Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study

William P. Tew, Michael W. Sill, Joan L. Walker, Angeles Alvarez Secord, Albert J. Bonebrake, Jeanne Schilder, Ashley Stuckey, Laurel Rice, Krishnansu S. Tewari, Carol A. Aghajanian

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). Patients and methods: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. Results: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73%, 1–2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66–1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72–1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were “other GI (mucositis)” (23 vs 1%) and “metabolic/nutrition” (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. Conclusion: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.

Original languageEnglish (US)
JournalGynecologic Oncology
DOIs
StateAccepted/In press - Jan 1 2018

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Fallopian Tubes
Carcinoma
Bevacizumab
Everolimus
Platinum
Disease-Free Survival
Mucositis
Exanthema

Keywords

  • Bevacizumab
  • Everolimus
  • Ovarian cancer
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma : An NRG oncology/gynecologic oncology group study. / Tew, William P.; Sill, Michael W.; Walker, Joan L.; Secord, Angeles Alvarez; Bonebrake, Albert J.; Schilder, Jeanne; Stuckey, Ashley; Rice, Laurel; Tewari, Krishnansu S.; Aghajanian, Carol A.

In: Gynecologic Oncology, 01.01.2018.

Research output: Contribution to journalArticle

Tew, William P. ; Sill, Michael W. ; Walker, Joan L. ; Secord, Angeles Alvarez ; Bonebrake, Albert J. ; Schilder, Jeanne ; Stuckey, Ashley ; Rice, Laurel ; Tewari, Krishnansu S. ; Aghajanian, Carol A. / Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma : An NRG oncology/gynecologic oncology group study. In: Gynecologic Oncology. 2018.
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abstract = "Purpose: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). Patients and methods: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. Results: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73{\%}, 1–2: 27{\%}), prior regimens (1: 37{\%}, 2: 47{\%}, 3: 16{\%}), prior BV (11{\%}), PFI (<6mos: 65{\%}) and measurable disease (81{\%}). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95{\%} CI, 0.66–1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95{\%} CI, 0.72–1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22{\%} vs 12{\%}). Study removal due to toxicity was higher with BV + EV (29{\%} vs 12{\%}). Toxicity (≥grade 3) from BV + EV were “other GI (mucositis)” (23 vs 1{\%}) and “metabolic/nutrition” (19 vs. 7{\%}); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. Conclusion: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.",
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author = "Tew, {William P.} and Sill, {Michael W.} and Walker, {Joan L.} and Secord, {Angeles Alvarez} and Bonebrake, {Albert J.} and Jeanne Schilder and Ashley Stuckey and Laurel Rice and Tewari, {Krishnansu S.} and Aghajanian, {Carol A.}",
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T1 - Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma

T2 - An NRG oncology/gynecologic oncology group study

AU - Tew, William P.

AU - Sill, Michael W.

AU - Walker, Joan L.

AU - Secord, Angeles Alvarez

AU - Bonebrake, Albert J.

AU - Schilder, Jeanne

AU - Stuckey, Ashley

AU - Rice, Laurel

AU - Tewari, Krishnansu S.

AU - Aghajanian, Carol A.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). Patients and methods: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. Results: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73%, 1–2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66–1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72–1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were “other GI (mucositis)” (23 vs 1%) and “metabolic/nutrition” (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. Conclusion: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.

AB - Purpose: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). Patients and methods: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. Results: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73%, 1–2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66–1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72–1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were “other GI (mucositis)” (23 vs 1%) and “metabolic/nutrition” (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. Conclusion: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.

KW - Bevacizumab

KW - Everolimus

KW - Ovarian cancer

KW - Targeted therapy

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