Andrea Necchi Department of Medical Oncology Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Treasurer – EORTC GU Cancers Group EAU Penile Cancer Guidelines Panel

Urothelial bladder cancer: Oral abstract session - Outline

Immuno-oncology trials (IOT) with immune-checkpoint

blockade: on the cusp of a sea change:

- The salvage setting: Updated results from IMvigor 210 (Cohort

2) – [Abstr. 355, J. Hoffman-Censits]

- The first-line setting: Results of GC + Ipi – [Abstr. 357, M.D. Galsky]

- Improving the molecular understanding of UC might imply to

better design IOT – [Abstr. 358, G. Sonpavde], [Abstr. 354, B. Faltas]

- Any role for radiotherapy in peri-operative (adjuvant) setting –

[Abstr. 356, B. Baumann]

Burning topics from Oral session @GU-ASCO 2016

Manuscript under review

[Abstract #355]

Disclosures

• Co-investigator & co-author of IMvigor 210, advisor of F. Hoffmann-La Roche Ltd.

• GU Advisor and research grant recipient, Merck Sharp & Dohme (MSD)

• Advisor, Bristol Myers Squibb (BMS) • Advisor, Astra Zeneca

First Country opened in EU 20 pts (19 INT Milano, 1 Arezzo) in <12 wks

FDA Breakthrough Therapy designation

A drug that receives Breakthrough Therapy designation is eligible for the following:1

• All Fast Track designation features

• Intensive guidance on an efficient drug development program, beginning as early as phase I

• Organisational commitment involving senior managers

• Eligibility for rolling review and priority review

Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a

serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy

on a clinically significant endpoint(s)1

1. FDA Breakthrough Therapy

Atezolizumab: two studies in first-line/second-line UC are under way

• Primary endpoint: ORR in IHC 2/31/2/3ITT

• Secondary endpoints: DoR, PFS, OS

• FPI: May 2014

• Primary endpoint: OS in IHC 2/31/2/3ITT

• Secondary endpoints: PFS, ORR, DoR

• FPI: Q4 2014

Atezolizumab 1200mg IV q3w

Patients with disease progression following or during platinum-containing treatment for MIBC or mUBC

(n=300 [100 PD-L1+])

Treatment-naive and cisplatin-ineligible MIBC or mUBC (n=100 [33 PD-L1+])

Atezolizumab 1200mg IV q3w

Patients with previously treated relapsed UBC (n=767 [230 PD-L1+])

Vinflunine, paclitaxel, or docetaxel IV q3w until progression

IMvigor 211/GO29294 (phase III)

http://www.clinicaltrials.gov/ct2/show/NCT02108652

FPI=first patient in; ITT=intent-to-treat

8

IMvigor 210/GO29293 (phase II)

[Abstract #355]

Hoffman-Censits et al.

[Abstract #355]

Hoffman-Censits et al.

[Abstract #355]

Hoffman-Censits et al.

[Abstract #355]

Hoffman-Censits et al.

Summary: pembrolizumab and atezolizumab in UC

*Defined as any staining in the stroma or in ≥1% of tumour cells **IHC status defined as IC3: ≥10% of IC expressing PD-L1; IC2: ≥5% but <10% of IC expressing PD-L1; IC1: ≥1% but <5% of IC expressing PD-L1; IC0: <1% of IC expressing PD-L1 (SP142 IHC assay) 1. Plimack, et al. ASCO 2015 2. Petrylak, et al. ASCO 2015 3. Hoffman-Censits, et al. GU-ASCO 2016

Pembrolizumab

KEYNOTE-012

(phase Ib)1

Atezolizumab

PCD4989g (phase Ia)2 IMvigor 210 (phase II)3

Target PD-1 PD-L1 PD-L1

Number of

evaluable patients 29 87 (IC2/3 = 46) 311 (IC2/3 = 100)

Study population PD-L1+* All comers** All comers**

Schedule q2wk q3wk q3wk

Grade 3–4 toxicity 15% 8% 16%

ORR 28% IC2/3 = 50% IC2/3 = 26%

Median OS 13 months IC2/3 = NR

(1 to 20+ months) IC2/3 = 11.4

(9.0, NE)

12-month OS rate 53% 57% 48%

13

Kick-off of IOT in UC holds promise, BUT:

• Atezolizumab breackthrough registration: for

whom? (i.e. PD-L1 unselected/selected patients)

• Results with Nivolumab (Ph2 –CA209-275) and

Pembrolizumab (Ph3 – KEYNOTE-045) are awaited

• Issue of companion diagnostics still open

• Inclusion criteria for IOT are probably suboptimal

(prior platinum-failure, ECOG PS 2 etc.)

