Sequencing of therapies in mrcc Ari Hakimi MD Assistant Professor Urology Service, Department of Surgery MSKCC
Old Paradigm Sequencing approved agents VEGF TKI Sunitinib Pazopanib Axitinib TKI TKI MTORi MTOR inhibitor Everolimus TKI MTORi TKI
NCCN Guidelines for First-Line arcc Agents NCCN Recommendations for First-Line Treatment of arcc (Predominant Clear Cell Histology) MSKCC Risk Category 1 Category 2A Category 2B Pazopanib Axitinib Good/Favorable Sunitinib High-dose IL-2 (for selected patients) Temsirolimus Bevacizumab IFN Sorafenib Pazopanib Intermediate Sunitinib Bevacizumab IFN Axitinib Sorafenib Temsirolimus Poor Temsirolimus --- --- Reference: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Kidney Cancer. V2.2016. National Comprehensive Cancer Network, Inc. 2015.
NCCN Recommendations for Second-Line Treatment of arcc (Predominant Clear Cell Histology) Prior Therapy Category 1 Category 2A Category 2B Axitinib Pazopanib Bevacizumab IFN TKI Cabozantinib Everolimus Sorafenib Sunitinib High-dose IL-2 (for selected patients) Temsirolimus Nivolumab Axitinib Bevacizumab IFN High-dose IL-2 (for selected patients) Cytokine Pazopanib Sorafenib Temsirolimus Sunitinib Reference: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Kidney Cancer. V2.2016. National Comprehensive Cancer Network, Inc. 2015.
Randomized data for TKI pre-treated patients PFS OS RECORD-1 1,2 AXIS 3,4 CheckMate 025 6,7 EVE: 4.9 mo PBO: 1.9 mo EVE: 14.8 mo PBO: 14.4 mo PFS AXI: 6.7 mo SOR: 4.7 mo AXI: 20.1 mo SOR: 19.2 mo PFS NIV: 4.6 mo EVE: 4.4 mo NIV: 25.0 mo EVE: 19.6 mo OS METEOR 8,9 Study 205 10 CAB: 7.4 mo EVE: 3.8 mo mos not reported P 0.0019 PFS LEN/EVE: 14.6 mo LEN: 7.4 mo EVE: 5.5 mo LEN/EVE: 25.5 mo LEN: 18.4 mo EVE: 17.5 mo PFS/OS by prior therapy 1 prior TKI: 5.4 vs 1.9 mo 2 prior TKIs: 4.0 vs 1.8 mo 1 prior TKI: 4.8 vs 3.4 mo 2 prior TKIs: no data 1 prior anti-vegf (any): 23.6 vs 19.9 mo 2 prior anti-vegf (any): NE vs 18.4 mo Prior SUN: 9.1 vs 3.7 mo Prior PD-1/L1: N.E. vs 4.1 mo No prior PD-1/L1: 7.4 vs 3.9 mo Not reported CR: 0% vs 0% CR: 0% vs 0% CR: 1% vs 1% CR: 0% vs 0% CR: 2% vs 0% vs 0% Tumor responses PR: 1.8% vs 0% PR: 19% vs 9% PR: 24% vs 5% PR: 21% vs 5% PR: 41% vs 27% vs 6% SD: 66.8% vs 32.4% SD: 50% vs 54% SD: 34% vs 55% SD: 62% vs 62% SD: 41% vs 52% vs 62% References: 1. Motzer RJ et al. Cancer. 2010;116(18):4256-4265. 2. Calvo E et al. Eur J Cancer. 2012;48:333-339. 3. Rini BI et al. Lancet. 2011;378(9807):1931-1939. 4. Motzer RJ et al. Lancet Oncol. 2013;14(6):552-562. 5. Motzer RJ et al. Ann Oncol. 2016;27(3):441-448. 6. Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813 7.. Motzer RJ et al. Poster presented at: 2016 Genitourinary Cancers Symposium. J Clin Oncol 34, 2016 (suppl 2S; abstr 498). 8. Choueiri TK et al. N Engl J Med. 2015;373(19):1814-1823. 9. Escudier BJ et al. Poster presented at: 2016 Genitourinary Cancers Symposium. J Clin Oncol 34, 2016 (suppl 2S; abstr 499). 10. Motzer RJ et al. Lancet Oncol. 2015;16(15):1473-1482.
