Liquid and tissue biopsies for identifying MET exon 14 skipping NSCLC: Analyses from the Phase II VISION study of tepotinib.

Objective: The VISION trial of tepotinib, a selective MET inhibitor, enrolled patients with NSCLC and prospectively detected MET exon 14 skipping (METex14) in liquid biopsies (LBx) and/or tissue biopsies (TBx). We evaluated patient characteristics and outcomes according to METex14 positivity in LBx (LBx-positive) or TBx (TBx-positive).

Methods: METex14 was centrally assessed by next-generation sequencing of ctDNA from LBx (Guardant360®/Archer®MET) and/or RNA from TBx (Oncomine Focus/Archer®MET) or, in Japan only, local TBx polymerase chain reaction. Parallel LBx/TBx testing was recommended but not mandatory. Eligibility required LBx-positive or TBx-positive status. ctDNA burden was analyzed in patients with baseline Guardant360® data.

Results: METex14 was detected in 469/7,937 prescreened/screened patients, of whom 313 were enrolled (TBx-positive, n=208; LBx-positive, n=178). LBx-positive patients had higher radiographic tumor burden than TBx-positive patients, including higher median sum of target lesion diameters per RECIST v1.1 (67.1 vs 55.2 mm), and more patients with ≥3 target lesions (27.5% vs 18.8%). In 180 TBx-positive patients with matching LBx results, objective response rates were slightly higher in TBx-positive/LBx-positive patients, but TBx-positive/LBx-negative patients had longer duration of response, progression-free survival (PFS), and overall survival (OS). In ctDNA analysis (n=165), detectable baseline ctDNA burden was associated with shorter PFS and OS.

Conclusions: Tepotinib had robust, durable activity in TBx-positive/LBx-negative and TBx-positive/LBx-positive patients. While LBx is a complementary method to TBx for detecting METex14, it may preferentially select patients with higher tumor burden and poorer prognosis. Undetectable METex14 in baseline ctDNA (due to low ctDNA shedding) may define more favorable treatment outcomes.