Exelixis may only have one drug on the market right now, but with phase 3 results for a potential new blockbuster on the horizon and a growing pipeline, the Cabometyx maker is aiming big. Specifically, the drugmaker intends to become a top 5 solid tumor company by U.S. sales.
“It’s all about building franchises,” Exelixis CEO Michael Morrissey, Ph.D., said in an interview with Fierce on the sidelines of the J.P. Morgan Healthcare Conference in San Francisco.
“It’s all about having the mindset that you’re not going to do one compound for one indication, because the economy of scale doesn’t work,” he added.
Since its first FDA approval more than 13 years ago in medullary thyroid cancer, cabozantinib—sold as Cabometyx and Cometriq—has been Exelixis’ sole approved drug, driving $2.1 billion in U.S. revenues in 2025, according to a preliminary calculation the company unveiled at JPM. Cabozantinib alone has put the California company at No. 10 on the U.S. solid tumor rankings by sales.
Morrissey described cabozantinib as a “franchise molecule,” having recently added its sixth and seventh indications in pancreatic and extra-pancreatic neuroendocrine tumors (NETs), respectively.
Now, Exelixis hopes to repeat the success with zanzalintinib, which the company considers “the foundation of future oncology franchises” with the potential to reach $5 billion in peak annual sales. The company has just filed the next-generation TKI with the FDA for use alongside Roche’s Tecentriq in previously treated metastatic colorectal cancer (mCRC). Several other phase 3 programs are either underway or being planned for earlier stages of disease and in other tumor types.
Zanzalintinib’s first phase 3 readout was not exactly the most exciting outcome that doctors were hoping for. The phase 3 Stellar-303 study linked zanzalintinib to a 20% reduction in the risk of death compared with Bayer’s Stivarga in patients with previously treated mCRC, meeting one of its dual primary endpoints. Patients’ median overall survival was improved by 1.5 months to 10.9 months with the investigational therapy. That limited magnitude of improvement, combined with an increase in grade 3 or higher adverse events, raised a question around whether the combo could be the new standard of care.
The answer to that question is partly dependent on the final analysis of the trial’s other primary endpoint, OS in a subgroup of patients without liver metastases, which Exelixis expects to read out mid-2026.
Despite the modest showing in the study, Morrissey noted that doctors have wanted to use an immunotherapy-based regimen for late-line colorectal cancer, and that Stellar-303 offers them their first hope after multiple prior pivotal trial failures within the PD-1/L1 class.
As for the non-liver metastases population, Morrissey noted that data were getting close to statistical significance at the last analysis. He acknowledged that showing an OS improvement in the subgroup is important “from a marketing point of view” when educating doctors about zanzalintinib’s overall profile, but added that “it’s not a must-have.”
In any case, the bigger fight is not in late-line mCRC. Instead, earlier treatment settings and expansions into other tumor types will be key to zanzalintinib’s success.
“We’re moving up,” Morrissey said, referring to the company’s efforts earlier in the treatment sequence.
Exelixis recently reached a collaboration with diagnostic company Natera, which will provide a ctDNA assay to identify patients with resected stage 2/3 CRC who have completed definitive therapy but still have molecular residual disease (MRD) to enroll in the phase 3 Stellar-316 trial. This is a high-risk population who likely will progress to metastatic disease within about six months to nine months after surgery and adjuvant chemotherapy, Morrissey noted.
Using its ctDNA assay to detect MRD, Natera recently helped Roche turn a previous failure in a broad group of muscle-invasive bladder cancer patients into a phase 3 win in a selective MRD-positive trial population.
Partnering with Natera could also save Exelixis some effort when selecting trial sites.
“They’ve been screening patients for years,” Morrissey said. “So they know the institutions that use it well, they know the investigators that use it a lot, and they know what patients are already MRD-positive. So it’s the ideal setup to be able to lock and load.”
CRC is only piece of the zanzalintinib puzzle. Another major opportunity for the TKI lies in kidney disease, for which Exelixis has formed a clinical development partnership with Merck & Co. In December, Litespark-033, the first Merck-sponsored pivotal trial under the collaboration, kicked off to evaluate zanzalintinib and Merck’s Welireg. A second phase 3 is being planned.
In another major milestone expected this year, the phase 3 Stellar-304 study pitting zanzalintinib and Bristol Myers Squibb’s Opdivo against Pfizer’s Sutent in previously untreated patients with advanced non-clear cell renal cell carcinoma is expected to read out mid-2026.
Collaborating with the competition
Exelixis already knows how to work with Big Pharma through Cabometyx, which Morrissey said highlights the idea of collaborating with the competition. Opdivo was once Cabometyx’s biggest competition in kidney cancer until the CheckMate-9ER trial showed the power of combining the two agents. Results from that trial helped drive a 2.5-fold increase in Cabometyx’s revenue in the ensuing five years, Morrissey said.
Exelixis’ franchise-in-a-molecule plan for zanzalintinib includes other tumor types, although Morrissey is letting data determine the biggest indication.
“Our job is to do the right selection and the right prioritization and then execute at the highest level, and then the data will tell us where to go,” he said.
Even with blockbuster sales pegged to their names, the two TKIs might not be enough to get Exelixis into the “top 5” spot, especially considering that cabozantinib is expected to face generics at the beginning of 2031.
“We probably need more,” Morrissey said.
The CEO, for now, also wouldn’t pick a potential third pillar of the company following zanzalintinib. Exelixis’ earlier-stage pipeline includes antibody-drug conjugates targeting DLL3, 5T4 and tissue factor; a PD-L1xNKG2A bispecific; and molecular glue and degraders targeting KRAS.
On the commercial side, Exelixis has been building out its gastrointestinal cancer sales force following Cabometyx’s NET approvals in March 2025. The hope is that the same sales force can cover zanzalintinib in CRC, too, although Morrissey recognized that the timing of the back-to-back launches may be tight.
“Those are good problems to have if you have to scale the organization, because you’re so successful clinically,” Morrissey said.
But seemingly running counter to a potential business expansion and its lofty corporate aspirations, Exelixis recently launched a reorganization that includes winding down a site in Pennsylvania and 130 layoffs. Morrissey described the overhaul as the final move in his push to implement a back-to-office policy after the pandemic.
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“It concentrates all of our critical mass and all of our brain power in Alameda, [California],” Morrissey said.
While the satellite operation outside of Philadelphia and its big remote workforce “worked okay,” it “wasn’t nearly as effective” as people working together in the same office, the CEO observed.
Exelixis first unveiled the goal to become a “top 5 solid tumor oncology company” during an R&D event in December. During his interview with Fierce, Morrissey put a “U.S.” parameter around that goal because the company has so far relied on partners to handle ex-U.S. markets, including Ipsen in Europe and Takeda in Japan. As the company grows, will it look to build a global footprint?
“We’re looking at that very carefully right now,” Morrissey said. “We’re really analyzing all the options that we have relative to ex-U.S. We have deep expertise, and our commercial organization in the U.S. competes with Big Pharma every single day very effectively. So, we’re obviously going to really retrench in the U.S., and then look carefully at how we operationalize the rest of the world.”