MET Tyrosine Kinase Inhibitors Research Articles

Abstract 6376: Effect of MET tyrosine kinase inhibitors on MET amplified gastro-esophageal cancer cells

Abstract Background: Many studies have suggested that MET protein overexpression or MET amplification plays a critical role in the progression of gastro-esophageal cancer (GC) and negatively affects survival in patients with GC. However, the criteria used to define overexpression of MET protein have differed among many studies, and in contrast to the initial phase II studies, the phase III trials failed to show any clinical benefit from anti-MET therapies in GCs, even in patients with MET-positive disease. Several studies have used consistent criteria to define MET amplification on FISH, and recent MET inhibitor trials for MET amplified cancers have been successful. Furthermore, hyperactivation of MET pathway are known to reduce the growth-inhibitory effect of trastuzumab in HER2 positive GC. Currently, there is no FDA approved MET inhibitors for GC. Capmatinib and savolitinib, which are selective MET inhibitors, has been evaluated for various MET positive cancers. The aim of this study was to test these MET inhibitors on MET amplified gastro-esophageal cancer (GC) cells. Material and Methods: Among a total of 37 GC cells in our lab, the following cells were positive for MET by copy number amplification (CNV > 10): SNU-620, ESO51, MKN-45, SNU-5 and OE-33. We assessed cytotoxic response of these GC cells to capmatinib or savolitinib alone by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. Western blots were performed to assess the cellular activity of capmatinib or savolitinib in MET signal pathway. Xenograft studies were performed to evaluate in vivo therapeutic efficacy of savolitinib with MKN-45 cells. Results: Savolitinib and capmatinib showed anti-proliferative activity against MET amplified GC cell lines in dose-dependent manner. There was no inhibitory effect on GC cells without MET amplification, such as SNU-216 and SNU-1750. Savolitinib inhibited phosphorylation of MET and down-stream signaling pathway, such as AKT or ERK, in MET amplified GC cells. We observed that treatment with savolitinib induced a significant decrease in the number of colonies formed in soft agar. In addition, Savolitinib exhibited dose-responsive anti-tumor efficacy in xenograft model with MKN-45 GC cells. Furthermore, the combination of Trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in OE-33 cells, which is positive for both HER2 and MET, and resistant to trastuzumab alone. Conclusion: Collectively, these data support that targeting MET with Savolitinib and capmatinib efficiently suppresses the growth of MET amplified GC cells. Moreover, MET inhibitor could synergize with trastuzumab to induce the therapeutic effect on the HER2 and MET amplified GC cells. Further studies are warranted to test this concept in clinical setting. Citation Format: Jin-Soo Kim, Sungyoul Hong, Mi Young Kim. Effect of MET tyrosine kinase inhibitors on MET amplified gastro-esophageal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6376.

Abstract 5239: Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation

Abstract Purpose: MET fusions are oncogenic drivers of multiple cancers including non-small cell lung cancer (NSCLC). While MET fusion-positive tumors can be sensitive to MET tyrosine kinase inhibitors (TKI), to date no mechanisms of TKI resistance have been identified or characterized for MET fusion-positive disease. Experimental Design: Serial targeted genomic sequencing (MSK-IMPACT) was performed in clinical samples from a MET fusion-positive NSCLC treated with the type Ia MET TKI crizotinib. Structural modeling and in vitro kinase assays were used to characterize crizotinib resistance and to test the activity of MET inhibitors with alternative binding modes. Results: A novel MET G1090A resistance mutation was identified in a patient with a CD47-MET-rearranged NSCLC after crizotinib progression. In silico structural modeling and simulations indicated that the 2,6-dichloro-3-fluorophenyl moiety present on crizotinib directly binds to the side chain of the Y1230 residue in the activation loop of the MET wild type (WT) kinase. In the MET G1090A mutant kinase, the position of the Y1230 residue is predicted to be flipped roughly 180°. As a result, the interaction between crizotinib and Y1230 is compromised; this in turn is predicted to reduce crizotinib’s binding affinity for the mutant kinase. Similar results were obtained when MET WT and G1090A mutant kinases were modeled in complex with selective type Ib MET TKI (i.e., capmatinib, savolitinib and tepotinib). Conversely, we found that type II agents (i.e., cabozantinib and foretinib) were not predicted to interact with Y1230. Therefore, their binding affinity to the mutant MET kinase was predicted to be retained. In vitro kinase assays performed using titrations of crizotinib and capmatinib (representative type I agents) and of cabozantinib (representative type II agent) showed that all three TKI were active against the MET WT kinase (calculated IC50 of 2.5nM, 3.89nM and 1.59nM, respectively). However, the calculated IC50 for crizotinib and capmatinib were 6.04- and 48.4-fold higher than the calculated IC50 for cabozantinib against the MET G1090A mutant kinase. Consistent with the prediction of type II inhibitor activity, the patient was transitioned to cabozantinib. A marked clinical, radiographic, and metabolic response was observed. Conclusions: In MET fusion-positive cancers, the novel MET G1090A resistance mutation drives resistance to type I MET kinase inhibition. Drug binding mode switching to type II MET inhibition overcomes preclinical and clinical resistance, highlighting the need for further rational type II inhibitor development. Citation Format: Yonina R. Murciano-Goroff, Srinivasaraghavan Kannan, Jason C. Chang, Ryma Benayed, Ilya Blokhin, Natasha Rekhtman, Ann Elizabeth Sisk, Jaime Gibson, Lia Judka, Lauren Kaplanis, Madeline Merrill, Erica Sgroe, Chandra S. Verma, Alexander Drilon, Emiliano Cocco. Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5239.

