Axitinib-nivolumab combination demonstrates efficacy in metastatic renal cell carcinoma
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SAN FRANCISCO — Axitinib combined with nivolumab demonstrated encouraging efficacy among treatment-naive patients with metastatic renal cell carcinoma, according to study results presented at ASCO Genitourinary Cancers Symposium.
The regimen conferred outcomes comparable to available approved combinations of immuno-oncology agents and VEGF tyrosine kinase inhibitors, Matthew R. Zibelman, MD, oncologist at Fox Chase Cancer Center, and colleagues concluded.
It also exhibited a safety profile comparable to other immunotherapy-tyrosine kinase inhibitor combinations.
“Axitinib [Inlyta, Pfizer] makes for an excellent partner to PD-1-targeting immune checkpoint inhibitors — whether nivolumab [Opdivo, Bristol Myers Squibb] or pembrolizumab [Keytruda, Merck] — based on its short half-life and safety profile,” Zibelman told Healio.
Systemic therapy with TKIs in combination with immune checkpoint inhibitors has become standard for patients with metastatic renal cell carcinoma.
Zibelman and colleagues conducted a phase 1/phase 2 study to evaluate the efficacy and safety of combining axitinib (Inlyta, Pfizer), a VEGF-targeted TKI, and nivolumab (Opdivo, Bristol Myers Squibb), an anti-PD-1 therapy, for this patient population.
“At the time this study was designed in 2016-2017, axitinib and nivolumab were both approved as a single agent for patients with metastatic renal cell carcinoma, and no randomized phase 3 trial had yet been reported documenting the benefit of an [immunotherapy-TKI] combination in the first line for [patients with metastatic renal cell carcinoma],” Zibelman said. “Given the tolerable toxicity profile of axitinib, its short half-life and its easy titratability with 1 mg tablets, it seemed like an ideal partner with a checkpoint inhibitor.”
Phase 1 — which included patients who received at least one prior TKI therapy — followed a 3+3 design to determine the recommended phase 2 dose of axitinib. Patients received 3 mg to 5 mg axitinib twice daily plus 480 mg nivolumab via IV every 4 weeks.
Researchers established a recommended phase 2 axitinib dose of 5 mg twice daily.
Phase 2 consisted of two parallel arms of patients with metastatic renal cell carcinoma. One included treatment-naive patients and another included patients previously treated with TKIs alone or with an immunotherapy combination.
At ASCO GU, Zibelman presented results from the treatment-naive cohort.
All patients had metastatic renal cell carcinoma with any clear cell component, with measurable disease and ECOG performance status of 0 or 1. Eligible patients had no history of autoimmune disease, and no known or symptomatic brain metastases.
Patients received axitinib at the recommended phase 2 dose plus nivolumab for up to 2 years.
Objective response rate per investigator assessment served as the primary endpoint. Secondary endpoints included PFS, OS and safety.
Researchers accrued 44 patients (median age, 65 years; range, 56-72; 84.1% men; 95.5% white) from four centers. Seventy-five percent had ECOG performance status of 0.
International Metastatic RCC Database Consortium risk group grading classified 18 patients (40.9%) as favorable risk, 23 patients (52.3%) as intermediate risk and three patients (6.8%) as poor risk.
One patient who withdrew from the study was excluded from the efficacy analysis but included in the safety analysis.
After median follow-up of 11.5 months, researchers reported an ORR of 59.5% (95% CI, 43.3-74.4).
One patient (2.4%) achieved complete response, 24 (57.1%) achieved partial response, 16 (38.1%) demonstrated stable disease and one (2.4%) exhibited progressive disease. This equated to a 97.6% disease control rate.
Researchers reported median PFS of 16.4 months (95% CI, 10.2-21.2), with estimated PFS rates of 60.8% (95% CI, 43.2-74.5) at 12 months and 25.3% (95% CI, 10.2-43.7) at 24 months.
Median OS had not been reached; however, researchers reported OS estimates of 87.1% (95% CI, 68.7-95.1) at 12 months and 69.4% (95% CI, 43.5-85.2) at 24 months.
“The results weren’t necessarily surprising, but they did demonstrate outstanding disease control on par with all of the other [immunotherapy-TKI] combinations currently available,” Zibelman said. “[Although] the excellent outcomes are in part due to the majority favorable/intermediate-risk population and the small sample size, the outcomes still demonstrate that this is a favorable combination.”
The regimen’s adverse event profile appeared consistent with published data for other immunotherapy-TKI combinations.
The most common grade 3 adverse events included hypertension (41.5%), diarrhea (9.8%), alanine aminotransferase increase (7.3%), colitis (7.3%) and proteinuria (7.3%).
“The safety profile was in line with what has been seen with other similar combinations, and the fact that no patients experiences a grade 4 or 5 adverse event is very encouraging,” Zibelman said.
Researchers reported an average daily axitinib dose of 8.21 mg. Twenty-four patients (54.5%) required axitinib dose reductions.
Nine patients (20.5%) discontinued axitinib due to adverse events, and eight patients (18.2%) discontinued nivolumab for the same reason.
Follow-up will continue to assess long-term outcomes in this cohort, as well as efficacy in the previously treated cohort, Zibelman said.
“I think axitinib should continue to be a good option in combination with an immune checkpoint inhibitor for first-line metastatic renal cell carcinoma,” Zibelman told Healio. “[Although] the randomized phase 3 results and FDA approval in combination with pembrolizumab should continue to make that the combination of choice, in my mind this lends further support that axitinib makes sense as the first-line [immunotherapy] partner, allowing cabozantinib [Cabometyx, Exelixis] and Lenvatinib [Lenvima, Eisai] — which we know have activity after prior axitinib — to be reserved for later lines of therapy.”
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Zibelman MR, et al. Abstract 291. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
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