crizotinib and Kidney-Neoplasms

MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.. We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.. Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.. Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.. National Institutes of Health and National Cancer Institute.

Topics: Aged; Anilides; Canada; Carcinoma, Renal Cell; Crizotinib; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazines; Pyridines; Sunitinib; Triazines; United States

The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.. Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.. This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.. No patients in the dose-escalation phase (. The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Crizotinib; Dose-Response Relationship, Drug; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Patient Safety; Tissue Distribution

Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET-).. Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET- sub-cohorts by the sequencing of exons 16-19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety.. Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8-93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8-96.1) and 1-year OS: 75.0% (95% CI: 12.8-96.1). Among 16 MET- patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2-30.2), 1-year PFSR: 27.3% (95% CI: 8.5-50.4) and 1-year OS: 71.8% (95% CI: 41.1-88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8-90.6), 1-year PFSR: 66.7% (95% CI: 5.4-94.5) and 1-year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET- case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%).. Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET- and MET? cases, suggesting the presence of other alterations of MET or alternative pathways.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Crizotinib; Disease-Free Survival; Europe; Female; Gene Amplification; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Mutation; Phenotype; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Time Factors; Treatment Outcome

Translocation renal cell carcinoma (tRCC) is a subtype that occurs predominantly in children and young individuals. Metastatic tRCC occurring in young patients is more aggressive than that occurring in older patients, and there are still no effective therapies. Organoids can mimic original tissues and be assessed by high-throughput screening (HTS). We aimed to utilize patient-derived organoids and HTS to screen drugs that can be repurposed for metastatic tRCC with PRCC-TFE3 fusion.. Tumor tissues were obtained from treatment-naïve metastatic tRCC patients who underwent surgery. Histopathology and fluorescence in situ hybridization (FISH) confirmed the tRCC. Organoids derived from the dissected tissues were cultured and verified by FISH and RNA-seq. HTS was performed to seek promising drugs, and potential mechanisms were explored by RNA-seq and cell-based studies.. We successfully established a metastatic tRCC organoid with PRCC-TFE3 fusion, a common fusion subtype, and its characteristics were verified by histopathology, FISH, and RNA-seq. An HTS assay was developed, and the robustness was confirmed. A compound library of 1816 drugs was screened. Eventually, axitinib, crizotinib, and JQ-1 were selected for further validation and were found to induce cell cycle arrest and apoptosis. RNA-seq analyses of posttreatment organoids indicated that crizotinib induced significant changes in autophagy-related genes, consistent with the potential pathogenesis of tRCC.. We established and validated organoids derived from tissues dissected from a patient with metastatic tRCC with PRCC-TFE3 fusion and achieved the HTS process for the first time. Crizotinib might be a targeted therapy worthy of exploration in the clinic for metastatic tRCC with PRCC-TFE3 fusion. Such organoid and HTS assays may represent a promising model system in translational research assisting in the development of clinical strategies.

Topics: Aged; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carcinoma, Renal Cell; Crizotinib; Humans; In Situ Hybridization, Fluorescence; Kidney Neoplasms; Oncogene Proteins, Fusion; Organoids; Translocation, Genetic

Translocation renal cell carcinoma (TRCC) is a rare form of RCC affecting mostly children and young adults with the occurrence of only 1-5% of all renal cell carcinomas. These carcinomas are associated with different translocations on a short arm of chromosome X in the region 11.2, which results in genetic modification of the p arm containing the transcription factor E3 gene.. Herein we report a case of a patient who was dia-gnosed with TRCC with c-Met overexpression and was treated with multiple targeted therapy agents and immunotherapy.. A 28-year old woman without a significant past medical history underwent left sided total nephrectomy for TRCC. Seven months later, she developed systemic relapse and was treated with multiple lines of targeted therapy including sunitinib, everolimus, sorafenib, crizotinib, and pazopanib as well as with anti-PD-L1 antibody nivolumab, with stable disease as a best response. The most pronounced disease stabilization was achieved with sorafenib, which lasted 18 months. The patient died 81 months after initial dia-gnosis and 74 months from the dia-gnosis of metastatic disease.. Improved survival observed in our patient could be related to the effectivity of tyrosine-kinase inhibitors, but notm-TOR inhibitors, even though disease stabilisation was observed as a best response. Identification of new treatment targets are warranted in this rare disease.