Abstract CT547: Neoadjuvant and adjuvant capmatinib in resectable non-small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial

Abstract Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy can improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation (METex14) and de novo MET amplification (METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with METex14 or METamp. In 2 treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the response rates and safety profile observed in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831), a Phase II, 2-cohort, 2-stage study, is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes in patients with METex14 or high-level METamp NSCLC. Methods: Adults with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 (cohort A) or high-level METamp (gene copy number ≥10; cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescence in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks before surgical resection, followed by 3 years of adjuvant capmatinib. In the 2-stage design, stage 1 will enroll 9 patients per cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. The primary endpoint is MPR rate (local assessment). Secondary endpoints are complete pathological response rate (central and local review), ORR (local assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is December 30, 2021. Citation Format: Jay M. Lee, Mark M. Awad, Teddy Saliba, Nydia Caro, Hiya Banerjee, Karen Kelly. Neoadjuvant and adjuvant capmatinib in resectable non-small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT547.

Real-world (rw) analysis of quantitative MET copy number (CN) as a biomarker in NSCLC.

9123 Background: MET amplification (amp) can be a de novo driver or mechanism of resistance to targeted therapy. We explored the genomic landscape of MET amp NSCLC, including co-driver alterations and amplicon size, and its association with outcomes to MET tyrosine kinase inhibitors (TKIs) using rw data. Methods: Comprehensive genomic profiling (CGP) results from 64,521 tissue and 5,177 liquid NSCLC samples were queried for MET amp (focal amplicons ≥4 copies above specimen ploidy). Sub analysis comparing focal (≤20Mbp) and non-focal (> 20Mbp) amp was performed. Using the nationwide (̃280 US cancer clinics) de-identified EHR-derived Flatiron Health-Foundation Medicine aNSCLC clinicogenomic database (CGDB) linked to tissue CGP (8/2014-9/2021), we assessed co-driver presence ( EGFR, ALK, RET, ROS1, NTRK, BRAF, KRAS) prior to therapy exposure and outcomes to MET TKIs. Results: MET amp was detected in 2,102 (3.3%) NSCLC tissue samples (median CN of 11, range 6-168). Evaluating full gene focal amplicons as well as non-focal MET amps (n = 398, median CN 7), smaller amplicon size significantly correlated with higher CN (p < 0.001). In 5,177 liquid samples, MET amp was detected in 40 (0.77%) cases; frequency increased to 3.2% (33/1,033) in those with a tumor fraction above 10%. In the CGDB, 261 (3.2%) pts had NSCLC with MET amp (median CN 11). Among 241 pts with MET amp detected prior to receipt of any targeted therapy, MET amp co-occurred with another driver in 32 (13%) cases (81% KRAS, 16% EGFR, 3.1% BRAF) and with a MET exon 14 skipping alteration ( METex14) in 25 (10%). MET CN negatively correlated with the presence of a co-driver (median 11 with MET amp alone vs 9 with a non- METex14 co-driver, p < 0.001); however, MET CN was similar in MET amp cases with and without METex14 (median 11 for both, p = 0.60). Co-occurring non- METex14 drivers were detected in 26% of MET amp cases with CN < 8 and 19% with CN 8-9, but in only 9.1% with CN 10-20 and 2.6% with CN > 20. Tumor mutational burden was not significantly correlated with MET CN. In 14 cases with an EGFR or ALK co-driver and MET amp detected post-treatment with an EGFR or ALK TKI, median MET CN was 13. Of 241 targeted therapy naïve MET amp pts, 39 received a MET TKI after CGP (30 crizotinib, 9 capmatinib) and 26 had rw response assessment available. Excluding 5 pts with co- METex14, 12/21 (57%) pts had a partial response and median rwPFS was 3.6 months. This rw cohort analysis was underpowered to assess the relationship between CN and outcome. Conclusions: MET amp was detected in 3.3% of NSCLC tissue samples and 3.2% of high tumor fraction blood samples. In TKI-naïve pts, MET CN negatively correlated with the presence of a concurrent NSCLC driver. MET amp was associated with response to MET TKIs. Further studies evaluating MET CN, amplicon size and presence of other potential drivers in both blood and tissue, as predictive biomarkers for MET TKIs and potential combination strategies for targeting MET amp, are warranted.

