Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial

Cesare Gridelli, Javier De Castro Carpeno, Anne Marie C. Dingemans, Frank Griesinger, Francesco Grossi, Corey Langer, Yuichiro Ohe, Konstantinos Syrigos, Nick Thatcher, Ashis Das-Gupta, Matt Truman, Margarita Donica, Vlatka Smoljanovic, Jaafar Bennouna

Research output: Contribution to journalArticle

Abstract

Importance: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non-small cell lung cancer (NSCLC). Objective: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. Design, Setting, and Participants: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. Interventions: Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator's choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. Results: Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4%] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90% CI, 10.2-13.7) vs 10.2 (90% CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90% CI, 0.71-1.00; P =.104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90% CI, 4.2-5.7) vs 4.0 (90% CI, 3.4-4.3) months (HR, 0.83; 90% CI, 0.70-0.98; P =.06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90% CI, 2.9-4.5) vs 2.6 (90% CI, 2.3-2.9) months (HR, 0.63; 90% CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5%]) vs SOC alone (140 [60.3%]). No new safety signals were observed. Conclusions and Relevance: The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P =.06 for PFS2 would conventionally be considered significant at a specified 2-sided α of.10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression.

Original languageEnglish
Article numbere183486
JournalJAMA oncology
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 1 2018

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Standard of Care
Non-Small Cell Lung Carcinoma
Disease Progression
Randomized Controlled Trials
Safety
Lung
Therapeutics
Bevacizumab
Survival
Platinum

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer : The AvaALL Randomized Clinical Trial. / Gridelli, Cesare; De Castro Carpeno, Javier; Dingemans, Anne Marie C.; Griesinger, Frank; Grossi, Francesco; Langer, Corey; Ohe, Yuichiro; Syrigos, Konstantinos; Thatcher, Nick; Das-Gupta, Ashis; Truman, Matt; Donica, Margarita; Smoljanovic, Vlatka; Bennouna, Jaafar.

In: JAMA oncology, Vol. 4, No. 12, e183486, 01.12.2018.

Research output: Contribution to journalArticle

Gridelli, C, De Castro Carpeno, J, Dingemans, AMC, Griesinger, F, Grossi, F, Langer, C, Ohe, Y, Syrigos, K, Thatcher, N, Das-Gupta, A, Truman, M, Donica, M, Smoljanovic, V & Bennouna, J 2018, 'Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial', JAMA oncology, vol. 4, no. 12, e183486. https://doi.org/10.1001/jamaoncol.2018.3486
Gridelli, Cesare ; De Castro Carpeno, Javier ; Dingemans, Anne Marie C. ; Griesinger, Frank ; Grossi, Francesco ; Langer, Corey ; Ohe, Yuichiro ; Syrigos, Konstantinos ; Thatcher, Nick ; Das-Gupta, Ashis ; Truman, Matt ; Donica, Margarita ; Smoljanovic, Vlatka ; Bennouna, Jaafar. / Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer : The AvaALL Randomized Clinical Trial. In: JAMA oncology. 2018 ; Vol. 4, No. 12.
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abstract = "Importance: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non-small cell lung cancer (NSCLC). Objective: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. Design, Setting, and Participants: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. Interventions: Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator's choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. Results: Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4{\%}] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90{\%} CI, 10.2-13.7) vs 10.2 (90{\%} CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90{\%} CI, 0.71-1.00; P =.104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90{\%} CI, 4.2-5.7) vs 4.0 (90{\%} CI, 3.4-4.3) months (HR, 0.83; 90{\%} CI, 0.70-0.98; P =.06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90{\%} CI, 2.9-4.5) vs 2.6 (90{\%} CI, 2.3-2.9) months (HR, 0.63; 90{\%} CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5{\%}]) vs SOC alone (140 [60.3{\%}]). No new safety signals were observed. Conclusions and Relevance: The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P =.06 for PFS2 would conventionally be considered significant at a specified 2-sided α of.10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression.",
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TY - JOUR

T1 - Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer

T2 - The AvaALL Randomized Clinical Trial

AU - Gridelli, Cesare

AU - De Castro Carpeno, Javier

AU - Dingemans, Anne Marie C.

AU - Griesinger, Frank

AU - Grossi, Francesco

AU - Langer, Corey

AU - Ohe, Yuichiro

AU - Syrigos, Konstantinos

AU - Thatcher, Nick

AU - Das-Gupta, Ashis

AU - Truman, Matt

AU - Donica, Margarita

AU - Smoljanovic, Vlatka

AU - Bennouna, Jaafar

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Importance: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non-small cell lung cancer (NSCLC). Objective: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. Design, Setting, and Participants: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. Interventions: Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator's choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. Results: Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4%] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90% CI, 10.2-13.7) vs 10.2 (90% CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90% CI, 0.71-1.00; P =.104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90% CI, 4.2-5.7) vs 4.0 (90% CI, 3.4-4.3) months (HR, 0.83; 90% CI, 0.70-0.98; P =.06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90% CI, 2.9-4.5) vs 2.6 (90% CI, 2.3-2.9) months (HR, 0.63; 90% CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5%]) vs SOC alone (140 [60.3%]). No new safety signals were observed. Conclusions and Relevance: The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P =.06 for PFS2 would conventionally be considered significant at a specified 2-sided α of.10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression.

AB - Importance: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non-small cell lung cancer (NSCLC). Objective: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. Design, Setting, and Participants: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. Interventions: Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator's choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. Results: Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4%] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90% CI, 10.2-13.7) vs 10.2 (90% CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90% CI, 0.71-1.00; P =.104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90% CI, 4.2-5.7) vs 4.0 (90% CI, 3.4-4.3) months (HR, 0.83; 90% CI, 0.70-0.98; P =.06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90% CI, 2.9-4.5) vs 2.6 (90% CI, 2.3-2.9) months (HR, 0.63; 90% CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5%]) vs SOC alone (140 [60.3%]). No new safety signals were observed. Conclusions and Relevance: The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P =.06 for PFS2 would conventionally be considered significant at a specified 2-sided α of.10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression.

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