MET-amplified Non-small Cell Lung Cancer Research Articles

Detailed characterization of combination treatment with MET inhibitor plus EGFR inhibitor in EGFR-mutant and MET-amplified non-small cell lung cancer.

Detailed clinical data about combination treatment with MET inhibitor (METi) and EGFR inhibitor (EGFRi) is lacking in patients with EGFR-mutant, MET-amplified, and EGFRi-resistant non-small cell lung cancer (NSCLC). This study aimed to report longitudinal data on the efficacy and safety of this combination treatment. We retrospectively analyzed 44 patients with advanced EGFR-mutant and MET-amplified NSCLC who were treated with any types of METi plus EGFRi after progression with EGFRi at the National Cancer Center Hospital. Longitudinal clinicogenomic data and plasma circulating tumor DNA (ctDNA) data were collected. The overall response rate was 74.4% and median progression-free survival (PFS) was 5.3 months [95% confidence interval (CI): 3.3-7.3]. Twenty-three patients (52.3%) required either or both treatment discontinuation due to adverse effects. The main cause of discontinuation was pneumonitis (69.2%). There was no significant difference in the PFS of patients with or without METi discontinuation [hazard ratio (HR), 0.93; 95% CI: 0.49-1.78; P=0.83]. Median clearance time of MET amplification in plasma ctDNA was measured as 63 days. Patients who stopped METi within 63 days of initiation showed poorer PFS compared to those who discontinued after (HR, 2.78; 95% CI: 1.00-7.75; P=0.050). Diverse resistance mechanisms including on-target mutations in MET (D1246H) and EGFR (C797S or T790M) were detected in 14 patients. One MET D1246H-mutant case and one EGFR C797S-mutant case responded to sitravatinib and amivantamab, respectively. A combination of METi and EGFRi showed a promising anti-tumor effect in advanced EGFR-mutant and MET-amplified NSCLC. Pneumonitis was the main adverse effects leading to treatment discontinuation. Early discontinuation of METi negatively affected the survival outcomes.

Genomic and Immune Landscape Comparison of MET Exon 14 Skipping and MET-Amplified Non-small Cell Lung Cancer

BackgroundMutation or amplification of the mesenchymal-epithelial transition (MET) tyrosine kinase receptor causes dysregulation of receptor function and stimulates tumor growth in non-small cell lung cancer (NSCLC) with the most common mutation being MET exon 14 (METex14). We sought to compare the genomic and immune landscape of MET-altered NSCLC with MET wild-type NSCLC. Methods18,047 NSCLC tumors were sequenced with Tempus xT assay. Tumors were categorized based on MET exon 14 (METex14) mutations; low MET amplification defined as a copy number gain (CNG) 6-9, high MET amplification defined as CNG ≥ 10, and MET other type mutations. Immuno-oncology (IO) biomarkers and the frequency of other somatic gene alterations were compared across MET-altered and MET wild-type groups. Results276 (1.53%) METex14, 138 (0.76%) high METamp, 63 (0.35%) low METamp, 27 (0.15%) MET other, and 17,543 (97%) MET wild-type were identified. Patients with any MET mutation including METex14 were older, while patients with METex14 were more frequently female and nonsmokers. MET gene expression was highest in METamp tumors. PD-L1 positivity rates were higher in MET-altered groups than MET wild-type. METex14 exhibited the lowest tumor mutational burden (TMB) and lowest neoantigen tumor burden (NTB). METamp exhibited the lowest proportion of CD4 T cells and the highest proportion of NK cells. There were significant differences in co-alterations between METamp and METex14. ConclusionsMETex14 tumors exhibited differences in IO biomarkers and the somatic landscape compared to non-METex14 NSCLC tumors. Variations in immune profiles can affect immunotherapy selection in MET-altered NSCLC and require further exploration.

