A combination of the immune checkpoint blocker, avelumab, plus the tyrosine kinase inhibitor (TKI), axitinib, significantly improved progression-free survival (PFS) in previously untreated patients with advanced renal cell carcinoma (RCC) in a phase 3 study, according to results presented at ESMO 2018 Congress

Median PFS was 13.8 versus 7.2 months in the combination arm compared to the sunitinib arm (HR = 0.61; p <.0001) in the  patients  with programmed cell death-ligand 1 positive (PD-L1 +) tumours, while median PFS in patients irrespective of PD-L1 expression was 13.8 versus 8.4 months (HR = 0.69; p = .0001) respectively. Confirmed objective response rate was 55.2 (CI 95 percent: 49.9, 61.2) and 25.5 (CI 95 percent: 20.6, 30.9) respectively.

"JAVELIN Renal 101 is the first positive phase 3 study combining an immune checkpoint blocker with TKI compared to TKI alone in the first line treatment of advanced RCC," remarked Dr. Robert Motzer, presenter and study lead from Memorial Sloan Kettering Cancer Center, New York City, US. 

"The findings support the potential of patients with advanced treatment for RCC, and the combination benefit was shown in all subgroups of patients, by independent review as well as by investigators, and whether tumour cells stained positive for PD- L1 or not, "I continued.

Despite available therapies, the outlook for patients with advanced RCC remains poor with less than 10% of patients surviving at five years post-diagnosis.

Tyrosine kinase inhibitors

New treatment options are needed. Avelumab is an IgG1 monoclonal antibody against the programmed cell death protein-ligand PD-L1 (checkpoint blocker), while axitinib is a TKI, and TKIs have been the mainstay of treatment.

"TKIs, and checkpoint blockers like avelumab, both may have potential immune-modulating functions, when combined, may provide clinical benefit in patients with advanced RCC that exceeds the effects of the respective drugs alone, without compromising toxicity," said Motzer.protein ligand PD-L1 (checkpoint blocker), while axitinib is a TKI, and TKIs have been the mainstay of treatment.

"TKIs, and checkpoint blockers like avelumab, both may have potential immune-modulating functions that, when combined, may provide clinical benefit in patients with advanced RCC that exceeds the effects of the respective drugs alone, without compromising toxicity," said Motzer.

In the JAVELIN Renal 101 global, randomized trial, 886  kidney cancer patients with all MSKCC (Memorial Sloan Kettering Cancer Center / Motzer score used for selection of mRCC patients for trial inclusion) prognostic subgroups (good, intermediate, and poor risk) were enrolled and were administered therapy as first-line treatment randomized trial, 886 

Avelumab was administered to 442 patients at 10 mg/kg intravenously (IV) every two weeks in combination with axitinib, 5 mg orally twice daily. The comparator group of 444 patients received sunitinib given at 50 mg orally and eleven a day on a schedule of four weeks on followed by two weeks off (4/2). The primary outcomes were PFS in PD-L1 + patients (up to 30 months); and overall survival in PD-L1 + patients up to five years.

Treatment-emergent adverse events of grade 3 and over were experienced by 71.2% versus 71.5% of patients in the combination versus sunitinib arms respectively and led to discontinuation of the drug in 22.8% versus 13.4% respectively.

Prof. Thomas Powles, a consultant oncologist at BartsHealth NHS Trust, London, UK, commented on the results. "The results are eye-catching. The response rates are twice as good as previous standards of care, and progression-free survival is entering into very impressive territory for a randomized trial. uncertainty around whether this will translate into a similarly impressive survival signal, as seen with other immunotherapy combinations. "