Μεταστατικός Καρκίνος Νεφρούθεραπευτική αντιμετώπιση

Nikolaos Tsoukalas MD, MSc, PhD

Medical Oncologist, MSc in BioinformaticsClinical Research Fellow in Oncology

Guy’s & St Thomas’ NHS Cancer CentreQueen Elizabeth Hospital

London UK

Disclosure

• No actual or potential conflict of interest in relation to this presentation.

• No real or apparent conflicts of interest to disclose.

Renal cell carcinoma• Renal cell carcinoma (RCC) accounts for 2%–3% of all

adult malignancies, representing the seventh most common cancer in men and the ninth most common cancer in women.

• Worldwide, there are ∼209 000 new cases and 102 000 deaths per year. The incidence of all stages of RCC has increased over the past several years, contributing to a steadily increasing mortality rate per unit population.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Current targets of therapies for RCC: VEGF and mTOR

Inhibition of some other target pathways are under investigation

Transcriptional activation

VEGF

HIF-1α

VHL

Protein synthesis

Angiogenesis

Bevacizumab

Growth and metabolism

mTOR

Growth factor receptor

PI3K

PIP2PIP3

PTEN

AKT

Temsirolimus, everolimus

Sunitinib, sorafenib, axitinib,

pazopanib

Tumour cell

Endothelial cell

VEGFR

EGF, epidermal growth factor; VHL, von Hippel–Lindau

ESMO Academy 2015

Patient outcomes

Therapeutic options

Median PFS4–5 months

Median PFS9–11 months

Median PFS4–5 months

? ?

~40–60%1,2~100% <20%3–5Eligible patients

SunitinibPazopanib

Bevacizumab + IFN-α

Temsirolimus

Axitinib(post-sunitinib/

cytokine)Everolimus

(post-VEGFR-TKI)Sunitinib

(post-cytokine)Pazopanib

(post-cytokine)Sorafenib

(post-cytokine)

Everolimus(post-VEGFR-TKI

× 2)

Neoadjuvant Adjuvant First-line Second-line Third-line

Progress in advanced kidney cancer, 2007–2014

Adapted from Larkin. ASCO GU 2014IFN-α, interferon-alpha; VEGFR-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor

1. Levy et al. Eur J Cancer 2013; 2. Sonpavde et al. Eur Urol 2012; 3. Iacovelli et al. Eur J Cancer 2013; 4. Pal et al. ASCO GU 2013; 5. Heng et al. ASCO 2013

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Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

• In the era of immunotherapy, cytoreductive nephrectomy was recommended in patients with good PS [I, A].

• Whether this recommendation will remain with current targeted therapies is currently being investigated in two prospective trials.

• In routine practice, cytoreductive nephrectomy is recommended in patients with good PS and large primary tumours with limited volumes of metastatic disease, and for patients with a symptomatic primary lesion. Cytoreductive nephrectomy is not recommended in patients with poor PS.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

• Metastasectomy can be considered and performed after multidisciplinary review for selected patients with solitary or easily accessible pulmonary metastases, solitary resectable intraabdominal metastases, a long disease-free interval after nephrectomy, or a partial response in metastases to immunotherapy or targeted therapy.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

ESMO Academy 2015

Targeted agents currently approved for mRCC in Europe

Sorafenib (oral)Advanced RCC after IFN‑α/IL-2 or if unsuitable for IFN-α/IL-22

Bevacizumab (+IFN-α) (IV)

First-line mRCC3

Everolimus (oral)Advanced RCC after

VEGF‑targeted therapy5

Axitinib (oral)Advanced RCC after sunitinib

or a cytokine7

Temsirolimus (IV)Advanced RCC with 3–6 prognostic risk factors4

2006 2007 2008 2009 2010 2011 2012 2013 2014

Pazopanib (oral)Advanced RCC6

Sunitinib (oral)Advanced/mRCC1

1. Sunitinib SmPC, Jan 2014; 2. Sorafenib SmPC, Feb 2013; 3. Bevacizumab SmPC, Feb 2014; 4. Temsirolimus SmPC, Oct 2013; 5. Everolimus SmPC, Nov 2013; 6. Pazopanib SmPC, Dec 2013; 7. Axitinib SmPC, Oct 2013.