Abstract 355, Hoffman-Censits et al. My thoughts

2014 2015 2016 2017 2018 2019 2020 2021

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

Bla

dd

er

1L+

A

dju

van

t Pivotal Bladder (Urothelial) Trials

U.S. and EU Approval Timelines

NCT02387996 (Ph II): 2L+ (n ≥ 250)

KEYNOTE 045 (Ph III): 2L+ (n = 470) **

NCT02108652 (Ph II): 1L (n ≥ 330 [1L+2L])

NCT02450331 (Ph III): (n = 440)

x

Biomarkers

√ PDL1

x

No Phase III confirmatory trial currently ongoing or planned

KEYNOTE 052 (Ph II): 1L (n = 350)

√

MSD: Pembrolizumab AZ: Durvalumab BMS: Nivolumab Roche: Atezolizumab Trial Design:

Data Analysis / Regulatory Review Regulatory Approval: FDA EMA

Avelumab

**Fast Track or Breakthrough designation needed for scenario to occur

Assumptions: trial completion is primary completion date Data analysis is 3 months for add on indication, 6 months for first indication BTD review is 4 months Priority review is 6 months Standard review is 10 months

Currently unclear if either of the Phase II studies are registrational as it is dependent on regulatory acceleration

NCT02108652 (Ph II): 2L+ (n ≥ 330 [1L+2L]) BTD

**

Updated 07/28/15

NCT02302807 (Ph III): 2L+ (n ≥ 767) BTD

PD-L1+ patients only

√

x

x

NCT02516241 (Ph III): 1L (n ≥ 525)

NCT02603432 (Ph III): 1L Maint (n ≥ 530) √

√

PFS in PD-L1 negative patients as secondary endpoint

[Abstract #357]

Ipilimumab “window” study before radical cystectomy (N=12)

Carthon BC, Clin Cancer Res 2010

Study Schema

Summary of major findings

Galsky et al.

[Abstract #357]

• Primary endpoint: PFS of combination therapy vs SOC CT

• Secondary endpoint: PFS in PD-L1-negative patients, OS, safety and tolerability, ORR, functional assessment of cancer therapy- bladder cancer (FACT-BL), immunogenicity, pharmacokinetics

• Study start date: October 2015

• Estimated study completion date: August 2019

• Estimated primary completion date: November 2017

DANUBE: A Phase III, Randomized, Open-label, Controlled, Multicenter, Global Study of First-Line MEDI4736 Monotherapy and MEDI4736 in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV

Urothelial Bladder Cancer

https://clinicaltrials.gov/ct2/NCT02516241

Durvalumab

Durvalumab + tremelimumab

SOC CT: Cisplatin + gemcitabine or Carboplatin + gemcitabine

Key eligibility • First-line histologically or cytologically confirmed

unresectable stage IV UBC • Eligible or ineligible for cisplatin-based CT • Cisplatin ineligible defined as meeting 1 of the below

criteria: − Creatinine clearance <60 mL/min; CTCAE grade ≥2

audiometric hearing loss; CTCAE grade 2 peripheral neuropathy; NY Heart Association class III heart failure

• Tumor PD-L1 status (IHC confirmed by reference laboratory) is required prior to randomisation

N=525

R

1:1:1

Prossimi Centri Attivi in Italia: - Fondazione IRCCS INT Milano (Centro Coordinatore) - IRCCS OSPEDALE SAN RAFFAELE - IRST IRCCS MELDOLA - Az. Osp. S. Luigi Gonzaga Orbassano - FONDAZIONE IRCCS POLICLINICO S. MATTEO PAVIA - FONDAZIONE IRCCS PASCALE-NAPOLI - OSP. S. DONATO-AREZZO

A myriad of next generation trials with monotherapy or combination therapy are underway

in almost all the clinical settings

• Pembrolizumab (EudraCT: 2014-004026-17

• Everolimus + intravesical GEM (NCT01259063)

Pembrolizumab + hypofractionated RT [RMH] Ph1 (NCT02560636)

PURE01: pembrolizumab>cystectomy (EudraCT: 2015-002055-10)

ABACUS: atezolizumab>cystectomy (EudraCT: 2015-001112-35)

Phase III: atezolizumab (NCT02450331)

Phase III: pembrolizumab (AMBASSADOR)

Phase III: nivolumab (CA209-274; EudraCT: 2014-003626-40)

Neoadjuvant Adjuvant

NMIUC: BCG failure/refractory

Phase II: KEYNOTE-052, pembrolizumab

(NCT02335424)

Phase III: Vinflunine; JASINT-2 (EudraCT: 2014-005396-82

Phase III: KEYNOTE-045, pembrolizumab

(NCT02256436)

