Mesenchymal-epithelial Transition Receptor Research Articles

A phase 2, open-label study of amivantamab in patients with previously treated advanced or metastatic gastric or esophageal cancer.

363 Background: Amivantamab (Ami) is a bispecific antibody targeting epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition receptor (Met) and has immune cell directing activity. Gastric cancer (GC), gastroesophageal junction (GEJ) cancer and esophageal cancer (EC) have been known to express EGFR and Met and these expressions have correlated with poor prognosis. Methods: This open-label, multicenter phase 2 study aims to evaluate the antitumor activity and safety of Ami monotherapy in patients (pts) with advanced or unresectable GC, GEJ cancer and EC who had received at least 2 prior lines (GC/GEJ) or 1 prior line (EC) of systemic therapy. Pts who express varying degrees of EGFR, Met, or both as determined by immunohistochemistry (IHC) were enrolled. Ami was administered intravenously at the recommended Phase 2 dose (RP2D) of 1,050 mg (or 1,400 mg if body weight ≥80 kg) in 28-day cycles. The primary endpoint was objective response rate (ORR) (RECIST 1.1). No hypothesis was planned but approximately 30 pts were to be enrolled in GC and EC cohorts, respectively. Secondary endpoints included disease control rate (DCR), pharmacokinetics (PK) and safety. Results: At the data cut-off of Jul-2023, a total of 59 pts received the RP2D. The 29 and 30 pts had GC/GEJ (all adenocarcinoma) and EC (29 squamous-cell and 1 adenocarcinoma), respectively. Median ages were 66 in GC/GEJ and 60 in EC, and 82.8% and 80.0% of pts were male, and median durations of study treatment were 0.99 and 2.64 months, respectively. The ORRs were 4.3% for GC/GEJ and 10.7% for EC and DCRs were 26.1% and 67.9%, respectively. The Met-high-expression (IHC score ≥2+) tended to be associated with better response of ORR 13.3% and DCR 80.0% compared to Met-low-expression (IHC score 1+/0) of ORR 7.7% and DCR 53.8% in EC. Transcriptomic analysis results from paired baseline/on-treatment EC biopsies will be presented. All 59 pts had adverse events (AEs) and 64.4% of them had AEs with the maximum grade of ≤2. Serious AEs occurred in 27.1% of pts. Conclusions: Ami showed clinical meaningful antitumor activity in EC, especially in Met-high-expression tumors. There was minimal monotherapy activity in GC. No new safety signals were identified in pts with GC and EC, which appeared to be acceptable. Clinical trial information: NCT04945733 .

Bispecific Nanobody-Aptamer Conjugates for Enhanced Cancer Therapy in Solid Tumors.

Bispecific antibodies possess exceptional potential as therapeutic agents due to their capacity to bind to two different antigens simultaneously. However, challenges pertain to unsatisfactory stability, manufacturing complexity, and limited tumor penetration hinder their broad applicability. In this study, a versatile technology is presented for the rapid generation of bispecific nanobody-aptamer conjugates with efficient tumor penetration. The approach utilizes microbial transglutaminase (MTGase) and click chemistry to achieve site-specific conjugation of nanobodies and aptamers, which are termed nanotamers. The nanotamers recognize and bind to two types of molecular targets expressed on cancer cells. As a prototype, a bispecific nanotamer is developed that binds both clusters of differentiation 47 (CD47) and mesenchymal epithelial transition receptor (Met) expressed on the tumor cell membrane. This CD47-Met nanotamer demonstrates high affinity and specificity toward tumor cells expressing both targets, exhibits improved receptor functional inhibition through a strong steric hindrance effect. Moreover, its capacity for deep tumor penetration greatly enhances the impact of conventional chemotherapy on antitumor efficacy. The as-developed nanotamer synthesis approach shows promise to customize bispecific molecular probes targeting different cancer types and different therapeutic goals.

TRLS-11. A PHASE 1 STUDY OF SAVOLITINIB IN RECURRENT, PROGRESSIVE, OR REFRACTORY MEDULLOBLASTOMA, HIGH-GRADE GLIOMA, DIFFUSE INTRINSIC PONTINE GLIOMA, AND CENTRAL NERVOUS SYSTEM (CNS) TUMORS HARBORING MET ABERRATIONS: A PEDIATRIC BRAIN TUMOR CONSORTIUM TRIAL

