“The efficacy benefit and the favorable safety profile support aveluamb plus axitinib as a new first-line standard of care for advanced RCC,” says researcher Robert J. Motzer, MD.
A combination of the immune checkpoint blocker avelumab (Bavencio) plus the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) significantly improved progression-free survival (PFS) compared with sunitinib (Sutent) in previously untreated patients with advanced renal cell carcinoma (RCC) in a pivotal phase III study.
The improvement in median PFS was observed in patients regardless of PD-L1 status and in all prognostic groups, said Robert J. Motzer, MD, lead investigator of the JAVELIN Renal 101 study. The findings were presented at the European Society for Medical Oncology annual congress in Munich.
“The efficacy benefit and the favorable safety profile support aveluamb plus axitinib as a new first-line standard of care for advanced RCC. This is the first phase III trial of a checkpoint inhibitor combined with a TKI, not only in advanced RCC but across all malignancies,” Dr. Motzer said.
The 39% relative improvement (p<.0001) per independent review committee (IRC) in PFS favoring avelumab plus axitinib over sunitinib in the PD-L1-positive group was “robust,” said Dr. Motzer, of Memorial Sloan Kettering Cancer Center, New York. In the overall study cohort, median PFS per IRC in patients irrespective of PD-L1 expression was improved by 31% in the combination arm relative to the sunitinib arm (p=.0001).
JAVELIN Renal 101 was an open-label randomized trial. Key eligibility criteria included treatment-naÃ¯ve advanced RCC with a clear cell component, ≥1 measurable lesion as defined by RECIST v1.1, tumor tissue available for PD-L1 staining, and an ECOG performance status of 0 or 1.
“There’s a strong rationale for combining avelumab plus axitinib. In addition to antiangiogenic effects, vascular endothelial growth factor receptor (VEGFR) blockade by axitinib has immunomodulatory effects. Simultaneous inhibition of PD-1/PD-L1 axis and VEGFR/VEGF had synergistic antitumor effects in preclinical models,” Dr. Motzer said.
The study randomized 866 patients, including 560 patients (63%) with PD-L1-positive tumors. The treatment arms were balanced with regard to baseline characteristics, and the PD-L1-positive and overall population were similar by the same characteristics. About two-thirds of the study cohort in each arm were intermediate/poor risk by IMDC prognostic risk and MSKCC prognostic risk. About 60% of the patients were enrolled in the United States.
A total of 442 patients were randomized to avelumab, 10 mg/kg intravenously every 2 weeks, in combination with axitinib, 5 mg orally twice daily. The comparator group of 444 patients was randomized to sunitinib, 50 mg orally once a day on a schedule of 4 weeks on followed by 2 weeks off.
The two primary endpoints were PFS by RECIST v1.1 per IRC in patients with PD-L1-positive tumors and overall survival (OS) in the PD-L1-positive group.
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After a median follow-up of 9.9 months in the combination arm and 8.4 months in the sunitinib arm, median PFS was 13.8 versus 7.2 months, respectively (HR=0.61; p<.0001) in the patients with PD-L1-positive tumors.
After a median follow-up of 10.8 months in the combination arm and 8.6 months in the sunitinib arm, median PFS per IRC, a secondary endpoint, in patients irrespective of PD-L1 expression was 13.8 versus 8.4 months (HR=0.69; p=.0001) respectively.
Investigator assessment of PFS was a secondary endpoint.
“The findings were consistent with those of the IRC in showing a strong benefit for aveluamb plus axitinib in both the PD-L1-positive group and in the overall population,” said Dr. Motzer. The HR was 0.51 (p<.0001) in favor of the combination in the PD-L1-positive group.
By IRC review, the confirmed objective response rates (ORRs) were 55.2% in the avelumab/axitinib arm and 25.5% in the sunitinib arm.
“The complete response rate of 4% [with combination therapy] is anticipated to increase as the follow-up of responders becomes longer, since 73% of objective responders continue on study with an ongoing response,” Dr. Motzer said. In 149 responding patients who were PD-L1-positive, the median time to response was 1.6 months.
“The OS data at this point are immature and the interpretation is inconclusive,” he said. Median OS has not been reached in either treatment arm (overall population), with a median follow-up of 12 months.
The hazard ratio for PFS favored the combination in all subgroups examined, including the PD-L1-negative subgroup and across each category of risk per IMDC and MSKCC.
About 50% in either arm had a grade 3 adverse event. The proportion with a grade 4 adverse event was 4% in the combination arm and 7% in the sunitinib arm. Hepatic toxicity was low in either group. The proportion with adverse events leading to discontinuation of study drug was 4% in the combination arm and 8% in the suntinib arm. Immune-related adverse events occurred in 38% of the combination arm (8% were grade 3), including 21% with hypothyroidism.
Although the tolerability of the combination is impressive, to know whether it’s better than sequencing therapies must await the OS and quality-of-life data, said invited discussant Victor GrÃ¼nwald, MD, of West German Cancer Center, Essen.
“I do believe that there is a niche in favorable-risk patients for this specific combination, and it could be a standard of care for patients with favorable risk,” he said.
Pfizer sponsored the study. Dr. Motzer has a financial interest in Pfizer, Bristol-Myers Squibb, Novartis, Eisai, Exelixis, Genentech/Roche, and Merck. Several of his co-authors have disclosures related to one or more pharmaceutical companies; for full disclosures, click here.
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