RENAL CELL CARCINOMAAnother “most fascinating” cancer entity.

Dr Christoph OingThe Christie NHS Foundation TrustManchester, UK

CONFLICT OF INTEREST DISCLOSURE Dr Christoph Oing

Personal financial interests• Honoraria speaker activity: Medac (2018), IPSEN (2017)Institutional financial interests• NoneNon-financial interests / Leadership role medical societies non-remunerated• Chairman “Junge DGHO” of the German Society of Hematology and Oncology

(DGHO)• ESMO YOC memberOther• Travel and conference attendance: IPSEN (2017)

PATHOPHYSIOLOGY

RISK CLASSIFICATION

TREATMENT

RENAL CELL CARCINOMAAgenda

Macroscopic hematuria

Lower back pain

Palpable lumbar mass

Anemia

Fatigue

Incidentally, asymptomatic (ultrasound, MR)

KIDNEY TUMOURSClinical presentation

Classic triad 10-15% of ptsX

RCC suspected: Abominopelvic CT (contrast-enhanced) or MRI Chest X-ray Bone scan (if clinically indicated)

Who needs a biopsy? If surgery anyways No

But you need a biopsy... To assess indeterminate (small) renal masses To select most suitable therapy strategy (“Treat or not to treat”)

KIDNEY TUMOURSDiagnostic work-up

Many different histologies

90% of kidney cancers RCC

Different clinical behaviour

Clear cell carcinoma Papillary type I Papillary type II Chromophobe Collective ducts Others

KIDNEY CANCERClassification

75%

10%

5%

1%

~4%

~13,000 new cases each year in the UK1

4,619 kidney cancer deaths in 2016 in the UK1

~400,000 new cases each year worldwide2

~175,000 kidney cancer deaths worldwide2

Approximately 3% of all adult cancers

♂ : ♀ = 1.5 : 1

KIDNEY CANCEREpidemiology

1 https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/kidney-cancer2 Bray F et al. Clobal Cancer Statistics 2018. CA Cancer J Clin 2018; 68:394-424

New cancer cases & deaths 20182

No. 16

Smoking (x4)

Obesity Chemical exposure

VHL disease (2-3%, clear cell RCC)

MET germline mutations (80% papillary type I RCC)

Familial (hereditary leiomyomatosis, etc.)

KIDNEY CANCERRisk factors & primary prevention

@nhssmokefree

KIDNEY CANCERTNM-Staging 8th Ed.

KIDNEY CANCERClinical stages

T1 N0 M0 T2 N0 M0

T1-2 N1 M0T3 Nany M0

T4 Nany M0Tany Nany M1

I II

III IV

KIDNEY CANCERPrognosis

Stage 5-year survival rateI 81%II 74%III 53%IV 8%

https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.hrml

Clinical behaviour

Prognosis

Treatment decision making

„Renal Cell Carcinoma“ ≠ ccRCC

Subtyping can be tricky (i.e. eosinophilic RCC, RCC NOS, familial cases)

KIDNEY TUMOURSSubtyping is critical

#BCritical

Most frequent histology (60-75%)

~90% driven by mutations or hypermethylation of the VHL gene on 3p26 (sporadic ccRCC)

Pseudohypoxia via lost HIF1a degradation

Constitutively active VEGF signalling

RENAL CELL CARINOMAClear cell carcinoma

CLEAR CELL RCCResult of angiogenesis

Strongly hypervascular tumors

RISK CLASSIFICATION

RENAL CELL CARCINOMARisk classification M1 disease

Klatte T & Stewart GD. Nat Rev Urol 2019; 16:332-3.

RENAL CELL CARCINOMA

Motzer RJ et al. J Clin Oncol 2002; 20:289-96.

MSKCC risk classification

5 mos

30 mos

14 mos

Median OS

Prop

ortio

n su

rvivi

ng

Years after IFN initiation

RENAL CELL CARCINOMA

Heng et al. Lancet Oncology 2013

IMDC risk classification

7.8 mos 22.5 mos 43.2 mos

CLEAR CELL RCC„Same, same – but different“

Okita K et al. Clin Genitourin Cancer 2019; 17:e440-6.

• Inflammatory reaction led to reclassification into a higher risk category of a relevant subset of patients

RENAL CELL CARCINOMAThus a matter of classification...

Okita K et al. Clin Genitourin Cancer 2019; 17:e440-6.

MSKCC IMDC

Commonly spreads to lymph nodes, lung, and bone

Prognostic role for site of metastasis Atypic

Pancreatic M1 special entitiy? Thyroid M1 special entitiy?

Oligometastatic (incl. Bone, Lung, Liver) Better outcomes Metastasectomy!? Different disease?

Bone M1 or liver M1 poor prognosis

RENAL CELL CARCINOMAClinical behaviour

TREATMENT

RENAL CELL CARCINOMAPrinciples of cancer treatment

TREATMENT „LOCALISED DISEASE“

RENAL CELL CARCINOMATreatment localised disease (stage I / II)

Capitanio U & Montorsi F. Renal Cancer. Lancet 2016; 387:894-906.

RENAL CARCINOMARadical nephrectomy

Only if organ-sparing approach not feasible (i.e. ≥ cT3) LND controversial in cN+ adds staging information, no survival benefit Also for cytoreductive nephrectomy in Stage IV patients

No RCT phase III data supporting use of adjuvant systemic treatment

Conflicting trial results for TKI S-TRAC SUNITINIB vs. PLACEBO OS immature ASSURE PAZOPANIB vs. PLACEBO No OS benefit PROTECT SUNITINIB vs. PLACEBO No OS benefit Toxicity↑ / QoL↓ vs. uncertain clinical benefit

Adjuvant sunitinib available for high risk patients in the US pT3 tumors │ N1 disease

IO to come?! (NIVO or DURVA±TREME vs. PLACEBO)

CLEAR CELL RCCAdjuvant therapy

TREATMENT „ADVANCED DISEASE“

SURGERY

CLEAR CELL RCCCytoreductive nephrectomy

Sunitinib aloneNephrectomy plus Sunitinib

Role of CN in TKI era questionable Still recommended for good risk patients Certainly no option for poor risk patients / high metastatic burden

Flanigan RC et al. New Engl J Med 2001; 345:1655-9. Méjean A et al. New Engl J Med 2018; 379:417-27.

RADIOTHERAPY

Low response rates to conventional RT (i.e. 2 Gy / fraction)

BUT High responses to high-dose-per-rate schedules

Stereotactic Ablative Radiotherapy (SABR) (i.e. 26 Gy / 1 fraction or40 Gy / 5 fractions)

Causes break down of blood supply

Sufficient local control and low toxicity Rarely used for primary RCC Regularly used for metastases (e.g. brain, bone)

CLEAR CELL RCCExternal Beam Radiotherapy

IMMUNOTHERAPY„OLD FASHIONED“

RCC are strongly immunogenic tumors

Historical treatment (and still in some US centers...) High dose IL-2 High dose Interferon α2

Provides durable responses in 10% of patients

Extremely toxic (IL-2) Massive capillary leakage, SIRS, organ failure due to cytokine

storm

RENAL CELL CARCINOMAImmunotherapy

ANTIANGIOGENICTHERAPY

CLEAR CELL RCCTackling Neo-angiogenesis

Rini B et al. Clin Cancer Res 2007XCell death from nutrient / oxygen starvation

Growth factorbinding ↓

Growth factorsignaling ↓

Extracellularcompartment

Cell membrane

Cytoplasm

Anti-VEGF tyrosine kinase inhibitors Block intracellular activation of VEGF pathway

Orally available

Good penetration of blood-brain barrier

CLEAR CELL RCCAvailable drugs: TKI

CLEAR CELL RCC1st-line standard Sunitinib

ORR 31% vs. 6% Unselected untreated ccRCC patients (~7% MSKCC poor risk)

Motzer RJ et al. JCO 2009; 27:3584-90.

Sunitinib (SutentTM) 50mg caps OD, 4w on 2w off Side effects: fatigue, hand-foot syndrome, stomatitis

Pazopanib (VotrientTM) 800mg OD Side effects: diarrhoea, hair discoloration

Axitinib (InlytaTM) 5mg BID Side effects: diarrhoea, dysphonia, fatigue

Tivozanib (FotivdaTM) 1,340µg OD, 3w on 1w off Side effects: dysphonia, diarrhoea, fatigue

CLASS EFFECTS: HYPERTENSION, HYPOTHYROIDISM

CLEAR CELL RCCTKI – First line

IMMUNOTHERAPY„MODERN WARFARE“

Anti-CTLA-4 monoclonal antibodies (Ipilimumab) First generation High incidence of auto-immune toxicity Moderate efficacy

Anti-PD-1 and anti-PD-L1 monoclonal antibodies (Nivolumab, Pembrolizumab, Avelumab, Atezolizumab) Second generation Less toxic More efficient

Combination therapy Higher response rate but also toxicity

CLEAR CELL RCCImmune checkpoint inhibitors 2019

CLEAR CELL RCCA new standard

Motzer RJ et al. New Engl J Med 2018; 378:1277-90.

15-20% responders to PD-1i are long term responders iRECIST important When to stop treatment? When to consider a cure of stage IV RCC?

No measure for proper response prediction Also PD-L1 negative tumours respond

Combinations with promising results PD-1i + CTLA-4i PD-L1i + TKI PD-L1i + VEGFi

CLEAR CELL RCCEvolution of concepts

IO

TKI

IO

CLEAR CELL RCCEAU guideline 2019

NON-CLEAR CELL RCCLimited evidence, limited options

Papillary type I RCC MET-driven Consider Cabozantinib

Papillary type II RCC Consider anti-VEGFR TKI

Chromophobe RCC Consider Temsirolimus (mTORi)

Collective duct / medullary RCC Chemotherapy according to urothelial cancers

Kidney tumours comprise a bunge of different entities

Consider carefully if you need a biopsy

Challenge your pathologist

Clear Cell Renal Cell Carcinoma most common RCC subtype

ccRCC related to VHL inactivation and Pseudohypoxia

Angiogenesis very important for ccRCC growth

LN, lungs and bones common sites for metastatic spread

TAKE HOME MESSAGE IRCC characteristics

TAKE HOME MESSAGE IIRCC treatment

Conventional chemo- and radiotherapy ineffective

Organ-sparing surgery whenever possible in localised disease

ccRCC‘s Achilles‘ heel: Angiogenesis and Immunogenicity

No role for adjuvant systemic TKI

Total resection for oligometastatic disease if feasible

Cytoreductive nephrectomy no more in poor risk mRCC patients

TKI still standard of care for good risk metastatic ccRCC

TKI and PD-1i ± key to success in intermediate / poor risk ccRCC

EMUC 2019… if you haven‘t been to Vienna!