Abstract C145: ANS014004, a novel small-molecule type II c-Met inhibitor effectively overcomes clinical-resistance MET mutations and exhibits antitumor activity in preclinical models of MET-amplified non-small cell lung cancer (NSCLC) and gastric cancer

Abstract Mesenchymal epithelial transition (MET) proto-oncogene receptor tyrosine kinase (RTK) is a cell surface receptor selective for hepatocyte growth factor (HGF), and is involved in embryogenesis regulation, wound healing, organ regeneration, angiogenesis, and immunomodulation. Aberrant MET oncogenic alterations include: MET exon 14 skipping (MET∆ex14) mutations; activating mutations in the kinase domain; MET gene amplification; MET fusions; and MET protein overexpression. These oncogenic alterations occur in a wide range of human solid cancers. Small-molecule type I c-Met inhibitors bind to the active (Asp-Phe-Gly “DFG-in” state) of c-Met within the adenosine triphosphate (ATP) binding pocket via the Y1230 residue, resulting in down-regulation of multiple pro-oncogenic downstream factors. Presently, type I c-Met inhibitors such as Capmatinib are used as monotherapies in patients with locally advanced or metastatic NSCLC with MET∆ex14 mutations. However, development of post-treatment resistance to type I c-Met inhibitors occurs clinically, including through acquired mutations in codons D1228 and Y1230. No drugs have been approved globally for MET alteration indications other than MET∆ex14 mutations. Next generation MET inhibitors are thus needed to treat patients harboring various MET oncogenic alterations beyond MET∆ex14, including post-treatment acquired mutations. ANS014004 is a newly developed small-molecule type II inhibitor of c-Met, binding to the inactive state of c-Met (“DFG-out”) in the ATP pocket. ANS014004 showed greater kinase inhibition activity against c-Met mutant kinases Y1230H and D1228A in vitro (IC50’s = 2.596 and 2.971 nM, respectively), when compared with Capmatinib, Cabozantinib, and Merestinib (IC50 values = >5000, ~10, and ~5 nM respectively). Further, ANS014004 showed a stronger anti-proliferative effect in MET mutant Ba/F3 cells TPR-Met D1228A and TPR-Met-Y1230H in vitro (IC50’s = 49.34 nM and 30.32 nM, respectively), when compared with Capmatinib (IC50 values>10000nM) and Merestinib (IC50 values: 37~100 nM). ANS014004 also showed potent antitumor effects in vitro in the human cancer tumor cell lines harboring various pathogenetic MET alterations: Hs-746T (gastric); MKN-45 (gastric); EBC-1 (NSCLC); NCI-H1993 (NSCLC); with IC50 ranging from 6.38~62.32 nM. In several subcutaneous xenograft tumor model studies using these same cell lines implanted in BALB/c nude mice, orally administered ANS014004 produced significant dose-dependent tumor growth inhibition, and the corresponding exposures of ANS014004 in plasma, tumor and brain samples increased with increasing dose. ANS0104001 was also observed to induce tumor regression in a MET-amplified intracranial xenograft model. Overall, the non-clinical studies of ANS014004 demonstrated it is a potent, orally-bioavailable type II c-Met inhibitor with activity against various pathogenetic MET alterations and with favorable absorption, distribution, pharmacokinetic, efficacy, and tolerability profiles in vivo. The molecule will enter a Phase 1 clinical study in the US soon. Citation Format: Gong Li, Hepeng Shi, Peilong Zhang, Xiangqiu Li, Wenli Lan, Linna Li, David Chung, Kevin Schaab. ANS014004, a novel small-molecule type II c-Met inhibitor effectively overcomes clinical-resistance MET mutations and exhibits antitumor activity in preclinical models of MET-amplified non-small cell lung cancer (NSCLC) and gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C145.

MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer

The objective of this study was to investigate the effects of inhibiting the MET receptor with capmatinib, a potent and clinically relevant ATP-competitive tyrosine kinase inhibitor, in combination with radiation in MET exon 14-mutated and MET-amplified non-small cell lung (NSCLC) cancer models. In vitro effects of capmatinib and radiation on cell proliferation, colony formation, MET signaling, apoptosis, and DNA damage repair were evaluated. In vivo tumor responses were assessed in cell line xenograft and patient-derived xenograft models. Immunohistochemistry was used to confirm the in vitro results. In vitro clonogenic survival assays demonstrated radiosensitization with capmatinib in both MET exon 14-mutated and MET-amplified NSCLC cell lines. No radiation-enhancing effect was observed in MET wild-type NSCLC and a human bronchial epithelial cell line. Minimal apoptosis was detected with the combination of capmatinib and radiation. Capmatinib plus radiation compared with radiation alone resulted in inhibition of DNA double-strand break repair, as measured by prolonged expression of γH2AX. In vivo, the combination of capmatinib and radiation significantly delayed tumor growth compared with vehicle control, capmatinib alone, or radiation alone. Immunohistochemistry indicated inhibition of phospho-MET and phospho-S6 and a decrease in Ki67 with inhibition of MET. Inhibition of MET with capmatinib enhances the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.

Effective treatment of MET-amplified non-small cell lung cancer patients with crizotinib: a case description.

Mingyue Tang, Xinwei Li, Yue Zhang, Huiyuan Li, Cancan Zhao, Menglin Zhao, Yanyan Wang, Chenchen Jiang, Fang Su

Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer.

In EGFR-mutant and MET-amplified lung cancer resistant to EGFR inhibitors, double blockade of EGFR and MET is considered as a reasonable strategy despite increasing toxicity. This study evaluated the single MET inhibition in these specific tumours. We investigated the efficacy of a single MET inhibitor in EGFR-mutant, MET-amplified lung cancer cells (HCC827GR) and the matched clinical cases and patient-derived cells. Acquired resistance mechanisms to single MET inhibitor were further explored. Single MET inhibitor sufficiently inhibited the EGFR downstream signalling and proliferation in the HCC827GR cells. The MET-inhibitor-sensitive clones had similar EGFR mutation allele frequency as the MET-inhibitor-resistant clones. The patients with EGFR-mutant, MET-amplified lung cancer resistant to EGFR inhibitors showed definite response to single MET inhibitor but the response duration was not durable. The MET gene copy number in their plasma circulating tumour DNA was significantly decreased during the treatment and was not re-increased after progression. In the cells resistant to single MET inhibitor, the EGFR pathway was reactivated, and gefitinib alone successfully suppressed their growth. Single MET inhibition produced a short-lived response in EGFR-mutant and MET-amplified lung cancer. A further study of a novel combination therapy schedule is needed to achieve long-lasting efficacy and less toxicity.

Abstract 417: Targeting aurora kinase b overcomes acquired resistance to met-tyrosine kinase inhibitor in met-amplified lung cancer

