The MET inhibitor TPX-0022 was safe and well tolerated in a phase 1 dose-escalation study, SHIELD-1, involving patients with advanced solid tumors harboring MET alterations, according to results presented during the 32nd Molecular Targets and Cancer Therapeutics Symposium.
David S. Hong, MD
The MET inhibitor TPX-0022 was safe and well tolerated in a phase 1 dose-escalation study, SHIELD-1 (NCT03993873), involving patients with advanced solid tumors harboring MET alterations, according to results presented during the 32nd Molecular Targets and Cancer Therapeutics Symposium hosted by the European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research.1
Further, pharmacokinetic data for TPX-0022 show a dose-dependent increase in exposure; the steady-state concentration trough at all doses was above the cellular IC95 for inhibition of MET phosphorylation, suggesting sustained MET inhibition throughout the dosing interval.
“TPX-0022 is a potent selective inhibitor of MET, SRC, and CSF1R, and targeting of SRC and CSF1R can potentially improve clinical efficacy,” lead author David S. Hong, MD, said during his presentation of the data.
The primary objective of the study was to evaluate the safety and tolerability and determine the maximum tolerated dose of the inhibitor, said Hong, who is deputy chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston.
MET-driven malignancies are well documented in multiple solid tumors, most notably in non–small cell lung cancer (NSCLC) and gastrointestinal cancers.
About 3% to 5% of gastric cancers are estimated to be driven by MET amplification. Similar rates of MET amplification have been observed with NSCLC, with an estimated 3% to 4% of tumors that are driven by exon 14 deletions. Historically, limited clinical activity has been observed in first-in-human studies of MET inhibitors.
Currently, capmatinib (Tabrecta) is the only FDA-approved MET inhibitor for the treatment of patients with NSCLC who harbor the MET exon 14–skipping mutation.2
In the study, patients were treated at doses ranging from 20 mg to 120 mg daily in a standard 3 plus 3 design. Patients were eligible if they had MET alterations determined by local testing, including exon 14 deletion, MET amplification, fusion, or oncogenic kinase domain mutations.
At the data cutoff, 22 heavily pretreated patients, with a median of 3 prior lines of therapy (range, 1-6), were enrolled. Median patient age was 63 years (range, 44-84), and 15 patients (68.2%) had an ECOG performance status of 1. There were 13 patients (59.1%) with NSCLC, 4 (18.2%) with gastric/gastroesophageal junction (GEJ) cancer, 4 (18.2%) with colorectal cancer (CRC), and 1 (4.5%) with glioblastoma multiforme (FIGURE on page 34).1
Most adverse effects (AEs) were grade 1 or 2 in severity, Hong reported. The most common all-grade treatment-emergent AEs (TEAEs) were dizziness (55%), attributed to off target TRK inhibition; increased lipase (32%); and fatigue (32%). Five patients (23%) experienced TEAEs that led to dose reduction, and 2 (9%) experienced TEAEs that led to dose discontinuation. The most common all-grade treatment-related AEs (TRAEs) were dizziness (46%), increased lipase (23%), and increased amylase (18%).
The maximum tolerable dose was not reached, and 1 dose-limiting toxicity was reported. Allgrade peripheral edema was reported in 9.1% of patients, none being grade 3 or higher. No grade 3 or higher alanine transaminase or aspartate aminotransferase elevation and no pneumonitis of any grade were reported.
Of the 10 patients who were TKI (tyrosine kinase inhibitor) naive, 5 achieved partial response (PR). Three responding patients had gastric/GEJ cancer, 1 had CRC, and 1 had NSCLC (TABLE).1 Three patients with confirmed PRs continue on treatment with a duration of response range from 1.0+ to 3.9+ months. The other 2 patients are on treatment pending response confirmation. Of the 5 patients who received prior TKI therapy, 3 had stable disease, and all 5 were treated at 20 mg or 40 mg once a day.
These initial data from the dose-finding portion of SHIELD-1 demonstrate a generally well-tolerated safety profile, said Hong during the presentation. The additional targeting of SRC and CSF1R makes TPX-0022 a novel therapeutic option with potential benefits in an area of high unmet need. Pan-tumor potential is suggested with responses observed in MET exon 14–deleted NSCLC and in MET amplified gastric/GEJ cancer and CRC, warranting further investigation. The sponsor of the trial plans to modify the study to include a potential registration for a subsequent phase 2 trial, Hong concluded.
1. Hong DS. First-in-human safety, pharmacokinetics, and preliminary efficacy of TPX-0022, a novel inhibitor of MET/SRC/CSF1R in patients with advanced solid tumors harboring genetic alterations in MET (SHIELD-1). Presented at: 32nd EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium. October 24-25, 2020. Virtual. https://bit.ly/3kM6ilc
2. FDA approves first targeted therapy to treat aggressive form of lung cancer. FDA. May 6, 2020. Accessed date. https://bit.ly/31Xa2Ja