Tyrosine Kinase Inhibitor Active in Heavily Treated Renal Cell Carcinoma

NASHVILLE, Tenn. — An investigational multitargeted drug produced objective responses in clear-cell renal cell carcinoma (ccRCC), irrespective of prior exposure to cabozantinib (Cabometyx), a small clinical trial showed.

Overall, 12 of 32 patients responded to zanzalintinib, including four of 17 evaluable patients with prior exposure to cabozantinib and eight of 14 without. All but one patient had some level of tumor shrinkage, and most responses proved durable.

No grade 4/5 treatment-related adverse events (TRAEs) occurred in the RCC cohort, reported Sumanta Pal, MD, of City of Hope in Duarte, California, at the International Kidney Cancer Symposium.

“In STELLAR-001, single-agent zanzalintinib demonstrated significant antitumor activity in patients with heavily pretreated disease,” said Pal. “I think there’s a certain uniqueness to this among the existing landscape of VEGF TKIs [tyrosine kinase inhibitors] with respect to both clinical activity, with response rates we’re seeing with subsequent use in advanced patients, and also with the safety profile.”

“Zanzalintinib is being evaluated in different combinations with immune checkpoint inhibitors in both the first- and second-line setting, and also in a phase III clinical trial in combination with nivolumab [Opdivo] in patients with previously untreated clear-cell renal cell carcinoma,” he stated.

During a discussion, an unidentified audience member pointed out that patients who progress on cabozantinib often respond again to rechallenge with the drug.

“What’s so special about the patients who responded to zanzalintinib?” he asked.

Pal said investigators are continuing to evaluate prior responses to cabozantinib, but three of four responses in the cabozantinib-treated subgroup involved patients with documented progression.

“Your point is very well taken,” said Pal.

On the other hand, another unidentified questioner in the audience called the data “really exciting…I wasn’t necessarily anticipating to see such a high response rate in patients previously treated with cabozantinib. Did you do any digging around in terms of how patients were doing initially on their first TKI? Is this a very responsive population? Or is this really a special drug?”

More of the latter, Pal responded, adding that “there’s something very unique about this drug.”

“You’ll see there are lots of patients with short-term responses to TKI-IO [immuno-oncology] combinations, followed by monotherapy, followed by monotherapy, followed by monotherapy, and then a beautiful response to zanzalintinib,” he continued. “I’ve observed that clinically [in my own patients].”

Zanzalintinib is a multitargeted TKI that inhibits VEGF receptor, MET, and TAM kinases, among others. The drug has a short half-life compared with other TKIs, which could translate into improved tolerability.

Pal reported findings from the phase I, open-label, dose escalation/expansion STELLAR-001 study involving patients with advanced solid tumors. The presentation was limited to the 32 patients with previously treated ccRCC. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) at 6 months.

The patients had a median age of 64 and men accounted for 72% of the ccRCC cohort. About 80% of the patients had intermediate-risk disease, 38% had liver metastases, 63% had lung metastases, and 34% had bone metastases. Two-thirds of the patients had three or more sites of metastasis.

More than 40% of the patients had received three or more prior lines of therapy, and all but one patient had prior exposure to an immune checkpoint inhibitor. Only three patients had responded to their last anticancer therapy, and half had stable disease as best response. About 70% of the patients had prior nephrectomy.

The primary analysis showed an ORR of 38% and a disease control rate of 88%, including 94% of the 17 patients with prior cabozantinib exposure and 86% of patients without. Median duration of response was 7.4 months in patients with no prior exposure to cabozantinib and not yet reached in cabozantinib-experienced patients.

The most common TEAEs (any grade) in the ccRCC cohort were diarrhea (69%); hypertension (41%); asthenia, decreased appetite, and proteinuria (31% each); increased lipase and nausea (25% each); and weight loss (22%). The most common grade ≥3 TEAE was hypertension (16%), followed by increased lipase (9%), asthenia (6%), and nausea (6%).

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