Metastatic renal cancer (mrcc): Evidence-based treatment

Metastatic renal cancer (mrcc): Evidence-based treatment José M. Ruiz Morales, M.D. Hospital Médica Sur April 18th, 2018 4th ESO-ESMO Latin American Masterclass in Clinical Oncology

Disclosures Consulting: Bristol-Myers Squibb México Travel, Accommodations, Expenses: Bristol-Myers Squibb México, Novartis

Epidemiology worldwide 2012 Incidence 337,860 (2.4%) Mortality 143,406 (1.7%) 14º http://globocan.iarc.fr

Epidemiology in México - 2012 Incidence 2,395 (3.7%) 8º Mortality 1,304 (3.4%) http://globocan.iarc.fr

Prognosis in kidney cancer Stage 5-Year Survival Rate I 81% II 74% III 53% IV 8% https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html

Histopathology 10 tumor subtypes in the current WHO classification Clear cell (70%) Papillary Chromophobe 90% to 95% of renal carcinomas Collecting duct tumors Renal Cancer: Contemporary Management. Springer 2013

Risk Models

Prognostic Factors for mrcc Two scales largely used: 1. Memorial Sloan Kettering Cancer Center (MSKCC) 2. International mrcc Database Consortium (IMDC)

MSKCC model Developed from patients treated with IFN-based regimens. 1. Poor performance status (Karnofsky <80%) 2. Less than a 1-year interval from diagnosis to treatment 3. High serum lactate dehydrogenase (LDH) level (>1.5 UNL) 4. High serum calcium level (>10 mg/dl) 5. Low hemoglobin concentration Motzer. J Clin Oncol 2002

MSKCC model Risk group Favorable Intermediate Poor OS, median 30 months 14 months 5 months Motzer. J Clin Oncol 2002

IMDC model Developed from patients treated with VEGF-TARGETED therapies. 1. Poor performance status (Karnofsky <80%) 2. Less than a 1-year interval from diagnosis to treatment 3. High absolute neutrophil count 4. High platelet count 5. High serum calcium level (>10 mg/dl) 6. Low hemoglobin concentration Heng. Lancet Oncol 2013

IMDC model # risk factors Risk group OS, median 0 Favourable 43 months 1 2 Intermediate 22 months 3 Poor 8 months Heng. Lancet Oncol 2013

Importance of prognostication 1. Patient counseling 2. Clinical trial risk stratification 3. Planning therapy Heng. Eur Urol 2014

Treatment for mrcc

Treatment for mrcc 1. Surgical 2. Radiation therapy 3. Systemic therapy

Surgery in mrcc

Cytoreductive nephrectomy: IFN era Prospective phase 3 trials: Survival advantage over no surgery 11.1 months vs. 8.1 months p = 0.05 17.0 months vs. 7.0 months p = 0.03 Flanigan. N Engl J Med 2001 Mickisch. Lancet 2001

Cytoreductive nephrectomy: targeted therapy era Retrospective analyses: Survival advantage over no surgery 17.1 months vs. 8.1 months 20.6 months vs. 9.6 months Hanna. J Clin Oncol 2016 Heng. Eur Urol 2014

Candidates for cytoreductive nephrectomy Most patients treated with targeted therapy EXCEPT (may not benefit from CN): 1. Patients with estimated survival times <12 months 2. or 4 IMDC prognostic factors Heng. Eur Urol 2014

Proposed decision-making strategy for the treatment of mrcc Kidney with primary tumor in place? Consider cytoreductive nephrectomy with or without metastasectomy Modified from: Motzer. NEJM 2017

Radiation therapy

Radiation therapy Radioresistant tumor Used for palliation of symptoms 30% of patients will require it for palliation Brain metastases Bone metastases Stereotactic ablative radiotherapy to metastatic sites? selected cases Shaikh. Urology 2015 Straka. J Clin Oncol 2013

Systemic therapy

Malignant solid-tumors systemic treatment: overview First-line treatment characteristics: 1. BEST overall response (OR) 2. BEST Progression-free survival (PFS) 3. BEST (if possible) Overall survival (OS) Exceptions: Toxicity Elderly McKibbin. Oncologist 2008

Therapies approved for mrcc (as march 2018) Axitinib Interleukin-2 Pazopanib Bevacizumab Interferon-alfa Sorafenib Cabozantinib Lenvatinib Sunitinib Everolimus Nivolumab Temsirolimus https://www.fda.gov/drugs/informationondrugs/approveddrugs/default.htm http://www.ema.europa.eu/ema

Systemic therapies approved for mrcc Not everything is a phase 3 trial in mrcc Phase 2 approvals: Interleukin-2 Sunitinib Lenvatinib + everolimus Not all of the drugs have been compared with each other Fyfe. J Clin Oncol 1995 Motzer. J Clin Oncol 2006 Motzer. Lancet Oncol 2015

