title: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. Phase II Trial and Correlative Genomic Analysis of Everolimus Plus Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma. Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma. A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma
abstract: PURPOSE Foretinib is an oral multikinase inhibitor targeting MET , VEGF , RON , AXL , and TIE-2 receptors . Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma ( PRCC ) . We aim ed to evaluate the efficacy and safety of foretinib in patients with PRCC . PATIENTS AND METHODS Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib : cohort A , 240 mg once per day on days 1 through 5 every 14 days ( intermittent arm ) ; cohort B , 80 mg daily ( daily dosing arm ) . Patients were stratified on the basis of MET pathway activation ( germline or somatic MET mutation , MET [ 7q31 ] amplification , or gain of chromosome 7 ) . The primary end point was overall response rate ( ORR ) . RESULTS Overall , 74 patients were enrolled , with 37 in each dosing cohort . ORR by Response Evaluation Criteria in Solid Tumors ( RECIST ) 1.0 was 13.5 % , median progression-free survival was 9.3 months , and median overall survival was not reached . The presence of a germline MET mutation was highly predictive of a response ( five of 10 v five of 57 patients with and without germline MET mutations , respectively ) . The most frequent adverse events of any grade associated with foretinib were fatigue , hypertension , gastrointestinal toxicities , and nonfatal pulmonary emboli . CONCLUSION Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations Purpose The decreased effectiveness of single-agent targeted therapies in advanced non-clear cell renal cell carcinoma ( ncRCC ) compared with clear cell renal cell carcinoma ( RCC ) supports the study of combination regimens . We evaluated the efficacy of everolimus plus bevacizumab in patients with metastatic ncRCC . Patients and Methods In this single-center phase II trial , treatment-naive patients received everolimus 10 mg oral once per day plus bevacizumab 10 mg/kg intravenously every 2 weeks . The primary end point was progression-free survival ( PFS ) at 6 months . Correlative analyses explored c and i date tissue biomarkers through next-generation sequencing . Results Thirty-five patients were enrolled with the following histologic subtypes : chromophobe ( n = 5 ) , papillary ( n = 5 ) , and medullary ( n = 2 ) RCC and unclassified RCC ( uRCC , n = 23 ) . The majority of patients had papillary growth as a major component ( n = 14 ) . For 34 evaluable patients , median PFS , overall survival , and objective response rate ( ORR ) were 11.0 months , 18.5 months , and 29 % , respectively . PFS varied by histology ( P < .001 ) , and ORR was higher in patients with significant papillary ( seven of 18 ) or chromophobe ( two of five ) elements than for others ( one of 11 ) . Presence of papillary features were associated with benefit , including uRCC , where it correlated with ORR ( 43 % v 11 % ) , median PFS ( 12.9 v 1.9 months ) , and overall survival ( 28.2 v 9.3 months ; P < .001 ) . Several genetic alterations seemed to segregate by histology . In particular , somatic mutations in ARID1A were seen in five of 14 patients with papillary features but not in other RCC variants . All five patients achieved treatment benefit . Conclusion The study suggests efficacy for this combination in patients with ncRCC characterized by papillary features . Distinct mutational profiles among ncRCCs vary according to specific histology Treatment options for metastatic clear cell renal cell carcinoma ( ccRCC ) have evolved markedly over the past decade , with multiple targeted therapies approved for the disease . In contrast , little improvement has been made in the management of metastatic non-clear cell RCC ( nccRCC ) . Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities , including but not limited to papillary , chromophobe , and sarcomatoid RCC . To date , prospect i ve studies have largely explored treatments for ccRCC ( e.g. , VEGF- and mTOR-directed therapies ) in trials that aggregate non-clear cell histologies . However , the studies do not acknowledge the varying biology of each non-clear cell subtype . Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies . An example of this is SWOG 1500 , a r and omized phase II study that will compare a  VEGF-inhibitor  to one of three  MET-directed therapies  in patients with metastatic papillary RCC . Until the biologic diversity of nccRCC is appreciated , outcomes are likely to remain dismal Lessons Learned Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from pre clinical models . Because of toxicity and lack of efficacy , BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma . Background . Allosteric inhibitors of the mammalian target of rapamycin complex 1 ( mTORC1 ) are approved for advanced renal cell carcinoma ( RCC ) . Pre clinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase ( PI3 K ) and mTOR kinase may establish superior anticancer effect . We aim ed to establish safety for BEZ235 , a potent inhibitor of both PI3 K and mTOR , in advanced RCC . Methods . Patients with advanced RCC who had previously failed st and ard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity . Primary endpoints were to identify the maximally tolerated dose ( MTD ) and to determine the recommended dose for the phase II study . Results . The study was terminated early because of high incidence of dose-limiting toxicities ( DLTs ) across all dose levels tested . Ten patients were treated with BEZ235—six  with clear cell and four with non-clear cell subtypes . Five of these patients suffered DLTs : 2 of 2 patients in the original 400 mg b.i.d . cohort , 1 of 6 in the 200 mg b.i.d . cohort , and 2 of 2 in the 300 mg b.i.d . cohort . DLTs included fatigue , rash , nausea and vomiting , diarrhea , mucositis , anorexia , and dysgeusia .  Five patients were evaluable for response : Two had stable disease as best response , and three had progressive disease . Conclusion . BEZ235 twice daily result ed in significant toxicity without objective responses ; further development of this compound will not be pursued in this disease
target: EVIDENCE SYNTHESIS The systematic review showed an absence of evidence for treating RKCs , with data only supporting sunitinib or MET inhibitors for some specific subtypes .
  PATIENT SUMMARY Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients , despite little evidence from r and omized trials .
  Molecular characterization of tumors to stratify patients may improve outcomes .
background: CONTEXT The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas ( RCCs ) , which showed a substantial lack of evidence for management recommendations .
  OBJECTIVE To improve the outcomes of patients with rare kidney cancers ( RKCs ) , we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways , involving key stakeholders with a global perspective to generate recommendations .