate cancer trial. The Coherus drug, an anti-CCR8 cytolytic monoclonal antibody, selectively targets tumor-infiltrating regulatory T cells, and using the drugs together may enhance their anti-cancer effects.
Coherus is also testing tagmokitug in combination with its own approved next-generation PD-1 inhibiting monoclonal antibody Loqtorzi for colorectal, head and neck, gastric and esophageal cancer. The dual approach may help overcome a major limitation that prevents PD-1 drugs from working in many patients. While PD-1 drugs can activate immune cells, some tumors don’t have any T-cells inside. Tagmokitug could let external T-cells infiltrate the tumor more effectively.
There are early signs that combination therapies are helping move the needle on outcomes. For example, one review published last year found that combination therapy improved overall survival by 3.8 months and progression-free survival by 1.9 months compared with monotherapy in patients with advanced lung cancer.
But that incremental improvement came at a price with higher rates of serious adverse events. Managing and preventing these risks is one of the primary challenges facing these approaches, which can increase the risk of toxicity. Companies need to balance potency and safety, although some combinations sidestep this drawback.
Coherus’s phase 2 anti-IL-27 antagonist monoclonal antibody casdozokitug, for example, didn’t appear to raise the risk of serious side effects when added to the standard chemotherapy regimen in liver cancer. Early data showed that the combo increased the rate of tumor elimination to 17%, compared with 8% with the standard of care alone, said Dr. Rosh Dias, chief medical officer at Coherus.
These multi-pronged approaches could offer new options for patients with challenging cancers.
“The real opportunity with immunotherapy is long-term survival and hopefully remission,” LaVallee said, noting that combo approaches serve to improve the odds of success.
