MET as a novel treatment target- the story of the sleeping beauty Balazs Halmos M.D. Montefiore Medical Center/Albert Einstein College of Medicine
MET as a novel treatment target MET as an oncogene MET in papillary renal cell carcinoma MET as a lung cancer oncogene and treatment target MET mutations MET amplification FISH testing Crizotinib experience MET exon 14 skipping Discovery Biology Actionability Acquired resistance The role of MET in acquired drug resistance Furlan et al, Ca Res 2014
MET as an oncogene Proto-oncogene located on chromosome 7q31.2 Activated by its ligand, HGF MET interacts directly with other signaling pathways, eg EGFR and can lead to a unique alternative activation pathway Met pathway activation Protein overexpression (transcriptional upregulation) IHC Hypoxia-mediated activation of the c-met promoter by hypoxia inducible factor 1a (HIF-1alpha) Increased HGF ligand expression Mutations DNA sequencing Gene amplification FISH Alternative splicing (exon 14 skipping) DNA sequencing Gelsomino et al, Crit Rev Hem/Onc 2014
MET biomarker selection by IHC- the MetMab story
MET targeting- initial series of failures Maroun/Rowlands, Pharm Ther, 2014
Papillary Renal Cell Carcinoma Germline mutations in MET present in 100% of hereditary cases of prcca Sporadic mutations in MET present in 13% of cases. PRCC accounts for 15-20% of kidney cancers MET inhibition somewhat effective- especially in hereditary type- foretinib experience
MET mutations in non-small cell lung cancer Kong-Beltran, Ca res 2006 Ma et al, Ca Res 2005
MET amplification as an actionable target? PROFILE 001 Ou et al JTO 2011 Camidge et al ASCO 2014
MET amplification as a better biomarker- where to draw the line? Noonan JTO 2016
The MET exon 14 story- Sarcomatoid lung carcinoma 1-2% of all non-small cell lung cancers with both epithelial and mesenchymal differentiation characteristics Very aggressive behavior Higher recurrence rates Resistance to standard therapy- 70% primary progression on doublet chemotherapy! Lack of understanding of genetic alterations explaining sarcoma-like features Patient s Epithelial component type 2 AD 4 AD 5 6 AD and SQC AD and SQC 16 AD 19 SQC 22-25 AD 31 AD 32 AD Sarcomatou s component type Spindle and giant cells Spindle and giant cells Spindle cells Spindle cells Spindle cells Spindle cells Spindle and giant cells Spindle cells Spindle cells Mutation types 5p splice site 16bp deletion including 1 coding bp c.c2975t, p.t992i 5p intron 28bp deletion point mutation c. G3028C, p. D1010H point mutation c. G3028C, p. D1010H c.c2975t, p.t992i 5p splice site first code synonymous point mutation GAT to GAC 5p intron frameshift insertion 116771796 CT insertion point mutation c. G3028C, p. D1010H Spindle and point mutation c. G3028C, p. D1010H giant cells Previous reports reported in colon cancer reported in colon cancer
Exon 14 skipping mutations as actionable targets in sarcomatoid lung cancer Liu et al, JCO 2016
Rapid and dramatic response to crizotinib in a patient with MET exon 14 skipped sarcomatoid lung cancer Nov 2014 Feb 2015
MET exon 14 skipping as an actionable novel oncogene Wild-type MET signaling MET exon 14 variant
Foundation One Frampton et al, Cancer Discov 2015 Ou et al JTO 2016
MSKCC experience Paik et al, Cancer Discov, 2016
Met exon 14 skipping- overall frequency/ overlap with amplification Awad, JCO 2016
Acquired drug resistance Ou et al, JTO, 2016 D1228N Heist et al, JTO, 2016
MET in bypass resistance Overall frequency likely around 5% Engelman Janne, Science 2007
Response to MET inhibitor in EGFR-mutant/METamplified case MGCD265
Bypass resistance
Acquired MET resistance- novel avenues Erlotinib- osimertinib/savolitinib Bahcall, Ca Discov 2016
Multiple studies assessing MET inhibition Study ID Experimental Drug Drug class Treatment Combination Phase Patient Population Biomarker Selection Targets NCT02468661 Capmatinib MET TKI Alone or with Erlotinib II Advanced EGFR-mutated NSCLC EGFRm+, MET GCN > 6 NCT02205398 Capmatinib MET TKI Cetuximab I/II Advanced Squamous Cell Carcinoma of Head and Neck, Metastatic Colorectal Cancer K-Ras/N-Ras- CRC, cmet-positive (combination of IHC and FISH) NCT01982955 Tepotinib (MSC2156119J) MET TKI Gefitinib I/II Advanced EGFR mutation+ NSCLC, failed prior EGFR TKI EGFRm+, (ph II limited to MET IHC+, T790M-) NCT02143466 Volitinib (AZD6094) MET TKI AZD9291 I/II Advanced EGFR-mutation+ NSCLC, failed prior EGFR TKI EGFRm+ (MET+ and T790M- for ph II) NCT02260531 Cabozantinib Multi-targeted TKI Trastuzumab (if ErbB2+) II Breast Cancer, Metastatic brain disease No biomarker selection NCT01644773 Crizotinib Multi-targeted TKI Dasatinib I Diffuse Intrinsic Pontine Glioma, High-grade Glioma No biomarker selection NCT01900652 LY2875358 Anti-MET Alone or with monoclonal antibody erlotinib II Advanced EGFR-mutation+ NSCLC, failed prior EGFR TKI MET IHC+
Novartis: Capmatinib (INC280)
When to consider MET testing/targeting Advanced NSCLC Testing for MET exon 14/high level amplification should be part of multi-gene panels for ALL patients!!! NGS +/- FISH best options ctdna testing evolving Crizotinib/cabozantinib or other MET inhibitor on study an effective choice for patients- unclear at what line of treatment but should NOT be missed! EGFR-mutated NSCLC At a minimum, MET testing by FISH at time of progression for T790M- patients (ideal is to include it as part of a multigene panel) Patients should be directed towards studies of combined EGFR/MET inhibition
Actionable MET translocations in pediatric glioblastoma Bender, Nature Med, 2016
When MET met its match! Costa/Huberman, JTO