The Therapeutic Landscape in Advanced Renal Cell Carcinoma

The Therapeutic Landscape in Advanced Renal Cell Carcinoma Cora Sternberg, MD, FACP Chairman, Department of Medical Oncology San Camillo-Forlanini Hospital Rome, Italy

What best describes the change in median overall survival (OS) for renal cell carcinoma (RCC) over the last 15 years?

Progress in the Treatment of RCC: Systemic Therapies Cytotoxic chemotherapy experiments performed 1 High-dose Interleukin 2 (IL-2) FDA approved 2 Interferon-alpha (IFN-α) shows improved survival versus hormonal therapy 3 Sorafenib: First targeted therapy licensed in the US. Sunitinib followed, then both licensed in the EU 5 Temsirolimus and bevacizumab + IFN licensed 5 Axitinib licensed 5 1940s 1980s 1995 1999 2004 2005/2006 2007 2009/2010 2012 IFN-α and high-dose IL-2 used for treatment of RCC in early 1980s TARGET: first evidence of progression-free survival (PFS) benefit with targeted therapy 4 Everolimus and pazopanib licensed 6 1. Abeloff MD, et al. Clinical Oncology. 4 th ed. Philadelphia, PA. Churchill Livingstone. 2008. 2. Coppin C, et al. Cochrane Database Syst Rev. 2005;(1):CD001425. 3. Costa LT, et al. Oncologist. 2007;12(12):1404-1415. 4. Escudier B, et al. N Engl J Med. 2007;356(2):125-134. 5. European Medicines Agency. Available at: www.ema.europa.eu. Accessed May 18, 2015.

Adipose Adrenal Blood vessel Bone Bone marrow Breast Cervic CNS Colorectal Endometrium Oesophagus Gallbladder Head & neck Heart Kidney Liver Lung Lymphoid Muscle Myometrium Neuroendocrine Ovary Pancreas Pituitary Placenta Prostate Skin Small intestine Soft tissue Stomach Testis Thymus Thyroid Urinary WBC VEGF Level Elucidation of Angiogenesis Pathways Has Led to the Development of Therapies That Affect the Vascular Endothelial Growth Factor (VEGF) Axis 6000 5000 Normal Diseased Invasive cancers 4000 3000 2000 1000 0 CNS, central nervous system; WBC, white blood cells Jubb AM, et al. J Clin Pathol. 2004;57:504-512.

As Well as the Mammalian Target of Rapamycin (mtor) Pathway Rini BI, et al. Lancet Oncol. 2009;10(10):992-1000.

Survival in Metastatic RCC (mrcc) Median OS has dramatically improved in mrcc: Medical Research Council study with IFN (1999): 8.5 months Crecy study (2000): 10 months Pazopanib pivotal trial (2010): 22 months COMPARZ study (2012): 29 months SWITCH study (2014): 31 months Median OS mainly improved in good, intermediate and poor prognostic groups Medical Research Council Renal Cancer Collaborators. Lancet. 1999;353(9146):14-17. Negrier S, et al. Cancer J Sci Am. 2000;Suppl 1:S93-S98. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. Motzer RJ, et al. N Engl J Med. 2013;369(8):722-731. Eichelberg C, et al. Eur Urol. 2015. [Epub ahead of print]

Survival According to Risk Groups MSKCC 1 IKCWG 2 IMDC 3 Year 1999 2011 2013 Good 19.9 26.9 43.2 Intermediate 10 11.5 22.5 Poor 3.9 3.9 7.8 MSKCC, Memorial Sloan Kettering Cancer Center; IKCWG, International Kidney Cancer Working; IMDC, International Metastatic Renal-Cell Carcinoma Database Consortium 1. Motzer R, et al. J Clin Oncol. 1999;17(8):2530-2540. 2. Manola J, et al. Clin Cancer Res. 2011;17(16):5443-5450. 3. Heng DY, et al. Lancet Oncol. 2013;14(2):141-148.

After treating a patient with metastatic RCC, at the time of disease progression on first-line VEGF tyrosine-kinase inhibitor (TKI), what would be your choice of second-line therapy?

EAU/ESMO Treatment Algorithm for mrcc Therapy 1,2 1 2 -st line -nd line Good/intermediate risk Prior cytokine Prior VEGFR-TKI Sunitinib a Pazopanib Everolimus Pazopanib a Sorafenib Axitinib Bevacizumab + IFN-α a Axitinib Sorafenib Poor risk Prior mtor inhibitor Temsirolimus b No recommendation a Level of evidence I, A (European Society for Medical Oncology [ESMO])/ 1b European Association of Urology [EAU]) b Level of evidence II, A (ESMO)/ 1b (EAU) 1. Ljungberg B, et al. Eur Urol. 2015;67(5):913-924. 2. Escudier B, et al. Ann Oncol. 2014;25(suppl 3):iii49-ii56.

