Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis: A Randomized Clinical Trial.

Importance: New, effective, and well-tolerated oral therapies are needed for treating psoriasis. Zasocitinib, a highly selective allosteric tyrosine kinase 2 (TYK2) inhibitor, is a potential new oral treatment for this disease. Objective: To assess the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis. Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, multiple-dose randomized clinical trial was conducted from August 11, 2021, to September 12, 2022, at 47 centers in the US and 8 in Canada. The study included a 12-week treatment period and a 4-week follow-up period. Key eligibility criteria for participants included age 18 to 70 years; a Psoriasis Area and Severity Index (PASI) score of 12 or greater; a Physician's Global Assessment score of 3 or greater; and a body surface area covered by plaque psoriasis of 10% or greater. Of 287 patients randomized, 259 (90.2%) received at least 1 dose of study treatment. Intervention: Patients were randomly assigned (1:1:1:1:1) to receive zasocitinib at 2, 5, 15, or 30 mg or placebo orally, once daily, for 12 weeks. Main Outcomes and Measures: The primary efficacy end point was the proportion of patients achieving 75% or greater improvement in PASI score (PASI 75) at week 12. Secondary efficacy end points included PASI 90 and 100 responses. Safety was also assessed. Results: In total, 259 patients were randomized and received treatment (mean [SD] age, 47 [13] years; 82 women [32%]). At week 12, PASI 75 was achieved for 9 (18%), 23 (44%), 36 (68%), and 35 (67%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and 3 patients (6%) receiving placebo. PASI 90 responses were consistent with PASI 75. PASI 100 demonstrated a dose response at all doses, with 17 patients (33%) achieving PASI 100 with zasocitinib, 30 mg. Treatment-emergent adverse events occurred for 23 patients (44%) receiving placebo and 28 (53%) to 31 (62%) patients receiving the 4 different doses of zasocitinib, with no dose dependency and no clinically meaningful longitudinal differences in laboratory parameters. Conclusions and Relevance: This randomized clinical trial found that potent and selective inhibition of TYK2 with zasocitinib at oral doses of 5 mg or more once daily resulted in greater skin clearance than placebo over 12 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04999839.

Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer.

PURPOSE: Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS: Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS: Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION: We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

Combination of Docetaxel Plus Savolitinib in Refractory Cancer Patients: A Report on Phase I Trial.

MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1 hour at 60 mg/m2 once every 3 weeks of a 21-day schedule plus savolitinib (level 1, 200 mg qd; level 2, 400 mg qd; level 3, 600 mg qd; level 4800 mg qd). In total, there were 17 patients enrolled on to this study [7 gastric cancer (GC) patients, 5 melanoma patients, 3 sarcoma patients, and 2 rectal cancer patients]. Most of the patients (14 of 17) were heavily pretreated (≥third line or greater lines of treatment). For the first 3 cohorts (200 mg savolitinib + docetaxel 60 mg/m2, 400 mg savolitinib + docetaxel 60 mg/m2, 600 mg savolitinib + docetaxel 60 mg/m2), there were no DLTs. In the fourth dose cohort (800 mg savolitinib + docetaxel 60 mg/m2), one DLT occurred with generalized edema grade 3 that required intensive management. One GC patient with both MET overexpression (3+) and MET amplification (MET/CEP7 ratio, 7.3) achieved a durable partial response for 297 days, and another MET-amplified GC patient (MET/CEP7 ratio, 7.6) achieved stable disease for 86 days. Due to the higher incidence of G4 neutropenia in cohort 4 (800 mg), we recommend savolitinib 600 mg qd in combination with docetaxel 60 mg/m2 as the RP2D for phase II trial. The combination therapy demonstrated a very promising antitumor activity with durable responses in MET amplified GC patients.