IFN-α, interferon-alpha; IL-2, interleukin-2; IV, intravenous

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Pivotal trials in the 2nd line setting

TRIAL TREATMENTSTARGET Sorafenib vs PlaceboAXIS Axitinib vs SorafenibRECORD-1 Everolimus vs PlaceboINTORSECT Temsirolimus vs SorafenibMETEOR Cabozantinib vs EverolimusCheckMate-025 Nivolumab vs Everolimus

Axitinib: a next-generation TKI

• Binds to VEGFR-1, -2 and -3• Fits tightly into the ‘deep pocket’

conformation of the kinase domain of VEGFRs, resulting in high potency and selectivity in vitro

Hu-Lowe DD, et al. Clin Cancer Res 2008;14:7272–83; Escudier B and Gore M. Drugs R D 2011;11:113–26; INLYTA®. Summary of Product Characteristics. 2012. Available at: www.medicines.org.uk/emc/.

Sorafenib 400 mg BD

Eligibility criteria included: mRCC with clear-cell

histology Failure of one prior first-

line regimen containing:– Sunitinib – Bevacizumab + IFN-α– Temsirolimus– Or cytokines

Stratification by prior regimen and ECOG PS

Phase III study of axitinib versus sorafenib insecond-line treatment of mRCC (AXIS)

Primary endpoints: PFS by independent central reviewSecondary endpoints: OS, ORR, safety and tolerability, duration of response, patient-reported outcomes

Axitinib5 mg BD*

N=723

Treat until PD, unmanageable AE, or withdrawal of consent

Rini BI, et al. Lancet 2011;378:1931–9.Sorafenib Summary of Product Characteristics. 2012. Available at: www.medicines.org.uk/emc/.

*Dose increase (to maximum of 10 mg BD) or reduction (to minimum of 2 mg BD) is recommended based on individual safety and tolerability; The dose could be decreased after initiation. AE=adverse event; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PD=progressive disease.

1:1

RANDOMISATION

AXIS Trial: PFS results

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

1.00.90.80.70.60.50.40.30.20.1

00 2 4 6 8 10 12 14 16 18 20

Prob

abili

ty o

f PFS

AxitinibSorafenib

Median PFS, Mos (95% CI)6.7 (6.3-8.6)4.7 (4.6-5.6)

Stratified HR: 0.665(95% CI: 0.544-0.812; P < .0001)

Pts at Risk, nAxitinib

Sorafenib256224

361362

202157

145100

9651

6428

3812

206

103

11

00

Months

Lenvima

Lenvatinib ± Everolimus in mRCC: Randomized, Open-Label Phase II Study

• Primary endpoint: PFS with lenvatinib ± everolimus vs everolimus alone• Secondary endpoints: PFS with combination vs lenvatinib alone, ORR, OS,

safety/tolerability

Lenvatinib 18 mg QD +Everolimus 5 mg QD

(n = 51)

Measurable metastatic or advanced RCC;

following progression≤ 9 mos after 1 prior

VEGF therapy (N = 153)

Stratified by hemoglobin (low vs normal) and corrected serum calcium

(≥ vs < 10 mg/dL)

Lenvatinib 24 mg QD(n = 52)

Motzer R, et al. ASCO 2015. Abstract 4506. Reprinted with permission.

Everolimus 10 mg QD (n = 50)

Treated until PD or unacceptable toxicity

Lenvatinib ± Everolimus in mRCC: Efficacy

Response Lenvatinib/Everolimus

(n = 51)

Lenvatinib(n = 52)

Everolimus(n = 50)

Median PFS, mos

14.6HR: 0.40; P < .001

vs everolimus

7.4HR: 0.61; P = .048

vs everolimus

5.5

ORR, % 43P < .001 vs everolimus

27P = .007 vs everolimus

6

Median OS,* mos 25.5HR: 0.51; P = .024

vs everolimus

19.1HR: 0.68; P =.118

vs everolimus

15.4

Motzer R, et al. ASCO 2015. Abstract 4506. Reprinted with permission.

*Updated analysis.

Cabozantinib

Cometriq

METEOR phase III study

Basic characteristics

Choueiri et al. NEJM 2015

Choueiri et al. NEJM 2015

Overall survival

Choueiri et al. NEJM 2015

Response rateCabozantinib Everolimus

21% 5%

40/187 9/188

P<0.001

Adverse Effects

Choueiri et al. NEJM 2015

Opdivo

Phase 3 trial of Nivolumab vs Everolimus following VEGF-targeted therapy

Motzer et al. NEJM 2015

Nivolumab produced higher response rates than everolimus (25% vs. 5%) and median overall survival was longer (by 5.4 months), to more than 2 years.

