Exelixis is a biopharmaceutical company headquartered in Alameda, California, that specializes in oncology. Working with both small molecules and biotherapeutics, it discovers, develops and commercializes treatments for difficult-to-treat cancers.
Exelixis has been on quite a journey over its 30-year history. How has its scientific focus evolved from when it began to where it is today?
I often say that success in biotech never follows a straight line, and our company name "Exelixis" – Greek for evolution – reflects a focus on constant growth and change. The company’s technology platform initially centered on studying model organisms like flies, fish, and worms to understand genetic pathways and networks relevant to human diseases. This was a controversial approach in the mid-90s but has since become widely accepted.
Over the years, we have evolved from biology-centric research to a drug discovery and development focus. When I became CEO in 2010, we prioritized cabozantinib, which has become a leading tyrosine kinase inhibitor (TKI) in kidney cancer. It was first approved in 2012 and now has multiple indications. This success allowed us to build a pipeline, including our next-generation molecule, zanzalintinib, which we believe will further advance oncology treatments.
Do you think we are on the cusp of breakthroughs in cancer treatment, or is it more of an evolving fight, as the company name suggests?
It is an excellent question. Fighting cancer is not a static battle; it is a constantly evolving challenge as tumors adapt to therapeutic interventions. This means most cancers cannot be controlled long-term with a single compound or approach. Progress typically comes in incremental steps with occasional breakthroughs, followed by plateaus. For instance, the immuno-oncology advances from 2010 to 2020, particularly with anti-PD-1 and -PD-L1 molecules, were the result of decades of foundational research to find an elegant way to unlock the immune system to fight cancer.
Despite significant efforts in the past decade to build on these successes, further breakthroughs in immuno-oncology have been elusive. Progress in oncology requires substantial investment in basic research and resilience in the face of frequent failures, especially in clinical trials. Even approved drugs don’t always guarantee commercial success, adding stress to the ecosystem. It is a tough business, but with continued innovation and persistence, we do make meaningful strides in fighting this complex disease.
What is the promise of tyrosine kinase inhibitors (TKIs) in cancer treatment?
TKIs target the signaling mechanisms of proteins involved in cellular communication, particularly at the cell surface. These kinases drive pathways like angiogenesis, which supports blood vessel formation in tumors, and tumor growth itself. Our focus on TKIs began in the mid-2000s, driven by the question of how to combat tumor resistance. Cabozantinib was developed to address both primary tumor drivers and resistance mechanisms within a single molecule—a concept based on fundamental tumor biology principles.
The challenge is in proving this approach in clinical trials. Drug development requires building a molecule capable of fulfilling its intended function and then demonstrating efficacy through rigorous, randomized trials. Each stage, from lab research to regulatory approval and commercial success, is independent, so success in one stage doesn’t guarantee the next. With cabozantinib, we have succeeded across these steps, helping tens of thousands of patients with kidney, liver, and thyroid cancers weekly.
What excites you most about Exelixis’ current pipeline?
Overall, we have a strong discovery effort and about 10 molecules in preclinical development and clinical trials. Our next-generation TKI, zanzalintinib, is currently in three pivotal trials, with three more planned soon. These trials are essential for proving efficacy and safety, with a second wave of studies to follow. We are also exploring antibody-drug conjugates (ADCs) that deliver targeted cytotoxic chemotherapies and bispecific antibodies, which enhance precision by targeting two cell types simultaneously.
Another ongoing process is our investigation of synthetic lethality, using combinations of molecules to selectively kill tumor cells. A standout is XL309, a USP1 inhibitor in early clinical evaluation. Across the board, our technologies—like cryogenic electron microscopy for atomic-level imaging and machine learning tools—are enhancing our discovery and development. We take a Darwinian approach to the pipeline based on generating decisive data to guide investments in promising molecules, while reallocating resources from less viable ones.
Exelixis’ efforts increasingly seem to bridge biotech and pharma. In what ways are those industries becoming intertwined?
Traditional pharma companies now have significant protein-based therapeutic portfolios, while smaller biotech firms like us are also exploring areas traditionally associated with pharmaceuticals, such as small molecules. The democratization of technology means everyone can access similar tools, so it is about creativity, asking the right questions, and having the right team to execute. This blend of biotech and pharma approaches is part of the charm of the current industry landscape.
At the end of 2024, Exelixis announced a clinical development collaboration with Merck to apply zanzalintinib in a combination therapy. Can you explain what that is?
We have historically partnered with competitors to combine molecules and achieve better outcomes for patients. For example, we collaborated with Bristol Myers Squibb on the cabozantinib-nivolumab combination in the CheckMate -9ER study, which was pivotal in kidney cancer. Similarly, we have worked with Roche/Genentech on cabozantinib and atezolizumab, and now with Merck on zanzalintinib and its molecules, pembrolizumab and belzutifan. These collaborations are a vital community effort where everyone—patients, companies, and investors—can benefit.
What clinical or commercial achievements can we expect from Exelixis in 2025?
We are in a dynamic phase of growth and 2025 promises to be an exciting year. Key milestones include the potential launch of cabozantinib for neuroendocrine tumors, pending FDA approval. This indication is significant, as only one new targeted molecular therapy has been approved in over a decade for these patients, who live with a slow-growing but debilitating disease. For zanzalintinib, we expect pivotal trial results in colon cancer in 2025. Additional zanzalintinib trials in kidney and head and neck cancers are progressing quickly, and early clinical data in kidney cancer could emerge in 2025 while phase 2 data in head and neck cancer will determine if we move forward with the phase 3 portion of the trial.
