OA 09.06 A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC

Yang, Jin‐Ji; Fang, Jian; Shu, Yongqian; Chang, Jianhua; Chen, G.; He, Jianxing; Li, W.; Liu, X.; Yang, Nong; Zhou, C.Z.; Huang, Jianan; Yang, Ling; Handzel, Amir A.; Frigault, Melanie M.; Ahmed, Ghada F.; Égile, Coumaran; Morgan, Shethah; Wu, Yi‐Long

doi:10.1016/j.jtho.2017.09.379

Cited by 15 publications

(8 citation statements)

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“…The safety of savolitinib has also been explored in other phase I studies in combination with osimertinib and gefitinib. The monotherapy toxicity profile of savolitinib at active doses makes combinations with other targeted therapies, such as osimertinib, feasible and such combination regimens are currently being investigated with preliminary data demonstrating a potentially acceptable tolerability profile (25,26).…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity

Gan

Millward

Ye³

et al. 2019

Clinical Cancer Research

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Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). Patients and Methods: This open-label, multicenter doseescalation and-expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 þ 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N ¼ 1, 800 mg N ¼ 1, and 1,000 mg N ¼ 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 hÁng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.

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Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity

Gan

Millward

Ye³

et al. 2019

Clinical Cancer Research

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“…Tepotinib plus gefitinib also showed significantly better progression-free survival (PFS) and OS than chemotherapy in patients with MET amplification (16.6 months vs. 4.2 months; 37.3 months vs. 17.9 months, respectively) [ 20 ]. Two phase Ib clinical trials revealed that a combination of savolitinib and osimertinib or gefitinib showed promising antitumor activity and tolerable toxicity in patients with acquired MET -amplified NSCLC [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors

Peng

Jie

et al. 2021

Exp Hematol Oncol

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Background MET amplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine–kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method for MET amplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS in MET amplification remains uncertain. Methods Forty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment. MET amplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number (CN) > 5. MET amplification by NGS was defined as gene copy number (GCN) ≥ 5. Results The concordance rate among FISH and NGS was 62.5% (25/40). MET amplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 with MET amplification) vs. 6.7% (1/15 without MET amplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P < 0.001). MET amplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, with MET GCN ≥ 5) vs. 40.0% (12/30, with MET GCN < 5); the median PFS was 4.8 months vs. 2.2 months (P = 0.357). The PR rate was 68.8% (11/16) and the median PFS was 4.8 months in patients with focal amplification by NGS. Conclusions MET amplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

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“…16 Recently, at the 2017 WCLC meeting, Yilong Wu reported another phase IB trial of savolitinib plus gefitinib for Chinese patients with EGFR-mutant MET-amplified advanced NSCLC and confirmed a partial response was reported in 11 patients (25%). 17 At present, the NCCN guideline is recommending the use of crizotinib in the treatment of patients with MET ex14skipping mutations. However, for MET amplification, the situation is relatively complex, and the best cutoff value for amplification needs to be further determined.…”

Section: Discussionmentioning

confidence: 99%

Responses to crizotinib can occur in c-MET overexpressing nonsmall cell lung cancer after developing EGFR-TKI resistance

Fan

2018

Cancer Biology & Therapy

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Evidence suggests that activation of the MET signaling pathway might be associated with EGFR-TKI resistance. EGFR TKI-resistant lung cancers often remain sensitive to inhibition of the EGFR pathway; thus, c-MET inhibitors are likely to be effective when combined with continued EGFR-TKI treatment. Here, we described a 56-year-old male who became refractory after first-line gefitinib therapy and was confirmed to have c-MET overexpression without a T790M mutation, c-MET amplification or MET exon 14 alterations. A complete response to crizotinib occurred in this patient. Our case report uncovered the underlying mechanism of c-MET overexpression in affecting EGFR-TKI sensitivity, and crizotinib may assist in overcoming this problem.

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OA 09.06 A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC

Cited by 15 publications

References 0 publications

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity

MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors

Responses to crizotinib can occur in c-MET overexpressing nonsmall cell lung cancer after developing EGFR-TKI resistance

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