MET Exon 14-skipping Mutations Research Articles

Effectiveness of standard treatments in non-small-cell lung cancer with METexon14 skipping mutation: a real-world study

Effectiveness of standard treatments in non-small-cell lung cancer with METexon14 skipping mutation: a real-world study

Abstract 2116: Telisotuzumab vedotin (Teliso-V)-mediated c-Met internalization, endolysosomal trafficking, and potent cytotoxic activity are unaffected by MET exon-14 skipping mutation

Abstract Background: Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate (ADC) composed of a c-Met (MET protein) antibody coupled to the microtubule inhibitor monomethyl auristatin E (MMAE). Teliso-V was granted FDA Breakthrough Therapy Designation for advanced/metastatic EGFR WT, NSQ NSCLC with high c-MET overexpression. For MMAE drug delivery, Teliso-V must first undergo receptor internalization and endolysosomal (EL) trafficking. Hepatocyte growth factor (HGF)-dependent MET EL trafficking and degradation depend on the E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL). METex14 skipping and CBL-binding site mutations, which delete the binding site for CBL, occur in ~ 3% of NSCLC. The role of CBL in Teliso-V-MMAE delivery and activity was assessed in this work. Methods: WT-human c-Met, c-Met-Y1003F/N (CBL binding site mutations in MET), and c-Met-ex14∆ (47 aa deletion to mimic ex14 skipping) or CBL-L620f, G807*, and W802* (CBL inactivating mutants) were expressed in NIH3T3, Ba/F3 cells, or A549 tumor cells using retroviral transduction. Genetically modified cells were then used to define the role of CBL in c-Met surface expression, intracellular signaling, EL trafficking (using pHrodo Red-labeled Teliso-V), and Teliso-V sensitivity in 2D/3D cell cultures. Results: c-Met expression was required for Teliso-V cytotoxicity and intracellular payload delivery in all cell lines. While minimal changes in cell surface c-Met levels were observed, CBL binding mutants had increased phosphorylated c-Met in the absence of HGF, and ex14∆-MET and CBL binding site mutants showed increased sensitivity to small molecule c-Met inhibitors. Compared to WT c-Met, ex14∆ and CBL-binding mutants showed similar EL trafficking and no change in sensitivity to Teliso-V. Co-treatment with a pan-CBL inhibitor also failed to alter Teliso-V EL trafficking and anti-tumor activity. Like most ADCs, EL trafficking was dependent on a dynamin-mediated process with reduced EL trafficking by co-treatment with Dyngo4a. To further understand the role of CBL in Teliso-V sensitivity, we expressed CBL inactivating mutations in A549 tumor cells. While the L602F and W802* mutants increased spheroid size, as well as activated p-MET, there was no change in sensitivity to Teliso-V. Conclusions: Loss of CBL-binding sites on c-Met via ex14 deletion or Y1003F/N leads to increased MET-targeted TKI sensitivity and increased phospho-c-Met levels but does not impact Teliso-V sensitivity or EL trafficking. Our results indicate that Teliso-V traffics to the EL via a dynamin-mediated process. Therefore, Teliso-V delivers MMAE through a robust ADC-mediated EL-dependent mechanism that is independent of CBL, suggesting that high c-Met expression in Ex14skipping or CBL binding site mutant NSCLC patients should be further investigated for response to Teliso-V. Citation Format: Izhar Batth, Ronald Pandoy, Shamim Khaja, Dolonchampa Maji, Tamar Uziel, Athan Vasilopoulos, Peter Ansell, PK Epling-Burnette. Telisotuzumab vedotin (Teliso-V)-mediated c-Met internalization, endolysosomal trafficking, and potent cytotoxic activity are unaffected by MET exon-14 skipping mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2116.

Real-World Treatment Outcomes of MET Exon14 Skipping in Non-small Cell Lung Cancer: GFPC 03-18 Study.

