EVERSUN: A phase II trial of everolimus alternating with sunitinib as first-line therapy for advanced renal cell carcinoma (aRCC) (ANZUP trial 0901)

Background: We hypothesized that alternating inhibitors of the VEGFR and mTOR pathways would delay the development of resistance in aRCC.

Methods: Single-arm, two-stage, multicenter, phase II trial to determine the activity, feasibility, and safety of sunitinib 50mg daily 4 weeks (wk) on / 2wk off, alternating with everolimus 10mg daily for 5 wk on / 1 wk off. Participants had aRCC of MSKCC good or intermediate risk. Primary endpoint: proportion alive and free of progression at 6 months (PFS6m). Secondary endpoints included feasibility, tumour response, overall survival (OS), and adverse events (AE). Imaging was done every 6 wk till wk 24, then q12wk. Planned sample size of 55 allowed distinction between a PFS6m rate of ≤64% versus ≥84% with type 1 and type 2 error rates of 5%.

Results: We recruited 55 eligible participants from Sept 2010 to Aug 2012: mean age 61, male 71%, good risk 16%, intermediate risk 84%. Feasibility: 80% could start cycle 2 within 14 weeks; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 wks of any treatment. Efficacy: PFS6m was 29/55 (53%; 95% CI: 40%-66%). The OR rate was 7/55 (13%; 95% CI 4%-22%, all partial). After a median follow-up of 20 months, 47 of 55 had progressed with a median PFS of 8 months (95% CI: 5 to 10), and 30 of 55 had died with a median OS of 17 months (95% CI: 12 to undefined). Safety: AEs were consistent with those expected for each single agent. The most common grade 3 or 4 AE (number of participants) were hypertension (13), anaemia (9), oral mucositis (7), fatigue (n=7), GGT increase (n=6), pain (n=5), and platelet count decreased (n=5).

Conclusions: The EVERSUN regimen was feasible and safe, but its activity did not meet prespecified values to warrant further research. This study supports the current approach of continuing first line anti-VEGF therapy until progression or prohibitive toxicity before switching to another drug. EVERSUN is an ANZUP Cancer Trials Group Ltd. trial coordinated by the NHMRC Clinical Trials Centre (ACTRN12609000643279). Clinical trial information: ACTRN12609000643279.