Zanzalintinib
XL092
Zanzalintinib is a third-generation oral TKI that inhibits the activity of receptor tyrosine kinases implicated in tumor angiogenesis, metastasis and immunosuppression, including VEGF receptors, MET and the TAM kinases (TYRO3, AXL, MER). Currently being investigated in phase 3 trials in combination with immune checkpoint inhibitors for nccRCC, CRC and SCCHN. Compared with CABOMETYX® (cabozantinib), the company’s flagship medicine that is approved broadly for advanced RCC, zanzalintinib has the potential advantages of being approved specifically for the ncc histology as well as a broader patient population that includes nccRCC, CRC and SCCHN.
About zanzalintinib
- Exelixis Inc
- Tyrosine kinase inhibitor (TKI) targeting VEGF receptors, MET and the TAM kinases (TYRO3, AXL, MER)
- Once-daily oral administration being investigated in non-clear-cell renal cell carcinoma (nccRCC), colorectal cancer (CRC) and squamous cell carcinoma of the head and neck (SCCHN)
- ~9K new cases of previously untreated (first-line) advanced or metastatic nccRCC in the G7 markets in 2024
- ~131K new cases of previously treated (third- and later-line) metastatic CRC in the G7 markets in 2024
- ~57K new cases of previously- untreated (first-line) recurrent or metastatic non-nasopharyngeal SCCHN in the G7 markets in 2024
Why is it a drug to watch?
Zanzalintinib represents Exelixis Inc’s first in-house compound to enter the clinic following its re-initiation of drug discovery activities in 2017 and represents an important component of the company’s lifecycle management strategy for CABOMETYX, which generated $1.6bn in revenue in the United States in 2023 and is due to come off patent in the United States in 2031. Exelixis Inc sought to build on its extensive experience with the kinase targeting profile of CABOMETYX while improving characteristics such as its pharmacokinetic half-life.
As such, zanzalintinib has a shorter half-life of approximately one day, which supports once-daily dosing and promises more favorable tolerability. With these characteristics and its promising anti-tumor activity, zanzalintinib is positioned to be a best-in-class VEGF-receptor TKI in a wide range of solid tumors when used as a monotherapy, as well as in combination regimens. Initial investigations of combination therapy involve OPDIVO® (nivolumab; Bristol Myers Squibb) for nccRCC, WELIREG® (belzutifan; Merck) for RCC, TECENTRIQ® (atezolizumab; Genentech, a member of the Roche Group) for CRC and KEYTRUDA® (pembrolizumab; Merck) for SCCHN.
The phase 1b/2 STELLAR-001 trial was a dose-escalation and expansion study of zanzalintinib as monotherapy and combination therapy for inoperable locally advanced or metastatic solid tumors. Within the ccRCC cohort, an ORR of 38% and disease control rate of 88% with single-agent zanzalintinib was achieved in previously treated ccRCC patients after a median 8.3 months.
The following pivotal phase 3 trials are currently underway to confirm and expand upon these findings:
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STELLAR-303: adults with microsatellite stable (MSS)/microsatellite instable (MSI)-low metastatic CRC (mCRC) and known RAS status who have progressed during or after or are intolerant to standard of care therapy
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Zanzalintinib plus TECENTRIQ vs STIVARGA® (regorafenib; Bayer)
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Primary analysis includes patients with non-liver metastases (NLM). Approximately 350 NLM patients will be enrolled, while enrollment of patients with liver metastases will be capped at approximately 524.
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Primary endpoint: OS in NLM patients
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Estimated primary completion: August 2025
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Estimated study completion: February 2026
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STELLAR-304: previously untreated adults with unresectable, advanced or metastatic nccRCC
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Zanzalintinib plus OPDIVO vs SUTENT® (sunitinib; Pfizer Inc)
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Primary endpoints: PFS and ORR
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Estimated primary completion: July 2025
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Estimated study completion: June 2028
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STELLAR-305: previously untreated adults with PD-L1-positive recurrent or metastatic SCCHN
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Zanzalintinib plus KEYTRUDA vs placebo plus KEYTRUDA
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Primary endpoints: OS and PFS
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Estimated primary completion: August 2028
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Estimated study completion: March 2029
Actual and expected launch:
- 2026: European Union, United States (CRC and nccRCC)
- 2028: European Union, United States (SCCHN)
Patents estimated to expire beginning in 2039
Drug Timeline & Success Rates
Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of October 31, 2024
How will zanzalintinib impact the market for colorectal cancer, renal cell carcinoma and squamous cell carcinoma of the head and neck?