MET-targeted tyrosine kinase inhibitors (TKIs) demonstrated efficacy in advanced non-small cell lung cancer (aNSCLC) with MET exon14 skipping mutations (METexon14); yet, data on the management of these patients in clinical practice is sparse. The aim of this study was to describe the management of METexon14 aNSCLC patients. This real-life, retrospective study analyzed the management of METexon14 aNSCLC. The primary endpoint was the median overall survival (mOS). Secondary endpoints were to assess investigator-progression-free survival (PFS) and mOS in different subgroups: patients treated with (a) crizotinib, regardless of treatment line; (b) anti-MET TKIs (crizotinib, tepotinib, capmatinib); and (c) immunotherapy. A total of 118 patients were included between December 2015 and January 1, 2020 in 13 centers. Median age was 73 years, 62.7% were female, 83.9% had adenocarcinoma, 92.4% at stage IV, and 27% had more than three metastatic sites. The majority of the patients (106, 89.8%) received at least one systemic treatment; 73% received at least one anti-MET TKI: crizotinib (68.6%), tepotinib (16%), capmatinib (10%). Only 10% received two anti-MET TKIs in their treatment sequences. With a median follow-up of 16 months (95% CI 13.6-29.7), mOS was 27.1 months (95% CI 18-31.4). There was no significant difference between mOS of patients treated and never treated with crizotinib, 19.7 (95% CI 13.6-29.7) and 28 (95% CI 16.4-NR) months, respectively (p=0.16); mOS of the TKI cohort and of the TKI-naïve patient cohort were 27.1 (95% CI 18-29.7) and 35.6 (95% CI 8.6-NR) months respectively, with no significant difference (p=0.7). In this real-life study, there was no evidence of benefit in mOS with anti-MET TKIs.

Detection of multiple types of cancer driver mutations using targeted RNA sequencing in non-small cell lung cancer.

DNA-based next-generation sequencing has been widely used in the selection of target therapies for patients with nonsmall cell lung cancer (NSCLC). RNA-based next-generation sequencing has been proven to be valuable in detecting fusion and exon-skipping mutations and is recommended by National Comprehensive Cancer Network guidelines for these mutation types. The authors developed an RNA-based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for the detection of fusions, single-nucleotide variants (SNVs), and insertion/deletion (indels). In total, 1253 formalin-fixed, paraffin-embedded samples from patients with NSCLC were analyzed by DNA and RNA panel sequencing in parallel to assess the performance of the RNA panel in detecting multiple types of mutations. In analytical validation, the RNA panel achieved a limit of detection of 1.45-3.15 copies per nanogram for SNVs and 0.21-6.48 copies per nanogram for fusions. In 1253 formalin-fixed, paraffin-embedded NSCLC samples, the RNA panel identified a total of 124 fusion events and 26 MET exon 14-skipping events, in which 14 fusions and six MET exon 14-skipping mutations were missed by DNA panel sequencing. By using the DNA panel as the reference, the positive percent agreement and the positive predictive value of the RNA panel were 98.08% and 98.62%, respectively, for detecting targetable SNVs and 98.15% and 99.38%, respectively, for detecting targetable indels. Parallel DNA and RNA sequencing analyses demonstrated the accuracy and robustness of the RNA sequencing panel in detecting multiple types of clinically actionable mutations. The simplified experimental workflow and low sample consumption will make RNA panel sequencing a potentially effective method in clinical testing.

Responses to the Tepotinib in Gastric Cancers with MET Amplification or MET Exon 14 Skipping Mutations and High Expression of Both PD-L1 and CD44.