Activating MET kinase domain mutations define a novel molecular subtype of non–small cell lung cancer that is clinically targetable with the MET inhibitor elzovantinib (TPX-0022).

9124 Background: In non-small cell lung cancer (NSCLC), MET exon 14 skipping (METex14) mutations and MET amplification can be targeted with MET inhibitors. Here, we describe a novel, actionable molecular subtype of NSCLC characterized by activating MET-tyrosine kinase domain (MET-TKD) mutations in the absence of METex14 mutations. Methods: Clinicopathologic and genomic data were abstracted from NSCLC cases included in a multi-institutional cohort of tumors that underwent genomic profiling in the GENIE v10, China PanCancer, and the International Cancer Genome Consortium/ The Cancer Genome Atlas (ICGC/TCGA) datasets. External validation of the prevalence of MET-TKD mutations was performed on an independent cohort of NSCLC tissue and liquid samples from the Foundation Medicine genomic database. Results: Among 14,099 NSCLC samples in the multi-institutional cohort, 71 (0.5%) harbored MET-TKD mutations without concurrent METex14 mutations: 55 of these had uncertain pathogenic significance and 16 had known oncogenic potential, including MET H1094Y/R, D1228H/N/V, N1100S, H1106D, V1188I, and M1250T, in order of decreasing prevalence. In a separate cohort of 91,515 NSCLC samples from the Foundation Medicine database, MET-TKD mutations lacking concurrent METex14 mutations were identified in 799 (0.9%) samples, including H1094Y, L1195V, D1228H/N, M1250T and others. Among 60 NSCLC samples harboring MET-TKD mutations without concurrent METex14 mutations with complete genomic data in the multi-institutional cohort, 36 (60%) had concurrent driver alterations in KRAS, EGFR, ROS1, BRAF, HER2, or RET, while 24 (40%) had no concurrent oncogenic drivers. Among patients with available demographic data in the multi-institutional cohort, those with MET-TKD-mutant NSCLC (N = 70) were significantly younger than patients with METex14-mutant NSCLC (N = 353) (median age 63 [range 30-86] vs 73 [range 44-88], p < 0.0001), and there was no significant difference in sex or self-reported race. Confirmed partial responses to the MET tyrosine kinase inhibitor elzovantinib (TPX-0022) were observed in two patients with MET-TKD-mutant NSCLC and no other detectable driver mutations: a 64-year-old man with MET H1094Y-mutant NSCLC, and an 80-year-old man with MET F1200I-mutant NSCLC. Conclusions: Potentially actionable MET-TKD mutations lacking concurrent METex14 mutations represent a novel genomic subtype in 0.5-0.9% of NSCLC, and occur in the absence of other known drivers in a subset of cases.

MET Exon 14 Skipping Mutations: Essential Considerations for Current Management of Non–Small-Cell Lung Cancer

MET Exon 14 Skipping Mutations: Essential Considerations for Current Management of Non–Small-Cell Lung Cancer

2MO Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC

Savolitinib, a highly selective MET tyrosine kinase inhibitor, has shown promising activity and tolerable safety in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other NSCLCs harboring MET exon14 skipping mutations (METex14+) (Lu, 2021). Here we report the long-term overall survival (OS), exposure and subgroup analysis results.

