EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

Ian Davis, Anne Long, Sonia Yip, David Espinoza, John F Thompson, Ganessan Kichenadsasse, Michelle Harrison, Ray M Lowenthal, Nick Pavlakis, Arun Azad, George Kannourakis, Christopher Steer, David A Goldstein, Jeremy Shapiro, Rozelle M Harvie, Lidija Jovanovic, Amanda L Hudson, Colleen C Nelson, Martin R Stockler, Axel V Martin

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)1118 - 1123
Number of pages6
JournalAnnals of Oncology
Volume26
Issue number6
DOIs
Publication statusPublished - 2015

Cite this

Davis, Ian ; Long, Anne ; Yip, Sonia ; Espinoza, David ; Thompson, John F ; Kichenadsasse, Ganessan ; Harrison, Michelle ; Lowenthal, Ray M ; Pavlakis, Nick ; Azad, Arun ; Kannourakis, George ; Steer, Christopher ; Goldstein, David A ; Shapiro, Jeremy ; Harvie, Rozelle M ; Jovanovic, Lidija ; Hudson, Amanda L ; Nelson, Colleen C ; Stockler, Martin R ; Martin, Axel V. / EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma. In: Annals of Oncology. 2015 ; Vol. 26, No. 6. pp. 1118 - 1123.
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title = "EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma",
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.",
author = "Ian Davis and Anne Long and Sonia Yip and David Espinoza and Thompson, {John F} and Ganessan Kichenadsasse and Michelle Harrison and Lowenthal, {Ray M} and Nick Pavlakis and Arun Azad and George Kannourakis and Christopher Steer and Goldstein, {David A} and Jeremy Shapiro and Harvie, {Rozelle M} and Lidija Jovanovic and Hudson, {Amanda L} and Nelson, {Colleen C} and Stockler, {Martin R} and Martin, {Axel V}",
year = "2015",
doi = "10.1093/annonc/mdv078",
language = "English",
volume = "26",
pages = "1118 -- 1123",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "6",

}

Davis, I, Long, A, Yip, S, Espinoza, D, Thompson, JF, Kichenadsasse, G, Harrison, M, Lowenthal, RM, Pavlakis, N, Azad, A, Kannourakis, G, Steer, C, Goldstein, DA, Shapiro, J, Harvie, RM, Jovanovic, L, Hudson, AL, Nelson, CC, Stockler, MR & Martin, AV 2015, 'EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma' Annals of Oncology, vol. 26, no. 6, pp. 1118 - 1123. https://doi.org/10.1093/annonc/mdv078

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma. / Davis, Ian; Long, Anne; Yip, Sonia; Espinoza, David; Thompson, John F; Kichenadsasse, Ganessan; Harrison, Michelle; Lowenthal, Ray M; Pavlakis, Nick; Azad, Arun; Kannourakis, George; Steer, Christopher; Goldstein, David A; Shapiro, Jeremy; Harvie, Rozelle M; Jovanovic, Lidija; Hudson, Amanda L; Nelson, Colleen C; Stockler, Martin R; Martin, Axel V.

In: Annals of Oncology, Vol. 26, No. 6, 2015, p. 1118 - 1123.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

AU - Davis, Ian

AU - Long, Anne

AU - Yip, Sonia

AU - Espinoza, David

AU - Thompson, John F

AU - Kichenadsasse, Ganessan

AU - Harrison, Michelle

AU - Lowenthal, Ray M

AU - Pavlakis, Nick

AU - Azad, Arun

AU - Kannourakis, George

AU - Steer, Christopher

AU - Goldstein, David A

AU - Shapiro, Jeremy

AU - Harvie, Rozelle M

AU - Jovanovic, Lidija

AU - Hudson, Amanda L

AU - Nelson, Colleen C

AU - Stockler, Martin R

AU - Martin, Axel V

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://annonc.oxfordjournals.org/content/26/6/1118.full.pdf+html

U2 - 10.1093/annonc/mdv078

DO - 10.1093/annonc/mdv078

M3 - Article

VL - 26

SP - 1118

EP - 1123

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 6

ER -