Highlights in the Managment of Urogenital Cancer Future directions for targeted therapies in advanced renal cell cancer Alessandro Morabito Unità Sperimentazioni

Highlights in the Managment of Urogenital Cancer

Future directions for targeted therapies in

advanced renal cell cancer

Alessandro Morabito

Unità Sperimentazioni Cliniche

Istituto Nazionale Tumori di Napoli

Roma, 10 maggio 2008

The past…

IL-2, interferon

Advances in last years

• In understanding the biology and genetics of renal cell carcinoma

• Availability of novel targeted approaches for the treatment of metastatic RCC

New target-based agents

Brugarolas, NEJM 2007

Temsirolimus

Everolimus

SunitinibSorafenib

Bevacizumab

ErlotinibCetuximab

Target-based agents: results of phase III trials

Author Agent Setting PtsPFS

(months)OR (%)

OS (months)

Motzer (NEJM, 2007)

Sunitinib vs IFN

1st line 750 11 vs 5 (p<0.0001)

31 vs 6 (p<0.001)

HR: 0.65 (p=0.02)*

Escudier (NEJM, 2007)

Sorafenib vs Placebo

2nd line 903 5.5 vs 2.8 (p<0.001)

10 vs 2 (p<0.001)

HR: 0.72 (p=0.02)*

Hudes (NEJM, 2007)

Temsirolimus vs IFN vs

TEMSR+IFN1st line 626

3.7 vs 1.9 vs 3.7

9 vs 7 vs 11

HR: 0.73 (p=0.0069)

Escudier (ASCO, 2007)

Bevacizumab + IFN vs

placebo+IFN1st line 649

10.2 vs 5.4 (p<0.0001)

31 vs 13 (p<0.0001)

HR: 0.75 (p<0.0026)*

* No statistically significant according to O’Brien-Fleming

The present…: an embarrassment of riches ?

Therapeutic algoritm

Patients SettingTherapy (level 1)

Options (level 2)

Naive

MSK Risk: good or

intermediate

Sunitinib(Bevacizumab + IFN)

HD IL-2

MSK Risk: poor Temsirolimus Sunitinib

Refractory

Cytokine refractory Sorafenib

Sunitinib

Bevacizumab

Refractory to angiogenesis

inhibitorsInvestigational Investigational

Future directions ?

Targeted therapies: challenges and future directions

• Combination therapy• New schedules • Sequential strategies• Role of cytokines• New agents• Predictive biomarkers• Adjuvant and neo-adjuvant therapy



Combination therapy

• What is the actual goal of therapy with combination of target based agents?

• What are the targets we want to direct therapy toward?

• How does one develop a rationale to proceed into the clinic with combination therapy?

Goal of combination therapy

• To increase the degree of the antitumor effects of single agents

• To induce more complete responses impeding the onset of refractory disease

• To overcome the resistance that develops with single-agent therapy

Morabito A, Ann Oncol 2006

Alternative end points for agents that are not expected to cause a major tumor regression…

• Phase II design for targeted agents is similar to that of cytotoxics

• Objective response seems to be a useful end-point and it is predictive for success of the drug

• Agents with high response rates tended to have high non-progression rates

• Renal cell carcinoma is the exception to this…

Non PD rates...

Targets for RCC therapy

• VHL or HIF mediated pathways– VEGF – VEGF receptors– EGFR– mTOR– PDGF

• Non-VHL-mediated pathways– Raf kinase– Phosphatidylinositol 3-kinase– Akt– Nuclear factor B

Rationale combinations of targeted therapies

• Horizontal blockade– Numerous target molecules downstream from HIF-

are inhibited

• Vertical blockade– The same pathway is targeted at two or more

different levels

Horizontal blockade

• Targets generally in different cell types (tumor, endothelial, pericyte)

• Inhibition by multiple specific agents or by multitargeted agents

• To prevent cancer cell proliferation, promote apoptosis, ablate angiogenesis

Sosman JA, Clin Cancer Res 2007

Horizontal blockade of VEGF and EGFR pathways

• Elevated levels of TGF- in RCC• TGF- is a growth factor for RCC

independent of stroma• Elevated expression of VEGF

has been considered to be a mechanism for acquired resistance to EGFR blockade

• Inhibition of EGFR results in suppression of VEGF expression in laboratory modelsBevacizumab

Sunitinib Sorafenib

Erlotinib Gefitinib

Combination of bevacizumab and erlotinib: results of a phase 2 study (positive…)

• Single agent bevacizumab: 10% objective responses

• Poor results with single-agent treatment against EGFR

Hainsworth JD, J Clin Oncol 2005

Bevacizumab Sunitinib Sorafenib

Erlotinib Gefitinib

Combination of bevacizumab and erlotinib: results of a randomized phase 2 study

(negative…!)