Abstract Mesenchymal-epithelial transition factor receptor (MET) mediated signaling emerged as an important clinical target for the treatment of many cancer types including non-small cell lung cancer. MET amplification is prevalent in 2%~4% of primary lung cancer and 15%~50% of EGFR-mutated lung cancer resistant to EGFR inhibitors. Currently, MET-targeting drugs have been actively investigated in these MET-amplified lung cancers. However, the acquired resistance mechanism for MET-targeted therapy remains unknown. Our study aims to provide effective treatment for overcoming MET-TKI-acquired resistance in MET-amplified non-small cell lung cancer. To discover the resistance mechanism, we established the resistant cell line (PR-S2) by chronic exposure of MET-amplified lung cancer cells (H1993) to MET kinase inhibitor, PHA665752. Through high-throughput screening of a custom library of 276 compounds, we found that Aurora kinase B (AURKB) inhibitor, barasertib was more sensitive to the PR-S2 cells than H1993 cells. AURKB inhibition by barasertib induced apoptotic cell death with G2/M arrest and polyploid cell formation in the PR-S2 cells. The expression of p-AURKB was increased with no change in the expression of p-histone H3, a major product of AURKB in the PR-S2 cells. AURKB knockdown using multiple siRNA sequences increases the sensitivity to PHA665752 in the PR-S2 cells. In mRNA sequencing data analysis, we found the expression of signal transducer and activator of transcription 3 (STAT3) was elevated in the PR-S2 cells compared to the H1993 cells. We confirmed increased STAT3 expression in both protein and mRNA levels in the PR-S2 cells. p-STAT3 expression was decreased after barasertib treatment in the PR-S2 cells. However, in the immunoprecipitation assay, there was no direct interaction between AURKB and STAT3. To know the target of STAT3, we checked the mRNA expression of downstream genes of STAT3. The expression of BCL-2, one of the downstream targets of STAT3 and the central apoptosis regulator, was highly upregulated in the resistant cells. The siRNA-mediated knockdown of STAT3 expression decreased BCL2 expression in the PR-S2 cells, whereas not in the H1993 cells. Furthermore, we investigated apoptosis-related gene expressions and found that the BH3-only proapoptotic member of the BCL-2 protein family, BIM was significantly decreased in the PR-S2 cells. AURKB inhibition induced BIMEL accumulation and reduced p-BIM expression. Collectively, our study suggests that AURKB activation induces resistance to MET-TKI through anti-apoptosis mechanism with upregulation of STAT3/BCL2 axis in MET-amplified lung cancer cells. Citation Format: Yura Choi, Mihwa Hwang, Sunshin Kim, Jae J. Song, Youngjoo Lee. Targeting aurora kinase b overcomes acquired resistance to met-tyrosine kinase inhibitor in met-amplified lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 417.

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model.

Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor (TKI) recommended as first-line treatment for patients with locally advanced/metastatic EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, MET amplification/overexpression is a common acquired osimertinib resistance mechanism. Savolitinib is an oral, potent, and highly selective MET-TKI; preliminary data suggest that combining osimertinib with savolitinib may overcome MET-driven resistance. A patient-derived xenograft (PDX) mouse model with EGFRm, MET-amplified NSCLC was tested with a fixed osimertinib dose [10 mg/kg for exposures equivalent to (≈)80 mg], combined with doses of savolitinib (0-15 mg/kg, ≈0-600 mg once daily), both with 1-aminobenzotriazole (to better match clinical half-life). After 20 days of oral dosing, samples were taken at various time points to follow the time course of drug exposure in addition to phosphorylated MET and EGFR (pMET and pEGFR) change. Population pharmacokinetics, savolitinib concentration versus percentage inhibition from baseline in pMET, and the relationship between pMET and tumor growth inhibition (TGI) were also modeled. As single agents, savolitinib (15 mg/kg) showed significant antitumor activity, reaching ∼84% TGI, and osimertinib (10 mg/kg) showed no significant antitumor activity (34% TGI, P > 0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, significant savolitinib dose-related antitumor activity was shown, ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg). Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination antitumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration-A Narrative Review.

Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys®) is highly selective mesenchymal epithelial transition (MET)-tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR-TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR-TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.

61 (PB051) - Capmatinib response in patients with advanced non–small cell lung cancer (NSCLC) harboring focal MET amplifications: Analysis from the phase 2, multicohort GEOMETRY mono-1 study

