Orpathys (savolitinib)

P2, N=114, Active, not recruiting, Assistance Publique Hopitaux De Marseille | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Oct 2024

P2, N=152, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2023 --> Dec 2024 | Trial primary completion date: Oct 2020 --> Oct 2023

Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

No abstract available

P1, N=8, Not yet recruiting, AstraZeneca

P1, N=344, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P2, N=60, Suspended, AstraZeneca | Recruiting --> Suspended

P2, N=200, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=600 --> 200

P2, N=248, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2025 --> May 2025 | Trial primary completion date: Nov 2025 --> May 2025

P2, N=600, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=44, Active, not recruiting, Guangdong Association of Clinical Trials | Recruiting --> Active, not recruiting

Our results suggest osimertinib and savolitinib combination is most effective for osimertinib resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal MET amplification may be evident in MET polysomy tumor progression, MET polysomy warrants close clinical follow up with phospho-MET IHC in parallel with FISH diagnostic.

Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines...Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

P3, N=60, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P2, N=999, Completed, UNICANCER | Active, not recruiting --> Completed

No abstract available

P2, N=360, Recruiting, AstraZeneca | Trial primary completion date: May 2024 --> Aug 2024

The most common adverse reactions (ARs) due to savolitinib administration are nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. This consensus was developed through two rounds of extensive national surveys involving multidisciplinary experts in China, aiming to guide clinicians to prevent and treat various ARs scientifically, and improve the efficacy of the drug and the quality of life of patients.

P2, N=250, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

P1/2, N=29, Recruiting, The First Affiliated Hospital of Guangzhou Medical University | Not yet recruiting --> Recruiting | Initiation date: Mar 2023 --> Jul 2023

The ORR of pts with MET ex14m received 1L savolitinib (savo mono), other MET inhibitor (METi) and chemotherapy (chemo)-based regimen were 56.3%, 16.7%, 36.3%, respectively...The ORR of post EGFR/ALK-TKI resistance pts with MET amp (resistant MET amp) received savo mono, savo plus osimertinib (osi), other METi and chemo-based regimen were 12.5%, 43.8%, 0, 14.2%, respectively...Conclusions The real-world analysis results showed the promising clinical benefit of savo in NSCLC pts with MET alterations and the acceptable safety. Follow-up of these pts are still ongoing.

The secondary objective is to assess the efficacy through Progression-Free Survival (PFS), Duration of Response (DoR), Disease Control Rate (DCR), Overall Survival (OS), 12 months OS rate using investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The exploratory objective is to assess efficacy in the MET-high (in 90% tumor cells IHC 3+) population.

Improvements with tepotinib vs comparators were also seen in VISION pts overall and pts in Asia, regardless of T+ status. Conclusions Based on available evidence (with limited capmatinib subgroup size), the MAICs show no clinically relevant differences in ORR and trends for longer PFS and/or OS with tepotinib vs savolitinib, gumarontinib, or capmatinib in pts in Asia in 1L and 2L+.

Safety (adverse events, vital signs, ECG, hematology and biochemistry parameters) will also be reported. The first patient was enrolled onto the study on 28 October 2021.

P2, N=44, Recruiting, Guangdong Association of Clinical Trials | Not yet recruiting --> Recruiting

Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.

P2, N=60, Recruiting, AstraZeneca | Trial completion date: May 2024 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P2; Active, not recruiting --> Terminated; inadequate accrual of subjects

FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.

Treatment with type 2 (cabozantinib) or type 1 (crizotinib, capmatinib, savolitinib) MET TKIs blocked growth of SJ-GBM2 cells with IC50 values of 0.3, 0.2, 0.1 and 0.04 μM, respectively, reflecting the sensitivity observed in H1993 and EBC1...Conclusions Our findings indicate MET fusions are widely distributed among tumor types and are sensitive to type 1 and type 2 MET TKIs. Clinical trials evaluating MET inhibitors for patients whose cancers are driven by MET fusions are ongoing.

Comparable efficacy was observed across EGFR mutant (EGFRm) models previously treated with single or multiple lines of first- (gefitinib, erlotinib), second- (afatinib), and/or third-generation (osimertinib) EGFR TKIs. Additionally, TR was observed in 3/3 (100%) of models previously treated with an EGFR TKI in combination with the cMET TKI savolitinib; high cMET expression by IHC was seen in >90% of the cells in these three models. Notably, 4/5 (80%) of models with prior exposure to the ALK TKI crizotinib demonstrated TR... In vivo efficacy of AZD9592 was demonstrated in PDX models across a broad spectrum of NSCLC molecular profiles. These included EGFRwt and EGFRm tumours harbouring varied EGFR mutations; groups with and without prior chemotherapy; and groups with and without prior treatment with ALK, EGFR, and/or cMET TKI. These observations suggest that AZD9592 may provide clinical benefit in areas of unmet need, including in patients previously treated with chemotherapy or targeted agents.

To precisely identify patients that could benefit from an additional MET blockade, histologic examination of immunohistochemically (IHC) stained tissue or fluorescence in-situ hybridization (FISH) are being used in clinical trials.Use of computational pathology-based tools like Quantitative Continuous Scoring (QCS) enables precise and accurate quantification of MET expression on tumor cells from IHC, potentially enabling improvements in scoring strategies and assay turnaround time. In a posthoc, exploratory analysis in the SAVANNAH clinical trial, QCS was performed on centrally stained MET IHC slides from patients treated with savolitinib 300mg QD + osimertinib 80mg QD (NCT03778229). In summary, we report the development and application of an image-analysis based computational pathology method for quantification of MET expression. Development and improvements of MET QCS from the SAVANNAH study will continue and be further tested in the SAFFRON [NCT05261399] clinical trial.

The data showed an encouraging efficacy and a tolerable safety profile of savolitinib in 1L treatment for METex14-mutated NSCLC, suggesting a potential use of 1L treatment with savolitinib for this patient population.

No abstract available

Finally, spheroid lung cancer cells expressing MET variants showed high sensitivity to savolitinib. Meanwhile, we are testing the cell response to two additional MET target drugs. Notably, cells expressing novel variants showed a more sensitive response to the drug, even more than those cells expressing the actionable and well-known MET exon 14 skipping variant, for which drugs had been indicated.ConclusionAs South American patients experience 7% of MET variants compared to the 3% of MET alterations in the US, Europe, and Asia, broadening the prescription of MET inhibitors could open more personalized therapy options.

P3, N=220, Recruiting, AstraZeneca | Trial primary completion date: Sep 2025 --> May 2025

No abstract available

The combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset.

Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination anti-tumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.

In METex14 skipping NSCLC patients, the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.

P2, N=75, Recruiting, Hutchison Medipharma Limited | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Dec 2024 --> Apr 2025