Summary Background Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. Methods In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov , NCT02143466 . Findings Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39–56) patients in part B and 23 (64%; 46–79) in part D. Interpretation The combination of osimertinib and savolitinib has acceptable risk–benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. Funding AstraZeneca.

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.29496

Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma.

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial

Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.

Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and in combination. Here, we describe the preclinical data of capmatinib, which supported the clinical biomarker strategy for rational patient selection. Experimental Design: The selectivity and cellular activity of capmatinib were assessed in large cellular screening panels. Antitumor efficacy was quantified in a large set of cell line– or patient-derived xenograft models, testing single-agent or combination treatment depending on the genomic profile of the respective models. Results: Capmatinib was found to be highly selective for MET over other kinases. It was active against cancer models that are characterized by MET amplification, marked MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF). In cancer models where MET is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments, for example, by the addition of apoptosis-inducing BH3 mimetics. The combinations of capmatinib and other kinase inhibitors resulted in enhanced anticancer activity against models where MET activation co-occurred with other oncogenic drivers, for example EGFR activating mutations. Conclusions: Activity of capmatinib in preclinical models is associated with a small number of plausible genomic features. The low fraction of cancer models that respond to capmatinib as a single agent suggests that the implementation of patient selection strategies based on these biomarkers is critical for clinical development. Capmatinib is also a rational combination partner for other kinase inhibitors to combat MET-driven resistance.

/pdf/capmatinib-inc280-is-active-against-models-of-non-small-cell-2mz83ppr3u.pdf

Capmatinib (INC280) Is Active Against Models of Non–Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation

Gastric cancer (GC) incidence rates are amongst the highest in Asian countries including; China, Japan and Korea(1). 5-year survival rates in early stage disease have improved through aggressive combinations of surgery and chemo/radiotherapy. In late stage disease however, despite Her2 molecular segmentation and trastuzumab therapy, prognosis remains dismal and novel therapeutic options are urgently required(2). The MET oncogene encodes the receptor tyrosine kinase for hepatocyte growth factor and controls genetic programs leading to cell growth, invasion and survival. Dysregulation of MET signaling is a common feature of a diverse range of human tumor types and thus represents a highly competitive and attractive therapeutic target. Volitinib (HMPL-504) is an orally bioavailable, highly selective and potent small molecule ATP-competitive inhibitor, which inhibits cMET autophosphorylation and downstream signaling (3). Volitinib is currently in Phase I clinical development. To evaluate the utility of volitinib in treating patients with GC, we established the incidence of cMET amplification and overexpression and attempted to correlate this with response to volitinib in primary GC tumor models. Elevated cMET gene copy number (amplification 5%, high polysomy 13%), and protein overexpression (12%, cases > IHC 2+, 16% > IHC1+) were detected in a cohort of 217 Chinese GC samples using fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) approaches. In vitro proliferation assays were performed on a panel of 26 GC cell lines and profound sensitivity to volitinib was demonstrated in lines harboring elevated cMET gene copy number (GI 50 range 6 to 49nM). In the cMET amplified GC xenograft model, Hs746t, once-daily oral dosing of volitinib (2.5mg/kg) elicited potent anti-tumour activity at well-tolerated doses (97% tumour growth inhibition after 16 days dosing, P Citation Format: Paul R. Gavine, Shiming Fan, Haihua Fu, Lu Han, Yuan Jie Liu, Jing Lv, Weiguo Qing, Yongxin Ren, Weiguo Su, Xinying Su, Huiying Wang, Liang Xie, Shirlian Xu, Wen Xu, XiaoLu Yin, Yongjuan Yu, Tianwei Zhang, Q.May Wang. Volitinib (HMPL504), a novel, selective and potent cMET inhibitor, is efficacious in primary tumor models of cMET-driven gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 928. doi:10.1158/1538-7445.AM2013-928

Abstract 928: Volitinib (HMPL504), a novel, selective and potent cMET inhibitor, is efficacious in primary tumor models of cMET-driven gastric cancer.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.molonc.2014.08.015

Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models

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Abstract 928: Volitinib (HMPL504), a novel, selective and potent cMET inhibitor, is efficacious in primary tumor models of cMET-driven gastric cancer.

Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models