Background: MET amplifications (METamp) occur in 1–6% of patients (pts) with NSCLC and are associated with a poor prognosis. Capmatinib is a highly selective and potent MET inhibitor (METi) with antitumor activity in pretreated and treatment-naive pts with MET-amplified (gene copy number [GCN] 310) NSCLC. Focal METamp are associated with a relatively high MET GCN and may be a predictor of benefit from METi. In this retrospective analysis from GEOMETRY mono-1 (NCT02414139), we aimed to determine the response to capmatinib according to focality of METamp detected in cell-free DNA (cfDNA) using a blood-based assay. Materials and Methods: Pretreated (1 or 2 prior lines) pts with EGFR wild-type, ALK-negative, MET exon 14 skipping–negative, stage IIIB/IV NSCLC were grouped into cohorts C1a, C1b, C2, and C3 based on different levels of MET GCN amp by FISH on tumor tissue. Pts received capmatinib 400 mg twice daily. cfDNA isolated from blood plasma samples collected at baseline was enriched using RNA-bait–based hybrid capture and analyzed using next-generation sequencing (PanCancer assay 1.0, NGDx, Novartis). Focal METamp were defined using the PureCN pipeline that estimates a gene-level log-ratio relative to normal samples, adjusting for gene probe signal variation. MET was called focally amplified if gene-level P value was <0.001 and gene-level log-ratio reached 90th percentile of all genes. The overall response rate (ORR) by Blinded Independent Review Committee was descriptively compared between pts with focal vs nonfocal METamp (data cutoff, August 2021). Results: 195 pts across the 4 cohorts had METamp by FISH. Of these, baseline cfDNA samples from 113 pts were successfully analyzed (C1a [n = 29], C1b [n = 32], C2 [n = 31], C3 [n = 21]). Baseline characteristics were comparable between pts who were analyzed by cfDNA (n = 113) vs not analyzed (n = 82) and between pts with focal (n = 18) vs nonfocal (n = 95) METamp. Of all pts with focal METamp, most were in high MET-amplified C1a (14 of 18 pts [78%]). In C1a, the distribution of GCN by FISH was similar in pts with focal vs nonfocal METamp but more responders were found in pts with focal vs nonfocal METamp (ORR, 57% vs 13%). In C1b, 3 of 32 pts (9%) had focal METamp; 2 were responders (Table).Tabled 1CohortMET GCN by FISHParameterFocal METampNonfocal METampPts analyzedAll pts in cohortC1a≥10N14152969ORR, n (%)8 (57)2 (13)10 (34)20 (29)C1b≥6 and <10N3293242ORR, n (%)2 (67)1 (3)3 (9)5 (12)C2≥4 and <6N0313154ORR, n (%)-2 (6)2 (6)5 (9)C3<4N1202130ORR, n (%)0 (0)1 (5)1 (5)2 (7) Open table in a new tab Conclusions: METamp status, including focal METamp, was successfully determined using cfDNA isolated from blood. For pts with high MET- amplified NSCLC by FISH, a numerically higher proportion of responders to capmatinib was observed in pts with focal vs nonfocal METamp. Given the small sample size, a larger study is needed to verify this result. Conflict of interest: Ownership: Juergen Wolf: None Markus Riester, Lexiang Ji, Anna Robeva, Aislyn Boran: Novartis stock Advisory Board: Juergen Wolf: Consulting or advisory role for Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Ignyta, Lilly, MSD Oncology, Novartis, Pfizer, Roche, Janssen, Loxo/Lilly, Blueprint Medicines, Amgen, Takeda, Bayer, Daiichi Sankyo Europe GmbH, Seattle Genetics Edward B. Garon: Consultant and/or advisor for Abbvie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio. Daniel S. W. Tan: Consulting/advisory role for Pfizer, Novartis, Takeda, Boehringer Ingelheim, Merck, Amgen, AstraZeneca, DKSH, Roche, C4 Therapeutics, GSK Board of Directors: Juergen Wolf: None Corporate-sponsored Research: Juergen Wolf: Research funding from Bristol-Myers Squibb, Novartis, Pfizer, Janssen Edward B. Garon: Grant/research support from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis Daniel S. W. Tan: Research funding (payments to institution) from AstraZeneca, Pfizer, ACM Biolabs, Amgen Rebecca S. Heist: To institution (not to self) from Agios, Abbvie, Lilly, Novartis, Turning Point, Daichii Sankyo, Mirati, Corvus, Exelixis, Erasca Other Substantive Relationships: Juergen Wolf: Honoraria from Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Roche, Amgen, Bayer, Blueprint Medicines, Chugai Pharma Europe, Daiichi Sankyo Europe GmbH, Ignyta, Janssen, Lilly, Loxo, Loxo/Lilly, Pfizer, Seattle Genetics, Takeda Sylvie Le Mouhaer, Markus Riester, Lexiang Ji, Anna Robeva, Lauren Fairchild, Aislyn Boran: Employment at Novartis Rebecca S. Heist: Consulting for Novartis, Daichii Sankyo, EMD Serono