Bukowski, J Clin Oncol 2007

Horizontal blockade of VEGF and EGFR pathways: other combinations

Agents Phase Pts Results

Sunitinib + Gefitinib*

1/2 42Sunitinib 37.5 mg + Gefitinib 250 mg

OR = 36%

Sunitinib + Erlotinib**

2 13Sunitinib 50 mg + Erlotinib 150 mg

Activity: 10/11 pts

Bevacizumab Sunitinib Sorafenib

Erlotinib Gefitinib

*Patel, ASCO 2007 **Ryan, Genitourinary Cancer Symposium 2008

Vertical blockade

• The same pathway is targeted at two or more different levels

• Vertical blockade could overcome an aspect of resistance that may develop through feedback mechanisms (ie. VEGF levels in response to blocking VEGFR)

Sosman JA, Clin Cancer Res 2007

Temsirolimus Everolimus

Bevacizumab

Sunitinib Sorafenib

Vertical blockade of VEGF pathway


Bevacizumab

Sunitinib Sorafenib


Bevacizumab + sunitinib*

1 16

Sunitinib feasible at 37.5 mg + bevacizumab 10 mg/kg

OR: 4/13 pts

Bevacizumab + sorafenib**

1-2 18

Sorafenib feasible at 200 mg + bevacizumab 3 mg/kg

10 PR and 4 SD / 24 pts

*Feldman DR, ASCO 2007 **Sosman JA, ASCO 2006



Bevacizumab

Sunitinib Sorafenib


Temsirolimus + sorafenib*

1 24

Evaluation of sorafenib 200 mg BID + temsirolimus 25 mg ongoing

Everolimus + sorafenib**

1 10

Sorafenib feasible at 400 mg BID + everolimus 5 mg ongoing

PR: 33%

*Patnaik A, ASCO 2007 **Rosenberg JE, Genitourinary Cancer Symposium 2008



Bevacizumab

Sunitinib Sorafenib


Bevacizumab + temsirolimus*

1-2 12

DLT: hypertriglyceridemia and stomatitis

Recommended dose of bevacizumab 10 mg/kg q 14 and temsirolimus 25 mg/w

Primary endpoint (phase 2): 6-month PFS

PR (phase 1): 67%

Bevacizumab + everolimus**

1 14Recommended dose of bevacizumab 10 mg/kg q 14 and everolimus 10mg

Bevacizumab + everolimus + erlotinib*** 1 34

Recommended dose of bevacizumab 5 mg/kg q 14, everolimus 5 mg and erlotinib 75 mg/die

Activity in RCC and CRC

*Merchan JR, ASCO 2007; ** Zafar Y, ASCO 2006; *** Bendell JC, ASCO 2007

Phase II Study of Bevacizumab, Sorafenib, and Temsirolimus in mRCC

(ECOG 2804 “BeST” Trial)

Eligibility criteria● Confirmed clear cell RCC● Measurable metastatic

disease● <25% of any other histology

(papillary, chromophobe, or oncocytic)

● Primary or metastatic lesion ● Not curable by standard

radiotherapy or surgery● Prior nephrectomy● No more than 1 prior

regimen containing vaccine- or cytokine-based immunotherapy

● No prior antiangiogenic therapy, bevacizumab or mTOR inhibitors

Bevacizumab i.v. over 30−90 min d1−15

+Temsirolimus 25i.v over 30 mind1, d8, d15, d22

Bevacizumab 10 i.v. over 30−90

min d1-15

Primary endpoint: PFS

Start Date: September 2007; recruiting

(N=360)

+Sorafenib 200

b.i.d. p.o., d1−28

Bevacizumab 5 i.v. over 30−90

min d1−15

+Sorafenib

p.o. b.i.d., d1−28

Temsirolimusi.v. over 30 mind1, d8, d15, d22

RANDOMIsATION

NCT00378703. www.clinicaltrials.gov.

SABRE-R: Phase II Study of Sunitinib With or Without Bevacizumab as First-line Therapy in

mRCC (USA)

Eligibility criteria● Histologically confirmed mRCC ● Measurable disease by

RECIST ● ECOG PS of 0 or 1 ● Prior nephrectomy ● No prior systemic or adjuvant

therapy● Adequately controlled

hypertension

(n=50)

(n=50)

Primary endpoint: PFS and safety

Secondary end points: ORR, duration of response, TTP, OS

(N=100)

+

RANDOM

ISATI

ON

Sunitinib50 mg p.o. o.d. 4/2 schedule

Bevacizumab 10 mg/kg i.v.

q2w

NCT00491738. www.clinicaltrials.gov.