Simple SummaryHigh MET copy-number variation (CNV) and high MET protein expression via MET exon 14 skipping mutation (METex14SM) are associated with tumorigenesis; however, METex14SM is rare in GC, so target therapy is rarely applicable. In this study, we analyzed GC panels using targeted next-generation sequencing in GC cell lines and found that tepotinib demonstrated therapeutic effects in MET-amplified GC and those with high expressions of PD-L1, CD44, and METex14SM. Our in vitro findings indicate that tepotinib prevents GC-associated MET amplification and MET mutation.Both MET exon 14 skipping mutation (METex14SM) and high copy-number variation (CNV) lead to enhanced carcinogenesis; additionally, programmed-death ligand 1 (PD-L1) is often upregulated in cancers. In this study, we characterized the expression of MET (including METex14SM), PD-L1, and CD44 in human gastric cancer (GC) cells as well as the differential susceptibility of these cells to tepotinib. Tepotinib treatments inhibited the growth of five GC cells in a dose-dependent manner with a concomitant induction of cell death. Tepotinib treatments also significantly reduced the expression of phospho-MET, total MET, c-Myc, VEGFR2, and Snail protein in SNU620, MKN45, and Hs746T cells. Notably, tepotinib significantly reduced the expression of CD44 and PD-L1 in METex14SM Hs746T cells. By contrast, tepotinib was only slightly active against SNU638 and KATO III cells. Migration was reduced to a greater extent in the tepotinib-treated group than in the control group. Tepotinib may have therapeutic effects on c-MET-amplified GC, a high expression of both PD-L1 and CD44, and METex14SM. Clinical studies are needed to confirm these therapeutic effects.

A lung adenocarcinoma patient with co-mutations of MET and EGFR exon20 insertion responded to crizotinib

BackgroundTargeted therapy has revolutionized the treatment of patients with malignancies harboring mutations in driver genes and has brought a favorable survival benefit to the population with actionable oncogenic mutations. In recent years, the MET exon14 skipping mutation has been recognized as a potentially promising therapeutic target in non-small cell lung cancer (NSCLC). These changes are mutually exclusive with molecular drivers such as EGFR, KRAS, HER-2, BRAF, ALK and ROS1. The prevalence rate of coexisting MET exon 14 mutations and EGFR sensitive mutations (L858R, exon 19 deletions) in Chinese population was reported to be 0.2% (3/1590). However, the coexistence of MET exon 14 mutations with EGFR exon 20 insertion mutations has never been reported and the management of this subtype is not identified.Case presentationA 69-year-old male with a right lung adenocarcinoma (T4N2M0, IIIB) was confirmed to be positive for MET exon 14 skipping (c.3028_3028+1delGGinsTT, 44.4%), MET amplification (copy number 4.4), and EGFR exon 20 insertion (p. N771_H773dup, 22.1%) mutations. After the progression of one cycle of chemotherapy (Pemetrexed 0.8 g d1), the patient was subsequently accepted treatment with Crizotinib (250 mg twice a day) and achieved an important clinical remission for six months until the development of brain metastases. Then, he was submitted to a cycle of anti-programmed cell death-1 (PD-1) therapy after failure of Crizotinib and eventually acquired resistance despite of the high expression of programmed death ligand-1 (PD-L1) and tumor mutational burden (TMB) status.ConclusionThis case report provides treatment strategies for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-untreated lung adenocarcinoma patients simultaneously carrying MET alterations and EGFR exon 20 insertion mutations. In addition, the signatures of PD-L1 or TMB expression were not the candidate for predicting the efficacy of immunotherapy in this context.

Responses to the MET inhibitor tepotinib in gastric cancers with MET amplification or both high PD-L1 expression and an MET exon 14 skipping mutation.

e16037 Background: Aberrant expression of MET involving MET exon 14 (METex14) alteration and high CNV, which leads to enhanced tumorigenesis. In addition, the PD-L1 (CD274) is often upregulated in cancers. This study characterized expressions of MET (including METex14 skipping mutation), PD-L1 and CD44 in human gastric cancer (GC) cell lines, and further characterized the differential susceptibility of these cell lines to tepotinib. Methods: We assessed the antitumor activity of tepotinib in GC cell lines. CNV analysis using targeted next-generation sequencing (NGS) techniques. The effect of tepotinib on cell viability (IC50), apoptotic cell death, migration, the PD-L1, CD44 and c-MET signaling were evaluated by MTS assay, flow cytometry, wound-healing assay, western blotting, and qRT-PCR. Results: Tepotinib treatment showed dose-dependent growth inhibition of c-MET-amplified SNU620, MKN45, Hs746T, SNU638 and KATO III cells with concomitant induction of apoptosis. Tepotinib treatment also significantly reduced expressions of phospho-c-MET, total c-MET, VEGFR2, Snail and c-Myc protein in SNU620, MKN45 and Hs746T cells. Especially, tepotinib significantly reduced the expressions of CD44 and PD-L1 in METex14 skipping mutated Hs746T cells. In contrast, this drug was only slightly active against KATO III and SNU638 cells. Migrations were more reduced in the tepotinib-treated group than in the control group. Conclusions: These data show the possibility that tepotinib may have therapeutic effects in c-MET-amplified GC and both high PD-L1 expression and an MET exon 14 skipping mutation, suggesting that clinical studies need to confirm the therapeutic effect.