1012P Resistance mechanisms to dual EGFR and MET inhibition in patients with EGFR-mutant MET-amplified non-small cell lung cancer

MET amplification is a known resistance mechanism to EGFR-mutant NSCLC with EGFR TKI treatment. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. There are currently clinical trials ongoing to evaluate such benefit formally. However, resistance mechanisms to dual MET-EGFR inhibition require further investigation and characterization.

1174P The MET inhibitor ABN401 in combination with the third-generation EGFR-TKI is effective MET-amplified and EGFR-mutant NSCLC with acquired resistance to third-generation EGFR-TKI in preclinical models

ABN401 is a highly selective MET kinase inhibitor, demonstrates a safety profile in the clinical study, and remarkably inhibits tumor cell harboring MET alterations. MET gene amplification is the most frequent cause of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients. Combining therapy of MET-TKI and EGFR-TKI has emerged as a promising therapeutic strategy to overcome EGFR-TKI resistance, but its mechanism and efficacy remain controversial.

Abstract CT559: Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification

Abstract Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ~5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in more than 10 countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment in the advanced NSCLC setting. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in, ~10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ~225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Citation Format: Yi-Long Wu, Ji-Youn Han, Terufumi Kato, Fabrice Barlesi, Edward B. Garon, Federico Cappuzzo, Yuji Shibata, Nathalie Smith, Sadhvi Khanna, Riccardo Belli, Alejandro Yovine, Daniel Tan. Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification [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 CT559.

Capmatinib plus osimertinib versus platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIb/IIIc or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification.

TPS9153 Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ̃5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in about ten countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment for advanced NSCLC. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in,̃10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ̃225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Clinical trial information: NCT04816214.

74TiP Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC/IV EGFR-mutant, T790M-negative, MET-amplified NSCLC

MET amplification can arise as a bypass mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) occurring in ∼5–26% of patients (pts) with EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). Few treatment options exist for these pts, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in more than 10 countries for the treatment of metastatic MET exon 14 skipping NSCLC. Preliminary studies have shown that capmatinib plus EGFR TKIs demonstrated antitumor activity in pts with EGFR TKI resistant EGFR-mutant NSCLC.

INNV-21. COMPLETE RESPONSE TO ADJUVANT TEPOTINIB IN A PATIENT WITH NEWLY DIAGNOSED DISSEMINATED GLIOBLASTOMA (GBM) HARBORING MET AMPLIFICATION

