1. Clonal evolution of resistance to sequential ALK inhibitor therapy.
Clonal evolution of resistance to sequential ALK inhibitor therapy. A, the treatment course of patient MGH086. Of note, the patient received several lines of therapy, including the EGFR inhibitor erlotinib, before identification of an ALK rearrangement. The points at which the patient underwent biopsies are indicated in red. B, fused positron emission tomography (PET)–computed tomography (CT) images demonstrate a hypermetabolic, left axillary lymph node (white arrow) that developed at the time of disease progression on crizotinib. WES revealed an ALKE1210K mutation [cancer cell fraction (CCF) 0.82]. This axillary lymph node initially responded to brigatinib but recurred after 12 months. WES of this brigatinib-resistant lesion (MGH086-0) demonstrated continued presence of the ALKE1210K mutation and a new ALKS1206C mutation. The patient remained on brigatinib. After an additional 9 months on brigatinib, he developed another recurrence in the left axilla (slightly more inferior than the prior lesion). Repeat WES (MGH086-1) revealed a new compound ALKE1210K+D1203N mutation. C, a model of clonal evolution of resistance to sequential ALK inhibitor therapy in patient MGH086. Using WES, we determined that a founder ALKE1210K subclone was not present in a pre-crizotinib biopsy but later developed on crizotinib. When the patient was switched to brigatinib, the ALKE1210K subclone expanded and ultimately acquired a new ALK mutation, S1206C. Surgical excision of this site of progression may have depleted the compound mutant (ALKE1210K+S1206C), but microscopic parental E1210K clones may have persisted, ultimately acquiring ALKD1203N in combination with ALKE1210K.
Justin F. Gainor et al. Cancer Discov 2016;6:
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