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

Abstract

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.

Targeting KRAS in Non-Small Cell Lung Cancer

“…SPH2 inhibition increases KRAS-GDP occupancy what it could increase the effect of direct KRAS G12C (OFF) inhibitors. This also has been demonstrated in preclinical studies of adagrasib combined with SHP2 inhibition (58,(66)(67)(68)(69). Based on this, several ongoing clinical studies with both sotorasib and adagrasib are evaluating the combination of Targeting KRAS in Non-Small Cell Lung Cancer a KRAS G12C (OFF) inhibitor and a SHP2 inhibitor (NCT04330664, NCT04699188, NCT04185883).…”

“…There are several SHP2 inhibitors in development. RMC-4630 has shown clinical activity with a DCR of 67% for all KRAS mutations, and 75% for KRAS G12C mutations (phase I NCT03989115) ( 11 , 58 , 68 , 69 ). TNO155 is a selective, allosteric, oral inhibitor of SHP2 and is being studied in a phase I trial in advanced solid tumors after disease progression following standard therapy (NCT03114319, NCT04330664) ( 68 , 69 ).…”

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

“…SHP2 inhibitor enhanced the efficacy of α-PD-1 in murine tumor models [252][253][254]. A clinical study exploring SHP2 inhibitor combined with α-PD-1 is still ongoing (NCT04000529), and the final data of this combination study are not yet available [255].…”

Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies

“…Notably, results of phase 1 first-in-human clinical trial showed that RMC-4630 led to a disease control rate of 71% in KRAS G12C mutated NSCLC patients (n=19), as a single-agent monotherapy ( 124 ). Likewise, TNO-155 is currently being tested in a phase 1 dose escalation/expansion trial (NCT03114319) in adults with advanced solid tumors alone ( 125 ) or in combination with JDQ443 (KRAS G12C inhibitor), in KRAS G12C patients with advanced solid tumors (NCT04699188).…”