Anthrax toxin receptor 2 is a potential therapeutic target for non-small cell lung carcinoma with MET exon 14 skipping mutations

Although MET tyrosine kinase inhibitors (TKIs) are generally effective against non-small cell lung carcinoma (NSCLC) with MET exon 14 skipping mutations (METΔex14), resistance to MET TKIs can occur, indicating the need to develop other therapeutic options. We found that Hs-746 T cells, which harbor METΔex14 plus amplification, were able to survive and grow in the absence of MET signaling, exhibiting primary resistance to MET TKIs. We also found a moderately positive correlation between MET and anthrax toxin receptor 2 (ANTXR2) mRNA expression in NSCLC cell lines using data from the Cancer Dependency Map database. As expected, Hs-746 T cells were positive for ANTXR2 expression. We used an antibody–drug conjugate (ADC) analog in the form of an anti-ANTXR2 monoclonal antibody, H8R23, conjugated to DT3C recombinant protein which consists of diphtheria toxin (DT) lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G (3C). H8R23-DT3C conjugates, which function in vitro like an ADC, induced Hs-746 T cells to undergo apoptosis, resulting in decreased viability. These findings collectively suggest that an ADC targeting ANTXR2 could be effective for the treatment of METΔex14-positive NSCLC.

Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.

MET-targeted therapies are clinically effective in MET-amplified and MET exon 14 deletion mutant (METex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.

Optimal Treatments for NSCLC Patients Harboring Primary or Acquired MET Amplification.

Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.

Abstract LBA046: Neoadjuvant and Adjuvant Capmatinib in Resectable Non-Small Cell Lung Cancer With MET Exon 14 Skipping Mutation or High MET Amplification: GEOMETRY-N Trial

Abstract Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy is well known to improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation (METex14) and de novo MET amplification (METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with either METex14 or METamp. In two treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the response rates and the safety profile observed in GEOMETRY mono-1 in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831) a Phase II, two-cohort, two-stage study is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes beyond those achieved with surgery, chemotherapy, and radiation in patients with METex14 or high-level METamp NSCLC. Methods: Adult patients with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 irrespective of MET gene copy number (GCN) (cohort A) or high-level METamp with GCN ≥10 (cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescent in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks prior to surgical resection, followed by 3 years of adjuvant capmatinib. In the two-stage design, stage 1 will enroll 9 patients in each cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. The primary endpoint is MPR rate based on local investigator assessment. Secondary endpoints are complete pathological response rate (central and local investigator review), ORR (local investigator assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is September 30, 2021. Citation Format: Karen Kelly, Mark M. Awad, Teddy Saliba, Nydia Caro, Beth Inserra, Hiya Banerjee, Jay M. Lee. Neoadjuvant and Adjuvant Capmatinib in Resectable Non-Small Cell Lung Cancer With MET Exon 14 Skipping Mutation or High MET Amplification: GEOMETRY-N Trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA046.

Intra-tumor and Inter-tumor Heterogeneity in MET Exon 14 Skipping Mutations and Co-mutations in Pulmonary Pleomorphic Carcinomas

BackgroundMET exon 14 skipping mutation is a driver mutation in lung cancer and is highly enriched in pulmonary pleomorphic carcinomas (PPCs). Whether there is intratumor or intertumor heterogeneity in MET exon 14 skipping status or in co-occurring genetic alterations in lung cancers driven by MET exon 14 skipping is unknown. MethodsWe analyzed tumor specimens obtained from 23 PPC patients (10 autopsied and 13 surgically resected). MET exon 14 skipping was detected by RT-PCR. For patients with MET exon 14 skipping mutation, further analyses were performed. Genomic DNA (gDNA) was extracted from various histological components for each patient who underwent surgical resection (to assess intratumor heterogeneity). In autopsied patients, gDNA and total RNA were extracted from all metastatic lesions (to assess intertumor heterogeneity). ResultsMET exon 14 skipping mutation was detected in 4 patients (4/23, 17.4%): two surgically resected and two autopsied patients. We found no intratumor or intertumor heterogeneity in MET exon 14 skipping mutation status in these patients. We observed intratumor and intertumor heterogeneity in the copy number variations and/or mutational status of cancer-related genes; some of these differences may have an impact on MET tyrosine kinase inhibitor (TKI) efficacy. ConclusionIn our exploratory analysis of four cases, we observed that MET exon 14 skipping mutations are distributed homogeneously throughout histological components and between metastatic lesions. Our results also suggest that there is marked intertumor and intratumor heterogeneity in co-occurring genetic alterations, and therapeutic implications of such heterogeneity should be evaluated in future studies.

