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Brief Report
December 13, 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

Author Affiliations
  • 1Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy
  • 2Division of Medical Oncology, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
  • 3Department of Pulmonology, Maastricht University Medical Center, Maastricht, the Netherlands
  • 4Department of Hematology and Oncology, University Department of Internal Medicine–Oncology, Pius-Hospital, University of Oldenburg, Oldenburg, Germany
  • 5Lung Cancer Unit, Ospedale Policlinico San Martino, Genova, Italy
  • 6Thoracic Oncology Unit, Abramson Cancer Center, University of Pennsylvania, Philadelphia
  • 7Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
  • 8Department of Medicine, National and Kapodistrian University, Athens, Greece
  • 9Christie Hospital NHS Trust, Manchester, United Kingdom
  • 10F. Hoffmann-La Roche Ltd, Basel, Switzerland
  • 11Roche Products Pty Ltd, Sydney, New South Wales, Australia
  • 12Now with OzBiostat Pty Ltd, Manly, New South Wales, Australia
  • 13Institut de Cancérologie de l’Ouest, Nantes, France
JAMA Oncol. 2018;4(12):e183486. doi:10.1001/jamaoncol.2018.3486
Key Points

Question  Is there a benefit of continuing bevacizumab treatment beyond disease progression in patients with non–small cell lung cancer (NSCLC)?

Findings  In this randomized clinical trial of 485 patients with advanced, nonsquamous NSCLC, the primary end point was not met; median overall survival was not significantly different between groups. No new safety signals were identified with bevacizumab treatment beyond disease progression.

Meaning  Continued bevacizumab treatment beyond disease progression did not demonstrate survival benefit.


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.

Trial Registration  clinicaltrialsregister.eu Identifier: 2010-022645-14; ClinicalTrials.gov identifier: NCT01351415