Medical Conference Updates – Day Two of Two

This Blog Post contains a summary of presentations from Day 2 of the International Kidney Cancer Symposium in Chicago (Oct 14/15 2011). Please note: while these notes have been prepared by a physician attending the conference on behalf of KCC, please refer to your oncologist for any specific questions regarding your kidney cancer care and treatment.

Day 2, Discussions were on several key topics. Full presentations may be accessed at the following link: http://kca.omnibooksonline.com/chicago2011/index.html

1) Molecular Insights in RCC

FOXo Transcription Factors in mTORC1, Dr.Boyi Gan:

    • FoxOs are a kind of transcription factor (signaling factor, which transmits signals to proteins of cell to do certain tasks)
    • Mammals possess FoxO1, FoxO3, FoxO4, FoxO6
    • 1/3/6 are regulated by P13/AKT signaling
    • Broad somatic deletion of all 3 Fox0s, is associated with cancer prone conditions such as hemangiomas and lymphomas
    • Inactivation of FoxO & TSC1 dramatically drives renal tumour progression
    • FoxOs are extininguished in many renal cell tumour types
    • Myc signaling is the key downstream effector of FoxO, in the regulation of renal tumours

Future research in targeted therapies should include a combination of mTOR & FoxO targets in RCC

Gene Polymorphisms in predicting efficacy and safety with Sunitinb, Dr. Astrid van der Veldt

  • Approximately 35% of metastatic RCC patients do not benefit from Sutent therapy
  • Sutent therapy is associated with a wide range of toxicities
  • Pre-treatment markers to help identify patients which will benefit from Sutent therapy are needed.
  • Study included 290 RCC patients from 6 Dutch centers
  • 37 polymorphisms in 15 candidate genes were analyzed.

Concluded that Pharmakokinetic polymorphisms are independent predictive factors of PFS (Progression Free survival) in Sutent treated patients. Polymorphisms in genes encoding metabolic enzymes, efflux transporters and drug targets are associated with Sutent toxicities.

Clinical Applications of genomic Classification in RCC, Dr. Brian Rini, Cleveland Clinic, Ohio
Genetic mutations in mRCC continue to evolve:

  • VHL (Von Hippel Lindau) inactivation does not seem to be a predictive factor, at present
  • PBRM1 & related mutations, recently discovered, clinical significance is yet to be made clear
  • SNPs (Singe nucleotide polymorphisms) have promise in RCC, further work is required
  • RNA gene expression in RCC is in initial stages of discovery

Clinical relevance is being studied

2) Surgery in treatment naïve RCC
Role of Cytoreductive Nephrectomy, Dr.Gerald Mickisch

  • Cytoreductive nephrectomy was well established in the era of immunotherapy with Interferon in RCC.
  • The role of Cytoreductive nephrectomy in the era of targeted therapy is yet to be determined. Clinical trials are underway and their outcome is eagerly awaited.
  • Meanwhile cytoreductive nephrectomy continues to be standard of care in RCC.

Systemic Therapy is the best initial treatment, Dr. Erich Jonasch, MD Anderson cancer Center
A significant number of patients are not candidates for upfront nephrectomy.
In these patients initial therapy and careful monitoring, enables better planning in the time of nephrectomy
This type of planning is especially helpful, if the initial tumour is unresectable, and then targeted therapy makes the tumour smaller and resectable.

3) Systemic Therapy, Dr. Bernard Escudier
Many combinations have been tested, many proven to have a lot of toxicities and very limited benefit

  • TKIs (Sutent & Sorafenib) & Avastin combination is too toxic
  • mTOR inhibitors (Afinitor & Torisel) & TKIs (Sutent & Sorafenib) combination has very limited benefit
  • Tivozaninb & Temsirolimus combination has shown some benefit in 10 patients, in a study, at their clinic
  • mTOR inhibitors (Torisel & Avastin) combination, shows some hope. Side effects are manageable. Efficacy is not outstanding
  • TORAVA study, showed best efficacy in the Avastin + IFN arm (PFS 16.8 months) versus the Sutent only arm (PFS 8.2 months)
  • Avastin + Afinitor combination showed PFS of 7.1 months and OS (Overall Survival) of 14.5 months. Data are good, but we are not sure, if they are better than Afinitor alone.
  • Large Phase 3 study, INTORACT, 2 arms (Avastin + Torisel versus Avastin + IFN) should report soon.
  • RECORD 2 (Avastin + IFN versus Afinitor +Avastin), Phase 2 study should report soon.
  • Phase 2, first line study of Sorafenib +/- AMG 386 ongoing
  • Phase 2, first line study of Sutent +/- AMG 386 ongoing

Other molecules being studied:

  • AGS-003: RNA loaded dendritic cell based vaccine
  • IMA 901: based on 10 naturally presented tumour associated peptides
  • Tremilimumab+ Sutent

Intermittent VEGF inhibition, Dr. Viktor Grunwald
Two studies enrolling 12 & 36 patients each were discussed. Patient were from European centers. In all patients were on different targeted therapies, and all had their treatment discontinued and then that patients were observed.
The studies showed:

  • Complete clearance of tumour is rare in RCC
  • Tumour relapse was seen in 67% of patients, after a median of 7 months, but long term DFS (Disease free survival) may occur
  • Clinical predictors of DFS could not be determined
  • Sensitivity to targeted treatments is retained at the time of relapse
  • Stopping of treatment remains a valuable option in selected RCC patients

Current Strategies to Overcome resistance, Dr. Thomas Hutson
Current Strategies include:

  • Increase dose of same targeted agent
  • Switch to another VEGF pathway blocker
  • Sutent after avastin
  • Axitinib after front line therapy
  • Axitinib after sorafenib
  • Drug holiday and Re-challenge: best demonstrated with Sutent
  • Switch to mTOR inhibitor, either alone or in combination

Newer therapies:

  • Fibroblast Growth Factor receptor is a target in RCC
  • TKI258 (Dovitinib), has shown promising activity in Phase 2
  • Phase 3 trial is ongoing: Dovitinib versus Sorafenib, after progression on VEGF targeted therapy
  • BNC 105 P produces necrosis in cell that express high level of mTOR
  • Ongoing study of BNC105 P in combination with Afinitor versus Afinitor alone

Problem of primary resistance to targeted therapies, which occurs in 20% of RCC patients remains a problem and is not clearly understood.

4) Side Effects
Nursing Issues in Toxicity management: Laura Wood, RN
Key issues nurses deal with on a daily basis are;

  • Drug Interactions
  • Chronic Kidney disease
  • Nutritional support
  • Drug interactions:

Common websites, which can be used to gain information on Drug Interactions, are:
• Lexicomp: http://www.kexi.com
• Up to date: http://www.uptodate.com
• Drug Information on Line: http://www.drugs.com
• Indiana University division of Clinical Pharmacy
It is very important to tell patients to keep a record of all medication they have taken, with start and stop dates. Insist on showing the list to the nurse at each visit.
Chronic Kidney Disease (CKD): Assessment is done by the Glomerular Filtration rate, Cockcroft Gault formula & estimated Glomerular Filtration rate.

If any sign of CKD, remedial measure should be taken immediately
Gastrointestinal Toxicity Management: Of note are:
• Diarrhea
• Nausea & Vomiting
• Mucositis
• Taste Changes
• Anorexia
Early management of diarrhea with loperamide, dietary management & lomotil is highly recommended.

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