Abstract CT158: ctDNA analysis in the savolitinib phase II study in Non-Small Cell Lung Cancer (NSCLC) patients (pts) harboring MET exon 14 skipping alterations (METex14)

Abstract Background: Savolitinib is a potent and selective MET tyrosine kinase inhibitor. It demonstrated clinical efficacy and a manageable safety profile in Chinese NSCLC pts with METex14 alterations in a phase 2 study (NCT028997479). Here, we report the post-hoc ctDNA analysis of METex14 at baseline and clearance upon treatment and the association of these findings with clinical outcome. In addition, concurrent gene alterations in ctDNA samples from the patients treated with savolitinib and impact on clinical efficacy is explored. Methods: Plasma samples were prospectively collected pre-dose and at tumor assessment visits, until disease progression or end of treatment. MET and other somatic gene alterations in the ctDNA samples were detected by next generation sequencing (425-gene panel, Geneseeq). Results: Sixty-six pts provided baseline plasma samples, of which METex14 ctDNA was detectable in 46 (70%) and undetectable in the remaining 20 pts (30%). Among the 46 ctDNA detectable pts, 19 were pulmonary sarcomatoid carcinoma (19/22, 86%) and 27 were other NSCLC (27/44, 61%), respectively. Of the 46 baseline-detectable pts, 24 were clearance evaluable and 22 had no qualified post baseline samples for clearance evaluation. Of the 24 clearance evaluable pts, 14 achieved ctDNA clearance (undetectable) with a median time to clearance of 1.4 months of treatment (Min 1.4 m, Max 4.2 m). The PFS and OS were compared for pts based on their METex14 ctDNA status at baseline and upon treatment. As shown in the table, METex14 baseline undetectable or clearance pts demonstrated significantly longer mPFS and mOS. Furthermore, in 21 pts with analyzable ctDNA samples at baseline and at disease progression, additional gene alterations were observed such as KRAS, NRAS, BRAF, PIK3CA as well as secondary MET mutations and FGF19 amplification in 12 pts (57%). These alterations might be associated with treatment resistance. Conclusions: The results suggest that ctDNA METex14 undetectable at baseline or clearance upon savolitinib treatment may define favorable treatment outcome. Confirmation of this finding and the predictive value of the ctDNA with larger sample size is desirable. METex14 ctDNAmPFS(mon, 95% CI)HR (95% CI)P valuemOS(mon, 95% CI)HR (95% CI)P valueBaseline undetectable (n=20)13.8(4.2, 22.1)--NC(10.9, NC)--Baseline detectable (n=46)5.6(4.1, 6.9)1.77(0.88, 3.57)0.10810.9(9.2, 14.0)3.26(1.35, 7.89)0.006- Clearance (n=14)30.3(6.8, NC)0.72(0.28, 1.87)0.50135.8(14, NC)0.89(0.25, 3.18)0.835- Non-clearance (n=10)5.5(0.66, 5.6)4.94(1.83, 13.36)0.0028.7(0.8, 10.6)7.06(2.39, 20.89)<0.001- Non-evaluable (n=22)4.1(4.0, 6.9)3.45(1.48, 8.03)0.00610.6(4.8, 12.0)5.88(2.24, 15.47)<0.001CI, confidence interval; HR, hazard ratio; NC, non-calculable Citation Format: Yongfeng Yu, Yongxin Ren, Jian Fang, Lejie Cao, Zongan Liang, Qisen Guo, Sen Han, Zimei Ji, Ye Wang, Yulan Sun, Yuan Chen, Xingya Li, Hua Xu, Jianying Zhou, Liyan Jiang, Ying Cheng, Zhigang Han, Jianhua Shi, Gongyan Chen, Rui Ma, Yun Fan, Sanyuan Sun, Longxian Jiao, Xiaoyun Jia, Linfang Wang, Puhan Lu, Jing Li, Qian Xu, Xian Luo, Weiguo Su, Shun Lu. ctDNA analysis in the savolitinib phase II study in Non-Small Cell Lung Cancer (NSCLC) patients (pts) harboring MET exon 14 skipping alterations (METex14) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT158.

P-111 PERSPECTIVE: Tepotinib plus cetuximab in patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer and acquired resistance to anti-EGFR antibody therapy due to MET amplification

MET amplification (METamp) is a secondary, or co-driving, genetic change in patients with metastatic colorectal cancer (mCRC) and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant patients with mCRC and METamp, MET inhibition plus an anti-EGFR agent may achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI), recently approved in the US and Japan for NSCLC harboring MET exon 14 skipping.

