Nivolumab Plus Axitinib Generates Promising Responses in Untreated Advanced RCC

The combination of nivolumab (Opdivo) and axitinib (Inlyta) achieved meaningful responses in treatment-naïve advanced renal cell carcinoma (RCC), according to results from a phase 1/2 trial (NCT03172754) presented at the 2022 Genitourinary Cancers Symposium.¹

Among patients with untreated advanced RCC in a phase 2 cohort (n = 44), nivolumab plus axitinib elicited an overall response rate (ORR) of 59.5% (95% CI, 43.3%-74.4%). One patient (2.4%) achieved a complete response and 24 (57.1%) had partial response. Additionally, investigators observed stable disease in 38.1% of patients and progressive disease in 1 patient (2.4%). The disease control rate was 97.6% (95% CI, 87.4%-99.9%).

“The landscape of metastatic RCC has changed dramatically over the past 5 years, with combination therapy, with immunotherapy/TKI combinations, or combined immune checkpoint inhibitors being the standard of care for most patients,” lead study author Matthew R. Zibelman, MD, associate professor, Department of Hematology/Oncology, Fox Chase Cancer Center, said during his presentation.

The phase 1 dose-escalation portion of the trial examined nivolumab and axitinib in patients who had received at least 1 prior line of therapy with a TKI. Patients received 3 mg to 5 mg doses of axitinib twice daily, plus 480 mg of intravenous (IV) nivolumab every 4 weeks. This established 5 mg of axitinib as the recommended phase 2 dose.

Phase 2 investigated the combination in 2 parallel cohorts, with 1 featuring treatment-naïve patients with advanced RCC, and the other enrolling patients with advanced RCC who received at least 1 prior therapy.

Eligible patients in the treatment-naïve arm of the phase 2 study were required to be at least 18 years old with histologically or cytologically confirmed metastatic RCC featuring any clear cell component and at least one measurable lesion as defined by RECIST v1.1.² Patients needed an ECOG performance status of 0 or 1, and those with autoimmune disease were excluded.

The primary end point of the study was ORR. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

The median age of patients in the treatment-naïve cohort was 65 years (interquartile range, 56-72). Most patients were male (84.1%), white (95.5%), and non-Hispanic (93.2%). Patients had an ECOG performance status of 0 (75%), 1 (22.7%), or undetermined (2.3%). Patients were classified with an IMDC risk category score of favorable (0; 40.9%), intermediate (1-2; 52.3%), or poor (3-6; 6.8%).

At a median follow-up of 11.5 months, the median PFS in the treatment-naïve cohort was 16.4 months (95% CI, 10.2-22.2). The estimated 12-month PFS rate was 60.8% (95% CI, 43.2%-74.5%), and the estimated 24-month PFS rate was 25.3% (95% CI, 10.2%-43.7%).

The estimated 12-month OS rate was 87.1% (95% CI, 68.7%-95.1%). The estimated 24-month OS rate was 69.4% (95% CI, 43.5%-85.2%).

Grade 3 adverse effects (AEs) included hypertension (41.5%), diarrhea (9.8%), increased ALT (7.3%), colitis (7.3%), proteinuria (7.3%), hyponatremia (4.9%), arthralgia (4.9%), dyspnea (4.9%), hypotension (4.9%), atrial fibrillation (2.4%), heart failure (2.4%), increased creatinine (2.4%), rectal fistula (2.4%), avascular necrosis (2.4%), and myalgia (2.4%).

The average daily dose of axitinib was 8.21 mg. Notably, 54.5% of patients had axitinib dose reductions to less than 10 mg per day, and 20.5% discontinued treatment due to AEs associated with axitinib. Additionally, 18.2% of patients discontinued treatment due to nivolumab-related AEs.

Additional follow-up will assess long-term outcomes of nivolumab and axitinib in the treatment-naïve cohort, plus the efficacy of the combination in the previously treated cohort.

“Axitinib remains a well-tolerated VEGF TKI that, with its easy titratability and short half-life, pairs well with anti–PD-1 targeted therapies and can achieve outcomes similar to other combinations [in advanced RCC],” Zibelman concluded.

References

1. Zibelman MR, Carducci MA, Ged Y, et al. A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):291. doi:10.1200/JCO.2022.40.6_suppl.291
2. Study of nivolumab and axitinib in patients with advanced renal cell carcinoma. ClinicalTrials.gov. Updated November 17, 2021. Accessed April 14, 2022. https://clinicaltrials.gov/ct2/show/NCT03172754