2019 ASCO Annual Meeting!
Session: Lung Cancer—Non-Small Cell Metastatic
Type: Oral Abstract Session
Time: Monday June 3, 8:00 AM to 11:00 AM
Location: Hall B1
MET inhibitor resistance in patients with MET exon 14-altered lung cancers.
Metastatic Non-Small Cell Lung Cancer
Lung Cancer—Non-Small Cell Metastatic
2019 ASCO Annual Meeting
J Clin Oncol 37, 2019 (suppl; abstr 9006)
Author(s): Robin Guo, Michael Offin, A. Rose Brannon, Andrew Chow, Lukas Delasos, Romel Somwar, Olivia Wilkins, Kerry Scott, Yuan Tian, Fabiola Cecchi, Todd A. Hembrough, Bob T. Li, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Natasha Rekhtman, Paul K. Paik, Marc Ladanyi, Ahmet Zehir, Alexander E. Drilon; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY; UConn Health, Farmington, CT; NantOmics, LLC, Rockville, MD; NantOmics, LLC, Santa Cruz, CA
Background: MET exon 14 alterations comprise a novel class of lung cancer drivers. MET tyrosine kinase inhibitors (TKIs) are active in patients with these cancers, but objective response rates (ORRs) are modest (~30%-40%). A subset of these cancers may harbor intrinsic resistance. Moreover, patients with initial benefit invariably develop acquired resistance. We set out to identify potential resistance mechanisms. Methods: We studied patients with stage IV MET exon 14-altered lung cancers who received a MET TKI. When feasible, tumor and/or plasma samples were collected, prioritizing paired pre- and post-TKI collection. Tumor samples underwent targeted mass spectrometry analysis (Nantomics) and DNA- (including MSK-IMPACT)/RNA-based (MSK-Fusion) next-generation sequencing (NGS). Plasma cfDNA underwent targeted NGS. ORR and progression-free survival (PFS) were assessed (RECIST v1.1). Results: 74 patients received a MET TKI (1 TKI n = 55; ≥2 TKIs n = 19). 91% received crizotinib as their 1st TKI. Pre-TKI MET levels in tumor tissue (range 0-2120 amol/µg) were associated with outcomes: ORR 63% (n = 7/11) and median PFS 6.9 mos with detectable MET vs ORR 0% (n = 0/5) and median PFS 4.6 mos with undetectable MET (HR for PFS 0.3). Pre-TKI RAS pathway activation was associated with response: ORR 0% (n = 0/6) with KRAS/NF1/RASA1 mutation vs ORR 29% (n = 25/87) in others. Similar outcomes were observed with pre-TKI KRAS expression (n = 16, all with detectable KRAS levels): ORR 0% (n = 0/2) in KRAS ≥700 amol/µg vs ORR 50% (n = 7/14) < 700 amol/µg. Acquired resistance (Jackman criteria) was seen in 29 patients, 9 with paired pre-/post-treatment samples. On-target acquired resistance was found in 2/9 patients (22%): MET D1228N (n = 1), HGF amplification (n = 1). Potential off-target acquired resistance mechanisms were found in 5/9 pts (44%): KRAS G13V (n = 1), RASA1 S742* (n = 1), MDM2 amplification (n = 2), EGFR amplification (n = 1). Conclusions: Lack of MET expression or RAS pathway activation is associated with poor MET TKI outcomes in MET exon14-altered lung cancers. On-target acquired resistance is found in < 25% of patients; HGF amplification is a novel mechanism. Off-target intrinsic/acquired resistance may be mediated by RAS/MDM2/EGFR pathway activation.