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Metastatic Renal Cell Carcinoma: Treatment of Non-Clear Cell RCC

Metastatic Renal Cell Carcinoma: Treatment of Non-Clear Cell RCC. Sumanta Kumar Pal, M.D. Assistant Professor, Department of Medical Oncology & Experimental Therapeutics Co-Director, Kidney Cancer Program City of Hope Comprehensive Cancer Center May 13, 2017. Non-Clear Cell RCC.

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Metastatic Renal Cell Carcinoma: Treatment of Non-Clear Cell RCC

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  1. Metastatic Renal Cell Carcinoma: Treatment of Non-Clear Cell RCC • Sumanta Kumar Pal, M.D. • Assistant Professor, • Department of Medical Oncology & • Experimental Therapeutics • Co-Director, Kidney Cancer Program • City of Hope Comprehensive Cancer • Center • May 13, 2017

  2. Non-Clear Cell RCC • Other (~5%): • Collecting Duct • Unclassified • Xp11.2 Translocation Sarcomatoid (10-15%)

  3. Non-Clear Cell RCC

  4. Genomics of Papillary RCC • Lessons from TCGA • 161 primary papillary RCC (PRCC) specimens • Type I PRCC: Associated with MET alterations • Type II PRCC • Associated with NRF2-ARE • CDKN2A loss • Stay tuned for update at ASCO 2017 (Pal/Foundation Medicine) • MET alterations much more prevalent in a metastatic population The Cancer Genome Atlas Research Investigators: Comprehensive molecular characterization of papillary renal cell carcinoma. NEJM 499:43-49, 2015

  5. Genomics of Collecting Duct RCC • N = 17 • NF2 GAs (26%) could be associated with everolimus sensitivity • SMARCB1 GAs (20%) could be associated with EZH2 inhibitor sensitivity Pal SK, Choueiri TK, Wang K, Khaira D, Karam JA, Van Allen E, Palma NA, Stein MN, Johnson A, Squillace R, Elvin JA, Chmielecki J, Yelensky R, Yakirevich E, Lipson D, Lin DI, Miller VA, Stephens PJ, Ali SM, Ross JS: Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol, 2015

  6. Genomics of Collecting Duct RCC • 75 year old male with metastatic collecting duct carcinoma • Failed 6 cycles of platinum-based chemotherapy • Comprehensive genomic profiling identified CDKN2A alteration • Patient has had profound radiographic and clinical response to palbociclib Pal et al JCO Precision Oncology 2017 (accepted; in press)

  7. Non-Clear Cell RCC

  8. The Previous Approach

  9. Clinical Management of Non-Clear Cell RCC: ESPN Sunitinib (Standard schedule) Sunitinib (Standard schedule) • mRCC • Non-clear cell histology • ECOG PS 0-1 • Measurable disease • Adequate organ function • No prior systemic therapy • No uncontrolled brain metastasis Crossover Randomization Everolimus (Standard schedule) Everolimus (Standard schedule) • Histologies permitted: Papillary, chromophobe, unclassified, translocation (Xp11.2) and clear-cell with ≥ 20% sarcomatoid features • Projected sample size: 108 patients

  10. Clinical Management of Non-Clear Cell RCC: ESPN No difference in 1st-line PFS

  11. Clinical Management of Non-Clear Cell RCC: ESPN Are these numbers just too small?

  12. Clinical Management of Non-Clear Cell RCC: ESPN • What other data might guide us? ESPN Sunitinib (Standard schedule) Sunitinib (Standard schedule) • mRCC • Non-clear cell histology • ECOG PS 0-1 • Measurable disease • Adequate organ function • No prior systemic therapy • No uncontrolled brain metastasis Crossover Randomization Everolimus (Standard schedule) Everolimus (Standard schedule)

  13. Clinical Management of Non-Clear Cell RCC: RECORD-3 • What other data might guide us? RECORD-3 NEGATIVE RECORD-3 Sunitinib (Standard schedule) Sunitinib (Standard schedule) • mRCC • Clear AND non-clear cell histology • ECOG PS 0-1 • No prior systemic therapy • No uncontrolled brain metastasis Crossover Randomization Everolimus (Standard schedule) Everolimus (Standard schedule)

  14. Clinical Management of Non-Clear Cell RCC: ASPEN • What other data might guide us? ASPEN NEGATIVE x ASPEN Sunitinib (Standard schedule) Sunitinib (Standard schedule) • mRCC • Non-clear cell (papillary, chromophobe and undifferentiated) • N=108 (study completed accrual) Crossover Randomization Everolimus (Standard schedule) Everolimus (Standard schedule)

  15. The Previous Approach • ASPEN • ESPN • RECORD-3 • Across all studies, pts did better with sunitinib v everolimus • How does this apply across subtypes?

  16. A Better Approach Apply rationally selected drugs Papillary Apply rationally selected drugs Sarcomatoid

  17. Clinical Management: Focus on Papillary RCC MET VEGFR P P P P P P P P Sunitinib Pazopanib Axitinib Sorafenib Lenvatinib PI3K Akt/PKB Ras TSC1/2 Raf mTOR Temsirolimus Everolimus S6K1 4E-BP1 elF-4E

  18. Clinical Management: Focus on Papillary RCC MET VEGFR P P P P P P P P Sunitinib Pazopanib Axitinib Sorafenib Lenvatinib PI3K Savolitinib Akt/PKB Ras TSC1/2 Raf mTOR Temsirolimus Everolimus S6K1 4E-BP1 elF-4E