Abstract MET oncogene encodes a receptor-tyrosine-kinase which drives cell proliferation, invasion and angiogenesis in a number of solid cancers including GBM where the incidence of MET amplification is 2-5%. Tepotinib is a highly selective blood-brain-barrier penetrant oral c-MET inhibitor recently FDA approved for MET-exon-14 altered non-small cell lung cancer (NSCLC). Here, we report complete radiographic response to tepotinib in a patient with newly-diagnosed disseminated GBM harboring MET amplification. A 29-years-old male presented with progressive headache. MRI brain showed a large heterogeneously enhancing intraventricular mass with epicenter in the right lateral ventricular trigone and enhancing nodules in bilateral cerebellum. MRI spine showed multifocal enhancement along the periphery of the cervicothoracic spinal cord and cauda equina concerning for leptomeningeal disease. He underwent right temporal lobectomy and subtotal resection of the mass. His KPS was 90 post-surgery due to dizziness. Pathology was consistent with GBM, IDH wild-type, MGMT-unmethylated and MET amplification at 7q31.2. He completed proton craniospinal irradiation at 3600cGy followed by boost to the tumor bed at 2400cGy without concurrent temozolomide (TMZ) due to the large radiation field. He completed two cycles of adjuvant TMZ which was put on hold due to myelosuppression. He subsequently started tepotinib monotherapy at 1000mg daily obtained on a compassionate IND. MRIs after one month of therapy showed resolution of areas of enhancement in the brain and spine. He had grade 1 creatinine elevation and abdominal discomfort and dose was reduced to 500mg daily after two cycles. Nineteen weeks after initiation of tepotinib, his complete response persists, and he remains clinically stable with mild chronic dizziness. Trials of targeted therapy in molecularly-unselected GBM have been largely disappointing, however, this case demonstrates the promise of targeting MET using tepotinib in GBM. A clinical trial of tepotinib in MET-amplified GBM and NSCLC brain metastasis is currently underway at MD Anderson.

4P Prevalence of MET exon 14-mutations or MET amplification in non-small cell lung cancer in Swiss patients

Background: MET-targeted treatment has improved by the introduction of highly selective MET inhibitors for advanced stage MET Exon 14-mutated or MET-amplified non-small cell lung cancer (NSCLC). MET exon 14 skipping mutations occur in 3% and MET amplification in 1 to 6% of unselected NSCLC. The aim of our study was to investigate the prevalence of these MET alterations in treatment-naïve pre-selected NSCLC from our routine clinical practice, were MET analyses were generally performed sequentially in NSCLC with high MET expression and wild type status for EGFR, KRAS, ALK and ROS1.

Capmatinib in MET Exon 14–Mutated or MET-Amplified Non–Small-Cell Lung Cancer

BackgroundAmong patients with non–small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.MethodsWe conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.ResultsA total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.ConclusionsCapmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.)

Abstract CT303: The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study

Abstract MET-amplification is a resistance mechanism seen in &amp;gt;25% of pts with EGFRm non-small cell lung cancer (NSCLC) and progression on osimertinib (1st/later line), a 3rd gen, irreversible, oral EGFR-TKI. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI. In Phase 1b 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 600/300 mg. Part B was split into cohorts (B1, B2 and B3) by prior therapy and T790M status. Pts in Part D (no prior 3rd gen EGFR-TKI, T790M negative; savolitinib 300 mg) had similar response rates and progression-free survival (PFS) to pts in cohort B2 (analogous cohort; savolitinib 600 mg). In osimertinib-treated pts with EGFRm NSCLC (AURA3, FLAURA), circulating tumor (ct)DNA clearance has been shown to correlate with PFS. We report EGFRm (Ex19del/L858R) ctDNA clearance at two doses of savolitinib + osimertinib 80 mg in TATTON Parts B and D. For this next generation sequencing-based analysis (Resolution Bioscience), ctDNA samples were collected pre-dose, cycle (C) 1 day (D) 1 and at least every 3-8 weeks until discontinuation. Part B pts evaluable for efficacy and with a baseline plus ≥1 longitudinal ctDNA sample at/before C6D1 were included. Data from ctDNA evaluable Part B pts (n=49) identified ctDNA clearance correlates with longer PFS and C3D1/C4D1 as optimal time points for PFS prediction, thus the first 20 pts from Part D with available plasma samples at C1D1 and C4D1 were included. The proportion of pts with detectable EGFRm at baseline was similar across groups (Table). ctDNA clearance was comparable at C3D1/C4D1 for cohort B2 and Part D. ctDNA clearance was similar between the two doses of savolitinib, suggesting efficacy is maintained at the lower dose (300 mg). These data also indicate that ctDNA clearance may be predictive of PFS in EGFRm MET-amplified NSCLC. TATTON Part B and Part D ctDNA analysisPart B: osimertinib 80 mg QD + savolitinib 600 mg QD (n=107)*Part D: osimertinib 80 mg QD + savolitinib 300 mg QD (n=42)#All Part BCohort B2 No prior third-generation EGFR-TKI (T790M negative)All Part D No prior third-generation EGFR-TKI (T790M negative)Number of patients492020Detectable EGFRm at baseline, n (%)38 (78)15 (75)16 (80)ctDNA clearanceNumber of pts evaluable at C3D1/C4D1451820ctDNA clearance at C3D1/C4D1, n (%)22 (45)10 (50)13 (65)‡*Interim data cut-off: 28 Feb 2018 #Interim data cut-off: 29 Mar 2019 ‡ctDNA clearance for patients at Part D was only assessed at C4D1 Citation Format: Ryan Hartmaier, Ji-Youn Han, Myung-Ju Ahn, Byoung Chul Cho, Mireille Cantarini, Paul Frewer, Melanie M. Frigault, Geoffrey Oxnard. The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT303.