Topics: Adult; Antineoplastic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carcinoma, Renal Cell; Chromosomes, Human, X; Crizotinib; Disease Progression; Everolimus; Fatal Outcome; Female; Humans; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Nivolumab; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrimidines; Sorafenib; Sulfonamides; Sunitinib; Tomography, X-Ray Computed

Crizotinib is a tyrosine kinase inhibitor that has been found to be effective in the treatment of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer. This targeted cancer therapy agent has been shown to have superior efficacy over standard chemotherapy in this small subset of lung cancer patients. An adverse effect of this drug therapy is the development of complex renal cysts. Here, we present a case of a 68-year-old patient with non-small cell lung cancer on Crizotinib therapy who developed complex bilateral renal cysts. It is important to recognize this drug-related complication in order to avoid mistaking it for disease progression, primary renal malignancy, or renal infection.

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Kidney Diseases, Cystic; Kidney Neoplasms; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples.. Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction.. ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes.. High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Kidney Neoplasms; Lactams; Lactams, Macrocyclic; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Middle Aged; Mutation; Piperidines; Pyrazoles; Xenograft Model Antitumor Assays

Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect.. Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models.. By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation.. These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683-94. ©2016 AACR.

Topics: A549 Cells; Animals; Carcinoma, Renal Cell; Cell Line; Cell Line, Tumor; Crizotinib; HEK293 Cells; HT29 Cells; Humans; Immunoassay; Indazoles; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Small Molecule Libraries; Stomach Neoplasms; Sulfonamides; Sulfones; Xenograft Model Antitumor Assays

Alternative pathways to the VEGF, such as hepatocyte growth factor or HGF/c-met, are emerging as key players in tumor angiogenesis and resistance to anti-VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting the VEGF and c-met pathways in clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O tumor pieces and treated with either a selective VEGF receptor tyrosine kinase inhibitor, axitinib (36 mg/kg, 2×/day); a c-met inhibitor, crizotinib (25 mg/kg, 1×/day); or combination. We further tested this drug combination in a human ccRCC patient-derived xenograft, RP-R-01, in both VEGF-targeted therapy-sensitive and -resistant models. To evaluate the resistant phenotype, we established an RP-R-01 sunitinib-resistant model by continuous sunitinib treatment (60 mg/kg, 1×/day) of RP-R-01-bearing mice. Treatment with single-agent crizotinib reduced tumor vascularization but failed to inhibit tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the sunitinib-resistant tumors. In contrast, axitinib treatment was effective in inhibiting angiogenesis and tumor growth in both models, with its antitumor effect significantly increased by the combined treatment with crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first- and second-line setting.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Male; Mice; Mice, SCID; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrroles; Sunitinib; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Biopsy; Carcinoma, Renal Cell; Crizotinib; Disease Progression; Drug Substitution; Humans; Immunohistochemistry; Kidney Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrrolidinones; Quinolines; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Novel personalized therapeutic approaches are urgently needed for patients with metastatic clear cell renal cell carcinoma (ccRCC).. We combined the development of a primary patient-derived ccRCC cell line with a phenotypic drug screen consisting of 101 approved anticancer compounds.. We identified the MNNG HOS transforming gene (MET)-anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitor crizotinib as the top hit of our drug screen, whereas compounds targeting the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) pathway showed no or only minor in vitro activity. Among the known major crizotinib targets MET, ALK, and ROS-1, only MET was expressed in our ccRCC cell line. Subsequent sequence analysis revealed a heterozygous R988C mutation of the MET gene and a VHL deletion in both the primary tumor and the tumor-derived ccRCC cell line. However, we were unable to show an activation of MET and, further, MET knockdown did not result in increased apoptosis or cytotoxicity. Therefore, our results suggest that MET R988C does not function as a major oncogenic driver mutation but rather represents a sequence variant. However, we provide evidence that the cytotoxic effect of crizotinib in our cell line model correlates with its ability to inhibit P-glycoprotein (ABCB1)-associated transport functions.. Our study shows that a phenotypic screen of a patient-derived tumor cell line can identify compounds with antitumor activity but with an unexpected mode of action. Our results underscore that target validation and phenotype-genotype correlations remain a major experimental challenge. The implications of our findings for a personalized management of patients with cancer are discussed.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Crizotinib; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genotype; Humans; Immunoblotting; Kidney Neoplasms; Molecular Targeted Therapy; Mutation; Phenotype; Precision Medicine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference