Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors.

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Titel: Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors

Beteiligte: Brana, Irene; Shapiro, Geoffrey; Johnson, Melissa Lynne; Yu, Helena Alexandra; Robbrecht, Debbie; Tan, Daniel Shao-Weng; Siu, Lillian L.; Minami, Hironobu; Steeghs, Neeltje; Hengelage, Thomas; Tan, Eugene; Biette, Kelly; Xu, Kun; Moody, Susan Elizabeth; Jove, Maria

Erschienen: American Society of Clinical Oncology (ASCO), 2021

Sprache: Englisch

DOI: 10.1200/jco.2021.39.15_suppl.3005

ISSN: 0732-183X; 1527-7755

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Beschreibung: 3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.

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