Abstract Aberrant mesenchymal epithelial transition receptor (MET) activation leads to neoplasia, promotes invasive tumor growth, angiogenesis, and metastasis. Deregulation of MET signaling pathway is frequently observed in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. A phase 1 first-in-children trial of the MET inhibitor savolitinib was performed in children with recurrent, progressive or refractory medulloblastoma, high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and other CNS tumors harboring MET aberrations. The study sought to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of savolitinib using a Rolling-6 design given orally once daily continuously, and to describe its toxicity profile and pharmacokinetics (PK). Once the MTD was established, a PK expansion cohort was opened to enrollment. This will be followed by an efficacy expansion cohort for patients whose tumors harbor activating genomic MET aberrations. Tumor tissue and blood were collected as part of correlative studies in consenting subjects. Twenty-eight patients enrolled (median age:12 years; range: 6-21); one patient was deemed ineligible, and 22 patients were evaluable for dose finding. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose limiting toxicities were reported in 2 subjects and consisted of grade 3 fatigue and grade 3 ALT elevation. The most common grade 3/4 toxicities were: neutropenia (7.7%) and lymphopenia (7.7%). One partial response was observed in a patient with recurrent HGG on dose level 1 (150 mg/m2). As of the most recent data freeze, the patient had completed 35 treatment courses. Sustained stable disease was experienced by 3 other patients with recurrent DIPG who remained on treatment for a median of 9 cycles (range: 4-24). Correlative studies are ongoing and will be presented. Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Antitumor activity was observed.

Amivantamab: A narrative drug review

ABSTRACT Epidermal growth factor receptor (EGFR) activating mutations are known oncogenic drivers in non-small-cell lung cancer (NSCLC), with 85% attributable to an exon 19 deletion or exon 21 L858R point substitution. The next most common is an exon 20 insertion mutation (Ex20Ins), which results in an altered active site that sterically interferes with tyrosine kinase inhibitor (TKI) binding, resulting in a poorer response rate to EGFR TKIs. Amivantamab (JNJ-61186372), a fully humanized EGFR- mesenchymal-epithelial transition receptor (MET) bispecific antibody has been approved for use in adults with locally advanced or metastatic NSCLC with EGFR Ex20Ins mutations, whose disease has progressed on or after platinum-based chemotherapy. To prepare this review, we searched various websites, including the European Medicines Agency Drug Manual, United States Food and Drug Administration, PubMed, Science Direct, and UpToDate using the search terms, “Amivantamab,” “NJ-61186372,” “amivantamab-vmjw,” and” “EGFRexon20ins.” We shortlisted 121 articles published between 2015 and 2023, of which 49 were included. This review discusses the clinical indications, adverse effects, safety, pharmacodynamics, pharmacokinetics, and the key research trials that investigated the use of amivantamab.

Frequency of MET exon 14 skipping mutations in non-small cell lung cancer according to technical approach in routine diagnosis: results from a real-life cohort of 2,369 patients.

BackgroundMesenchymal epithelial transition receptor (MET) alterations, including MET exon 14 skipping mutation, are oncogenic in non-small cell lung cancer (NSCLC) and may confer sensitivity to targeted therapy. Given the rarity and the diversity of exon 14 skipping mutations, diagnosis may be challenging on small-biopsy specimens.MethodsBetween March 2014 and May 2018, tissue samples from patients with metastatic NSCLC were analysed for MET exon 14 skipping mutation as part of routine practice in the Pathology Department of the Hospices Civils de Lyon, France. Over the study period, Sanger sequencing and/or two different DNA-based next generation sequencing (NGS) assays were used.ResultsGenomic alterations of MET exon 14 were detected in 2.6% (62/2,369) samples of NSCLC analysed for MET exon 14 mutations. Patients were mainly women (38/62, 61%) without smoking history (22/39, 56%) and the median age was 75 years. MET exon 14 skipping mutations were diagnosed by NGS in 50 cases and by classical Sanger sequencing in 12 cases. The frequency of MET mutations was 15.4% when Sanger sequencing was performed at the request of the clinician and 4.1% when the DNA-based NGS assay coverage included the 3' and 5' parts of the MET exon 14 and performed systematically.ConclusionsThe frequency of genomic alterations is highly dependent on patient selection and the technical approach.

Management of Adverse Events Associated with Cabozantinib Therapy in Renal Cell Carcinoma.

Cabozantinib leads to improved survival outcomes in renal cell carcinoma patients compared with everolimus. However, management of the adverse event profile is crucial to achieve optimum adherence and outcomes with the use of cabozantinib. This review aims to provide appropriate guidance that will minimize the impact of adverse events and help to maximize the utility of this agent in patients with advanced renal cell carcinoma.