  19. Clinical Management: Focus on Papillary RCC Savolitinib in PRCC (n=111) Choueiri T …. Pal SK (ASCO GU 2017)

  20. Clinical Management: Focus on Papillary RCC MET VEGFR P P P P P P P P Sunitinib Pazopanib Axitinib Sorafenib Lenvatinib PI3K Savolitinib Akt/PKB Ras Crizotinib TSC1/2 Raf mTOR Temsirolimus Everolimus S6K1 4E-BP1 elF-4E

  21. Clinical Management: Focus on Papillary RCC Crizotinib in Type 1 PRCC • Not all Type 1 pts were characterized as having abnormalities in MET • Emphasizes need for understanding MET status Schoffski et al: EORTC CREATE Trial (Reported at AACR 2016)

  22. Clinical Management: Focus on Papillary RCC MET VEGFR P P P P P P P P Sunitinib Pazopanib Axitinib Sorafenib Lenvatinib PI3K Savolitinib Akt/PKB Ras Crizotinib TSC1/2 Raf Cabozantinib mTOR Temsirolimus Everolimus S6K1 4E-BP1 elF-4E

  23. Clinical Management: Focus on Papillary RCC Cabozantinib in PRCC • RENCA reflects ccRCC; ACHN reflects PRCC • Cabozantinib and crizotinib may be more active in PRCC • Preclinical models are being devised Courtesy of Jeremy Jones, PhD

  24. Clinical Management: Focus on Papillary RCC MET VEGFR • What is the optimal strategy for MET inhibition? P P P P P P P P Sunitinib Pazopanib Axitinib Sorafenib Lenvatinib PI3K Savolitinib • Need comparative data! Akt/PKB Ras Crizotinib TSC1/2 Raf Cabozantinib mTOR Temsirolimus Everolimus S6K1 4E-BP1 elF-4E

  25. Clinical Management: SWOG 1500 for mPRCC • PI: S. Pal (City of Hope) • Translational PI: B. Shuch (Yale) • BISQFP funding for genomic characterization • Requires 41 pts/arm  164 pts total* • Assuming 10% ineligibility  180 pts total • Discussion re: Brazilian treatment arm have occurred We need you!

  26. Where does PD-1/PD-L1 inhibition fit in this approach? Apply rationally selected drugs Papillary Apply rationally selected drugs Sarcomatoid

  27. Understanding the biology of PD-L1 in rare subtypes • 11/101 (10.9%) were PD-L1+ in tumor cells: • 2/36 (5.6%) of chromophobe RCC • 5/50 (10%) of papillary RCC • 3/10 (30%) of Xp11.2 translocation RCC • 1/5 (20%) of collecting duct carcinoma • PD-L1+ in tumor cells was significantly associated with higher stage and grade, and shorter OS • 57/101 (56.4%) were PD-L1+ in TIMC: • 13/36 (36.1%) of chromophobe RCC • 30/50 (60%) of papillary RCC • 9/10 (90%) of Xp11.2 translocation RCC • 5/5 (100%) of collecting duct carcinoma Negative Control Positive Control Papillary +TC Chromophobe +TC Xp11.2 translocation +TIMC Xp11.2 translocation +TC TC=Tumor cells, TIMC=Tumor Infiltrating Mononuclear Cells Choueiri TK, Fay AP, Gray KP, Callea M, Ho TH, Albiges L, Bellmunt J, Song J, Carvo I, Lampron M, Stanton ML, Hodi FS, McDermott DF, Atkins MB, Freeman GJ, Hirsch MS, Signoretti S. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol. 2014 Nov;25(11):2178-84

  28. Understanding the activity of PD-L1 in rare subtypes Atezolizumab Adjuvant (An SUO-CTC Trial) • Principal Investigators: S. Pal (COH), R. Uzzo (Fox Chase), Axel Bex (Netherlands) • Sarcomatoid features permitted • A possibility for LARCG? We need you!

  29. Summary Emerging biological data regarding rare subtypes of RCC Existing studies have lumped multiple subtypes together Emerging studies will use targeted drugs or immunotherapy in relevant subtypes

  30. Thank you Mark your calendars for the 2017 City of Hope – Brazil Collaboration Meeting December 15 in Los Angeles, California Steering Committee: Dr. Paulo Bergerot (Co-Chair) Dr. Manuel Maia (Co-Chair) Dr. Steno Zequi Dr. Rafael Brandao Dr. Gilberto Lopes Dr. Gustavo Fernandes E-mail spal@coh.org for more information • City of Hope / Beckman Research Institute • Jeremy Jones, PhD (Molecular Pharm) • Paul Frankel, PhD (Biostatistics) • Xiwei Wu, PhD (Genomics) • Marcin Kortylewski, PhD (Immunology) • Stephen Forman, MD (Immunology) • Clayton Lau, MD (Urology) • Kevin Chan, MD (Urology) • Ravi Salgia, MD (Medical Onc) • Przemyslaw Twardowski, MD (Med Onc) • Jacob Berlin, PhD (Nanotechnology) • External Collaborators • Dr. Stenio Zequi • Dr. Gilberto Lopes • @montypal

  31. Thank you • City of Hope / Beckman Research Institute • Jeremy Jones, PhD (Molecular Pharm) • Paul Frankel, PhD (Biostatistics) • Xiwei Wu, PhD (Genomics) • Marcin Kortylewski, PhD (Immunology) • Stephen Forman, MD (Immunology) • Clayton Lau, MD (Urology) • Kevin Chan, MD (Urology) • Ravi Salgia, MD (Medical Onc) • Przemyslaw Twardowski, MD (Med Onc) • Jacob Berlin, PhD (Nanotechnology) • External Collaborators • Dr. Stenio Zequi • Dr. Gilberto Lopes • @montypal City of Hope – AC Camargo – LARCG Fellowship Sponsored by City of Hope 4 residents per year (from AC Camargo and LARCG) 2 month rotation at City of Hope Experience in urologic oncology Lodging and flights covered

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