Medical Management of Renal Cell Carcinoma

Transcription

1 Medical Management of Renal Cell Carcinoma Lin Mei, MD Hematology-Oncology Fellow Hematology, Oncology and Palliative Care Virginia Commonwealth University

2 Educational Objectives Background of RCC (epidemiology, pathology and stage) Management of metastatic RCC (new drugs and mechanism) Controversy in adjuvant treatment in high risk advanced RCC Cytoreductive nephrectomy mrcc in the era of targeted therapy

3 Epidemiology

4 Histological Classification of RCC RCC Type Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma Incidence (%) 75% 5% 10% 5% 5% Associated mutations VHL c-met FH BHD BHD BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. Modified from Linehan WM et al. J Urol. 2003;170:

5 Stage AJCC Stage (2010) Description 5-Year Survival (%) Stage I T1, N0, M0 95 Stage II T2, N0, M0 88 Stage III T1-2, N1 or T3, N Stage IV T4 (any N or M) or N2 (any T or M) or M1 20

6 Proportion Surviving MSKCC Risk Factor Model in mrcc risk factors (n=80 patients) 1 or 2 risk factors (n=269 patients) 3, 4, or 5 risk factors (n=88 patients) MS: 20 mo 10 mo 4 mo Risk factors associated with worse prognosis KPS <80 Low serum hemoglobin (13 g/dl/11.5 g/dl: M/F) High corrected calcium (10 mg/dl) High LDH (300 U/L) Time from Dx to IFN- <1 yr Time From Start of treatment (years) Motzer RJ et al. J Clin Oncol. 2002;20:

7 Medical Management of mrcc

8 Treatment of mrcc

9 Historical treatment of mrcc Chemotherapy RCC is highly resistant, <10% ORR IFN- 15% ORR, but responses rarely complete or durable HD IL-2 15% ORR in stage IV patients, only 5% were CR Urgent need for additional options in late-stage RCC

10 Pathophysiology of RCC

11 VEGF Signaling Mechanisms Antibodies to VEGF or VEGFR mtor inhibitors Tyrosine kinase inhibitors

12 VEGF Correlated With Poorer Survival Jacobsen J, et al. BJU Int. 2004;93:

13 VEGF inhibitor (Bevacizumab) Bevacizumab as monotherapy is not curative Usual combined with other medications with different mechanism of action (eg. IFN- ) Side effects: Hypertension, proteinuria, impaired wound healing, GI perforation

14 Sunitinib (Sutent ) Oral broad-spectrum multitarget TKI (VEGF, PDGF, FLT3 and c-kit) Dose: 50mg daily, 4 weeks on and 2 weeks off PFS (11 mos) and OS (26.4 mos) compared with IFN- 90% undergone nephrectomy with good- or intermediate-risk Motzer, et al. NEJM, 2007;356:

15 Pazopanib (Votrient ) Similar kinase targets as sunitinib Dose: 800mg once daily Improved PFS and OS in both treatment-naïve and cytokineresistant patients Non-inferior to sunitinib (COMPARZ trial) Favorable: less fatigue, hand-foot syndrome, thrombocytopenia Side-effect: higher incident of transaminitis Sternberg et al. JCO. 2010; 28: Motzer et al. NEJM. 2013; 369:

16 Sorafenib (Nexavar ) Oral multikinase inhibitor (RAF, VEGF, PDGF, FLT3 and c-kit) Dose: 400mg twice daily 2 nd line treatment (TARGET trial) 1 st line treatment: in selected patients with stage IV RCC (Category 2A, NCCN) Ratain, et al. JCO, 2006;24:

17 Temsirolimus (Torisel ) mtor inhibitor Dose: 25mg IV once weekly ARCC trial: include 3 or more unfavorable prognostic factors (high risk) patients Category 1 recommendation for 1 st line treatment of poor-risk patients Hudes et al. NEJM. 2007; 356:

18 Everolimus (Afinitor ) Oral mtor inhibitor Dose: 10mg once daily (2 nd line treatment) RECORD-1 trial: mrcc progressed on sunitinib, sorafenib or both (First study to evaluate disease progression on VEGFi) Side effect: Rash, mucositis, nausea, myelosuppression, hyperglycemia, pneumonitis etc. Motzer et al. Lancet. 2008; 372:

19 Axitinib (Inlyta ) Oral 2 nd generation VEGF inhibitors (VEGF1-3) Dose: initiate with 5mg twice daily AXIS trial: compared with sorafenib in 2 nd line setting NCCN: can be considered in 1 st line treatment option (Category 2A) Rini et al. Lancet. 2011; 378:

20 Cabozantinib (Cabometyx ) Oral multitarget TKI (VEGF, MET, AXL) Dose: 60mg once daily (2 nd line treatment) METEOR trial: compared with everolimus, showed improved PFS and OS Side effect: hypertension, diarrhea, fatigue. CABOSUN trial: evaluate intermediate- or poor-risk mrcc compared with sunitinib in 1 st line setting Choueiri et al. NEJM. 2015; 373: Choueiri et al. JCO. 2017; 35:

21 Lenvatinib (Lenvima ) Oral multitarget TKI (VEGF, FGF) Dose: 18mg once daily (combined with everolimus) as 2 nd line treatment Phase II trial, lenvatinib alone or combined with everolimus, compared with everolimus monotherapy NCCN: Category 1 for 2 nd line treatment Mozter et al. Lancet Oncol. 2015; 16:

22 Combination therapy May improve response rate, however, result in increased toxicity Failed to improve PFS RECORD-3 trial: support 1 st line sunitinib followed by 2 nd line everolimus upon progression Mozter et al. JCO. 2014; 32:

23 Immune therapy

24 Nivolumab (Opdivo ) Monoclonal antibody against PD-1 receptor Dose: 240mg IV once every 2 weeks Checkmate 025 trial: 2 nd line setting compared with everolimus with improved OS Side effect: autoimmune reaction (rash, colitis, endocrinopathy, hepatitis, pneumonitis) Mozter et al. NEJM. 2015; 373:

25 Pathway and current drugs in mrcc

26 Decision-making strategy Choueiri TK and Motzer RJ. NEJM. 2017; 376:

27 Adjuvant therapy in high-risk RCC

28 Risk of recurrence Curative therapy is surgery Nephrectomy either radical or nephron-sparing 20% of these population eventually relapse Median time to relapse: 18 months, within 2-3 years after surgery

29 High risk population Poor PS, obesity, weight loss, presence of symptoms, paraneoplastic syndrome Leibovich score: tumor stage, reginal LN, tumor size, nuclear grade, tumor necrosis SSIGN score (mayo clinic), Karakiewicz et al. UISS (UCLA system) Molecular test is controversial Patel et al. CAHO. 2016; 14:

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31 ASSURE & S-TRAC Trials Patel et al. CAHO. 2016; 14:

32 Difference S-TRAC ASSURE Population Higher risk group (pt3-4) Greater than pt1b Pathology Only clear cell All subtypes Toxicity Better tolerance High dropout rate Evaluation Central review No central review Maturation Immature data (OS) Matured Design Question DFS (primary endpoint) OS (secondary endpoint) May just delay time to recurrence without changing OS DFS (primary endpoint)

33 Challenge in adjuvant treatment for RCC Population selection Revisit previous negative trials Molecular marker, oncogenomics Evaluation of newer agents and immune therapy

34 Cytoreductive nephrectomy in mrcc

35 History of cytoreductive nephrectomy (CN) SWOG 8949 EORTC Flanigan et al. NEJM. 2001; 345: 1655 Mickisch et al. Lancet. 2001; 358: 966

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37 CN in patients treated with VEGF therapy Choueiri et al. J Urol. 2011; 185: 60-66

38 International mrcc database consortium Heng et al. Eur Urol. 2014; 66:

39 National Cancer Database Study Retrospective study with 15,390 with TT, 35% underwent CN between 2006 and Median OS (CN: 17.1 mos vs. non-cn: 7.7 mos) Hanna et al. JCO. 2016; 34:

40 Summary CN before systemic therapy is recommended Patient selection is important Lung-only metastases Good PS and good prognostic feature Palliative nephrectomy Expected survival < 12 months based on risk factors is unlikely to be benefited from CN

41 Thank you!