Effect of the tyrosine kinase inhibitor nilotinib in patients with hypereosinophilic syndrome/chronic eosinophilic leukemia: analysis of the phase 2, open-label, single-arm A2101 study

IntroductionEvobrutinib (M2951) is a highly specific oral inhibitor of Bruton’s tyrosine kinase, a key regulator of B cell and macrophage functions implicated in MS.MethodsIn this double-blind, phase 2 study (NCT02975349), adult patients (≤65 years) with relapsing MS (RMS) were randomized to evobrutinib 25 mgQD, 75 mgQD, 75 mgBID, placebo, or open-label dimethyl fumarate (240 mgBID; reference arm) for 48 weeks; placebo-treated patients switched to evobrutinib 25 mgQD after 24 weeks. The primary endpoint was the total number of T1 gadolinium-enhancing (T1Gd+) lesions at Weeks 12, 16, 20, and 24. Secondary endpoints included annualized relapse rate (ARR), MRI measures at Weeks 24 and 48, and safety.ResultsAmong 261 patients, the sum of T1Gd+ lesions over Weeks 12–24 was reduced with evobrutinib 75 mgQD (p=0.002) and 75 mgBID (p=0.03); a dose response was observed (p=0.001). There was no evidence of change in effect on T1Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mgQD (0.28±0.91 to 0.85±2.87; p=0.57) or 75 mgBID (0.24±0.88 to 0.49±1.22; p=0.23). ARR (unadjusted [95%CI]) was 0.25 (0.12–0.44) for evobrutinib 75 mgQD and 0.11 (0.04–0.25) for 75 mgBID over 48 weeks, and 0.37 (0.17–0.70) for placebo over 24 weeks. Evobrutinib appeared well-tolerated. Shifts to Grade 3–4 ALT and AST elevations from normal (grade 0) occurred in 8 (5.4%) and 6 (3.9%) evobrutinib-treated patients respectively, driven by events with onset within the first 24 weeks.ConclusionsEvobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in RMS. The observed benefit-risk profile supports further clinical development.

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Safety and efficacy of abivertinib (AC0010), a third-generation EGFR tyrosine kinase inhibitor, in Chinese patients with EGFR-T790M positive non-small cell lung cancer (NCSLC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9091 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9091-9091 ◽

Cited By ~ 2

Author(s):

Qing Zhou ◽

Lin Wu ◽

Luo Feng ◽

Tongtong An ◽

Ying Cheng ◽

...

Keyword(s):

Adverse Events ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Chinese Patients ◽

Third Generation ◽

Phase 2 ◽

Egfr Tyrosine Kinase Inhibitor ◽

Egfr Tki ◽

Egfr T790m

9091 Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were ≥ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment-related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE (≥2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR-TKI. Clinical trial information: NCTNCT02330367.

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