Novel TKI Zanzalintinib Confers Promising Antitumor Activity in Advanced ccRCC

Patients with previously treated advanced clear cell renal cell carcinoma (ccRCC) receiving single-agent zanzalintinib (XL092) demonstrated promising antitumor activity with a manageable toxicity profile, according to initial results from the STELLAR-001 trial (NCT03845166) presented at the 2023 congress. International Symposium on Kidney Cancer.1

Antitumor activity was observed in patients regardless of whether or not they had been previously treated with cabozantinib (Cabometyx). The majority of patients in both groups (naïve or exposed to cabozantinib) achieved disease control.

“In STELLAR-001, we saw that zanzalintinib had significant antitumor activity in patients with heavily pretreated disease,” said Sumanta Kumar Pal, MD, professor in the department of medical oncology and therapeutic research at City of Hope Comprehensive Cancer Center in Duarte, California. during the presentation. “I think there’s some uniqueness here among the existing landscape of VEGF TKIs with respect to both the clinical activity with the responses we’re seeing with subsequent use in advanced patients, but also with respect to the safety profile of the therapy.” “.

Findings presented at the meeting focused on single-agent zanzalintinib in patients with ccRCC, including evaluation of outcomes categorized by prior cabozantinib exposure.

“This public is well aware that VEGF TKIs, including cabozantinib, truly represent a cornerstone of the treatment of advanced renal cell carcinoma,” Pal said.

Zanzalintinib is a novel tyrosine kinase inhibitor that targets VEGFR, MET, and TAM kinases.

“We hypothesized that, due to its short half-life, (zanzalintinib) may have improved tolerability,” Pal said during the presentation. “VEGF receptors, MET and TAM kinases are involved in tumor growth, angiogenesis and immunosuppression within the tumor microenvironment. “And we believe that targeting MET and TAM kinases, in addition to VEGF receptors, can potentially prevent resistance to VEGF receptor inhibition.”

The researchers analyzed data from 32 adult patients with advanced, metastatic, or recurrent ccRCC, and those with sarcomatoid presentation were allowed. Patients also had to have an ECOG score of 1 or 0, have inoperable, locally advanced, or metastatic disease, and have previously received 1 to 3 prior systemic anticancer therapies. Patients in this ccRCC expansion cohort were treated with a daily dose of 100 mg of zanzalintinib.

The primary endpoints of this study included objective response rate (ORR) and progression-free survival (PFS) at 6 months according to RECIST v1.1 by the investigator. The secondary endpoint was safety, with exploratory endpoints including PFS and duration of response (DOR) per RECIST v1.1 by the investigator, as well as overall survival (OS).

Pal noted that the age and gender distribution of patients in this study was typical of the CRC population, with a median age of 64 years (range, 39-74) and 72% male. Eighty-one percent of patients had intermediate-risk disease.1

“The patient characteristics here really suggest a bit of an aggressive phenotype within this cohort; “38% and 34% of patients included in this cohort had liver and bone metastases,” Pal said.

It also noted that 41% of patients had received at least 3 prior lines of therapy, 97% of patients had previously received immune checkpoint inhibitors, and 81% of patients had previously received VEGF TKIs, and more than half of the patients had previously received cabozantinib.1

The ORR was 38% in this group of patients, of whom Pal noted that he was “impressed to see…with this kind of overall aggressive phenotype achieve very profound responses to therapy.” Patients had a disease control rate of 88%. Looking only at patients previously treated with cabozantinib, they had an overall response rate of 24% and a disease control rate of 94%. For patients who had not previously been treated with cabozantinib, the response rate was 57% with a disease control rate of 86%.

The investigators also evaluated responses in approximately 80% of patients who had previously received VEGF TKIs. When cabozantinib was included, the response rate was 35% with a disease control rate of 92%. Once cabozantinib was excluded, the response rate was 63% and all patients achieved disease control.1

“Importantly, 3 of the 4 (cabozantinib)-exposed patients who responded to zanzalintinib had actually discontinued prior cabozantinib treatment due to prior disease progression on (cabozantinib),” Pal said during the presentation.

The median DOR for cabozantinib-naïve patients (n = 14) was 7.4 months (95% CI, 3.3, not evaluable (NE)), while it was not yet reached in patients who were exposed to cabozantinib (n = 17). At a median follow-up of 8.3 months (range, 5.7-13.7), half of patients were continuing treatment and 75% of responses occurred at the first postbaseline tumor evaluation. Pal noted that this included all responders who had previously received cabozantinib therapy.

Safety was assessed in 81 patients in the safety population and compared to 32 patients in the ccRCC cohort. Median treatment exposure was similar in both groups (6.8 months vs. 6.4 months, respectively). There were no grade 4/5 treatment-related adverse events with zanzalintinib therapy in both patient groups in this analysis.

In the ccRCC cohort, dose modifications occurred in 56% of patients, while doses were maintained in 84% of those in this group. These rates were 53% and 80%, respectively, in the security population. Discontinuation due to treatment-related adverse events occurred in 9% of patients in the ccRCC cohort and 12% in the safety cohort.1

“One of the things I will point out is that the rates of diarrhea, hypertension, asthenia, side effects that we have become accustomed to among TKI strategies, appear to be a little lower with zanzalintinib, particularly with respect to grades 3/4 . side effects,” Pal said. “In particular, in my opinion, the rates of stomatitis and hand-foot syndrome were particularly low.”

Pal noted at the end of the presentation that zanzalintinib is currently being evaluated in different combinations with immune checkpoint inhibitors both in the first and second line, in addition to a phase III trial evaluating zanzalintinib with nivolumab (Opdivo) in patients with diseases previous. untreated non-cc CRC.

“These findings underscore the potential that zanzalintinib may have for patients with refractory kidney cancer, including those who have previously progressed on cabozantinib,” said Amy Peterson, MD, executive vice president of product development and medical affairs and chief medical officer of Exelixis, in a press release from the pharmaceutical company that makes zanzalintinib. “As STELLAR-001 and our Phase 3 STELLAR trials progress, we hope to elucidate the potential of zanzalintinib in kidney cancer, as well as other advanced solid tumors.”2

2. Exelixis announces encouraging results from the expansion cohort of the Phase 1b STELLAR-001 trial evaluating Zanzalintinib in patients with advanced kidney cancer at IKCS 2023. Press release. Exelixis, Inc. November 10, 2023. Accessed November 10, 2023. phase-1b

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