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

Baseline Characteristics (1)

Baseline Characteristics (2)

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

Overall Survival

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

Nivolumab Everolimus

24% 5%

103/410 22/411

P<0.001

Response rate

Overall Survival in Subgroup Analyses

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

Progression-free Survival

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

Overall Survival according to PD-L1 Expression Level

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

AEs (≥10%) of treated patients in either group (1)

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

Motzer RJ et al. N Engl J Med 2015;373:1803-1813

AEs (≥10%) of treated patients in either group (2)

2nd line trials (non-immunotherapy)Author Agent Phase RR PFS

Pili et al. Abstr 4549 Aflibercept II 2-3% 8-11mo

McKay et al. Abstr 4559 Buparlisib (PI3K) + Bev I 13% 9mo

Keefe et al, Abstr 4543 CRLX101 (HIF) +Bev Ib/IIa 23% 10mo

Voss et al, Abstr 4567 Dalantercept (ALK) + axitinib

II 25% 8mo

Hainsworth et al, Abstr 4547 LY2510924 (CXCR4) + sunitinib

II rand 39% 12mo

Peterson et al, Abstr TPS4580

RX-0201 (AKT1) + Everolimus

I (ongoing)

Twarowski et al, Abstr 4523 Tivantinib (MET) +/- Erlotinib

II rand 0% 2-5mo

Dorff et al, Abstr 4542

Bevacizumab +/-TRC105 (Endoglin)

II rand 3%

ASCO 2015

2nd (+/- 1st) line trials (immunotherapy)

Author Agent Phase

RR PFS

Amin et al. ASCO 2014 Nivolumab+Pazopanib I 45% 55% (6m)

Amin et al. ASCO 2014 Nivolumab+Sunitinib I 52% 78% (6m)

NCT02423954 Nivolumab+Temsirolimus I

NCT01668784 Nivolumab vs Everolimus III

Rini et al, Cancer 2011 Tremelimumab+Sunitinib I 43% Toxic

Plimack et al, ASCO 2015 CheckMate-010

Nivolumab II OS=25m

Choueiri et al. ASCO 2015 CheckMate-009

Nivolumab II Association with biomarkers

Hammers et al. ASCO 2015 CheckMate-016

Nivolumab+Ipilimumab III ~40% ≥13m

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

• Radiotherapy has a limited role in the primary management of renal cancer. However, it is used in many different clinical situations particularly for unresectable local recurrences and metastatic disease.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

• Bisphosphonate therapy with zoledronic acid has been shown to reduce skeletal-related events in patients with bone metastasis due to mRCC and they should be considered for zoledronic acid treatment, weighting the potential benefits of the treatment (supposed benefit in terms of OS) with the potential harms (risk of osteonecrosis of the jaw) [II, A].

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

1 Lipton A et al Zoledronic acid delays the onset of skeletal-relatedevents and progression of skeletal disease in patients with advanced renal cellcarcinoma. Cancer 2003.2 Aapro M et al. Guidance on the use ofbisphosphonates in solid tumours: recommendations of an international expertpanel. Ann Oncol 2008.

RCC systemic treatments

1st lineSunitinib

PazopanibIFN-α + Bev

TemsirolimusHD IL-2

mPFS= 9 mo

2nd lineEverolimus

AxitinibSorafenibSunitinib

mPFS= 4-5 mo

3rd lineEverolimusSorafenib

mPFS= 4-5 mo

RCC systemic treatments

1st lineSunitinib

PazopanibIFN-α + Bev

TemsirolimusHD IL-2

mPFS= 9 mo

2nd lineEverolimus

AxitinibSorafenibSunitinib

CabozantinibNivolumab

Lenvatinib+Eve?

mPFS= 4-5 mo

3rd lineEverolimusSorafenib

mPFS= 4-5 mo

2nd line treatment after…1st line 2nd line

Cytokine

SorafenibSunitinibPazopanibAxitinibTivozanibBavacizumab

Anti-angiogenic agent

EverolimusTemsirolimusAxitinibSunitinibSorafenibCabozantinibNivolumabLenvatinib+Everolimus

mTOR inhibitor Sunitinib

Treatment decisions in the clinic

Efficacy is the key factor used to select treatments Safety profiles of individual drugs may also impact on treatment decisions

HypertensionDysphonia

Hand–foot syndromeWeight lossConstipation

Axitinib2Everolimus1

StomatitisInfections

CoughRash

Peripheral oedemaDyspnoea

Pyrexia

FatigueDiarrhoea

NauseaAnorexiaVomiting

Frequent all-causality AEs (≥20%)*

1. Escudier B, et al. Cancer 2010:4256–65; 2. Rini BI, et al. Lancet 2011;378:1931–9

*Outcomes from different clinical trials should not be compared directly due to differences in trial design and patient populations

Turning mRCC into a chronic disease

Larkin and Gore. Lancet 2010.