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Sales of RCC drug therapies in the G7 markets are expected to increase from $9.0bn in 2023 to $12.7bn in 2033 (3.5% CAGR), heavily shaped by the entry of new combination regimens, including zanzalintinib plus OPDIVO for nccRCC.
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The first-line treatment of advanced or metastatic RCC is the largest and therefore most lucrative RCC population, capturing more than 50% of the total RCC market throughout the forecast period. We forecast that sales of the zanzalintinib plus OPDIVO regimen will account for 27% of total RCC sales in this setting in 2033.
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Major-market sales of angiogenesis inhibitors for RCC treatment are expected to decline from $4.5bn in 2023 to $3.9bn in 2033, largely as a result of generic erosion. However, the entry of novel anti-angiogenics for nccRCC will somewhat offset this decline, and zanzalintinib is forecast to be the top-selling angiogenesis inhibitor in 2033 for RCC, with major-market sales of over $1.4bn.
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Major market sales of CRC drug therapies are expected to increase slightly from $9.6bn in 2023 to $12.0bn in 2033 (2.3% CAGR), driven by anticipated drug approvals and label expansions.
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Angiogenesis inhibitors, such as zanzalintinib, and cytotoxic agents are forecasted to dominate the overall CRC market, accounting for 55% of the overall market share in 2033.
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Zanzalintinib will likely help boost sales of TECENTRIQ and other immune checkpoint inhibitors when used in combination therapy for mCRC.
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G7 sales for SCCHN therapies are also expected to increase from $1.6bn in 2023 to $4.3bn in 2033 (10.6% CAGR), driven mainly by the expected approval of high-cost emerging therapies such as zanzalintinib, which is expected to account for 40% of total sales by 2033.
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The first-line treatment of recurrent or metastatic SCCHN represents the bulk of the SCCHN market, accounting for 73% of total market share in 2023. Growth in this setting will also likely be driven by the expected approval zanzalintinib, which could also boost KEYTRUDA sales and further erode patient shares of doublet and triplet chemotherapy regimens, including the EXTREME regimen.
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Collectively, pembrolizumab and zanzalintinib are projected to generate 93% of sales in this setting of first-line treatment of recurrent or metastatic SCCHN in 2033.
What gaps in treatment does zanzalintinib fill?
Approximately 20-25% of patients with RCC have nccRCC, which is a heterogenous group of rare, histologic subtypes with a poor prognosis and limited treatment options. Zanzalintinib could be the first therapy specifically approved for this histology. Patients with SCCHN are often relegated to immunotherapy plus chemotherapy but could benefit from a chemo-free option. Current therapies for mCRC are largely palliative, highlighting a gap in treatments that offer durable benefits in advanced stages. Novel treatment options supported by data from robust clinical trials are needed for all of these indications, and zanzalintinib offers a promising choice for these patients.
What hurdles might it need to overcome to reach blockbuster status?
The aggressive nature of the targeted diseases results in short treatment durations, constraining the sales potential of therapies including zanzalintinib. In addition, combination treatment with zanzalintinib is expected to be significantly more expensive than current standard treatments for the target diseases, which could impact the overall market by potentially limiting patient access and therefore deterring uptake, especially in cost-sensitive regions. Finally, the strong molecular similarities between zanzalintinib and its predecessor cabozantinib could limit sales, along with the launch of cabozantinib generics in Japan in 2030 and in the U.S. and E.U. in 2031. As a result, zanzalintinib will be competing with cabozantinib in RCC, where cabozantinib has a broad label for advanced disease.
