Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung cancer: Phase II ABCD-study

Lung Cancer. 2024 Nov:197:107988. doi: 10.1016/j.lungcan.2024.107988. Epub 2024 Oct 5.

Abstract

Introduction: Many clinical studies showed a synergy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors. We hypothesized afatinib plus bevacizumab exerts clinical potency after developing various osimertinib resistant mechanisms.

Methods: EGFR-mutant non-small cell lung cancer patients were enrolled after osimertinib resistance. Afatinib at 30-40 mg/day and bevacizumab at 15 mg/kg tri-weekly were administered until progression. Plasma/histologic rebiopsied samples after osimertinib failure were analyzed to examine resistant mechanisms: gene alterations/copy-number gain using cancer personalized profiling by deep sequencing.

Results: Between January 2018 and October 2020, 28 patients were enrolled. Response and disease control rates were 17.9 % and 78.6 %, respectively. Median duration of response was 9.0 (range, 4.2-22.3) months. Median progression-free and overall survivals were 2.7 and 9.3 months, respectively. Twenty-eight (100 %) plasma and/or 21 (75 %) histologic rebiopsies identified: 17 (61 %) TP53; 15 (54 %) T790M; 9 (32 %) uncommon EGFR; 9 (32 %) MET; 6 (21 %) C797S; 3 (11 %) BRAF; 2 (7 %) HER2; 2 (7 %) KRAS; and 2 (7 %) PI3K mutations. One (17 %) of 6 C797S patients showed complete response. Three (33 %) of 9 uncommon EGFR-mutated patients achieved radiographic response. Neither 15 T790M-positive nor 6 EGFR downstream signaling mutations: BRAF; KRAS; or PI3K-positive patients responded, but 5 (38 %) of 13 T790M-negative patients responded. Adverse events ≥ grade 3 and incidence ≥ 5 % were: hypertension (29 %); proteinuria (7 %); and diarrhea (7 %). There were neither treatment-related death nor interstitial lung disease.

Conclusions: Selected population could obtain clinical benefit from afatinib plus bevacizumab, based on rebiopsy results after osimertinib resistance.

Keywords: Afatinib; And non-small cell lung cancer; Bevacizumab; Epidermal growth factor receptor; Osimertinib resistance.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Acrylamides* / therapeutic use
  • Adult
  • Afatinib* / therapeutic use
  • Aged
  • Aged, 80 and over
  • Aniline Compounds* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Bevacizumab* / administration & dosage
  • Bevacizumab* / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / mortality
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Drug Resistance, Neoplasm* / genetics
  • ErbB Receptors* / genetics
  • Female
  • Humans
  • Indoles
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / mortality
  • Lung Neoplasms* / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines

Substances

  • osimertinib
  • Acrylamides
  • ErbB Receptors
  • Bevacizumab
  • Afatinib
  • Aniline Compounds
  • EGFR protein, human
  • Protein Kinase Inhibitors
  • Indoles
  • Pyrimidines