Time

Tum

our

volu

me

Untreated tumour

cells

Treated tumour cells

Back up slides

ESMO Academy 2015

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

• Recommendations mainly relate to clear-cell histology, since most of the pivotal trials have been done in this common histological subtype.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

• Patients are stratified according to the presence of six risk factors [International Metastatic RCC Database Consortium (IMDC) criteria] 0, 1-2, 3-6:

• Karnofsky performance status (PS) <80%• Haemoglobin <lower limit of normal• Time from diagnosis to treatment of <1 year• Corrected calcium above the upper limit of normal• Platelets greater than the upper limit of normal• Neutrophils greater than the upper limit of normal

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

first-line treatment of patients with good or intermediate prognosis

• Because some RCC have a very indolent course, a period of observation before starting treatment should be considered, especially in patients with limited tumour burden and few symptoms.

• 3 treatments have demonstrated efficacy in pivotal phase 3: bevacizumab (IFN-α), sunitinib and pazopanib [I, A].

• Improvement of PFS over either IFN-α or placebo.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

1 Escudier B et al. Bevacizumab plus interferon alfa-2afor treatment of metastatic renal cell carcinoma: a randomised, double-blind phaseIII trial. Lancet 2007.2 Motzer R et al. Sunitinib versus interferon alfa inmetastatic renal-cell carcinoma. N Engl J Med 2007.3 Sternberg CN et al. Pazopanib in locally advanced ormetastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol2010.4 Motzer RJ et al. Pazopanib versus sunitinib in metastatic renalcellcarcinoma. N Engl J Med 2013.

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

first-line treatment of patients with good or intermediate prognosis

• Sorafenib [II, B], high-dose interleukin-2 [III, C] and low-dose IFN-α combined with bevacizumab [III, A] are options.

• Single agent IFN-α, the losing arm of three randomised, controlled trials, should no longer be regarded as a standard option [I, D].

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

first-line treatment of patients with poor prognosis

• Temsirolimus is currently the only drug with level I evidence of activity in this patient population [II, A]. The pivotal trial demonstrated improvement of OS compared with IFN-α or combination of temsirolimus and IFN-α.

• Based on subgroup analysis from the pivotal trial as well as expanded access programmes, sunitinib is another reasonable option in this setting [II, B]. Sorafenib based on expanded access programmes is another possible alternative [III, B]. It is clear that, for some poor prognosis patients, best supportive care remains the only suitable treatment option.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014Hudes G et al. Temsirolimus, interferon alfa, or both foradvanced renal-cell carcinoma. N Engl J Med 2007.

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

second-line treatment• Evidence that TKIs are active after cytokines has been

demonstrated with sorafenib [I, A], pazopanib [II, A] and recently axitinib [I, A]. Sunitinib also has activity in this setting [III, A].

• However, since VEGF-targeted therapy is now the first-line standard of care, the number of patients treated with cytokines is decreasing.

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

1 Sternberg CN et al. Pazopanib in locally advanced ormetastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol2010.2 Escudier B et al. Sorafenib in advanced clear-cell renal-cellcarcinoma. N Engl J Med 2007.3 Rini BI et al. Comparative effectiveness of axitinib versussorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.Lancet 2011.

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

second-line treatment• After first-line treatment with VEGF-targeted therapy○ Both axitinib [I, B] and everolimus [II, A] are active. Both

drugs have shown significantly improved PFS over placebo (everolimus) or sorafenib (axitinib), but not OS.

○ Based on recent phase III trials, sorafenib can be used as an option [II, A].

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

1 Rini BI et al. Comparative effectiveness of axitinib versussorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.Lancet 2011.2 Motzer RJ et al. Efficacy of everolimus in advanced renalcell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.Lancet 2008.3 Hutson TE et al. Randomized phase III trial of temsirolimusversus sorafenib as second-line therapy after sunitinib in patients with metastaticrenal cell carcinoma. J Clin Oncol 2014.

Metastatic Renal Cell Carcinoma: ESMO Clinical Practice Guidelines

third-line treatment • Beyond second-line treatment, enrolment into

clinical trials is recommended where possible. However, some recent trials have been reported, helping to define two different scenarios:

• In patients already treated with two TKIs (or a TKI and bevacizumab), everolimus is recommended [II, A].

• In patients previously treated with VEGF-targeted therapy and mTOR inhibitor, sorafenib [I, B] has shown activity. Another TKI or rechallenge with the same TKI is considered as an option [IV, B].

Annals of Oncology 25 (Supplement 3): iii49–iii56, 2014

Motzer RJ et al. Dovitinib versus sorafenib for third-linetargeted treatment of patients with metastatic renal cell carcinoma: an open-label,randomised phase 3 trial. Lancet Oncol 2014.