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

U.S. health utility in advanced non-small cell lung cancer (NSCLC) patients harboring MET exon 14 (METex14) skipping mutations treated with tepotinib.

319 Background: To complement the clinical findings, utilities were analyzed based on patient-reported outcomes (PROs) from VISION trial (Cohort A; data cut: July 1, 2020), a Phase II trial showed durable clinical activity of tepotinib in advanced NSCLC METex14+. Methods: The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaires were completed at Day 1, every 6 weeks for 9 months, then every 12 weeks, for up to 30 days after the last tepotinib dose. The Quality of Life Utility Measure-Core 10 dimensions (QLE-C10D) and EQ-5D-5L utilities were derived using the utility algorithm from published literature and the US crosswalk, respectively. Utilities are preference-based, health-related quality of life (HRQoL) metrics expressed on a scale including 0 (dead) and 1 (full health). Linear mixed regression models were used to analyze utilities at baseline, pre-progression, and post-progression, and to understand the relationship between EQ-5D and QLE-C10D. Utilities were assessed by both independent review committee (IRC) and investigators. Results: Utilities were estimated for 150 of 152 pts, with 983 observations for EORTC and 907 for EQ-5D. Mean EORTC utilities increased after tepotinib initiation, from 0.691 at baseline to 0.722 in the IRC-assessed progression-free period, and decreased after progression (0.671). Consistent trends were identified when progression was based on investigator's assessment. Analyses of EQ-5D utilities yielded similar findings and utilities. The two questionnaires were generally highly correlated (Table). Prior treatment (yes/no; p=0.554), adenocarcinoma (p=0.881), or squamous histology (p=0.841) were not statistically significant predictors of EQ-5D utility, while progression status significantly predicted utility in all progression-based models (p≤0.002). Conclusions: VISION is the first trial of a MET inhibitor to provide data on PROs and utilities in NSCLC harboring METex14 skipping mutation. EORTC and EQ-5D (minimally important difference: 0.08) utilities show an increase in HRQoL from baseline during tepotinib treatment until progression. Utility with tepotinib did not vary by prior treatment status or histology. Clinical trial information: NCT02864992. [Table: see text]

Budget impact of capmatinib for adults with metastatic non-small cell lung cancer harboring a MET exon 14 skipping mutation in the United States

Aims To estimate the budget impact of adding capmatinib, the first FDA approved MET inhibitor, to a US commercial or Medicare health plan for patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors have a mutation that leads to MET exon 14 (METex14) skipping. Methods Target population size was estimated using published epidemiology data. Clinical data were obtained from the GEOMETRY mono-1 capmatinib trial and published trials. Treatments in the market mix included crizotinib, pembrolizumab, ramucirumab, and chemotherapy. Uptake of capmatinib and testing rates were based on market research. All costs (drug acquisition and administration, pre-progression, progression, terminal care, adverse event, and testing) were estimated based on public sources (2020 USD). Results The number of patients eligible for capmatinib in the first three years was estimated to be 2–3 in a hypothetical 1 million member commercial plan and 34–44 in a hypothetical 1 million member Medicare plan each year. The estimated total budget impact ranged from $9,695 to $67,725 for a commercial plan and $141,350 to $985,695 for Medicare. With capmatinib included, a marginal per member per month budget impact was estimated (commercial: $0.0008 to $0.0056; Medicare: $0.0118 to $0.0821). Capmatinib inclusion resulted in lower medical costs (commercial: –$0.0003 to –$0.0007; Medicare: –$0.0037 to –$0.0106), partially offsetting increased drug costs ($0.0011 to $0.0064; $0.0154 to $0.0928, respectively), and were primarily driven by reductions in progression and terminal care costs (–$0.0003 to –$0.0009; –$0.0037 to –$0.0125, respectively). The results were most sensitive to capmatinib market share, capmatinib price, and treatment duration. Limitations Certain assumptions were applied to the model to account for inputs with limited evidence. Conclusions The estimated budget impact of including capmatinib for mNSCLC with a METex14 skipping mutation is minimal, and the increased drug costs were partially offset by savings in AEs, and progression-related and terminal care costs.

SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations.

SummaryTepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with MET amplification or METex14 skipping mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in cells prior to tepotinib exposure and become more prominent upon tepotinib resistance. In a small cohort of patients with lung cancer with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. An Src homology 2 domain-containing phosphatase 2 (SHP2) inhibitor delayed the emergence of tepotinib resistance and synergized with tepotinib in treatment-naive and tepotinib-resistant cells as well as in xenograft models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with an SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.

Analysis of multigene detection in patients with advanced lung adenocarcinoma using cytological specimens

ObjectiveTo investigate the mutation status and clinical characteristics of multigene detection in advanced lung adenocarcinoma using cytological specimens. Materials and Methods137 advanced lung adenocarcinoma patients with 10 driver genes detection in the Fourth Hospital Hebei Medical University from January 2019 to November 2019 was analysized. 137 cytological specimens including fine-needle aspiration specimens and maligant serous cavity effusion (pleural effusion, peritoneal and pericardial effusion). Ten driver mutations of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA and MET were detected by the amplification refractory mutation system (ARMS). Meanwhile, 90 of 137 patients were detected with biopsies for parallel gene detection. Results78.10 % (107/137) of patients with advanced lung adenocarcinoma harbored at least one of 10 driver mutations. The three main mutations were EGFR (69.16 %, 74/137), ALK (6.57 %, 9/137)and ROS1 (3.65 %, 5/137) mutations. Besides, we found 6 cases including two concomitant mutations: EGFR Exon19 del/HER2 (1/137), EGFR Exon21 L858R/PIK3CA (2/137), EGFR Exon21 L858R/RET (1/137), and ALK/KRAS (2/137). Among 137 patients, women aged 64 or older were more likely to have the mutations (P < 0.05). Female patients (P = 0.003) older or equal to 64 years (P = 0.015) with non-smoking habbit (P = 0.027) were more detected with EGFR mutations, while ALK was more detectable in patients yonger than 64 years. Parallel analysis showed that rates of single EGFR, ALK, ROS1, RET, KRAS, NRAS, HER2, MET mutations and concomitant different mutations were not significantly different between cytological specimens and matched histological specimens. ConclusionsIn the study, cytological specimens and biopsy samples have a very high coincidence rate of gene detection. EGFR, ALK and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma.We speculate that EGFR and ALK are more prone to concomitant mutations respectively and the treatment of advanced lung adenocarcinoma patients with concomitant mutations deserves further study. The rate of KRAS, NRAS, BRAF, PIK3CA, RET and MET exon14 skipping mutation were low but may had a significant impact on the targeted therapy of patients with advanced lung adenocarcinoma.

Clinicopathologic and Imaging Features of Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