NCCN Treatment Guidelines for Clear-Cell RCC Relapse or stage IV medically or surgically unresectable predominant clear-cell histology 1 -st line Clinical trial Pazopanib [1] Prior VEGF-TKI Clinical trial Axitinib [1] 2 -nd line Prior cytokine Clinical trial Pazopanib [1] Sunitinib [1] Everolimus [1] Sunitinib [1] Bevacizumab + IFN-α [1] Sunitinib [2A] Sorafenib [1] Temsirolimus a Bevacizumab [2A] Axitinib [1] High-dose IL-2 b Sorafenib [2A] Bevacizumab [2A] Sorafenib Temsirolimus [2B] Temsirolimus [2A] selected patients Pazopanib [3] IL-2 [2B] [Category of evidence] a Category 1 for poor-prognosis patients; category 2B for selected patients of other risk groups b Patients with excellent PS and normal organ function IL-2 [2B] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. v3.2015. Available at: http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed May 18, 2015.

What is the preferred sequence of targeted agents? 1.TKI mtor TKI First-line Second-line Third-line mtor mtor 2.TKI TKI mtor TKI TKI 3.TKI TKI TKI TKI mtor TKI

Adaptive Resistance to VEGF Inhibition Early phase: response to anti-vegfr2 treatment No angiogenesis VEGF Hypoxia Cancer cells Late phase: evasion to anti-vegfr2 treatment VEGF Reactivation of angiogenesis FGFs and others Cancer cells Endothelial cells Endothelial cells Casanovas O, et al. Cancer Cell. 2005;8(4):299-309.

What About Third-Line Therapy? GOLD: Dovitinib vs Sorafenib After TKI and mtor mrcc with clear-cell histology Measurable disease 2 prior therapies 1 TKI and 1 mtor Progressive disease within 6 months of last targeted therapy N = 564 1:1 R A N D O M I Z A T I O N Dovitinib 500mg 5 days on/ 2 days off + best supportive care (BSC) Sorafenib 400 mg twice daily + BSC Primary endpoint: PFS Secondary endpoints: OS, ORR, safety, QoL Motzer RJ, et al. Lancet Oncol. 2014;15(3):286-296.

Probability of PFS, % GOLD: Dovitinib Did Not Achieve Improved PFS Over Sunitinib (Independent Review) 100 80 Median PFS Dovitinib (n = 284): 3.7 months (95% CI: 3.5-3.9) Sorafenib (n = 286): 3.6 months (95% CI: 3.5-3.7) HR: 0.86 (95% CI: 0.72-1.04) P =.063 60 40 PFS was not better between a VEGFR inhibitor Sorafenib and a dual FGFR -VEGFR inhibitor dovitinib 20 0 0 3 6 9 12 15 18 21 Time, Months Motzer RJ, et al. Lancet Oncol. 2014;15(3):286-296.

% Change from Baseline Cabozantinib Is Active in RCC (n = 21) 20 10 0 Number of prior systemic agents 1 2-4 >4 Prior Tx* -10-20 -30-40 -50-60 -70 cprs *V = VEGF pathway inhibitor; M = mtor inhibitor; C = cytokine; G = gemcitabine; O = other Choueiri TK, et al. Ann Oncol. 2014;25(8):1603-1608.

METEOR: Phase III Study of Second-Line Treatment With Cabozantinib vs Everolimus in mrcc Eligibility: mrcc with clear-cell component One prior VEGF-targeted therapy Primary endpoint: PFS N = 650 R A N D O M I Z A T I O N Cabozantinib 60 mg orally daily Everolimus 10 mg orally daily Study assumes median PFS of 5 months for everolimus and 7.5 months for cabozantinib. This provides for a HR of 0.67 and 90% power and requires 259 PFS events among the first 375 patients randomized. Secondary endpoints: OS, ORR Assumes a median OS of 15 months for everolimus and 20 months for cabozantinib. This provides for a HR of 0.75 and 80% power and requires 413 events. Exploratory endpoints: Patient-reported outcomes, biomarkers, safety, pharmacokinetic (PK) National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/results?term=nct01865747. Accessed: May 18, 2015.

Would histopathology (papillary rather than clear cell) cause you to change your treatment recommendation for a patient with metastatic RCC?

Kidney Cancer Is Not a Single Disease Clear cell Papillary type 1 Chromophobe Hybrid Oncocytoma Papillary type 2 TFE3 Angiomyolipoma Oncocytic Clear/chromophobe Linehan M. Genome Res. 2012;22(11):2089-2100.

Pathology and Gene Expression Clear cell Papillary type 1 Chromophobe Hybrid Oncocytoma VHL Met FLCN Papillary type 2 FH fumarate hydrase TFE3 Angiomyolipoma Oncocytic Clear/chromophobe TFE3, TFEB, MITF TSC1, TSC2 SDHB, SDHC, SDHD succinate dehydrogenase PTEN Linehan M. Genome Res. 2012;22(11):2089-2100.

True or false: Biomarkers that can assist in the determination of best sequence of therapies for metastatic RCC have recently been identified.