Abstract CT024: Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D

Abstract Background/Purpose: MET-amplification is a resistance mechanism seen in ≤22% of patients (pts) with epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC) following progression on osimertinib, a third generation (3G), irreversible, oral EGFR tyrosine kinase inhibitor (TKI). In the Ph1b TATTON (NCT02143466) expansion cohorts (Parts B and D), pts with MET-amplified EGFRm advanced NSCLC and progression on a prior EGFR TKI, received osimertinib 80 mg + savolitinib 600 or 300 mg once daily; savolitinib is an oral, potent and highly selective MET TKI. Part B was split into three cohorts by prior therapy and tumor T790M status. Part D pts had received no prior 3G EGFR TKI and were T790M negative. For pts who eventually develop resistance to the combination, it is unclear which driver mutation(s) mediates this resistance. Methods: In this analysis, paired plasma samples collected at baseline and following disease progression and/or treatment discontinuation up to data cut-off date 4 March 2020, were assessed. Next generation sequencing (Guardant Health, Guardant360 73 gene panel or Omni 500 gene panel) was used to analyze the plasma ctDNA samples. All 73 genes on the Guardant360 panel were included in the Omni 500 gene panel. Analyses from each pt were reported only for genes included across the panels used. Genomic alterations were identified using Guardant Health's pipeline, which included mutations and amplifications of EGFR and MET. Disease progression was assessed by the investigator, according to the RECIST version 1.1. Assessments were completed for pts with progression-free survival (PFS) of over 2 months. Results: Of 180 pts who received study treatment, 70 provided baseline and progression/discontinuation ctDNA plasma samples. Of these, 45 pts were used for the analysis: 18/70 were not evaluable for ctDNA detection and 7/70 had a PFS of 2 months or shorter. Of the evaluable samples, the following acquired mutations were recorded (exclusivity between genes in most pts): MET D1228X, Y1230X, L1212X (20%, 9/45), EGFR C797X (16%, 7/45), KRAS G12X, G13X (11%, 5/45) and PIK3CA E545K (4%, 2/45). Most pts who developed MET-based resistance (7/9) developed more than one MET mutation, suggestive of polyclonal resistance. Across both Parts B and D, the resistance profiles appeared similar by prior EGFR TKI status and by savolitinib dose. Conclusions: In this analysis, approximately half of all evaluable pts had an identifiable acquired resistance mechanism; resistance appeared to be predominantly mediated by either MET, EGFR or KRAS. Co-occurring mutations across multiple genes were rarely detected. However, multiple acquired mutations were often detected in a specific gene, particularly MET, suggesting individual tumors showed inherent resistance dependencies. Citation Format: Aleksandra Markovets, Ji-Youn Han, Byoung Chul Cho, Mireille Cantarini, Pasi A. Janne, Ryan Hartmaier. Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT024.

Sequencing of systemic therapies in advanced NSCLC with MET exon 14 skipping mutation: A multicenter experience.

e21123 Background: The treatment landscape for patients with metastatic non-small cell lung cancer (mNSCLC) with a MET exon 14 skipping mutation ( MET ex14) is rapidly changing, with recent approvals of MET selective tyrosine kinase inhibitors (TKIs) and reports of durable response to immune checkpoint inhibitors (ICI), particularly among those with sarcomatoid histology. Currently there are no published data that inform the sequencing of TKIs and ICI regimens. We sought to characterize treatment patterns and outcomes in this population at 3 Ontario cancer centres. Methods: We reviewed all mNSCLC patients with MET ex14 identified by tissue or plasma NGS in the last 4 years. Patients with EGFR co-mutation or MET amplification alone were excluded. All systemic therapies and outcomes of overall response (ORR), progression free survival (PFS), overall survival (OS), and adverse events (AEs) were captured. Results: We identified 43 patients with MET alterations, of whom 29 had MET ex14: median age 73 years (54-92), 66% female, 79% non-smokers. Tumor histology was adenocarcinoma in 76%, pleomorphic/sarcomatoid in 21% and adenosquamous in 3% of patients. 69% of patients had PD-L1 ≥50%. At presentation, 20% of patients had high disease burden and ECOG ≥2. Among 15 patients who received ICI, ORR with ICI monotherapy was 45% (10/11 had PD-L1 ≥50%) and ORR with ICI plus chemotherapy was 75% (4/4 had PD-L1 0-49%). Responses were seen in 50% of non-smokers (7/12 had PD-L1 ≥50%). The median PFS with ICI was 10.6 months (1.7-NR). MET TKIs were received by 18 patients (16 crizotinib, 1 capmatinib, 1 cabozantinib), with an ORR of 28% (30% amongst those who received crizotinib first line). The median PFS with TKIs was 2.6 months (1.2-8.9). Median OS for the entire cohort was 24.4 months (10.1-48.3). Patients who received initial ICI (n = 13) compared to those who received initial TKI (n = 11) had significantly longer OS (48.3 vs 13.6 months; p = 0.005), not controlled for prognostic factors. All patients who progressed after ICI (9/13) received further treatment while only 50% of patients who progressed after TKI (8/11) received subsequent therapy. 7 patients received TKI therapy after ICI with a median time to TKI of 35 days (24-181). 6 patients (85.7%) experienced an early grade ≥3 AE (4 transaminitis, 2 pneumonitis) resulting in permanent discontinuation of TKI in half of patients. There were no treatment-related deaths. Conclusions: Patients with MET ex14 NSCLC benefit from ICI irrespective of PD-L1 expression and smoking history. ORR and PFS with earlier generation TKIs (crizotinib) were poor. Increased toxicity is seen when a TKI is used after ICI and careful monitoring is necessary. Future studies focusing on the optimal sequencing of TKIs and ICI-containing therapy should be prioritized, as well as broader access to newer generation MET TKIs with greater activity.

