Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously-negative patients?

Abstract

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinaseinhibitors (TKIs) are markedly effective for T790M-positive patients. To confer theirclinical benefit to more patients, a novel therapy to induce positive conversion inT790M-negative patients may be possible. We retrospectively reviewed medicalrecords of patients who had received rebiopsy after completion of ABC-study: aprospective phase II study of Afatinib plus Bevacizumab Combination (ABC)-therapyafter acquired resistance to EGFR-TKI. Between October 2014 and September 2016,32 eligible patients were enrolled in ABC-study at our institutes. Eighteen patientswere T790M-negative and 14 were T790M-positive before ABC-therapy. Rebiopsy wasperformed on 13 T790M-negative and 5 T790M-positive patients after progressionof ABC-therapy. In 8 (62%) of 13 T790M-negative patients, T790M status changedfrom negative to positive after ABC-therapy. Seven of these 8 patients underwentosimertinib therapy. The response rate and median time to treatment failure were86% and 12.2 months, respectively. There were no adverse events =grade 3, nor anytreatment-related deaths. On the other hand, T790M remained positive after ABCtherapy in all 5 previous T790M-positive patients. ABC-therapy could induce positiveconversion of T790M even in previously-negative patients. We hypothesize that ABCtherapy could provoke "clonal selection", which purifies T790M-positive cancer cellsin heterogeneous tumors. Further studies are warranted to confirm this phenomena.