Abstract 392: Combined targeting of MET and PI3K improves efficacy in breast cancer models with concurrent MET/PI3K aberrations

Abstract Introduction: Detailed understanding of the genetic abnormalities that drive subsets of cancer has led to the development of highly specific inhibitors targeting key oncogenic pathways. Growing evidence implicates aberrations of both mesenchymal epithelial transition receptor (MET) and its key downstream phosphatidylinositol 3-kinase (PI3K) signaling with poorer prognosis in breast cancer. Co-targeting MET/PI3K and identifying mechanisms of response and resistance could ultimately inform a novel therapeutic strategy for breast cancer treatment. Based on these finding, we hypothesized that concurrent aberrations in PI3K and MET will render breast cancers resistant to therapies targeting each pathway, and that combination therapy targeting the PI3K and MET pathway will improve the efficacy by preventing the acquisition of resistance. Methods: We established cell models that stably express human wild type (WT) MET or MET-T1010I, a functional germline single nucleotide polymorphism, or mutant PI3K-H1047R alone, or variable concurrent aberrations in PI3K and MET using MCF-10A, a non-transformed mammary epithelial cell line, and HCC1954, a breast cancer cell line with an endogenous PI3KCA-H1047R mutation. Cell behaviors, including survival, invasion and response to MET one arm monoclonal antibody onartuzumab (MetMAb, Genentech Inc) and/or pan class I PI3K inhibitor GDC 941 (pictilisib, Genentech Inc), were detected. HCC1954 expressing WT MET or MET-T1010I along with PI3K-H1047R were transplanted into the mammary fat pad of hepatocyte growth factor-transgenic mice on a severe combined immunodeficiency background. Statistical analyses were carried out using the ANOVA and the Student t test. Result: Expression WT MET or MET-T1010I act coordinately with PI3K-H1047R to increase colony formation (P < 0.01, respectively). Concurrent MET-T1010I, but not WT MET, acts coordinately with PI3K-H1047R to increase cell invasion (P < 0.0001). Expression MET-T1010I or WT MET induced cells resistance to GDC941, with MET-T1010I stronger than WT MET. Combined targeting MET with onartuzumab and targeting PI3K with GDC941 significantly inhibited cell growth in matrigel, dose dependently than each monotherapy (P < 0.0001, respectively). Invasion assay showed similar pattern. Combined onartuzumab and GDC941 significantly inhibited invasion, dose dependently (P < 0.001). The effects were confirmed using PI3K/mTOR inhibitor, GDC980. Consistently, combination of onartuzumab/GDC941 significantly inhibited tumor growth (P < 0.01 versus GDC941; P < 0.0001 versus onartuzumab alone). Conclusions: Concurrent aberrations of MET and PI3K render breast cancer cells resistant to therapies blocking either pathway. Targeting both MET and PI3K increases inhibitory efficacy. Citation Format: Shuying Liu, Naoto T. Ueno, Bailiang Wang, Mihai Gagea, Prahlad T. Ram, Mark Merchant, John Mendelsohn, Debasish Tripathy, Gordon B. Mills, Ana M. Gonzalez-Angulo. Combined targeting of MET and PI3K improves efficacy in breast cancer models with concurrent MET/PI3K aberrations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 392.

Abstract 836: In vivo PET imaging of MET receptor in human cancer using [11C]SU11274

Abstract The mesenchymal-epithelial transition (MET) receptor plays prominent role in human tumorigenesis, tumor progression and metastasis. Overexpression or mutation of MET results in activation of oncogenic signaling pathways and leads to upregulation of diverse tumor cell functions. Mounting evidence has validated MET receptor as novel target for anticancer therapy. For efficacy evaluation of various MET-targeted anticancer therapies currently under development, it is critical to develop an imaging tool that permits detection and quantification of MET expression in vivo. To date, a number of small molecule MET inhibitors have been developed, including SU11274, which is a specific, reversible MET inhibitor that induces apoptosis in cells transformed by activated MET kinase. Here, we report the radiosynthesis and evaluation of a molecular imaging probe, [11C]SU11274, for quantification of MET receptors in human cancers in vivo. The radiolabeling with C-11 was accomplished through radiomethylation using 3-[3,5-Dimethyl-4-(piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihyro-1H-indole-5-sulfonic acid (3-chlorophenyl)-methyl amide hydrochloride as a key precursor. Following the synthesis of the precursor that was achieved in 10 steps with a total yield of 9.7%, [11C]SU11274 was obtained through radiomethylation in a range of 5-10 % radiochemical yield and over 95% radiochemical purity. For in vivo PET studies, two human lung adenocarcinoma cancer xenograft models were established using MET-positive H1975 and MET-negative H520 cell lines. The time-radioactivity curves showed that the uptake of [11C]SU11274 in the H1975 xenograft was significantly higher than in the H520 xenograft (p = 0.00019). Compared to H520, the H1975 xenograft mice exhibited an increased tumor uptake of [11C]SU11274 throughout the entire measurement period of 90 min. At 65 min post-injection, the radioactivity concentration ratio of H1975/H520 reached a statistically significant and enhanced ratio of 2.1, and peaked at 2.6 at 80 min. The PET imaging results were consistent with their corresponding immunohistochemical tissue staining patterns of MET receptors from the same animals. Hence, our results suggest that [11C]SU11274-PET is a specific imaging marker that can differentiate and quantify MET receptor expression in vivo. These studies demonstrated that [11C]SU11274-PET can facilitate the clinical development of MET-targeted cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 836.