Zanzalintinib a potential ‘novel breakthrough’ in advanced clear cell renal cell carcinoma
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NASHVILLE, Tenn. — Zanzalintinib monotherapy showed promising antitumor activity among patients with previously treated clear cell renal cell carcinoma, according to findings presented at International Kidney Cancer Symposium: North America.
The agent also exhibited a manageable toxicity profile, researchers reported.
“We have reached a bit of a plateau in terms of treatment for metastatic renal cell carcinoma, and we’re really in dire need of new therapies,” Sumanta Kumar Pal, MD, FASCO, co-director of City of Hope’s kidney cancer program and a Healio | HemOnc Today Editorial Board member, told Healio. “Zanzalintinib, I think, represents a very unique and novel breakthrough for kidney cancer.”
VEGFR-targeted tyrosine kinase inhibitors are standard care for advanced renal cell carcinoma.
Zanzalintinib (XL092, Exelixis) — a next-generation tyrosine kinase inhibitor in development for multiple tumor types — targets VEGFR, MET and TAM kinases. Its short half-life may result in improved tolerability, according to study background.
The STELLAR-001 trial evaluated zanzalintinib as a single agent or in combination with the anti-PD-1 monoclonal antibody atezolizumab (Tecentriq, Genentech) for patients with locally advanced or metastatic solid tumors.
Pal presented results of an expansion cohort that evaluated zanzalintinib monotherapy for patients with advanced, metastatic or recurrent clear cell renal cell carcinoma.
The analysis included 32 adults (median age, 64 years; range, 39-79; 72% male) with measurable disease per RECIST 1.1 criteria and ECOG performance status of 0 or 1. All patients developed radiographic progression on at least one prior systemic therapy for inoperable, locally advanced or metastatic disease.
Most (81%) had intermediate-risk disease per International Metastatic RCC Database Consortium criteria, and 6% had poor-risk disease. Approximately one-third had liver metastases (38%) or bone metastases (34%), and 21 patients (66%) had three or more metastatic sites.
Patients had received a median two prior therapies (range, 1-3). Thirteen patients (41%) had received at least three prior therapies, 31 (97%) had received prior immune checkpoint inhibitor therapy, 26 (81%) had received prior VEGFR TKI and 17 (53%) had received prior cabozantinib (Cabometyx, Exelixis).
A higher percentage of cabozantinib-exposed than cabozantinib-naive patients had ECOG performance status of 1 (59% vs. 36%) and had received three or more prior lines of therapy (59% vs. 14%).
Patients received zanzalintinib at a starting dose of 100 mg once daily. Objective response rate and PFS at 6 months per investigator assessment served as key outcome measures. Safety served as a secondary endpoint.
Researchers evaluated outcomes in the entire cohort, as well as by prior exposure to cabozantinib.
Median follow-up was 8.3 months (range, 5.7-13.7), and 50% of patients remained on study treatment at data cutoff.
Researchers reported a 38% ORR, with 12 patients achieving partial response and 16 exhibiting stable disease. This equated to an 88% disease control rate.
A higher percentage of cabozantinib-naive patients than cabozantinib-exposed patients responded to treatment (57% vs. 24%). Most patients in the cabozantinib-naive and cabozantinib-exposed groups exhibited disease control (86% vs. 94%).
Analyses of patients who received prior VEGFR TKI therapy but had not received prior cabozantinib showed a response rate of 63%, with all patients achieving disease control.
“Most individuals looking at TKI therapy in renal cell carcinoma would not necessarily expect to see such high response rates in the salvage setting,” Pal told Healio. “The cumulative response rate of 38%, and a response rate that surpasses 60% for TKI-pretreated, cabozantinib-naive patients is quite exceptional.”
Researchers reported median response durations of 7.4 months (95% CI, 3.3 to not estimable) among cabozantinib-naive patients and not yet reached (95% CI, 3.7 to not estimable) among cabozantinib-exposed patients.
Safety analyses included the 32 patients from the expansion cohort plus 49 patients from a dose-escalation cohort who received single-agent zanzalintinib for different solid tumors.
Results showed no treatment-related grade 4 or grade 5 adverse events.
In the combined safety cohort, 43 patients (53%) required dose reductions and 65 (80%) required dose holds due to treatment-emergent adverse events. Sixteen patients (20%) discontinued therapy due to treatment-emergent adverse events and 10 (12%) discontinued therapy due to treatment-related adverse events.
“Rates of diarrhea, hypertension and asthenia — side effects we have become accustomed to with TKI strategies — appear to be a bit lower with zanzalintinib — particularly with regard to grade 3 or grade 4 effects,” Pal said. “Also, rates of stomatitis and hand-foot syndrome were particularly low.”
Zanzalintinib is being evaluated in combination with immune checkpoint inhibitors in first- and second-line treatment for clear cell renal cell carcinoma, and a phase 3 study is underway to assess the agent in combination with nivolumab (Opdivo, Bristol Myers Squibb) for patients with previously untreated non-clear cell renal cell carcinoma.
“There is a lot of promise with zanzalintinib,” Pal said. “I think this is an agent that we will be exploring in-depth across multiple disease settings, and there are multiple avenues that are being looked at with zanzalintinib as part of combination therapy.”
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Pal S, et al. Abstract 1. Presented at: IKCS: North America; Nov. 9-11, 2023; Nashville, Tenn.
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