Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer

Choueiri, Toni K.; Plimack, Elizabeth R.; Arkenau, Hendrik Tobias; Jonasch, Eric; Heng, Daniel Y.C.; Powles, Thomas; Frigault, Melanie M.; Clark, Edwin; Handzel, Amir A.; Gardner, Humphrey; Morgan, Shethah; Albigès, Laurence; Pal, Sumanta K.

doi:10.1200/jco.2017.72.2967

Cited by 152 publications

(112 citation statements)

References 37 publications

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“…Savolitinib is a potent small-molecule reversible MET kinase inhibitor that inhibits MET kinase with an IC 50 of 4 nmol/L in MET-amplified cancer cell lines. A phase II trial of savolitinib monotherapy in 44 patients with METaltered papillary renal cell carcinoma showed very promising results, including 8 PRs (32). Our savolitinib monotherapy arm met the prespecified 6-week PFS rate, indicating that this treatment is worthy of phase III exploration in the METamplified subset of patients with gastric cancer (3%-5%; refs.…”

Section: Discussionmentioning

confidence: 71%

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

et al. 2019

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The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RIC-TOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. SIGNIFICANCE:Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility.

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Section: Discussionmentioning

confidence: 71%

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

et al. 2019

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“…Copy‐number alterations were detected in 81% of type 1 PRCC patients and in 46% of type 2 PRCC patients. Savolitinib, a specific MET inhibitor, was effective for MET ‐driven PRCC . The mPFS was 6.2 months in MET ‐driven PRCC and 1.4 months in MET ‐independent diseases ( P < 0.001).…”

Section: Papillary Rccmentioning

confidence: 99%

Recent advances in the systemic treatment of metastatic non‐clear cell renal cell carcinomas

Ito

2019

Int J of Urology

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Abbreviations & Acronyms AA = anti-angiogenic ALK = anaplastic lymphoma kinase ARE = anti-oxidant responsive element ccRCC = clear cell renal cell carcinoma CDC = collecting duct carcinoma ChRCC = chromophobe renal cell carcinoma CR = complete response CTLA-4 = cytotoxic Tlymphocyte antigen 4 EV = everolimus FH = fumarate hydratase IMDC = International Metastatic Renal Cell Carcinoma Database Consortium INF-a = interferon-a IO drug = immuno-oncology drug ISUP = International Society of Urological Pathology LOH = loss of heterozygosity MET+ = MET mutation+ METÀ = MET mutationÀ MiT = microphthalmiaassociated transcription mOS = median overall survival mPFS = median progressionfree survival mPRCC = metastatic papillary renal cell carcinoma mRCC = metastatic renal cell carcinoma MSKCC = Memorial Sloan-Kettering Cancer Center mTORi = mammalian target of rapamycin inhibitor MTSCC = mutinous tubular and spindle cell carcinoma NA = not availableAbstract: There is still no standard treatment for non-clear cell renal cell carcinomas. Sunitinib is the most examined drug because of its effectiveness in retrospective studies and clinical trials, and is the preferred first-line drug in the National Comprehensive Cancer Network guideline. Temsirolimus is an option as a first-line drug, especially for poor-risk non-clear cell renal cell carcinoma patients. Everolimus, pazopanib, axitinib and nivolmab might also be viable options. Clinical trials are still required to gather evidence regarding non-clear cell renal cell carcinoma treatment. Because each non-clear cell renal cell carcinoma has a different genetic background and molecular features, specific treatment for each non-clear cell renal cell carcinoma should be established. From the results of a Japanese multicenter study, tyrosine kinase inhibitors might be better used for metastatic papillary renal cell carcinoma in both first-and second-line settings. Both tyrosine kinase inhibitors and mammalian target of rapamicin inhibitors are effective for metastatic chromophobe renal cell carcinoma, but the preferred first-line drug has not been determined. Platinum-based chemotherapies are currently recommended for metastatic collecting duct carcinoma, and anti-angiogenic drugs are effective in some cases. Tyrosine kinase inhibitors, especially sunitinib, appear to be effective for X11.2 translocation renal cell carcinoma among the microphthalmia-associated transcription family of translocation renal cell carcinomas. Evidence is still lacking regarding the treatment for other rare non-clear cell renal cell carcinomas. Appropriate sequential therapies using antivascular endothelial growth factor therapies, mammalian target of rapamicin inhibitors and immuno-oncology drugs should be established for each nonclear cell renal cell carcinoma. None declared. References 1 Ito K. Recent advances in the systemic treatment of metastatic non-clear cell renal cell carcinoma. Int. J. Urol. 2019; 26: 868-77. 2 Teishima J, Inoue S, Hayashi T, Matsubara A. Current status of prognostic factors in ...

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“…Savolitinib (or volitinib) monotherapy has been investigated in patients with advanced papillary renal cell cancer [80]. For NSCLC, preliminary results in combination therapy are available [81].…”

Section: Brief Reflection On Other Met-tkis In Developmentmentioning

confidence: 99%

Capmatinib for the treatment of non-small cell lung cancer

Vansteenkiste

Kerkhove

Wauters

et al. 2019

Expert Review of Anticancer Therapy

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Introduction: Activation of the MET pathway through MET amplifications or mutations is present in 3-4% of stage IV non-squamous non-small cell lung cancers (NSCLC). High MET amplifications and exon 14 skipping mutations are associated with poor prognosis: new treatments are needed for these patients. Capmatinib is a highly selective, potent small-molecule MET inhibitor with antitumor activity in NSCLC in vitro and in vivo. Areas covered: This article provides an overview of the capmatinib clinical development program in NSCLC, both as monotherapy in NSCLC with a dysregulated MET pathway, and in combination with epidermal growth factor receptor (EGFR) inhibitor therapy in EGFR-mutant NSCLC with MET-based acquired resistance to previous EGFR inhibition. Expert opinion: In the GEOMETRY Mono-1 study, treatment with capmatinib resulted in high response rates in stage IV NSCLC with MET exon 14 skipping mutations, particularly in first line, supporting testing for this biomarker at the time of diagnosis. Durable responses have been reported and results in MET-amplified NSCLC are eagerly anticipated. In EGFR-mutant NSCLC, notable responses have been observed in combination with an EGFR-tyrosine kinase inhibitor (TKI) in case of acquired resistance to EGFR-TKIs based on high MET amplification.

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Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer

Cited by 152 publications

References 37 publications

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

Recent advances in the systemic treatment of metastatic non‐clear cell renal cell carcinomas

Capmatinib for the treatment of non-small cell lung cancer

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