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Presidential Symposium 2

ESMO 2018: RCC -Doubling the response with avelumab plus axitinib

JAVELIN Renal 101 presented at ESMO 2018 is the first positive phase-III trial to test the combination of an immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor in the treatment of advanced renal cell carcinoma.

The global, randomized phase-III trial evaluated the efficacy of the combination of the PD-L1 inhibitor avelumab (10mg/kg IV Q2W) and the tyrosine kinase inhibitor axitinib (5mg PO BID, 6-week cycle) in the first-line treatment of patients with advanced renal cell carcinoma (aRCC) compared to sunitinib monotherapy (50mg PO QD, 4 weeks on, 2 weeks off).

The trial enrolled 886 previously untreated patients of all prognostic stages according to the Memorial Sloan Kettering Cancer Center score (good 21%, median 62% and poor risk [16%]). 442 patients received avelumab and axitinib, 444 sunitinib. The primary endpoint was improved PFS or overall survival (OS) in patients with PD-L1 expression in the tumor. Per protocol, the trial was designed to extend the analysis to the PFS and OS of the global study population as secondary endpoints, if one of the primary endpoints was reached.

Investigator Dr. Robert Motzer of the Memorial Sloan Kettering Cancer Center, New York, US, presented the PFS as primary endpoint of the trial: in patients with PD-L1 positive tumors (63.2% of the total population) the median PFS of the combination therapy was 13.8 – compared to 7.2 months in the sunitinib arm (HR = 0.61, p<0.0001).
This finding was independent of PD-L1 expression levels in the tumor: a median PFS of 13.8 versus 8.4 months was achieved in the entire study population (HR = 0.69, p = 0.0001). The objective response rate of the combination therapy was 55.2 (95% CI 49.9-61.2) compared to 25.5 (95% CI 20.6-30.9) percent with sunitinib. The determination of PFS and ORR was confirmed by an independent review committee. The final OS analysis of JAVELIN Renal 101 is ongoing.

Motzer reported that the combination showed no new side effects. Treatment-related adverse events of grade 3 and higher occurred in 71.2 percent of the combination arm and 71.5 percent in the sunitinib arm. Treatment discontinuation was more frequent under combination (22.8 vs.13.5%, 0.7 versus 0.2 percent died of treatment-related adverse events).

Combination is Key

Despite improvement of available therapy options, the prognosis of patients with advanced RCC is still poor – less than ten percent of patients survive the first five years after diagnosis. «This type of cancer is one of the hardest to treat. Although the introduction of anti-angiogenetic agents has revolutionized the treatment, it remains a terrible disease.

»Soon more combinations will be tested and a lot is going to happen in the next few years”, Motzer announced. «Our results highlight the potential of Avelumab plus axitinib as a new therapeutic standard in patients with advanced RCC. The combination therapy was beneficial in all subgroups – independent of PD-L1 expression. »

Prof. John Haanen, of Netherlands Cancer Institute commented on the trial: »These substances complement each other, Anti PD-L1 inhibitors can take away some of the disadvantages of anti-angiogenic drugs.”

Prof. Thomas Powles, consultant oncologist at Barts Health 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 randomised trial. 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.”


Motzer RJ et al., JAVELIN Renal 101: A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). ESMO 2018 Kongress, LBA6_PR