Exelixis has confirmed the initiation of STELLAR-304, a phase 3 pivotal trial evaluating zanzalintinib in combination with nivolumab (Opdivo®; Bristol-Myers Squibb) versus sunitinib (Sutent®; Pfizer) in patients with advanced non-clear cell renal cell carcinoma (nccRCC).
The American Cancer Society’s 2022 statistics cite kidney cancer as among the top 10 most commonly diagnosed forms of cancer among both men and women in the U.S/  Clear cell RCC is the most common type of kidney cancer in adults.  nccRCC represents about 20-25% of RCC cases, with fewer treatment options available and poorer outcomes compared with clear cell RCC. 
If RCC is detected in its early stages, the five-year survival rate is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 14%.  Approximately 33,000 patients in the U.S. and more than 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2022, with over 15,000 patients in need of a first-line treatment in the U.S. 
Next-generation tyrosine kinase inhibitor
Zanzalintinib, which was adopted as the generic name for XL092, is a next-generation tyrosine kinase inhibitor (TKI) in development for multiple advanced tumor types.
The investigational drug is a next-generation oral TKI that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and resistance to multiple therapies, including ICIs.
In designing zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life.
Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary cancers, as a monotherapy and in combination with ICIs.
Phase 1 data
“In September at ESMO 2022, we presented zanzalintinib phase 1 data which demonstrated promising clinical activity across a range of tumors with a manageable safety profile. We were particularly encouraged by the activity of zanzalintinib in advanced kidney cancer patients, including patients with non-clear cell subtypes,” noted Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis.
“Based on this zanzalintinib data and given that nivolumab has shown activity in non-clear cell kidney cancer, we are excited to evaluate this combination regimen in this population in STELLAR-304,” Goodman added.
“STELLAR-304 is the first and only randomized controlled phase 3 study to focus specifically across non-clear cell renal cell carcinoma subtypes, a patient population with limited clinical data and poorer treatment outcomes. We look forward to continuing our legacy of working towards improving care for all kidney cancer patients,” Goodman further said.
Phase 3 Study design
STELLAR-304 is a global, multicenter, randomized phase 3 open-label study that will enroll approximately 291 patients with unresectable, locally advanced or metastatic nccRCC with no prior systemic anticancer therapy. One prior systemic adjuvant therapy, including immune checkpoint inhibitor (ICI) therapy and excluding sunitinib, is allowed for completely resected RCC and if recurrence occurred at least six months after the last dose of adjuvant therapy. Patients will be randomized 2:1 to receive either zanzalintinib in combination with nivolumab or sunitinib monotherapy.
The primary objective of the study is to evaluate the efficacy of the combination, as measured by duration of progression-free survival and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the Blinded Independent Radiology Committee. The secondary endpoint is duration of overall survival.
STELLAR-304 is sponsored by Exelixis, and Bristol Myers Squibb is providing nivolumab for the trial.
Study of XL092 + Nivolumab vs Sunitinib in Subjects With Advanced or Metastatic Non-Clear Cell Renal Cell Carcinoma (STELLAR-304) – NCT05678673
 American Cancer Society: Cancer Facts & Figures 2022. Online. Last accesses December 22, 2022.
 Jonasch, E., Gao, J., Rathmell, W., Renal cell carcinoma. BMJ. 2014; 349:g4797.
 Bilen, M.A. Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities. Cancers (Basel). 2021; 13(15):3652.
 Decision Resources Report: Renal Cell Carcinoma. October 2014 (data on file at Exelixis)
Featured image: Human kidney cross section. Photo courtesy: © 2019 – 2022 Fotolia/Adobe.