First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors.

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials

Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study

BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma

A Note on Superdistributions and Wavefront Set

We present a simple and new method of constructing superdistributions on superspace over a Grassmann-Banach algebra, which close to the de Rham's ``currents'' defined as dual objects to differential forms. The paper also contains the extension of the H\"ormander's description of the singularity structure (wavefront set) of a distribution to include the supersymmetric case.Comment: Version to appear in International Journal of Theoretical Physic

Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with <i>MET</i> Gene Amplification in FFPE Tumor Tissue

Background: Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for ‘high Met’ expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue.Methods: After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH).Results: Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R2 = 0.898). IHC did not correlate well with SRM (n = 44; R2 = 0.537) nor FISH GCN (n = 31; R2 = 0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69–1) and 100% specific (95% CI 0.92–1) for MET amplification.Conclusions: The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC.</p

Redefining tumor classification and clinical stratification through a colorectal cancer single-cell atlas

Colorectal cancer (CRC), a disease of high incidence and mortality, exhibits a large degree of inter- and intra-tumoral heterogeneity. The cellular etiology of this heterogeneity is poorly understood. Here, we generated and analyzed a single-cell transcriptome atlas of 49,859 CRC cells from 16 patients, validated with an additional 31,383 cells from an independent CRC patient cohort. We describe subclonal transcriptomic heterogeneity of CRC tumor epithelial cells, as well as discrete stromal populations of cancer-associated fibroblasts (CAFs). Within CRC CAFs, we identify the transcriptional signature of specific subtypes that significantly stratifies overall survival in more than 1,500 CRC patients with bulk transcriptomic data. We demonstrate that scRNA analysis of malignant, stromal, and immune cells exhibit a more complex picture than portrayed by bulk transcriptomic-based Consensus Molecular Subtypes (CMS) classification. By demonstrating an abundant degree of heterogeneity amongst these cell types, our work shows that CRC is best represented in a transcriptomic continuum crossing traditional classification systems boundaries. Overall, this CRC cell map provides a framework to re-evaluate CRC tumor biology with implications for clinical trial design and therapeutic development. Competing Interest Statement: The authors have declared no competing interest

Immune-Checkpoint Inhibition in the Treatment of Gastro-Esophageal Cancer: A Closer Look at the Emerging Evidence

To date, several trials have evaluated the safety and efficacy of immune-checkpoint inhibitors (ICI) for the treatment of gastroesophageal cancers (GEC). In the US, ICIs have established indications for second-line treatment of microsatellite unstable tumors, while their use in third-line settings was recently withdrawn. Notably, the use of ICIs for first-line therapy of GEC is rapidly evolving, which currently includes high PD-L1 expressing tumors, irrespective of HER2 status, and in the adjuvant setting after neoadjuvant chemoradiotherapy in select patients. In this article, we review the results of studies that have evaluated the utility of ICI in the third-line, second-line, first-line, and peri-operative treatment settings of GECs. Considerations should be made before making any cross-trial comparisons since these trials vary in chemotherapy backbone, anatomical and histological eligibility, biomarker assessment, PD-L1 diagnostic antibodies, and definition of PD-L1 positivity. Regardless, the totality of the data suggest that first-line ICI use may most benefit GEC patients with high PD-L1 combined positivity score (CPS) &ge;5 or &ge;10, irrespective of histology or anatomy. Moreover, although PD-L1 by CPS has a good negative predictive value for significant benefit from ICIs, it has a low positive predictive value. Therefore, there is a pressing need to identify better biomarkers to predict benefit from ICIs among these patients

MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma

MET gene amplification and Met protein overexpression may be associated with a poor prognosis. The MET/Met status is typically determined with fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Targeted proteomics uses mass spectrometry-based selected reaction monitoring (SRM) to accurately quantitate Met expression. FISH, IHC, and SRM analyses were compared to characterize the prognostic value of MET/Met in gastroesophageal adenocarcinoma (GEC)