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Avelumab-axitinib combination may be new first-line standard for advanced renal cell carcinoma
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MUNICH — The combination of avelumab and axitinib significantly improved PFS compared with standard sunitinib among previously untreated patients with advanced renal cell carcinoma, according to randomized phase 3 study results presented at European Society for Medical Oncology Congress.
The combination also exhibited a favorable safety profile.
“These results support avelumab plus axitinib as a new first-line standard of care for patients with advanced renal cell carcinoma,” study author Robert J. Motzer, MD, medical oncologist and chair in oncology at Memorial Sloan Kettering Cancer Center, said during a press conference.
An estimated 65,000 cases of kidney cancer are diagnosed each year in the United States. Early treatment typically consists of surgical resection but, because there are few early warning signs of the disease, about 50% of patients will be found to have metastases at initial diagnosis or after nephrectomy.
Sunitinib (Sutent, Pfizer), a multitargeted tyrosine kinase inhibitor, has been a standard kidney cancer treatment since the FDA approved it in 2006.
Several compounds are now similar to sunitinib. One of them is axitinib (Inlyta, Pfizer), a small molecule tyrosine kinase inhibitor approved for second-line treatment of kidney cancer.
“Axitinib has an advantage over sunitinib in that it has less toxicity, especially liver toxicity, so it combines better with other medications,” Motzer said.
Immune checkpoint inhibitors also have become a primary treatment option.
In the JAVELIN Renal 101 trial, Motzer and colleagues compared the combination of axitinib and avelumab (Bavencio; EMD Serono, Pfizer) — a fully human monoclonal antibody that targets PD-L1 — with sunitinib for first-line treatment of clear cell advanced renal cell carcinoma.
The analysis included 886 patients with ECOG performance status 0 or 1 who received no prior systemic therapy. All prognostic risk groups were included (21% favorable risk, 62% intermediate risk, 16% poor risk, < 1% not reported).
Researchers randomly assigned 442 patients to IV avelumab 10 mg/kg every 2 weeks plus oral axitinib 5 mg twice daily in 6-week cycles. The other 444 patients received oral sunitinib 50 mg daily on a 4-weeks-on, 2-weeks-off schedule.
Primary endpoints included PFS — assessed by blinded independent central review — and OS among patients with PD-L1-positive tumors (n = 560), defined as 1% or greater expression on immune cells. Secondary endpoints included PFS and OS irrespective of PD-L1 expression, as well as objective response and safety.
The axitinib-avelumab combination appeared associated with longer median PFS in the subgroup of patients with PD-L1-positive disease (13.8 months vs. 7.2 months; HR = 0.61; P < .001), as well as in the entire cohort regardless of PD-L1 expression (13.8 months vs. 8.4 months; HR = 0.69; P = .0001).
Researchers also reported higher objective response rates among patients assigned the investigational combination in both the PD-L1-positive subgroup (55.2% vs. 25.5%; stratified OR = 3.73; P < .0001) and the entire cohort (51.4% vs. 25.7%; stratified OR = 3.09; P < .0001).
Fewer than 16% of patients had experienced events at data cutoff, so OS data were immature.
The safety profiles of axitinib and avelumab appeared consistent with prior studies of each drug.
“Safety is of paramount importance when assessing a new combination,” Motzer said.
A comparable percentage of patients assigned axitinib-avelumab and sunitinib monotherapy experienced grade 3 or higher treatment-emergent adverse events (71.2% vs. 71.5%).
The most common grade 3/grade 4 toxicities were diarrhea (55% vs. 55%) and hypertension (24% vs. 15%). A higher percentage of sunitinib-treated patients experienced grade 3 neutropenia (7 vs. < 1), anemia (5 vs. < 1) or thrombocytopenia (5 vs. < 1).
A higher percentage of patients assigned the combination discontinued the study drug due to adverse events (22.8% vs. 13.4%). Less than 1% of patients in each treatment group died due to treatment toxicity (0.7% for combination vs. 0.2% for sunitinib).
“The results are eye-catching,” Thomas Powles, MD, consultant oncologist at Barts Health NHS Trust in London, said in a press release.
“The response rates are twice as good as previous standards of care, and profession-free survival is entering into very impressive territory for a randomized trial,” added Powles, who was not involved with the study. “This approach involves giving combinations of most active agents upfront; therefore, there is uncertainty around whether this will translate into a similarly impressive survival signal as seen with other immunotherapy combinations.” – Mark Leiser
Reference:
Motzer RJ, et al. Abstract LBA6_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.
Disclosures: Pfizer sponsored the trial, part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany. Motzer reports research funding from or consultant/advisory roles with Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, GlaxoSmithKline, Incyte, Merck Sharpe & Dohme, Novartis and Pfizer.