Il disegno e la

conduzione delle

sperimentazioni cliniche

nell’era dell’oncologia di

precisione: cosa sta

cambiando?

Emmanuele De Luca

Scuola di Specializzazione Oncologia Medica,

AO Ordine Mauriziano, Torino

Dipartimento di Oncologia

Università di Torino

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ASCO 2001 Grand Rounds: Molecular Oncology Symposium

Jaap Verweji, 2001:

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Tuesday, May 23rd, 2017

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Approval agnostic of cancer site:

The case of pembrolizumab (MSI-H- dMMR

tumors)

Lemery S, Keegan P, Pazdur R.

N Engl J Med. 2017 Oct 12;377(15):1409-1412.

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Approval agnostic of cancer site:

The case of pembrolizumab

Lemery S, Keegan P, Pazdur R.

N Engl J Med. 2017 Oct 12;377(15):1409-1412.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

Basket trials

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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.

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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.

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Statistical Analysis

• An adaptive Simon two-stage design was used

for all tumor-specific cohorts in order to minimize

the number of patients treated if vemurafenib

was deemed ineffective for a specific tumor type.

• The primary efficacy end point was the response

rate at week 8.

Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.

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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.

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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.

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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.

• In conclusion, we found that the BRAF V600

mutation is a targetable oncogene in some, but not

all, cancer types.

• Histology-independent, biomarker-selected basket

studies are feasible and can serve as a tool for

developing molecularly targeted cancer therapy.

• Confirmation of promising activity identified in basket

studies will often necessitate additional studies.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

“Umbrella” trials

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BFAST: Trial Schema

PS = performance status; FMI = Foundation Medicine; ctDNA = circulating tumor deoxyribonucleic acid;

bSMP = blood somatic mutation profiling; bTMB = blood tumor mutational burden; RP2D = recommended phase 2 dose

Sample (-) for BFAST alteration

Sample (+) for BFAST alteration

Patients not enrolled in Treatment Cohorts

Closed Complete enrollment

Closed

Alectinib 600 mg PO BID until PD (n = 78)

ALK+

Alectinib PO at 900, 1,200, or 750 mg PO BID until PD

(n = 50 - 62; dose finding) RET+

Atezolizumab 1,200 mg IV q3w until PD or loss of clinical benefit

bTMB+ Randomized 1:1, n = 440

Platinum-based chemotherapy for 4 or 6 cycles

Entrectinib 600 mg PO daily until PD (n = 50) ROS1+

Real World Data Cohort

Physicians will receive overall

results from bSMP assay

*All cohorts have additional, treatment-specific inclusion/exclusion criteria

Blood to FMI for ctDNA testing

(bSMP and bTMB)

Screening Inclusion/Exclus

ion Criteria*

• Age > 18 yo

• Unresectable, Stage IIIB or IV NSCLC • Measurable disease • Treatment naïve • PS 0-2

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BATTLE-1 trial: study schema

Liu S, Lee JJ. An overview of the design and conduct of the BATTLE trials.

Chin Clin Oncol. 2015 Sep;4(3):33.

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Woodcock J, LaVange LM.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.

N Engl J Med. 2017 Jul 6;377(1):62-70.

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Piattaforma «esploratoria»

Catenacci DV. Mol Oncol. 2015 May;9(5):967-96.

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Piattaforma “esploratoria”

Vantaggi

• Aiuta nell’identificare, con un numero

di pazienti relativamente contenuto, i

casi in cui il farmaco è più promettente

• Si “adatta” all’eterogeneità inter-

paziente

• Disegni statistici “adaptive”

consentono di approfondire gli iniziali

segnali di attività

• Disegno “flessibile” e “dinamico”: è

possibile aggiungere altri farmaci “in

corsa”

Catenacci DV. Mol Oncol. 2015 May;9(5):967-96.

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Piattaforma “esploratoria”

Svantaggi

• Richiede un numero relativamente

elevato di pazienti

• All’inizio, il trattamento non è

veramente “personalizzato”

• In presenza di una forte evidenza

preclinica di interazione, il disegno non

è ideale

• Richiede, almeno teoricamente,

coordinamento tra più aziende

farmaceutiche.

Catenacci DV. Mol Oncol. 2015 May;9(5):967-96.

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Disegno “expansion platform”

Catenacci DV. Mol Oncol. 2015 May;9(5):967-96.

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NCI-MATCH

(Molecular Analysis for Therapy Choice)

«The largest and most rigorous

precision oncology trial in history»

Clifford Hudis, ASCO 2015

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NCI-MATCH Distribution of Nearly 1100 Trial Sites

www.cancer.gov/nci-match

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www.cancer.gov/nci-match

• Patients with solid tumors or lymphomas whose disease

has progressed following at least one line of standard

systemic therapy (or with tumors that do not have standard

therapy)

• Tumor accessible to biopsy and patient willing to undergo

biopsy

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• Master protocol with multiple phase II treatment arms

– Eligibility defined by molecular characteristics

• Single agents or combinations with recommended phase

II dosage(s) known

– FDA-approved for another indication or investigational

– Treatment arms open and close without affecting

others

NCI-MATCH design

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NCI-MATCH’s Customized Thermo Fisher OncomineTM Assay