First-line

Approved first-line treatment options for mrcc Phase Control arm PFS (months) OS (months) ORR (%) 1. High-dose IL 2 3 SC IL 2 + IFN α 3.1 vs. 3.1 HR non-reported (NS) 17 vs. 13 (NS) 23.2 vs. 9.9 (CR 8.4%) 2. Sunitinib 3 4. IFN α + bevacizumab 3. Pazopanib 3 noninferiority 3 2 5. Cabozantinib (only intermediate & poor-risk patients) 6. Temsirolimus 3 (only poor-risk patients) IFN α 11 vs. 5 HR 0.53 Sunitinib 8.4 vs. 9.5 HR 1.04 IFN α + placebo 10.2 vs. 5.4 HR 0.63 Sunitinib 8.2 vs. 5.6 HR 0.66 IFN - α 5.5 vs. 3.1 HR non-reported 26.4 vs. 21.8 HR 0.82 28.3 vs. 29.1 HR 0.92 47 vs. 12 31 vs. 25 23.3 vs. 21.3 (NS) 30.6 vs. 12.4 30.3 vs. 21.8 HR 0.80 10.9 vs. 7.3 HR 0.73 33 vs. 12 8.6 vs. 4.8 1. Mcdermott. J Clin Oncol 2005 2. Motzer. J Clin Oncol 2009 3. Motzer. NEJM 2013 4. Escudier. Lancet 2007 5. Choueiri. J Clin Oncol 2017 6. Hudes. NEJM 2007

Proposed decision-making strategy for the treatment of mrcc Kidney with primary tumor in place? Consider cytoreductive nephrectomy with or without metastasectomy First-line options: Pazopanib Sunitinib IFN-α + Bevacizumab Cabozantinib (only intermediate & poor-risk patients) Temsirolimus (only poor-risk patients) Modified from: Motzer. NEJM 2017

Second-line

Treatment sequencing New concept Can refer to: 1. Drug combinations 2. Treatment order 3. Both Requires: Drug availability Clinical activity before and after each line Mechanism of resistance Burris 3rd. Cancer Chemother Pharmacol 2013.

Treatment sequencing in mrcc retrospective data International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) 2106 Patients Non-clear cell: 12% Median follow-up: 36 months Second-line: 907 (43%) Third-line: 318 (15%) Sequencing VEGF mtor vs. VEGF VEGF HR (adjusted for IMDC risk-groups) 0.833 (95% IC 0.66 1.03) p = 0.10 Alimohamed. Clin Genitourin Cancer 2014

Treatment sequencing in mrcc retrospective data 7,438 IMDC patients Sunitinib: 6,519 Pazopanib: 919 No IMDC risk-groups differences ORR Pazopanib 28% Sunitinib 30% Ruiz-Morales. Eur J Cancer. 2016

Treatment sequencing in mrcc retrospective data Second-line outcomes: Non-affected by first-line treatment choice 2nd-line Sorafenib Axitinib Everolimus Others 2667 / 6519 (41%) 585 / 2667 (22%) 225 / 2667 (8%) 1194 / 2667 (45%) 673 / 2667 (25%) 290 / 919 (32%) 6 / 290 (2%) 57 / 290 (20%) 154 / 290 (53%) 73 / 290 (25%) Ruiz-Morales. Eur J Cancer. 2016

Approved second-line treatment options for mrcc Phase Control arm PFS (months) OS (months) ORR (%) 1. Nivolumab 3 Everolimus 4.6 v 4.4 HR 0.88 (NS) 25 vs. 19.6 HR 0.73 25 vs. 5 2. Cabozantinib 3 Everolimus 7.4 vs 3.8 HR 0.51 21.4 vs. 16.5 HR 0.66 17 vs. 3 3. Axitinib 3 Sorafenib 6.7 vs 4.7 HR 0.66 20.1 vs. 19.2 HR 0.96 (NS) 23 vs. 12 4. Everolimus 3 Placebo 4.9 vs. 1.9 HR 0.33 14.8 vs. 14.4 HR 0.87 (NS) 1.8 vs 0 5. Sorafenib 3 Placebo 5.5 vs. 2.8 HR 0.44 19.3 vs. 15.9 HR 0.77 11 vs. 2 6. Lenvatinib + everolimus 2 Lenvatinib 14.6 v 7.4 HR 0.66 (NS) Everolimus 14.6 vs. 5.5 HR 0.40 25.5 v 19.1 HR 0.68 (NS) 25.5 vs. 15.4 HR 0.51 43 v 27 (NS) 43 vs. 6 1. Motzer. NEJM 2015 2. Choueiri. NEJM 2016 3. Motzer. Lancet Oncol 2013 4. Motzer. Lancet 2008 5. Escudier. NEJM 2007 6. Motzer. Lancet 2015

