Combining an immune checkpoint inhibitor and a tyrosine kinase inhibitor (TKI) significantly improved progression-free survival (PFS) in treatment-naïve patients with advanced renal-cell carcinoma (RCC) compared with a TKI alone.
In the pivotal phase 3 study called JAVELIN Renal 101, first-line treatment with the combination of avelumab (Bavencio) and axitinib (Inlyta) reduced the risk for disease progression or death by 39% compared with sunitinib (Sutent) alone, said Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, at the ESMO 2018 Congress.
“The efficacy benefit and the favorable safety profile support avelumab plus axitinib as a new first-line standard of care for advanced renal-cell carcinoma,” Dr Motzer said. “The combination benefit was shown in all subgroups of patients, by independent review as well as by investigators, and whether tumor cells stained positive for PD-L1 or not,” he added.
“This is the first phase 3 trial of a checkpoint inhibitor combined with a TKI, not only in advanced RCC but across all malignancies,” Dr Motzer emphasized.
Despite available therapies, the outlook for patients with advanced RCC remains poor: less than 10% of patients survive to 5 years postdiagnosis.
JAVELIN Renal 101
In a previous phase 1b study, the combination of avelumab and axitinib produced an objective response rate of 58% and a favorable safety profile, providing the rationale for JAVELIN Renal 101.
This phase 3, international, open-label randomized clinical trial included 866 patients with untreated advanced RCC with a clear-cell component, including 560 (63%) with PD-L1–positive tumors who were randomized to avelumab 10mg/kg IV every 2 weeks, in combination with oral axitinib 5 mg twice daily, or oral sunitinib 50 mg once daily on a schedule of 4 weeks on, followed by 2 weeks off.
The PD-L1–positive group made up the primary target for this interim analysis. Approximately 66% of the study cohort in each arm had intermediate or poor risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk and MSKCC prognostic risk. Approximately 60% of the patients were enrolled in the United States.
With a median follow-up of 9.9 months in the combination arm and 8.4 months in the sunitinib arm, the median PFS was 13.8 in the immunotherapy arm and 7.2 months with sunitinib alone (hazard ratio [HR], 0.61; P <.0001), by Independent Review Committee in the patients with programmed PD-L1positive tumors.
The median PFS per the Independent Review Committee, a secondary end point, in all patients, regardless of PD-L1 expression, was 13.8 months versus 8.4 months, respectively (HR, 0.69; P = .0001), with a median follow-up of 10.8 months and 8.6 months in the 2 arms, respectively.
Investigator assessment of PFS was a secondary end point. “The findings were consistent with those of the Independent Review Committee in showing a strong benefit for avelumab plus axitinib in both the PD-L1–positive group and in the overall population,” Dr Motzer said. The HR was 0.51 in the PD-L1–positive group, a 49% decrease in risk for progression or death.
The HR for PFS favored the combination in all subgroups examined, including the PD-L1–negative subgroup and across each category of risk according to the MSKCC and the IMDC.
By Independent Review Committee review, the confirmed objective response rate in the PD-L1–positive group was 55.2% in the combination arm and 25.5% in the sunitinib arm.
“The complete response rate of 4% [in the combination arm] is anticipated to increase as the follow-up of responders becomes longer, since 73% of objective responders continue on study with an ongoing response,” said Dr Motzer.
The overall survival data are immature, “and the interpretation is inconclusive,” he said. At a median follow-up of 12 months, the median overall survival has not been reached in either treatment arm.
The combination was well-tolerated. Approximately 50% of patients in either arm had a grade 3 adverse event. The proportion of patients with grade 4 events was 4% in the combination arm and 7% in the sunitinib arm. Adverse events leading to discontinuation of the study drug were 4% in the combination arm and 8% in the sunitinib arm.
Immune-related adverse events were reported in 38% of the combination arm, including 21% with hypothyroidism.
“Without survival or quality-of-life data, it’s uncertain whether the combination is ready for prime time,” commented invited discussant Viktor Grünwald, MD, Clinic for Cancer Research and Clinic for Urology, University Hospital Essen, Westdeutsches, Germany.
The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) has demonstrated a clinically relevant overall survival advantage in patients with intermediate- or high-risk advanced RCC and should therefore remain the standard of care in this population.
“I do believe that there is a niche in favorable-risk patients for the avelumab-axitinib combination,” said Dr Grünwald.
Other immunotherapy combinations are now being explored in advanced RCC, he said.