Phase II study of crizotinib in patients with MET amplification and MET exon 14 deletion: Results from NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocols C1 and C2.
Authors: Coleman Niamh , Wei Zihan , Hong David S. , Mitchell Edith P. , Zwiebel James A. , Sharon Elad , Gray Robert James , Wang Victoria , McShane Lisa , Rubinstein Larry V. , Patton David R. , Williams P. Mickey , Tricoli James V. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith , Hamilton Stanley R. 
Published: June 2023

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Background: The NCI-Molecular Analysis for Therapy Choice (MATCH) platform trial enrolled patients with solid tumors, lymphomas, or multiple myeloma to trials of targeted therapies based on matching genomic alterations. Subprotocols C1 and C2 evaluated MET tyrosine kinase inhibitor crizotinib in pts with MET amplification ( METamp; C1) or MET Exon 14 mutation/deletion ( METex14; C2). Methods: Pts whose tumors had METamp or METex14 were eligible for C1 and C2, respectively. Results were confirmed by MATCH Oncomine assay if possible; C2 explored METex14 quantification at DNA level retrospectively using cases with sufficient tissue for analysis of DNA mutations surrounding MET exon 14 and control samples with a variable amount of MET exon 14 counts using Anchored Multiplex PCR. Pts in C1 and C2 received crizotinib orally BD daily in 28-day cycles until progression or unacceptable toxicity. Tumor assessment occurred every 2 cycles. Primary endpoint was ORR; PFS; secondary endpoints: 6-month PFS, OS, and predictive biomarkers. Results: C1 enrolled 44 pts, of which 28, representing a variety of histologies, were eligible, received treatment, and included in the primary efficacy analysis as prespecified by protocol; GI (n=17) and lung (n=7) were most common. Median age: 67 (range 28- 82), 9 pts were women. Median MET copy number was 16.8 (min 7.1, max 78.0). Of 28 pts, 4 had PR; 10 had SD, 13 had PD as best response; disease control rate (DCR) 50% (14/28); one pt was unevaluable. ORR was 14% (4/28, 90% CI: 5.0%-29.8%). Median PFS was 3.4 mo (90% CI: 1.8–3.7); median OS 7.1 mo (90% CI: 5.0–11.5). 4 pts with confirmed PR were lung (n=2), GI (n=1), melanoma (n=1); 1 pt had SD >6 mo (NSCLC). Most pts had ≥1 co-occurring gene alteration (n=27; 96%), TP53 co-mutation most frequently (n=23, 82%); 21 pts had ≥3 co-occurring mutations. C2 enrolled 20 pts, 14 evaluable received treatment: GI (n=5); lung (n=6); other (n=3). Median age for the 14 pts was 68 (range 57-78); 6 pts were women, 9 (64%) had ≥3 lines of prior therapy. Most pts had ≥1 co-occurring gene alteration (n=13; 93%, range 1-4); TP53 co-mutations were frequent (n=7, 50%). Of 14 pts, 2 had PR (both NSCLC); 4 had SD, 4 had PD as best response, and DCR was 43% (6/14). 2 pts had SD >6 mo (1 lung, 1 bladder). ORR was 14% (2/14, 90% CI: 2.6%-38.5%). Median PFS 2.0 mo (90% CI: 1.4–4.1). On quantification by Met count ≥50,000 mPFS 8.8 months (90% CI: 2.1–NA), MET count <50,000 mPFS 1.7 mo (90% CI: 1.1–3.7). All lung cancer pts with confirmed PR/SD >6 mo had documented MET count >50,000. Most common reason for permanent treatment discontinuation was disease progression. No new toxicity signals were identified. Conclusions: We demonstrate clinical activity using crizotinib across tumors in patients with METampand METex14. In METex14, differentiating true pathogenic variants from low-level splice variant transcripts may be clinically meaningful. Clinical trial information: NCT02465060 .