MET exon 14 (METex14) skipping mutations are an emerging potentially targetable oncogenic driver mutation in non-small-cell lung cancer (NSCLC). The imaging features and patterns of metastasis of NSCLC with primary METex14 skipping mutations (METex14-mutated NSCLC) are not well described. Our goal was to determine the clinicopathologic and imaging features that may suggest the presence of METex14 skipping mutations in NSCLC. This IRB-approved retrospective study included NSCLC patients with primary METex14 skipping mutations and pre-treatment imaging data between January 2013 and December 2018. The clinicopathologic characteristics were extracted from electronic medical records. The imaging features of the primary tumor and metastases were analyzed by two thoracic radiologists. In total, 84 patients with METex14-mutated NSCLC (mean age = 71.4 ± 10 years; F = 52, 61.9%, M = 32, 38.1%; smokers = 47, 56.0%, nonsmokers = 37, 44.0%) were included in the study. Most tumors were adenocarcinoma (72; 85.7%) and presented as masses (53/84; 63.1%) that were peripheral in location (62/84; 73.8%). More than one in five cancers were multifocal (19/84; 22.6%). Most patients with metastatic disease had only extrathoracic metastases (23/34; 67.6%). Fewer patients had both extrathoracic and intrathoracic metastases (10/34; 29.4%), and one patient had only intrathoracic metastases (1/34, 2.9%). The most common metastatic sites were the bones (14/34; 41.2%), the brain (7/34; 20.6%), and the adrenal glands (7/34; 20.6%). Four of the 34 patients (11.8%) had metastases only at a single site. METex14-mutated NSCLC has distinct clinicopathologic and radiologic features.

Abstract 1321: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling

Abstract Aberrant activation of the HGF/MET pathway has frequently been found in human cancers via MET mutation, gene amplification and translocation, as well as HGF paracrine or autocrine upregulation. The abnormal HGF/MET signaling not only acts as an oncogenic driver but also confers resistance to many cancer therapies, such as EGFR targeted therapy in NSCLC. One key downstream effector for activated MET is SRC, which is also involved in malignancy formation, tumor metastasis and drug resistance. In the tumor microenvironment, CSF1R plays an important role in regulation of tumor associated macrophages, which promote tumor progression and angiogenesis. Therefore, the polypharmacological inhibition of MET/SRC/CSF1R has great potential for more effectively targeting cancers with abnormal HGF/MET signaling via targeting both tumor intrinsic signaling and the tumor microenvironment. TPX-0022, a novel macrocyclic compound, has been designed and optimized to inhibit MET/CSF1R/SRC with enzymatic kinase inhibition IC50s of 0.14, 0.76 and 0.12 nM, respectively. TPX-0022 potently inhibited cell proliferation of the MET-amplified MKN-45 and SNU-5 gastric cancer cells, with IC50s &amp;lt;0.2 nM, which ranked TPX-0022 as one of the most potent MET inhibitors. TPX-0022 caused suppression of MET auto-phosphorylation at an IC50 of approximately 0.3 nM in MKN-45 cell line. TPX-0022 also potently inhibited the phosphorylation of MET downstream signaling effectors, including AKT, ERK, STAT3 and PLCγ2 in a dose-dependent manner. In the cancer cell line- and patient-derived xenograft tumor models from gastric, lung and liver cancers harboring MET amplification or MET exon14 skipping mutations, TPX-0022 caused dramatic tumor regression and tumor growth inhibition, without overt abnormality and body weight loss in treated mice. Furthermore, the tumor inhibitory effect was associated with drastic inhibition of MET activity. Overall, TPX-0022 is a novel and potent MET inhibitor and has demonstrated desirable drug-like properties, a good preclinical safety profiles, that warrants further clinical development and an IND submission is currently planned. Citation Format: Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, Yuelie Lu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui. TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1321.

The molecular and immune characteristics, antitumor activity of crizotinib in non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping alterations.

e20588 Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P&lt; 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( &lt; 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.

OA06 Tepotinib in Non-Small Cell Lung Cancer with MET Exon 14-Skipping Mutations or MET Amplification: a Phase 2 Trial in Progress

OA06 Tepotinib in Non-Small Cell Lung Cancer with MET Exon 14-Skipping Mutations or MET Amplification: a Phase 2 Trial in Progress

493O - Tepotinib in patients with advanced non-small lung cancer (NSCLC) and MET exon 14-skipping mutations: Phase II data

493O - Tepotinib in patients with advanced non-small lung cancer (NSCLC) and MET exon 14-skipping mutations: Phase II data

P3.01-76 Clinical Background and Response to Chemotherapy in NSCLC Patients with MET Exon14 Skipping Mutation or High MET Gene Copy Number