New Paradigms 2016 VEGF TKI MTOR inhibitor CPI VEGF Cabo LEV
Predictive Biomarkers Currently Lacking Serum markers - inconsistent Genomic markers inconclusive/limited Immune markers - inconclusive/limited
VEGF TKI - biomarkers Winer, Motzer and Hakimi UCNA 2016
RECORD-3 - Design and Results 9 SC RE E N R A N D O M I Z E 1 : 1 Everolimus n=238 Sunitinib n=233 1st Line Crossover upon progression Sunitinib n=108 Everolimus n=99 2nd Line Study endpoints Primary PFS 1 st -line noninferiority of everolimus to sunitinib Key Secondary PFS combined OS Safety Primary endpoint analysis: Median PFS first-line (mo) Everolimus Sunitinib OS, overall survival; PFS, progression-free survival. 7.9 10.7 Hazard Ratio = 1.4 2-Sided 95% CI [1.2 1.8] Motzer RJ et al. J Clin Oncol. 2014 Hsieh et al ASCO 2015
Mutation Frequency by MSKCC Risk Group 10 PBRM1 SETD2 BAP1 Favorable (n=103) 40% 22% 14% Intermediate (n=132) 42% 29% 19% Poor (n=25) 40% 40% 24% 0% 25% 50% 0% 25% 50% 0% 25% 50% Percent Mutation Hsieh et al ASCO 2015
Survival Probability PBRM1 Mutation Status and First-line PFS 11 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 Months Censored MT PBRM1 Everolimus WT MT PBRM1 Sunitinib WT Treatment Population n n Events PFS (months) Median (95%CI) Hazard Ratio (95% CI) Log-rank p-value* Everolimus Sunitinib WT MT WT MT 79 49 75 57 64 35 48 41 5.3 (3.1-8.3) 11.5 (8.1-16.2) 8.3 (7.1-13.9) 11.0 (8.4-13.4) Hazard ratio (95% CI) estimated using Cox model stratified by MSKCC risk groups, with treatment, baseline LDH, number of metastatic sites and histology as covariates. *log-rank test p-values not adjusted for multiple testing 0.6 (0.4-0.9) 0.003 0.9 (0.6-1.5) 0.413 Hsieh et al ASCO 2015
Survival Probability 12 BAP1 Mutation Status and First-line PFS 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 Months Censored MT BAP1 Everolimus WT MT BAP1 Sunitinib WT Treatment Population n n Events PFS (months) Median (95%CI) Hazard Ratio (95% CI) Log-rank p-value* Everolimus WT MT 105 23 79 20 10.2 (6.5-12.0) 5.3 (2.9-8.1) 1.9 (1.1-3.2) 0.018 Sunitinib WT MT 110 22 74 15 11.3 (8.4-13.8) 8.1 (5.7-11.3) 1.7 (0.9-3.1) 0.068 Hsieh et al ASCO 2015
Survival Probability 13 KDM5C Mutation Status and First-line PFS 1.0 0.8 Censored 0.6 0.4 MT KDM5C Everolimus WT MT KDM5C Sunitinib WT 0.2 0.0 0 10 20 30 Months Treatment Population n n Events PFS (months) Median (95%CI) Hazard Ratio (95% CI) Log-rank p-value* Everolimus WT MT 117 11 89 10 8.1 (5.4-10.5) 9.8 (2.2-16.6) 1.0 (0.5-1.9) 0.424 Sunitinib WT MT 111 21 78 11 8.4 (8.1-11.3) 20.6 (12.4-27.3) 0.6 (0.3-1.3) 0.051 Hsieh et al ASCO 2015
Using mutations to predict response Voss et al CCR 2014
Using mutations to predict response Voss et al CCR 2014
Kwitikowski et al CCR 2015
MET alterations and Foratenib Choueiri et al JCO 2012
ccrcc Distinctly infiltrated Yoshihara et al Nat Comm 2013
ccrcc Distinct cytotoxic infiltration Rooney et al. Cell 2015
ccrcc responsive to immunotherapy despite low mutational load Herbst et al, Nature, 2014
Exonic Missense Mutations E x o n ic M is s e n s e M u ta tio n s # n o n s y n o n y m o u s m u ta tio n s /tu m o r Exonic Missense Mutations Candidate biomarkers for CPI therapies: mutational burden p = 0.0 0 2 4 p = 0.0 0 0 8 1 2 0 0 3 0 0 0 1 0 0 0 8 0 0 6 0 0 2 0 0 0 1 0 0 0 611 363 4 0 0 2 0 0 299 127 0 L B, All Durable Benefit R e s p o n s e N B, All No Durable Benefit 0 D C B Durable Benefit N D B No Durable Benefit Melanoma / CTLA4 Snyder et al., NEJM 2014 NSCLC / anti-pd1 Rizvi et al., Science 2015
Mutation Burden and Anti-PD1