Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung cancer: Phase II ABCD-study
Mené sur 28 patients atteints d'un cancer du poumon non à petites cellules de stade avancé ayant développé des mécanismes de résistance à l'osimertinib et présentant des mutations EGFR, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse et de la durée de la réponse, et la toxicité de l'afatinib en combinaison avec le bévacizumab
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