Published February 18, 2022 | Version Version 1, database frozen as of Jul 31, 2021
Dataset Open

Bevacizumab plus erlotinib versus erlotinib alone as first line treatment of patients with EGFR-mutated advanced nonsquamous non-small cell lung cancer. BEVacizumab plus ERLotinib studY (BEVERLY): an academic, multicenter, randomised phase III trial.

Authors/Creators

  • 1. Clinical Trials Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
  • 2. Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy
  • 3. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy
  • 4. Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
  • 5. Medical Oncology Unit, AUSL of Romagna, S. Maria delle Croci Hospital, Ravenna, Italy
  • 6. Oncology and Hematology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy
  • 7. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS Dino Amdori, Meldola, Italy
  • 8. Medical Oncology and Hematology, Mirano ULSS 3, Serenissima Regione Veneto, Mirano, Italy
  • 9. Oncology Department, Azienda Sanitaria Universitaria Friuli Centrale, Udine; Italy
  • 10. Medical Oncology and Hematology, Department of Precision Medicine, Università degli Studi della Campania ''Luigi Vanvitelli'', Napoli; Italy
  • 11. Medical Oncology Unit, Senatore Antonio Perrino Hospital, Brindisi; Italy
  • 12. Medical Oncology Unit, S. Chiara Hospital, Trento; Italy
  • 13. Medical Oncology Unit, Degli Infermi Hospital in Rimini and Cervesi Hospital in Cattolica, Rimini; Italy
  • 14. Medical Oncology Department, Policlinico Universitario Campus Bio Medico; Roma; Italy
  • 15. Promise Department, Università of Palermo "La Maddalena Clinic for Cancer", Palermo; Italy
  • 16. Oncological Pneumology Unit, S. Camillo Forlanini Hospital, Roma; Italy
  • 17. Medical Oncology Unit, Nuovo Ospedale di Prato - Santo Stefano, Prato; Italy
  • 18. Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova; Italy
  • 19. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano; Italy
  • 20. Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli; Italy
  • 21. Medical Oncology Unit, AUSL of Romagna, S. Maria delle Croci Hospital, Ravenna; Italy
  • 22. Oncology and Hematology Department, Guglielmo da Saliceto Hospital, Piacenza; Italy
  • 23. Clinical Trials Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli; Italy
  • 24. Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milano; Italy
  • 25. Cellular Biology and Biotherapy, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli; Italy
  • 26. Medical Statistics, Università degli Studi della Campania "Luigi Vanvitelli", Napoli; Italy
  • 27. Medical Oncology Unit, S.Giuseppe Moscati Hospital, Avellino; Italy

Description

Background. Adding bevacizumab to erlotinib prolonged PFS of patients with EGFR-mutated advanced NSCLC in the Japanese NEJ026 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized phase III trial of bevacizumab plus erlotinib versus erlotinib alone as first-line treatment of advanced EGFR-mutated NSCLC.

Methods. Eligible patients were randomized 1:1 to erlotinib (150mg daily) plus bevacizumab (15mg/kg iv q3w) or erlotinib alone, until disease progression or unacceptable toxicity. Center, ECOG PS and type of mutation (ex19 deletion vs ex21 L858R vs others) were stratification variables. Investigator-assessed PFS (IA-PFS) and blinded-independent centrally-reviewed PFS (BICR-PFS) were co-primary endpoints. With 80% power in detecting a 0·60 HR and 2–sided α error 0·05, 126 events out of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17.

Findings. From Apr 11, 2016 to Feb 27, 2019, 160 pts were randomized to erlotinib pus bevacizumab (80) or erlotinib alone (80). Baseline characteristics were balanced between arms; 34 (42·5%) patients in erlotinib plus bevacizumab arm and 43 (53·8%) in erlotinib arm were former or current smokers. At a median follow-up of 36·3 months, 140 PFS events (87·5%) were reported, 68 with erlotinib plus bevacizumab and 72 with erlotinib. Median IA-PFS was 15·4 months (95% CI 12·2–18·6) with erlotinib plus bevacizumab and 9·6 months (95% CI 8·2–10·6) with erlotinib (HR 0·66; 95%CI: 0·47–0·92). BICR-PFS analysis confirmed this result. A significant interaction with treatment effect was found for smoking habit (P=0·0323): former or current smokers receiving erlotinib plus bevacizumab had a longer PFS (16·9 months [95% CI 10·2–21·8] versus 8·8 months [95% CI 5·6–9·6]) than those receiving erlotinib alone.

Hypertension (grade≥3: 24% vs 5%), skin rash (grade≥3: 31% vs 14%), thromboembolic events (any grade: 11% vs 4%), and proteinuria (any grade: 23% vs 6%) were more frequent with the combination treatment.

Interpretation. The addition of bevacizumab to first-line erlotinib significantly prolonged PFS in Italian patients with EGFR-mutated NSCLC, without unexpected safety issues.

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