Proposed decision-making strategy for the treatment of mrcc Kidney with primary tumor in place? Consider cytoreductive nephrectomy with or without metastasectomy Expected disease control: Maintain VEGFR-inhibitor principle First-line options: Pazopanib Sunitinib IFN-α + Bevacizumab Short-time or non-disease control: Change mechanism of action Second-line option: Cabozantinib (if not previously used) Lenvatinib + Everolimus Cabozantinib (only intermediate & poor-risk patients) Temsirolimus (only poor-risk patients) Second-line option: Nivolumab Modified from: Motzer. NEJM 2017

Third-line

Third-line of treatment Limited information Based: Experience and availability Poor scientific evidence Motzer. Lancet Oncol 2014

Third-line possible treatment options for mrcc Fase Nivolumab 3 28% of patients in both arms had two previous lines of VEGR inhibitors (sunitinib, pazopanib & axitinib) Cabozantinib 3 27% of patients in both arms had two previous lines of VEGR inhibitors (sunitinib, pazopanib & axitinib) Control arm PFS (months) OS (months) ORR (%) Everolimus 4.6 v 4.4 25 vs. 19.6 25 vs. 5 HR 0.88 (NS) HR 0.73 Everolimus 7.4 vs 3.8 HR 0.51 21.4 vs. 16.5 HR 0.66 17 vs. 3 Everolimus 3 26% of patients in both arms had two previous lines of VEGR inhibitors (sunitinib & sorafenib) Placebo 4.9 vs. 1.9 HR 0.33 14.8 vs. 14.4 HR 0.87 (NS) 1.8 vs 0 1. Motzer. NEJM 2015 2. Choueiri. NEJM 2016 3. Motzer. Lancet 2008

Proposed decision-making strategy for the treatment of mrcc Kidney with primary tumor in place? Consider cytoreductive nephrectomy with or without metastasectomy Expected disease control: Maintain VEGFR-inhibitor principle First-line options: Pazopanib Sunitinib IFN-α + Bevacizumab Short-time or non-disease control: Change mechanism of action Second-line option: Cabozantinib (if not previously used) Lenvatinib + Everolimus Cabozantinib (only intermediate & poor-risk patients) Temsirolimus (only poor-risk patients) Second-line option: Nivolumab Third-line option: Nivolumab Third-line option: Cabozantinib Modified from: Motzer. NEJM 2017

Proposed decision-making strategy for the treatment of mrcc Kidney with primary tumor in place? Consider cytoreductive nephrectomy with or without metastasectomy Expected disease control: Maintain VEGFR-inhibitor principle Second-line option: Cabozantinib (if not previously used) Lenvatinib + Everolimus First-line options: Pazopanib Sunitinib IFN-α + Bevacizumab Cabozantinib (only intermediate & poor-risk patients) Temsirolimus (only poor-risk patients) Short-time or non-disease control: Change mechanism of action Second-line option: Nivolumab Third-line option: Nivolumab Modified from: Motzer. NEJM 2017 Fourth-line options (only PFS benefit): Axitinib Everolimus Sorafenib Third-line option: Cabozantinib

Non-clear mrcc

Non-clear mrcc General approach to treatment, mirrors that for clear-cell mrcc Treatments are generally less effective International guidelines recommend: Enrolling patients in clinical trials for first-line systemic therapy Valenca. Clin Adv Hematol Oncol 2015 Vera-Badillo. Eur Urol 2015

Future of treatment sequencing in mrcc Immune biomarker MET biomarker mtor biomarker VEGFR biomarker Nivolumab Cabozantinib Everolimus Temsirolimus Pazopanib Sunitinib Axitinib Lenvatinib Stukalin. Oncology Reviews 2016

Take-home messages: mrcc treatment If feasible and justifiable: debulking nephrectomy before systemic therapy FIRST-LINE For good-risk patients, start with: VEGFR inhibitors (pazopanib, sunitinib or IFN-α + bevacizumab) For intermediate-risk patients, start with: Cabozantinib or another VEGR inhibitor For poor-risk patients, start with: Temsirolimus or Cabozantinib

Take-home messages: mrcc treatment SECOND-LINE Progression after VEGR inhibitor AND expected disease control: Maintain mechanism of action; use lenvatinib + everolimus or cabozantinib (if not previously used) Progression after VEGR inhibitor AND short-time or non-disease control: Change mechanism of action; use nivolumab

Take-home messages: mrcc treatment THIRD-LINE Use cabozantinib or nivolumab; the one that you didn't use previously FOURTH-LINE (only PFS benefit) Axitinib, everolimus or sorafenib NON-CLEAR RENAL CELL CARCINOMA General approach to treatment, mirrors that for clear-cell mrcc

Gracias. José M. Ruiz-Morales, MD. ruiz82@gmail.com