Phase II two-arm study of tepotinib plus osimertinib in patients with EGFR-mutant NSCLC and acquired resistance to first-line osimertinib due to MET amplification: INSIGHT 2.

TPS9136 Background: METamp is a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). METamp occurs in ̃30% of patients who progress on EGFR TKI therapy as measured using fluorescence in situ hybridization (FISH). There is an unmet need for targeted treatment options in these patients. Combination treatment with a MET TKI may overcome MET-related osimertinib resistance. Tepotinib is an oral, once daily (QD), highly selective, potent MET TKI. In the INSIGHT study (NCT01982955), the combination of tepotinib and the EGFR TKI gefitinib improved outcomes in patients with EGFR-mutant METamp NSCLC and EGFR TKI resistance compared to chemotherapy (INSIGHT). Median progression-free survival (PFS) was 16.6 vs 4.2 months (hazard ratio [HR] = 0.13; 90% confidence interval [CI]: 0.04, 0.43) and median overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). Methods: INSIGHT 2 is a global, open-label, Phase II trial of tepotinib + osimertinib in patients with advanced EGFR-mutant NSCLC. Following a protocol amendment in Apr 2020, the study is enrolling patients with acquired resistance to 1L osimertinib (radiological documentation of disease progression following previous objective clinical benefit) due to METamp by FISH (GCN ≥5 or MET/CEP7 ratio ≥2). Patients must be ≥18 years old, have an Eastern Cooperative Oncology Group performance status of 0/1, and normal organ function. Both tissue and liquid biopsy, obtained at the time of progression to osimertinib, will be sent for central confirmation of METamp. Liquid biopsy samples will also be used for exploratory biomarker evaluation. Enrollment is allowed based on local FISH testing while awaiting central confirmation of METamp. Patients will receive 500 mg QD (450 mg active moiety) tepotinib + 80 mg QD osimertinib until disease progression, unacceptable toxicity, or consent withdrawal. The study is anticipated to enroll 120 patients. The primary endpoint is objective response rate (ORR) by independent review (RECIST v1.1) in patients with METamp, centrally confirmed by FISH. Secondary endpoints include ORR by investigator assessment, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety. An exploratory tepotinib monotherapy arm will enroll 12 patients to assess the contribution of tepotinib to the activity of the combination. At progression (determined by independent review committee), monotherapy patients can switch to combination treatment. These patients will be analyzed separately. Recruitment is ongoing, with > 300 patients prescreened. Approximately 100 sites in 17 countries in Europe, Asia, and North America are expected to participate. Approximately 15 sites will recruit patients in the US. Clinical trial information: NCT03940703.

Financial impact of tepotinib for the treatment of adult patients with metastatic non-small cell lung cancer bearing METex14 skipping in the United States.

