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Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung
Akito Hata1, Nobuyuki Katakami2, Naoto Takase2
1Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Japan.
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.
Insights
Afatinib plus bevacizumab showed clinical benefit in patients with EGFR-mutant non-small cell lung cancer resistant to osimertinib. Rebiopsy analysis guided treatment selection for this resistant population.
Area of Science:
- Oncology
- Medical Genetics
Background:
- Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors show synergistic effects in clinical studies.
- Osimertinib resistance is a significant challenge in EGFR-mutant non-small cell lung cancer (NSCLC) treatment.
Purpose of the Study:
- To evaluate the clinical efficacy of afatinib plus bevacizumab in patients with EGFR-mutant NSCLC who developed resistance to osimertinib.
- To investigate the molecular mechanisms of resistance and their correlation with treatment response.
Main Methods:
- A prospective study enrolled 28 patients with EGFR-mutant NSCLC after osimertinib failure.
- Patients received afatinib and bevacizumab until disease progression.
- Plasma and/or tissue rebiopsies were analyzed for genetic alterations using deep sequencing.
Main Results:
- The response rate was 17.9% and the disease control rate was 78.6%.
- Median progression-free survival was 2.7 months and overall survival was 9.3 months.
- Common resistance mechanisms included TP53, T790M, uncommon EGFR mutations, and MET amplification. Patients with C797S or uncommon EGFR mutations showed some response, while T790M-positive or downstream signaling mutations did not respond.
Conclusions:
- Afatinib plus bevacizumab can provide clinical benefit in a selected population of NSCLC patients with acquired osimertinib resistance.
- Rebiopsy and molecular profiling are crucial for guiding treatment decisions in this patient group.
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