– Results for Exelixis’ next-generation tyrosine kinase inhibitor demonstrated an objective response rate of 38% and a disease control rate of 88% –
– Anti-tumor activity was observed in patients who had progressed on prior VEGFR-tyrosine kinase inhibitors, including cabozantinib –
ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced initial results from an expansion cohort of STELLAR-001 evaluating single-agent zanzalintinib in patients with previously treated clear cell renal cell carcinoma (ccRCC). STELLAR-001 is a phase 1b trial evaluating zanzalintinib alone and in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. The findings are being presented today at 2:35 p.m. CST during the Oral Abstracts session at the 2023 International Kidney Cancer Symposium (IKCS): North America.
“Following promising activity in the dose-escalation stage, I am further encouraged by the anti-tumor activity observed in the monotherapy expansion cohort suggesting that zanzalintinib may be an effective therapy following disease progression after prior treatments,” said Sumanta Pal, M.D., Clinical Professor, City of Hope Comprehensive Cancer Center, who is presenting the findings. “Many of these patients with advanced kidney cancer have exhausted their treatment options, having progressed on both immune checkpoint inhibitors and tyrosine kinase inhibitors including cabozantinib, so these results showing strong response rates and durable responses are encouraging for this group of patients.”
In this ccRCC cohort, 97% of patients had received prior immunotherapy and 81% had received prior VEGFR-tyrosine kinase inhibitor (TKI), including 53% who had received cabozantinib. Eighty-one percent of patients were intermediate risk by International Metastatic RCC Database Consortium.
At a median follow-up of 8.3 months, 12 of the 32 patients enrolled in the expansion cohort had a confirmed partial response for an objective response rate of 38%; the disease control rate was 88%. Additional efficacy outcomes by prior therapy subgroups are shown in Table 1.
All patients |
Patients who received a prior VEGFR-TKI |
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TABLE 1 |
Overall (n=32) |
Cabozantinib-exposed (n=17) |
Cabozantinib-naïve (n=14) |
Any VEGFR-TKI, including cabozantinib (n=26) |
Non-cabozantinib VEGFR-TKI (n=8) |
Objective response rate, % |
38 |
24 |
57 |
35 |
63 |
Disease control rate, % |
88 |
94 |
86 |
92 |
100 |
Subgroups are not mutually exclusive. Prior cabozantinib exposure was unknown for one patient. VEGFR-TKI: vascular endothelial growth factor receptor-tyrosine kinase inhibitor. |
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At data cutoff, 50% of patients were continuing treatment. The median duration of response was 7.4 months for the cabozantinib-naïve group and not estimable for the cabozantinib-exposed group.
“These findings underscore the potential zanzalintinib may hold for patients with refractory kidney cancer, including those who have previously progressed on cabozantinib,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “As STELLAR-001 and our phase 3 STELLAR trials progress, we look forward to elucidating the potential of zanzalintinib in kidney cancer as well as in other advanced solid tumors.”
The safety population (n=81) included 32 patients from the ccRCC expansion cohort treated at 100 mg plus 49 patients across different solid tumors from the dose-escalation stage who received single-agent zanzalintinib at doses ranging from 10-140 mg. The safety profile was similar between the ccRCC cohort and the safety population. Discontinuations due to treatment-related adverse events (AEs) occurred in 9% of patients in the ccRCC cohort and 12% of patients in the safety population. There were three grade 5 treatment-emergent AEs in the ccRCC cohort and two more in the safety population; none were treatment-related, nor was the single grade 4 event. Of note, the rate of palmar plantar erythrodysesthesia was low with zanzalintinib (9% in the ccRCC cohort and 12% in the safety population, all grade 1-2).
About STELLAR-001
STELLAR-001 (NCT03845166) is a global, open-label phase 1b/2 study of zanzalintinib as a single agent or in combination with atezolizumab in patients with inoperable locally advanced or metastatic solid tumors. The trial is divided into two parts: a dose-escalation stage and an expansion cohort stage. The expansion cohorts evaluating zanzalintinib as a single agent or in combination with atezolizumab include patients with: ccRCC, non-clear cell RCC, breast cancer that is hormone receptor-positive and HER-2 negative, castration-resistant prostate cancer and colorectal cancer. More information about the trial is available at ClinicalTrials.gov.
About Zanzalintinib
Zanzalintinib 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 immune checkpoint inhibitors. With 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, colorectal and head and neck cancers.
Zanzalintinib is not approved for ccRCC.
About RCC
Kidney cancer is among the top 10 most commonly diagnosed forms of cancer among both men and women in the U.S.1 An estimated 81,800 Americans will be diagnosed with kidney cancer in 2023.1 The most common type of kidney cancer in adults is ccRCC.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 15%.3 In 2022, approximately 32,200 patients with advanced kidney cancer required systemic therapy in the U.S., with over 20,000 patients receiving first-line treatment.4
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.
CABOMETYX IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and 3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in