Abstract 3017: Using a pharmacodynamic biomarker led approach to explore and quantify the combination effect of savolitinib and osimertinib in the LG1208 NSCLC PDX model

Abstract MET-amplification has been identified as a resistance mechanism in &amp;gt;5% of patients with non-small cell lung cancer (NSCLC) and 25% of those that progress on 1st/2nd or 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). There are no approved therapies specifically indicated to treat EGFR mutation-positive (EGFRm)/MET amplified NSCLC patients. We report preclinical data of savolitinib (AZD6094, HMPL-504, volitinib, a potent and selective MET inhibitor) plus osimertinib (3rd generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR sensitizing mutation and EGFR T790M) in an EGFRm/MET amplified model. Combination efficacy of savolitinib and osimertinib was tested in an EGFRm (L858R) and MET-amplified LG1208 PDX model, resistant to osimertinib. As single agents, and at doses that deliver clinically relevant exposures, osimertinib (10 mg/kg) and savolitinib (15 mg/kg) showed minimal (32% tumor growth inhibition [TGI]) and moderate (81% TGI) anti-tumor activity, respectively. Upon combination, at a fixed dose of osimertinib (10 mg/kg), anti-tumor activity increased with savolitinib dose, ranging from 1 mg/kg (99.8 % TGI) to 15 mg/kg (77.9% regression). Pharmacokinetic-pharmacodynamic (PKPD) modelling was also conducted linking exposure of savolitinib to inhibition of phosphorylated MET (pMET), and osimertinib to inhibition of pEGFR. A combination effect on pEGFR was observed whereby the maximum inhibition of pEGFR increased from approximately 50% with no savolitinib to approximately 90% with 15 mg/kg of savolitinib. The exposure-dependent effect of savolitinib on pEGFR was accounted for in the PKPD model by incorporating an interaction term such that the inhibition of pEGFR is modelled as a function of savolitinib and osimertinib exposure. This PKPD model was successfully used to link to the anti-tumor activity and provide biomarker-led rationale for the combination benefit seen for efficacy in this model. Overall, the PKPD analysis describes the biomarker changes linking to efficacy and provides supporting insight into the exposure requirements for combination dosing in the clinic. Savolitinib plus osimertinib was tested in the TATTON study (NCT02143466) where patients with EGFRm, MET-amplified NSCLC with prior progression on EGFR-TKIs had encouraging responses to this combination therapy. A phase 2 trial, SAVANNAH (NCT03778229), is testing the combination of osimertinib and savolitinib in patients with EGFRm, MET-amplified NSCLC with prior progression on osimertinib only. Citation Format: Rhys Jones, Awlin Schuller, Klas Petersson, Ghada Ahmed, Stein Schalkwijk, Areya Tabatabai, Andrew Mortlock, Rana Anjum. Using a pharmacodynamic biomarker led approach to explore and quantify the combination effect of savolitinib and osimertinib in the LG1208 NSCLC PDX model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3017.