+Sunitinib

50 mg p.o. o.d. 4/2 schedule

Placebo

Start Date: August 2007; recruiting

Phase II Open-label Study of Bevacizumab plus Temsirolimus for First-line Treatment of mRCC

(n=40)

(n=40)

(n=80)

Eligibility criteria● Metastatic RCC● No prior

systemic treatment

● ECOG PS ≤2

Bevacizumab 10 mg/kg every 2 weeks + temsirolimus

25 mg/week

Sunitinib 50 mg/day4/2 schedule

(N=160)

Bevacizumab 10 mg/kg every 2 weeks + IFN- 9 MU q.i.w.

RANDOMISATION

PIs: Escudier and Negrier

Primary endpoint: PFS at 48 weeks

Secondary endpoints: ORR, response duration, OS, QoL, safety



New schedules

• Dose escalation of Sorafenib*– Phase 2 study of intra-patient dose escalation of sorafenib, up to

800 mg BID

– 91% of pts escalated to 1200 mg or 1600 mg per day

– OR: 52%

• Continuous daily administration of Sunitinib**– 107 pts, refractory to cytokines, randomized in a phase 2 study

(morning vs evening)

– Manageable safety profile

– OR: 19% and SD: 40%

* Amato RJ, ASCO 2007 ** Srinivas S, ASCO 2007

Renal EFFECT: Phase II Trial of Sunitinib CD

vs the 4/2 Schedule in First-line mRCC

Primary end point: TTPSecondary end points: safety and tolerability, ORR, OS, QOL

Eligibility criteria

● Advanced RCC

● Clear-cell histology

● Measurable disease

● No prior systemic therapy

● No brain metastasis

(N=282)

RANDOMISATI

ON

Sunitinib50 mg p.o. daily on 4/2 schedule

Sunitinib37.5 mg p.o.

continuous daily

NCT00267748. www.clinicaltrials.gov.Start Date: December 2005; recruiting



Sequencial strategies

• Is there a role?– TKIs have antitumor activity in RCC pts previously

treated with antiangiogenic therapy

• Which agent?– Type of anti-angiogenic therapy received does not

predict response to subsequent therapy

• Is there an optimal sequence?– Current data support use of sequential TKIs;

prospective studies in progress will define efficacy and toxicity

Sequential TKIs in advanced RCC: retrospective analyses

Sequence Pts CR+PR SDSorafenib Sunitinib

Tamaskar et al.1 3 1 (33%) -

Escudier et al.2 34 8 (24%) 22 (64%)

Sunitinib Sorafenib

Tamaskar et al.1 5 0 4 (80%)

Escudier et al.2 14 3 (21%) 8 (57%)

Tamaskar et al. ASCO 2006; Escudier et al. ASCO 2007

START: Randomised Phase II Sequential Two-agent Assessment in RCC Therapy (Proposed)

Eligibility criteria●mRCC of any type●PS 0/1●No brain mets●No prior systemic

therapy

Sunitinib

(N=240)

(n=120)

(n=120)Bevacizumab

Sunitinib

Bevacizumab

Temsirolimus

Temsirolimus

(n=60)

(n=60)

(n=60)

(n=60)

Stratification:• Clear cell vs non–clear cell• Prior nephrectomy (yes/no)• PS (0/1)

Progression

RANDOM

ISATI

ON

R

R

Objectives:Estimate TTP1 and ORR with each drug (first-line setting)Estimate TTP2 and ORR with each drug (second-line setting)Estimate and rank TTP1 + TTP2 for each sequence

Randomised Phase III Study of Temsirolimus vs Sorafenib as second-line Therapy in

mRCC

Primary end point: PFS

Secondary end points: OS, ORR, QoL, Safety

Temsirolimus 25 mg i.v.+

Best supportive care

Sorafenib+

Best supportive care

N=440

Eligibility criteria• Metastatic clear cell RCC• Measurable disease• Failed sunitinib • Karnofsky PS ≥70%• ≥1 measurable lesion by

