ESMO 2018: JAVELIN Renal 101: A Randomized, Phase 3 Study of Avelumab + Axitinib vs Sunitinib as First-Line Treatment of Advanced Renal Cell Carcinoma

Munich, Germany ( Frontline therapy for advanced renal cell carcinoma (RCC) has rapidly evolved over the past decade, with the addition of several new vascular endothelial growth factor (VEGF)-directed agents as well as immune checkpoint inhibitors. For patients with intermediate or high-risk disease, cabozantinib and combination ipilimumab+nivolumab have emerged as preferred frontline options based on data from CABOSUN and Checkmate 2141,2.
For patients with good risk disease, sunitinib and pazopanib have substantial data showing comparable efficacy3. Currently, a number of phase III trials are studying combination immune checkpoint inhibition in combination with VEGF inhibition, with the theory that VEGF typically promotes an immune suppressive enviroment4. In pre-clinical models, VEGF was shown to directly induce Treg proliferation and promote the expansion of myeloid-derived suppressor cells4. Immotion1515 is an example of a combination VEGF inhibition + immune checkpoint inhibitor which has shown improvement in progression-free survival over sunitinib (11.2 months vs 7.7 months, p=0.02).

In this phase 3 three study, the combination of avelumab and axitinib was compared against sunitinib for the front line therapy of advanced RCC. Avelumab is an anti-PD-L1 IgG1 monoclonal antibody and axitinib is a potent VEGFR TKI, currently approved in the second line for advanced RCC.

JAVELIN Renal 101 is a large randomized phase 3 clinical trial, comparing first-line sunitinib to combination axitinib + avelumab for patients with advanced RCC. Patients were randomly assigned in a 1:1 ratio, stratified by performance status and geography. 

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Patients must have had tumor tissue available for PD-L1 staining in this study. Patients on axitinib and sunitinib were allowed to have dose modifications per standard of care. There were co-primary endpoints: one was PFS by RECIST 1.1 per an independent review committee in patients with PD-L1 positive tumors and the other was overall survival in the PD-L1+ group.

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A total of 886 patients were randomly assigned to therapy, resulting in 444 patients receiving sunitinib and 442 patients receiving avelumab + axitinib. Most patients were an intermediate risk, but about 20% of patients were a favorable risk by IMDC criteria, and about 13-16% of patients depending on the cohort were poor risk. 

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In terms of the primary endpoint, the combination of avelumab + axitinib significantly improved median PFS in the PD-L1 positive cohort (13.8 months vs 7.2 months, HR 0.61, p<0.001). Median follow up time is only 6 months and the median follow time is 9.9 months at this time. 

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Axitinib+avelumab also improved PFS in the overall population (13.8 months vs 8.4 months, HR 0.69, p=0.0001). In terms of confirmed objective responses, 51% of all patients had an objective response with axitinib+avelumab, compared with 26% of patients on sunitinib. In the PD-L1 positive population, a similar benefit was seen (55% vs 26%). Waterfall plots show dramatic response data. 

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108 patients have an ongoing response at this time and the time to response was rapid, with a median of 1.6 months (range 1.2 months – 10.1 months).

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At the time of this abstract report, overall survival data is still immature, with less than 14% of events in the axitinib+avelumab and 17% of events in the sunitinib arm. 

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In terms of safety, about half of the patients in each arm had grade 3 or 4 treatment related adverse event. In terms of immune related AEs, 12% of patients on avelumab experienced an infusion reaction. Very few patients had liver function abnormalities, which has been seen before when checkpoint inhibitors are combined with TKIs. 

In summary, this abstract provides very promising data regarding the safety and efficacy of avelumab + axitinib for patients with advanced RCC. At this time, survival data is immature so it is unknown if upfront therapy with both TKI plus immune checkpoint inhibitor is superior to each therapy alone in sequence.  

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As has been mentioned in an earlier session, there are numerous ongoing combination trials, which may change how we treat advanced RCC, this being one of them. Reported a few days ago was the combination of pembrolizumab + axitinib significantly improved overall survival and progression-free survival – these results have yet to be published or presented but may be practice changing given the benefit in overall survival. 

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The discussant mentions that at this time, while the data presented data was exciting, ipilimumab + nivolumab likely remains the main treatment of choice for patients with intermediate or unfavorable risk. However, for patients with favorable-risk disease, axitinib + avelumab would not be an unreasonable option. 

UroToday ERUS2018 Locations of positive lymph nodes

Presented by: Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, US

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany