Medical Management of Renal

Cell Carcinoma

Lin Mei, MD

Hematology-Oncology Fellow

Hematology, Oncology and Palliative Care

Virginia Commonwealth University

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

Epidemiology

Histological Classification of RCC

BHD=Birt-Hogg-Dubé; FH=fumarate hydratase;

VHL=von Hippel-Lindau.

Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.

RCC

Clear cell

75%

Type

Incidence (%)

Associated mutations

VHL

Papillary type 1

5%

c-Met

Papillary type 2

10%

FH

Chromophobe

5%

BHD

Oncocytoma

5%

BHD

AJCC Stage (2010)

Stage Description5-Year

Survival (%)

Stage I T1, N0, M0 95

Stage II T2, N0, M0 88

Stage III T1-2, N1 or T3, N0-1 59

Stage IVT4 (any N or M) or

N2 (any T or M) or M120

MSKCC Risk Factor Model in mRCC

0 risk factors (n=80 patients)

1 or 2 risk factors (n=269 patients)

3, 4, or 5 risk factors (n=88 patients)

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

Pro

po

rtio

n S

urv

ivin

g

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 1614131195436 151210876

Motzer RJ et al. J Clin Oncol. 2002;20:289-296.

MS:

20 mo

10 mo

4 mo

Time From Start of treatment (years)

Medical Management of mRCC

Treatment of mRCC

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

Pathophysiology of RCC

VEGF Signaling Mechanisms

Antibodies to VEGF

or VEGFR

mTOR

inhibitorsTyrosine kinase inhibitors

VEGF Correlated With Poorer Survival

Jacobsen J, et al. BJU Int. 2004;93:297-302.

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

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: 115-124.

Pazopanib (Votrient®)

• Similar kinase targets as sunitinib

• Dose: 800mg once daily

• Improved PFS and OS in both treatment-naïve and cytokine-

resistant 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; 28:1061-1068Motzer et al. NEJM. 2013; 369: 722-731

Sorafenib (Nexavar®)

• Oral multikinase inhibitor (RAF, VEGF, PDGF, FLT3 and

c-KIT)

• Dose: 400mg twice daily

• 2nd line treatment (TARGET trial)

• 1st line treatment: in selected patients with stage IV RCC

(Category 2A, NCCN)

Ratain, et al. JCO, 2006;24: 2505-2512.

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 1st line treatment of

poor-risk patients

Hudes et al. NEJM. 2007; 356:2271-2281

Everolimus (Afinitor®)

• Oral mTOR inhibitor

• Dose: 10mg once daily (2nd 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; 372:449-456.

Axitinib (Inlyta®)

• Oral 2nd generation VEGF inhibitors (VEGF1-3)

• Dose: initiate with 5mg twice daily

• AXIS trial: compared with sorafenib in 2nd line setting

• NCCN: can be considered in 1st line treatment option

(Category 2A)

Rini et al. Lancet. 2011; 378:1931-1939

Cabozantinib (Cabometyx®)

• Oral multitarget TKI (VEGF, MET, AXL)

• Dose: 60mg once daily (2nd 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 1st line setting

Choueiri et al. NEJM. 2015; 373: 1814-1823Choueiri et al. JCO. 2017; 35: 591-597

Lenvatinib (Lenvima®)

• Oral multitarget TKI (VEGF, FGF)

• Dose: 18mg once daily (combined with everolimus) as 2nd line

treatment

• Phase II trial, lenvatinib alone or combined with everolimus,

compared with everolimus monotherapy

• NCCN: Category 1 for 2nd line treatment

Mozter et al. Lancet Oncol. 2015; 16: 1473-1482.

Combination therapy

• May improve response rate, however, result in increased

toxicity

• Failed to improve PFS

• RECORD-3 trial: support 1st line sunitinib followed by 2nd

line everolimus upon progression

Mozter et al. JCO. 2014; 32: 2765-2772.

Immune therapy

Nivolumab (Opdivo®)

• Monoclonal antibody against PD-1 receptor

• Dose: 240mg IV once every 2 weeks

• Checkmate 025 trial: 2nd line setting compared with everolimus with

improved OS

• Side effect: autoimmune reaction (rash, colitis, endocrinopathy,

hepatitis, pneumonitis)

Mozter et al. NEJM. 2015; 373: 1803-1813

Pathway and current drugs in mRCC

Decision-making strategy

Choueiri TK and Motzer RJ. NEJM. 2017; 376: 354-366.

Adjuvant therapy in high-risk RCC

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

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: 907-914

ASSURE & S-TRAC Trials

Patel et al. CAHO. 2016; 14: 907-914

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 DFS (primary endpoint)

OS (secondary endpoint)

DFS (primary endpoint)

Question May just delay time to

recurrence without

changing OS

Challenge in adjuvant treatment for RCC

• Population selection

• Revisit previous negative trials

• Molecular marker, oncogenomics

• Evaluation of newer agents and immune therapy

Cytoreductive nephrectomy in mRCC

History of cytoreductive nephrectomy (CN)

Flanigan et al. NEJM. 2001; 345: 1655 Mickisch et al. Lancet. 2001; 358: 966

SWOG 8949 EORTC 30947

CN in patients treated with VEGF therapy

Choueiri et al. J Urol. 2011; 185: 60-66

International mRCC database consortium

Heng et al. Eur Urol. 2014; 66: 704-710.

National Cancer Database Study

• Retrospective study with 15,390 with TT, 35% underwent CN between

2006 and 2013.

• Median OS (CN: 17.1 mos vs. non-CN: 7.7 mos)

Hanna et al. JCO. 2016; 34: 3267-3275

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

Thank you!