e21108 Background: MET exon 14 ( METex14) skipping is found in approximately 3% of the non-small cell lung cancer (NSCLC) population and is associated with poor prognoses. We estimated the financial impact to US Medicare and commercial plans of reimbursing the receptor tyrosine kinase inhibitor (TKI) tepotinib for adult patients with metastatic NSCLC bearing METex14 skipping. Methods: We developed an Excel-based economic model to project plan financial outlays with or without tepotinib from 2021-2023. The number of patients eligible for treatment with MET TKIs was estimated from epidemiological data, real-world evidence, and forecasted biomarker testing rates. It was assumed this population has access to other TKIs (capmatinib and crizotinib) and non-targeted standards of care, including immune checkpoint inhibitors, anti–vascular endothelial growth factor (VEGF) medications, and chemotherapy. It was also assumed most patients receiving tepotinib would otherwise be treated with another TKI. Efficacy and safety inputs were obtained from the Phase II VISION study (July 2020 data cut-off), published literature and prescribing information. Resource utilization and costs (2020 US dollars) were informed by online pricing databases, CMS fee schedules, Healthcare Cost and Utilization Project (HCUP) and trial data, expert opinion, and publicly available sources. Results: In hypothetical Medicare and commercial plans with one million members each, an estimated 160 and 32 adult patients with metastatic NSCLC would test positive for METex14 skipping between 2021-2023, respectively. Of these, 26 Medicare and 5 commercial plan members would receive tepotinib. Introducing tepotinib reduced cumulative financial outlays by $661,379 and $151,700 for Medicare and commercial payers respectively, or $0.0061 and $0.0014 per patient per month, primarily due to lower overall drug acquisition and disease management costs relative to a treatment mix without tepotinib. Results are most sensitive to the clinical efficacy of tepotinib and capmatinib. Conclusions: Using tepotinib in adult patients with metastatic NSCLC bearing METex14 skipping is expected to have minimal financial impact on Medicare and commercial payers in the US.[Table: see text]

PERSPECTIVE: Tepotinib + cetuximab in patients (pts) with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC) and acquired resistance to anti-EGFR antibody therapy due to MET amplification (METamp).

TPS3616 Background: METamp is a secondary, or co-driving, genetic change in pts with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant pts with mCRC and METamp, MET inhibition + an anti-EGFR agent may achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI), recently approved in the US for NSCLC harboring MET exon 14 skipping. Tepotinib + gefitinib demonstrated improved outcomes in pts with EGFR-mutant METamp NSCLC and acquired EGFR TKI resistance vs chemotherapy (INSIGHT: NCT01982955). In these pts, progression-free survival (PFS) was 16.6 vs 4.2 months (HR = 0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). In pts with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib + anti-EGFR antibody cetuximab may be active and provide an effective therapeutic option. Methods: This Phase II, multicenter, single-arm, open-label study will assess preliminary safety and tolerability, antitumor activity, and explore pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp (NCT04515394). A safety run-in (6–12 pts) will evaluate the recommended Phase II dose of tepotinib to be used in combination with cetuximab (endpoint: dose-limiting toxicities). Enrollment is based on a confirmed advanced left-sided CRC diagnosis ( RAS/BRAF wild-type), documented previous anti-EGFR therapy and acquired resistance on most recent anti-EGFR antibody and METamp confirmed by liquid and/or tissue biopsy. Pts must be ≥18 years old, have ECOG PS of 0/1 and normal organ function. The study will screen sufficient pts to account for setting-specific heterogenecity in reported METamp incidence. Approximately 42 pts are planned to receive study treatment: ̃22 in Cohort A (second-line, outside US) and 20 in Cohort B (≥third-line, US only). Primary endpoint: investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR), PFS (RECIST 1.1) and OS, tolerability and safety (NCI-CTCAE v5.0), and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab PK profiles, and expression of biomarkers of resistance (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial information: NCT04515394.

Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges.

MET exon 14 skipping mutation (MET∆ex14) is present about 3% of non-small cell lung cancers (NSCLCs). NSCLC patients with MET∆ex14 are characterized by an average age of over 70 years at diagnosis, a smoking history and a higher frequency in pleomorphic carcinoma and adenosquamous cell carcinoma than in adenocarcinoma. It has also been reported that NSCLCs with MET∆ex14 often have codriver alterations such as EGFR amplification (6–28%), FGFR1 alterations (5–17%), KRAS alterations (~8%), BRAF alterations (~21%), or PIK3CA mutation/amplification (~14%). In 2020, the approval of two MET-tyrosine kinase inhibitors (TKIs), capmatinib and tepotinib, for NSCLCs carrying MET∆ex14 dawned a new era for MET-targeted therapy. These drugs yielded progression-free survival of 5.4−12.4 months in clinical trials; however, it has also been reported that one-third to half of patients show inherent resistance to MET-TKIs. In addition, the emergence of acquired resistance to MET-TKIs is inevitable. In this review, we summarize the clinical and molecular characteristics of NSCLCs with MET∆ex14, the efficacy and safety of capmatinib and tepotinib, the inherent and acquired resistance mechanisms to MET-TKIs, and new treatment strategies for NSCLCs with MET∆ex14 in the near future.