RECIST• No prior mTOR inhibitors• No brain metastases

RANDOM

ISATI

ON

NCT00474786. www.clinicaltrials.gov

Start Date: July 2007; recruiting

Expected Completion Date: October 2010

MD Anderson: Study Proposal



Role of cytokines

• VEGF has been shown to suppress immune function by:– blocking maturation of myeloid cells into mature dendritic

cells– inducing the immature myeloid cells to suppress normal

T-cell responses

• Anti-VEGF therapy may reverse these immunosuppressive effects

Bukowski RM, Berlin 2008

Interferon and…. bevacizumab

*Bracarda S, Genitourinary Cancer Symposium 2008; **Gollob J, ASCO 2006; ***Ryan W, ASCO 2006 § Kondagunta GV, ASCO 2007

Interferon and…. VEGFR inhibitors

Schedules Phase Pts Results

Sorafenib + interferon*2,

randomized100 OR: 34%; clinical benefit: 80%

Sorafenib + interferon ** 2 31 OR: 42%; clinical benefit: 88%

Sorafenib + interferon *** 2 67 OR: 19%; clinical benefit: 66%

Sunitinib + interferon § 1 25Recommended dose: sunitinib 37.5 mg and IFN 3 MUI

OR: 12%; clinical benefit: 92%

IL-2 and…bevacizumab

Schedules Phase Pts Results

Low dose IL-2 + bevacizumab*

2 24 OR: 9%; clinical benefit: 36%

Low dose IL-2 + bevacizumab + Gem + 5-FU*

1-2 32 OR: 30%; clinical benefit: 60%

*Tamaskar IR, Genitourinary Cancer Symposium 2008; Buti S, ASCO 2007



New agents• VEGFR inhibitors

– Axitinib– AZD2171– Pazopanib– Everolimus (RAD001)

• Integrin inhibition– M200 (volociximab)

• Akt/MAP kinase inhibition– Perifosine– Tie 2 inhibition– AMG 386

• C-Met inhibition– ARQ 197– XL880

New VEGFR inhibitors in RCC

Agent Phase Pts Results

AG-013736 (Axitinib)*as second line in patients

refractory to sorafenib2 62 OR: 14%; clinical benefit: 50%

AZD2171 (Cediranib)** as first line

2 24 OR: 38%; clinical benefit: 75%

Pazopanib*** as first/second line

2 RDT 60 OR: 40%; clinical benefit: 82%

*Rini BI, ASCO 2007; **Sridhar SS; ASCO 2007; ***Hutson TE, ASCO 2007

Everolimus 10 mg/d + BSC

Everolimus: Phase III in RCC (RECORD-1 study)

● Oral inhibitor of mTOR

● Patients with metastatic RCC and PD after receiving sunitinib and/or sorafenib

● Stratified by number of prior treatments and MSKCC risk criteria (favourable vs intermediate vs poor)

● The trial was stopped after a planned interim results showed significantly better progression-free survival with everolimus….Complete results will be presented at ASCO 2008

Placebo + BSC

N=3622 : 1

RAD001 : Placebo


Patients SettingTherapy (level 1)

Options (level 2)

Naive

MSK Risk: good or

intermediate

Sunitinib(Bevacizumab + IFN)

HD IL-2

MSK Risk: poor Temsirolimus Sunitinib

Refractory

Cytokine refractory Sorafenib

Sunitinib

Bevacizumab

Refractory to angiogenesis

inhibitorsInvestigational Investigational

The next algorithm…?

Everolimus?



Predictive biomarkers

• Serum/plasma markers:– VEGF– sVEGFR

• Tissue/cells:– HIF expression– VHL gene mutation

Bukowski RM, ASCO 2007

Bukowski RM, ASCO 2007

VHL status and clinical outcome

• Hypothesis: tumors with VHL gene inactivation should exhibit a greater objective response rate to VEGF-targeted therapy

• 123/189 pts treated with:– sunitinib (n=63)

– axitinib (n=15)

– bevacizumab (n=17)

– sorafenib (n=28)

Choueiri et al. ASCO 2007

Choueiri et al. ASCO 2007

53% 0%



S-TRAC: Sunitinib Phase III Trial in

Adjuvant Renal Cancer Treatment

High-risk patients according to UISS Staging System*

N=236

*T3 N0 or NX, M0, Fuhrman’s grade ≥2, ECOG ≥1 or T4 N0 or NX, M0, any Fuhrman’s grade, and any ECOG status or Any T, N1-2, M0, any Fuhrman’s grade, and any ECOG status

• Endpoint:

Disease-freesurvival


NEPHRECTOMY

RANDOMISE

Sunitinib 50 mg/day 4 weeks on/2 weeks off for 1 year

Sunitinib 50 mg/day 4 weeks on/2 weeks off for 1 year

Placebo for 1 yearPlacebo for 1 year

Stratify

Primary end point: Disease-free survival

Secondary end points: OS, safety, patient-related outcomes, association of molecular markers with regression - free survival

