I D Davis1, A Long2, S Yip2, D Espinoza2, J F Thompson3, G Kichenadasse4, M Harrison5, R M Lowenthal6, N Pavlakis7, A Azad8, G Kannourakis9, C Steer10, D Goldstein11, J Shapiro12, R Harvie13, L Jovanovic14, A L Hudson15, C C Nelson16, M R Stockler17, A Martin2. 1. Monash University Eastern Health Clinical School, Melbourne; ANZUP Cancer Trials Group, Sydney. Electronic address: ian.davis@monash.edu. 2. ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney. 3. ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney. 4. ANZUP Cancer Trials Group, Sydney; Flinders Centre for Innovation in Cancer, Flinders University, Adelaide. 5. ANZUP Cancer Trials Group, Sydney; Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Sydney; Liverpool Hospital, Liverpool. 6. ANZUP Cancer Trials Group, Sydney; Royal Hobart Hospital and Menzies Institute for Medical Research, University of Tasmania, Hobart. 7. ANZUP Cancer Trials Group, Sydney; Royal North Shore Hospital, University of Sydney, Sydney. 8. ANZUP Cancer Trials Group, Sydney; Austin Health, Melbourne. 9. ANZUP Cancer Trials Group, Sydney; Ballarat Oncology & Haematology Services and Fiona Elsey Cancer Research Institute, Ballarat; Federation University, Ballarat. 10. ANZUP Cancer Trials Group, Sydney; Border Medical Oncology, Wodonga. 11. ANZUP Cancer Trials Group, Sydney; Prince of Wales Clinical School and Prince of Wales Hospital, University of New South Wales, Sydney. 12. ANZUP Cancer Trials Group, Sydney; Cabrini Hospital, Melbourne. 13. ANZUP Cancer Trials Group, Sydney; Bill Walsh Translational Cancer Research Laboratories, Kolling Institute, Sydney. 14. Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane. 15. Bill Walsh Translational Cancer Research Laboratories, Kolling Institute, Sydney. 16. ANZUP Cancer Trials Group, Sydney; Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane. 17. ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney; Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Sydney; Concord Cancer Centre, Concord, Australia.
Abstract
BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.
BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.
Authors: Nick Pavlakis; Katrin M Sjoquist; Andrew J Martin; Eric Tsobanis; Sonia Yip; Yoon-Koo Kang; Yung-Jue Bang; Thierry Alcindor; Christopher J O'Callaghan; Margot J Burnell; Niall C Tebbutt; Sun Young Rha; Jeeyun Lee; Jae-Yong Cho; Lara R Lipton; Mark Wong; Andrew Strickland; Jin Won Kim; John R Zalcberg; John Simes; David Goldstein Journal: J Clin Oncol Date: 2016-06-20 Impact factor: 44.544