Phase I study of the safety and efficacy of INC280 in patients with advanced MET-dependent solid tumors.

Bang, Yung‐Jue; Su, Wu‐Chou; Nam, Do‐Hyun; Lim, Wan‐Teck; Bauer, Todd M.; Braña, Irene; Poon, Ronnie Tung‐Ping; Hong, David S.; Lin, Chia‐Chi; Peng, Bin; Zhang, Yingxi; Zhao, Sylvia; Kumar, Arun; Akimov, Mikhail; Ma, Brigette

doi:10.1200/jco.2014.32.15_suppl.2520

Cited by 41 publications

(49 citation statements)

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“…Capmatinib (INC280) is an oral, highly selective and potent MET inhibitor that is well tolerated and has shown clinical activity in advanced solid tumors (36,37). Phase I and II clinical trials are ongoing to investigate the efficacy of capmatinib in cancers including melanoma, HCC, NSCLC, glioblastoma, colorectal cancer, and papillary renal cancer.…”

Section: Resultsmentioning

confidence: 99%

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

et al. 2018

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Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.

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Section: Resultsmentioning

confidence: 99%

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

et al. 2018

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“…This phase I, dose‐escalation study was conducted in Japanese patients with advanced solid tumors who had progressed despite standard therapy or for whom no effective therapy exists. The expansion was not initiated because sufficient data for further development were already available from other clinical studies of capmatinib …”

Section: Discussionmentioning

confidence: 99%

“…The capsule formulation at 600 mg b.i.d. was initially selected as the RP2D . A tablet formulation was subsequently developed to improve patient compliance, as this allowed for higher dosage strengths and therefore fewer tablets compared with capsules.…”

Section: Introductionmentioning

confidence: 99%

Phase I dose‐escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors

et al. 2019

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Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open‐label, multicenter, dose‐escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose ( MTD ) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose‐limiting toxicities ( DLT ) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug‐related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration ( T max ) was 1.0‐4.0 hours; absorption was more rapid after dosing using tablets, with median T max of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.

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“…Recently, in a small series, the objective response rate (ORR) to crizotinib (a MET/ALK/ROS1 inhibitor) dramatically differed between cases with different MET /CEP7 ratios (ratio ≥1.8−≤2.2 ORR 0%; ratio >2.2−<5 ORR 17%; ratio ≥5 ORR 67%) (24). In EGFR mutant NSCLC with acquired resistance to EGFR TKIs, the ORR to the combination of an EGFR inhibitor and a MET inhibitor (INC280) was 0% among those with a mean MET /cell of <5 and 40% among those with mean MET /cell ≥5 (30). …”

Section: Introductionmentioning

confidence: 99%

Identifying the Appropriate FISH Criteria for Defining MET Copy Number–Driven Lung Adenocarcinoma through Oncogene Overlap Analysis

Noonan

Berry

et al. 2016

Journal of Thoracic Oncology

148

149

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Introduction MET gene copy number gain (CNG) may be a predictive biomarker for MET inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain. Methods MET copy number was assessed by fluorescence in situ hybridization (FISH) in lung adenocarcinoma. Positivity criteria included mean MET/cell ≥5 (low ≥5 – <6, intermediate ≥6 –<7, high ≥7) and MET/CEP7 ratio ≥1.8 (low ≥1.8 – ≤2.2, intermediate >2.2 – < 5, high ≥5). Associated clinical and molecular characteristics were captured. Results 99/686 cases (14%) had mean MET/cell ≥ 5, 52/1164 (4.5%) had MET/CEP7 ≥1.8. Other oncogenic drivers (in EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 or RET) were detectable in 56% of the mean MET/cell ≥ 5 group and 47% of the MET/CEP 7 ratio ≥1.8 group, suggesting many MET ‘positive’ cases are not truly MET-addicted. Concomitant drivers in low, indeterminate and high categories of mean MET/cell were 32/52 (62%), 12/19 (63%) and 11/27 (41%) (p=0.2) and in MET/CEP7: 15/29 (52%), 9/18 (50%) and 0/4 (0%) respectively (p=0.04). MET/CEP7 ≥1.8, in the absence of other oncogenes, was associated with a higher rate of adrenal metastases (p=0.03), but not with never smoking status. Conclusions FISH MET/CEP7 ≥ 5 defined a MET ‘positive’ group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition it represents the clearest definition of a MET CNG-addicted state. However, a MET-associated phenotype may also exist across MET/CEP7 ≥ 1.8 cases when no other oncogene overlap occurs.

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Phase I study of the safety and efficacy of INC280 in patients with advanced MET-dependent solid tumors.

Cited by 41 publications

References 0 publications

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

Phase I dose‐escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors

Identifying the Appropriate FISH Criteria for Defining MET Copy Number–Driven Lung Adenocarcinoma through Oncogene Overlap Analysis

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