Phase III: atezolizumab (GO29294), NCT02302807

Phase III: ramucirumab+docetaxel (RANGE, NCT02426125) Phase III: MEDI4736 vs MEDI4736 + tremelimumab vs chemotherapy

(DANUBE, NCT02516241)

Maintenance Tx

Refractory

Phase III: avelumab (EudraCT: 2015-003262-86)

Phase II: regorafenib (NCT02459119)

Phase II: JNJ-42756493 (NCT02365597) Phase I: BGJ-398 (NCT01004224) Atezolizumab + bevacizumab Atezolizumab + Rad223

Pembrolizumab+ACP-196 (NCT02351739) AD4547/MEDI4736 AZD8186/MEDI4736 Olaparib/MEDI4736 Wee1/MEDI4736 Olaparib/MEDI4736/Tremelimumab Etc.

Sources: http://ClinicalTrials.gov; http://www.bcan.org

Phase III: GC+Bevacizumab (CALGB, NCT00942331)

First-line therapy

[Abstract #358]

Circulating Tumor DNA (ctDNA) as Liquid Biopsy Study Design

Guardant360™

55 pts with either: - Metastatic disease (N=25) - MIBC (N=18) - Unavailable (N=12)

[Abstract #358] Sonpavde et al.

Circulating Tumor DNA (ctDNA) as Liquid Biopsy Key findings

• Spectrum of mutations similar to that described in TCGA

• For the types of alterations, there were not significant differences between Metastatic and Non metastatic pts

• Metastatic pts harboured an higher burden of molecular alterations

• Serial ctDNA monitoring might provide insights into the shifting UC biology over treatment

[Abstract #358]

[Abstract #354]

[Abstract #354]

Faltas et al.

Neoantigen load & heterogeneity

Faltas et al. [Abstract #354]

Sharma P & Allison JP. Science 2015

Atezolizumab: two studies in first-line/second-line UC are under way

• Primary endpoint: ORR in IHC 2/31/2/3ITT

• Secondary endpoints: DoR, PFS, OS

• FPI: May 2014

• Primary endpoint: OS in IHC 2/31/2/3ITT

• Secondary endpoints: PFS, ORR, DoR

• FPI: Q4 2014

Atezolizumab 1200mg IV q3w

Patients with disease progression following or during platinum-containing treatment for MIBC or mUBC

(n=300 [100 PD-L1+])

Treatment-naive and cisplatin-ineligible MIBC or mUBC (n=100 [33 PD-L1+])

Atezolizumab 1200mg IV q3w

Patients with previously treated relapsed UBC (n=767 [230 PD-L1+])

Vinflunine, paclitaxel, or docetaxel IV q3w until progression

IMvigor 211/GO29294 (phase III)

http://www.clinicaltrials.gov/ct2/show/NCT02108652

FPI=first patient in; ITT=intent-to-treat

28

IMvigor 210/GO29293 (phase II)

[Abstract #356]

[Abstract #356]

Baumann et al.

[Abstract #356]

Baumann et al.

No significant differences in DFS

across the study arms, BUT:

• Chemo arm was not originally

planned, the statistical

assumptions are unclear

• Original hypothesis (e.g.

improvement of CT+RT over RT

alone) was based on the

“provincial” (Egyptian) benchmark

of RT as the standard of care

• Reasons for U.S. “intellectual

contribution” not fully

acknowledged

CA209274 (CheckMate 274). A phase 3 randomized, double-blind, placebo controlled study of adjuvant nivolumab in subjects with high risk residual disease following neo-adjuvant chemotherapy and radical resection for muscle invasive urothelial carcinoma (MIUC or MIBC), or in subjects who underwent radical resection without neoadjuvant chemotherapy and are not eligible for or are refusing adjuvant cisplatin based chemotherapy.

HYPOTHESIS: Treatment with nivolumab will extend disease-free survival, compared with placebo, as adjuvant therapy in all randomized patients and in patients with PD-L1 expressing tumors (membranous staining in ≥1%) with high risk residual disease after radical resection of MIBC.

Approximately 600 subjects will be randomized in a blinded fashion 2:1

REASONS OF CISPLATIN INELIGIBILITY: a. Creatinine Clearance (using the Cockcroft-Gault formula): <60 mL/min b. CTCAE version 4, grade 2 or above audiometric hearing loss c. CTCAE version 4, grade 2 or above peripheral neuropathy d. ECOG PS 2

EUDRACT Number 2014-003626-40

Other Ph3 adjuvant trials: • WO29636 Trial • (Atezolizumab) • AMBASSADOR trial

(Pembrolizumab)

Gruppo di ricerca italiano sulle neoplasie vescicali Una prospettiva multi-stakeholder & work in progress

andrea.necchi@istitutotumori.mi.it @AndreaNecchi