The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion to recommend approval of the combination of avelumab and axitinib for the frontline treatment of adult patients with advanced renal cell carcinoma.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion to recommend approval of the combination of avelumab (Bavencio) and axitinib (Inlyta) for the frontline treatment of adult patients with advanced renal cell carcinoma (RCC).1
The recommendation is based on findings from the phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib (Sutent) in an intent-to-treat population (ITT) of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.2
The European Commission will now review the CHMP positive opinion and make a decision on the approval in the fourth quarter of 2019, stated EMD Serono and Pfizer, which have a global strategic alliance to jointly develop and commercialize avelumab, in a press release.
"Today's positive CHMP opinion is a significant step toward potentially transforming the treatment landscape and bringing much needed options to people living with advanced renal cell carcinoma in Europe,” Luciano Rossetti, head of Global R&D for EMD Serono, stated in a press release. “We believe that the combination of Bavencio plus axitinib has the potential to help address a significant need for patients with advanced renal cell carcinoma for first-line treatments with a benefit across all prognostic risk groups, and we look forward to a decision from the European Commission.”
The JAVELIN Renal 101 trial enrolled 886 patients with advanced or metastatic RCC, and randomized them 1:1 to receive 10 mg/kg of avelumab intravenously every 2 weeks plus 5 mg of oral axitinib twice daily in 6-week cycles or 50 mg of oral sunitinib once daily for a 4-weeks-on/2-weeks-off schedule. Patients with all MSKCC/Motzer Criteria with good- (21%), intermediate- (62%), and poor-risk disease (16%) were included.
The overall population included 560 (63.2%) PD-L1—positive patients. In the PD-L1–positive group, 270 patients received the combination and 290 patients were treated with sunitinib.
In the overall group, 442 patients were treated with the combination while 444 received sunitinib. The primary endpoints were progression-free survival (PFS) by blinded independent central review and overall survival (OS) in the PD-L1—positive group; secondary endpoints were PFS and OS in the overall population irrespective of PD-L1 status, ORR, and safety.
In the PD-L1—positive population, the median PFS was 13.8 months (95% CI, 11.1-NE) with avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) with sunitinib, leading to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95%, 0.475-0.790; P <.0001). The ORR with the combination was 55.2% (95% CI, 49.0-61.2), which included 4 complete responses (CRs) and 51 partial responses (PRs); the ORR with sunitinib was 25.5% (95% CI, 20.6- 30.9). Twenty-seven patients in the combination arm had stable disease (SD) and 11 had progressive disease (PD).
In the overall population, the median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months (95% CI, 11.1-NE) and 8.4 months (95% CI, 6.9-11.1), respectively (HR, 0.69; 95% CI, 0.563-0.840; 2-sided P = .0002). Moreover, the ORR with avelumab/axitinib was 51.4% (95% CI, 46.6-56.1) and 25.7% (95% CI, 21.7-30.0) with sunitinib. In the combination arm, the ORR included 3 CRs and 48 PRs; 30 patients had SD and 12 patients had PD.
In the PD-L1—positive and overall population arms, 73% and 70% of patients remained on avelumab/axitinib treatment, respectively, versus 65% and 71% of those on sunitinib. Median duration of response was not yet reached in either treatment arm in either population.
At a follow-up for median OS of 19 months, the OS endpoint remain immature with 27% of deaths in the ITT population. Pfizer, which co-develops avelumab with Merck, stated in a press release that the trial is continuing as planned.
Regarding safety, the immunotherapy/TKI regimen was found to be favorable. Fifty-one (4%) patients on the combination arm and 48 (7%) patients on the sunitinib arm experienced grade 3/4 treatment-related adverse events (TRAEs), the most common being diarrhea (5% vs 3%). All-grade TRAEs were similar between arms. Four percent of TRAEs led to avelumab/axitinib discontinuation versus 8% with sunitinib; 1 patient on avelumab/axitinib died due to TRAEs.
Grade ≥3 TRAEs were reported in 71.2% of patients in the combination arm versus 71.5% of patients in the sunitinib arm, and led to treatment discontinuations in 22.8% versus 13.4%, respectively.
In May 2019, the FDA approved the combination of avelumab and axitinib in the frontline setting for patients with advanced renal cell carcinoma, also based on the JAVELIN Renal 101 data.