MET exon14 skipping mutation (SM) and high gene copy number (HGCN) are present in 3-4% and ≤1% of NSCLCs. The response to MET inhibitor treatment has been reported in ongoing clinical trials; however, the response to chemotherapy, including immunotherapy, is currently unknown. We conducted a retrospective analysis of patients with MET gene alteration. We collected the clinicopathological data of NSCLC patients with MET gene alteration. The response to chemotherapy was evaluated according to RECIST v1.1. Systemic chemotherapy was given to 10 patients: SM (n=5) and HGCN (n=5). The median age was 67.5 (range 41- 77) years. Thirty percent of the patients were female and 40% were never smokers. The most common histology was adenocarcinoma (40%), followed by pulmonary sarcomatoid carcinoma (20 %). The tumor PD-L1 expression was >50% in 57% (4/7) of the cases and 1-49% in 43% (3/7) of the cases. Platinum doublet, MET inhibitor, immunotherapy (I-O), and I-O+chemotherapy were given to 6, 8, 2 and 1 patients. The overall response rate was 50%, 83%, 0% and 100%, respectively. Hyper-progressive disease after immunotherapy was observed in one patient with SM. The responses to platinum doublet and MET inhibitor treatment were good, while the response to immunotherapy was poor in NSCLC patients with MET gene alteration. MET gene alterations should be identified before the administration of immunotherapy.

OA12.01 Phase II Data for the MET Inhibitor Tepotinib in Patients with Advanced NSCLC and MET Exon 14-Skipping Mutations

OA12.01 Phase II Data for the MET Inhibitor Tepotinib in Patients with Advanced NSCLC and MET Exon 14-Skipping Mutations

P3.04-16 A Seven-Gene Expression Signature Reveals Unique Immune-Phenotypes Related to Major Oncogenic-Drivers in NSCLC

In oncogenic-driven non-small cell lung cancer (NSCLC), programmed death ligand 1 (PD-L1) expression is the result of a constitutive oncogenic activation leading to an immunosuppressive microenvironment. However, the relationship between the major driver mutations (KRAS, EGFR and ALK) and PD-L1 and other immune markers remains unclear. Gene expression signatures incorporating not only PD-L1 but also other components of the stroma might better capture the immune-context of these oncogenic subgroups. A 7-gene ‘immune signature’ comprising CD4, CD8, PD-1, PD-L1, IFNG, GZMM and FOXP3 was included in a customized nCounter panel (NanoString Technologies), used in our clinical institution on a routine basis and designed to simultaneously screen for gene fusion drivers (ALK, ROS1, RET and NTRK1), MET overexpression and MET exon 14-skipping mutations in formalin-fixed paraffin embedded (FFPE) samples. A total of 296 advanced NSCLC patients from two different institutions were analyzed by the panel. Among them, 115 patients (38.9%) were also submitted to next-generation sequencing (NGS, Ion Torrent PGM® or GeneReader) . Analyses of variance (ANOVA) were used to describe statistical significance between immune response genes in the two major oncogenic groups: KRAS mutant (n=33) andALK rearranged (n=44), compared to wild-type (WT) tumor samples (n=38). Oncogenic genes (ALK, KRAS) were mutually exclusive. The analysis of the 7-gene signature revealed distinct expression patterns in the oncogenic biomarker groups. A significantly higher mRNA expression of CD4 and PD-L1 was found in ALK rearranged tumors compared to the KRAS mutant, and WT groups (p=0.0014 and p=0.0467, respectively). In addition, a trend was observed between GZMM mRNA levels and the oncogenic groups (p= 0.0665) whereas no association was found with the other immune genes (CD8, PD-1, IFNG, FOXP3). There was a significant linear correlation between CD4 and PD-L1 in ALK positive patients (p= 0.0214), but not in KRAS mutant samples (p= 0. 112). Unsupervised clustering across mRNA expression data from 296 samples using 7-immune-related genes showed two clusters, high expression for ALK-rearranged patients and low expression for KRAS mutant patients. The correlation between each of the immune genes was performed and a high correlation was found between PD-1 and FOXP3 (r=0.9) and PD-1 with GZMM (r=0.8). NSCLC tumors with ALK alterations show a distinct CD4 and PD-L1 immune profile when compared to KRAS and WT samples.