Treatment Will Be Guided by Genomics Clear-cell RCC Brugarolas J, et al. Presented at 10 th European International Kidney Cancer Symposium;April 24-25, 2015: Lyon, France.

Prognosis and Treatment Will Be Based on Genomic Classification Peña-Llopls S, et al. Cancer Res. 2013;73(14):4173-4179.

Overall Survival, % Overall Survival, % 100 80 60 40 BAP1 and PBRM1 Are Prognostic of OS Survival Shorter for BAP1 Mutated Tumors PBRM1 BAP1 Median OS (95% CI) 10.6 years (9.8-11.5) 4.6 years (2.1-7.2) University of Texas Southwestern Medical Center (UTSW) cohort (n = 145) Number at risk PBRM1 BAP1 20 HR 2.7 (95% CI 0.99-7.6) Log-rank P =.044 0 0 3 6 9 12 Time from surgery, years 100 80 78 21 25 6 10 2 PBRM1 BAP1 7 1 2 0 Median OS (95% CI) 5.4 years (4.0-6.8) 1.9 years (0.6-3.3) BAP1 and PBRM1 mutations are largely mutually exclusive high-risk BAP1 mutated; favorable PBRM1-mutant 60 The Cancer Genome Atlas (TCGA) cohort (n = 327) 40 Number at risk PBRM1 BAP1 20 HR 2.8 (95% CI 1.4-5.9) Log-rank P =.004 0 0 2 4 6 8 Time from surgery, years 74 20 52 8 21 6 3 3 Kapur P, et al. Lancet Oncol. 2013;14(2):159-167. Boorjian S. Urol Oncol. 2014;32(6):934-935. 0 0

True or false: Novel immunotherapies will soon have an important role in the treatment of mrcc.

Targeted Immunotherapy Will Be Part of Our Treatment Strategy Chen DS, et al. Immunity. 2013;39(1):1-10.

CheckMate 214: Phase III Study of Nivolumab in Combination With Ipilimumab in First-Line mrcc Eligibility: Patients with advanced RCC Treatment-naive N = 1070 R A N D O M I Z A T I O N Nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3wk* Sunitinib 50 mg (4 wk on/ 2 wk off) Primary endpoints: PFS, OS Secondary endpoints: Overall response rate (ORR), adverse event rate *Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks for 4 doses then nivolumab 3 mg/kg National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/results?term=nct02231749. Accessed: May 18, 2015.

RAPID: Phase II Study of MPDL3280A as Monotherapy or in Combination With Bevacizumab vs Sunitinib in Untreated Advanced RCC Eligibility Locally advanced or metastatic RCC with clear-cell and/or sarcomatoid component Previously untreated with any systemic therapy Karnofsky PS 70 www.clinicaltrials.gov (NCT01984242) N = 150-300 R A N D O M I Z A T I O N MPDL3280A 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w MPDL3280A 1200 mg IV q3w Sunitinib 50 mg/day 4/2 Primary endpoints: PFS per RECIST v.1.1 via central ICR assessment Secondary endpoints: PFS using investigator assessment per immune-related criteria, ORR, duration of response, OS, duration of response and PFS in patients progressing on sunitinib and MPDL alone arms who subsequently cross over to combination, safety, PK of MPDL3280A alone and in combination with bevacizumab National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/results?term=nct01984242. Accessed: May 18, 2015.

CheckMate 025: Phase III Study of Nivolumab (Anti-PD-1) vs Everolimus in Locally Advanced Metastatic RCC With Prior Anti-Angiogenic Therapy 1,2 Eligibility: Advanced or metastatic RCC with clear-cell component Received prior antiangiogenic therapy Progression on or after most recent therapy (within 6 months of study enrolment) Karnofsky PS 70 N = 822 R A N D O M I Z A T I O N Nivolumab 3 mg/kg IV every 2 weeks Everolimus 10 mg orally daily Treatment until disease progression or unacceptable toxicity Primary endpoint: OS 1:1 HR of 0.76 (32% increase in median OS) required for positive study outcome Assumes a 4-month improvement in median OS from 14 to 18 month Secondary end points: PFS, ORR, duration of response, duration of OS in PDL1-positive vs PDL1- negative subgroups, safety, disease-related symptom progression rate 1. National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/results?term=nct01668784. Accessed: May 18, 2015. 2. Motzer et al. J Clin Oncol. 2013;31(suppl): Abstract TPS4592.

Upcoming Results of RCC Clinical Trials SURTIME CARMENA Nephrectomy SORCE ASSURE PROTECT S-TRAC ATLAS EVEREST Adjuvant IMPRINT RAPID MPDL3280 +/- bevacizumab ADAPT ALLIANCE A031203 (cabozantinib vs sunitinb) Axitinib + pembrolizumab CheckMate 214 (ipilimumab + nivolumab vs sunitinb) 1 st Line METEOR (cabozantinib vs everolimus) TRC105 + axitinib CheckMate 025 (nivolumab vs everolimus) DART (dalantercept + axitinib) 2 nd Line 2 nd Line and Beyond 2015 2016 2017 2018