Start Date: September 2007; recruiting

Non-metastatic RCC

Disease stage II–IV

N=1,332

ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavourable RCC

NEPHRECTOMY

Stratify*

RANDOMISE

Sunitinib 50 mg/day 4 weeks on/2 weeks offTotal = 9 cycles†

Sunitinib 50 mg/day 4 weeks on/2 weeks offTotal = 9 cycles†

Placebo twice daily for 6 weeks Total = 9 cycles†

Placebo twice daily for 6 weeks Total = 9 cycles†

Sorafenib 400 mgtwice daily for 6 weeks Total = 9 cycles†

Sorafenib 400 mgtwice daily for 6 weeks Total = 9 cycles†

• Duration: 1 year

• Primary endpoint: DFS

*UISS (II–V); Histologic subtype clear cell/non-clear cell†Biopsy at recurrence


ECOG-sponsored, randomised, double-blind, multicentre phase III trial; currently recruiting

Start Date: May 2006; recruiting

SORCE: Sorafenib in Patients with Resected Primary RCC at High or Intermediate Risk of

Relapse

Stratify

Sorafenib 400 mg b.i.d. for 3 years

Placebo for 3 years

Sorafenib 400 mg b.i.d. for 1 year then

placebo for 2 years

Endpoint: time to metastases

Duration: 1 vs 3 years

Patients with high- and intermediate- risk resected RCC

N=1420

NEPHRECTO

MY

RANDOMISATION

NCT00492258. www.clinicaltrials.gov.Start Date: June 2007; recruiting

Phase II study of neoadjuvant Sunitinib for Patients with RCC

● Non-randomised, open label, uncontrolled, single group assignment, safety/efficacy study

● Primary outcome measures– radiological response rate associated with 2 cycles of sunitinib

● Secondary outcome measures:– change in tumour vascularity– assessment of tissue markers– safety and tolerability

● Enrollment: 30● Inclusion/exclusion criteria

– locally confined tumour ≤7 cm– has not undergone nephrectomy and is a candidate for surgical treatment of

RCC– ECOG performance status 0 or 1– no prior therapy of any kind for RCC (including nephrectomy, immunotherapy,

chemotherapy, radiation, hormonal, or investigational therapy)● University Health Network, Toronto

Start Date: October 2007(University of Toronto) NCT00480935. www.clinicaltrials.gov.

Group 3– Oral sorafenib twice

daily on days 1−28– Cytoreductive

nephrectomy on day 29– Oral sorafenib twice

daily on days 43−84

Group 2 – Oral sorafenib twice

daily on days 1−7– Cytoreductive

nephrectomy on day 8

– Oral sorafenib twice daily on days 22−84

Group 1– Cytoreductive

nephrectomy on day 1

– oral sorafenib twice daily on days 15−84

Sorafenib for Patients Who Are Undergoing Surgery for Metastatic Kidney Cancer

● Objectives:– determine the efficacy and toxicity of neoadjuvant sorafenib in patients

(N=45) with mRCC who are undergoing cytoreductive nephrectomy ● Non-randomised study – patients are sequentially assigned to 1 of 3

treatment groups

NCT00126659. www.clinicaltrials.gov.Start Date: January 2006; ongoing, not recruiting

● Non-randomised, open-label, uncontrolled, single group assignment, safety/efficacy study

● Primary objectives– time to progression and safety

● Secondary objectives (Clinical)– response rate, duration of response, OS

● Enrollment: 50● Inclusion/exclusion criteria

– patients with histologically or cytologically confirmed clear cell metastatic RCC who are eligible for cytoreductive nephrectomy

– ECOG performance status less than or equal to 1

– patients must not have received any systemic anticancer therapy Radiation therapy is allowed if >/= 2 weeks from study drug administration

NCT00113217. www.clinicaltrials.gov.Start Date: February 2005; recruiting

Neoadjuvant phase II clinical trial of bevacizumab for RCC

In the next years....

• Ongoing studies will clarify:

– The role of combination therapy (also including cytokines)

– The optimal sequence of therapy – Therapy for resistant disease– Molecular biomarkers defining groups

benefiting from anti-VEGF therapy

The future …: an embarrassment of results?

Documents

Highlights in the Managment of Urogenital Cancer Future directions for targeted therapies in advanced renal cell cancer Alessandro Morabito Unità Sperimentazioni