ALK

RET

ROS1

NTRK1

NTRK3

FGFR1

FGFR2

FGFR3

BRAF

RAF1

ERG

ETV1

ETV4

ETV5

ABL1

AKT3

AXL

EGFR

ERBB2

PDGFRA

PPARG

ABL1

AKT1

ALK

AR

ARAF

BRAF

BTK

CBL

CDK4

CHEK2

CSF1R

CTNNB

1

DDR2

DNMT3

A

EGFR

ERBB2

ERBB3

ERBB4

ESR1

EZH2

FGFR1

FGFR2

FGFR3

FLT3

FOXL2

GATA2

GNA11

GNAQ

GNAS

HNF1A

HRAS

IDH1

IDH2

IFITM1

IFITM3

JAK1

JAK2

JAK3

KDR

KIT

KNST

RN

KRAS

MAGO

H

MAP2

K1

MAP2

K2

MAPK

1

MAX

MED1

2

MET

MLH1

MPL

MTOR

MYD88

NFE2L2

NPM1

NRAS

PAX5

PDGFR

A

PIK3CA

PPP2R1

A

PTPN11

RAC1

RAF1

RET

RHEB

RHOA

SF3B1

SMO

SPOP

SRC

STAT3

U2AF1

XPO1

ACVRL1

AKT1

APEX1

AR

ATP11B

BCL2L1

BCL9

BIRC2

BIRC3

CCND1

CCNE1

CD274

CD44

CDK4

CDK6

CSNK2

A1

DCUN1

D1

EGFR

ERBB2

FGFR1

FGFR2

FGFR3

FGFR4

FLT3

GAS6

IGF1R

IL6

KIT

KRAS

MCL1

MDM2

MDM4

MET

MYC

MYCL

MYCN

MYO18A

NKX2-1

NKX2-8

PDCD1L

G2

PDGFR

A

PIK3CA

PNP

PPARG

RPS6KB

1

SOX2

TERT

TIAF1

ZNF217

APC

ATM

BAP1

BRCA1

BRCA2

CDH1

CDKN2A

FBXW7

GATA3

MSH2

NF1

NF2

NOTCH1

PIK3R1

PTCH1

PTEN

RB1

SMAD4

SMARCB1

STK11

TET2

TP53

TSC1

TSC2

VHL

WT1

Hotspot Genes,

N=73

Copy

Number

Variants,

N=49

Fusion

Drivers,

N=22

Full-Gene

Coverage

, N=26

• 143 genes

• 2530

amplicons in

DNA panel

• 207 amplicons

in RNA panel

Chih-Jian Lih et al,

The Journal of Molecular Diagnostics, Vol 19, Issue 2, March 2017

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NCI-MATCH’s 30 Current Arms/

Gene Abnormalities

Continued on next slide

Arm Drug(s) Abnormality Accrual Goal

(Actual as of

08/27/2017)

A afatinib EGFR mut 35 (0)

B afatinib HER2 mut 70* (40)

C1 crizotinib MET amp 35 (14)

C2 crizotinib MET exon 14 sk 35 (16)

E AZD9291 EGFR T790M 35 (4)

F crizotinib ALK transloc 35 (2)

G crizotinib ROS1 transloc 35 (1)

H dabrafenib and trametinib BRAF V600E or V600K 35 (25)

I taselisib PIK3CA mut 70* (70) COMPLETE

J trastuzumab and pertuzumab HER2 amp 35 (11)

* Accrual goal expanded Outside Assay Required

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Y Arm Drug(s) Abnormality Accrual Goal

(Actual as of

08/27/2017)

L TAK-228 mTOR mut 35 (5)

M TAK-228 TSC1 or TSC2 mut 35 (8)

N GSK2636771 PTEN mut 35 (24) CLOSED

P GSK2636771 PTEN loss 35 (35) COMPLETE

Q ado-trastuzumab emtansine HER2 amp 35 (38) COMPLETE

R trametinib BRAF nonV600 35 (35)

S1 trametinib NF1 mut 70* (50)

S2 trametinib GNAQ or GNA11 35 (3)

T vismodegib SMO or PTCH1 35 (16)

U defactinib NF2 loss 35 (28)

* Accrual goal expanded Outside Assay Required

NCI-MATCH’s 30 Current Arms/

Gene Abnormalities

Continued on next slide

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Arm Drug(s) Abnormality Accrual Goal

(Actual as of

08/27/2017)

V sunitinib malate cKIT mut 35 (6)

W AZD4547 FGFR pathway aberrations 70* (52)

X dasatinib DDR2 mut 35 (0)

Y AZD5363 AKT1 mut 35 (35) COMPLETE

Z1A binimetinib NRAS mut 70* (53) SUSPENDED

Z1B palbociclib CCND1, 2, or 3 amp 70* (37)

Z1C palbociclib CDK4 or CDK6 amp 35 (17)

Z1D nivolumab dMMR status 70* (47) SUSPENDED

Z1E larotrectinib (LOXO-101) NTRK fusions 35 (1)

Z1I AZD1775 BRCA1 or BRCA2 mut 35 (33)

TOTAL: 1295 (706) * Accrual goal expanded Outside Assay Required

NCI-MATCH’s 30 Current Arms/

Gene Abnormalities

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Disegno “expansion platform”

Principali vantaggi

• Dall’inizio assegna i pazienti sulla base del presunto

biomarker predittivo

• E’ costituito da più “moduli” indipendenti

• E’ possibile aggiungere farmaci “in corsa”

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Expansion platform design

Principali svantaggi

• Richiede un coordinamento ottimale tra i moduli

• Ciascun farmaco richiede il proprio dimensionamento di

studio, e quindi i numeri di pazienti sono alti

• Richiede uno studio di fase III “confirmatorio” per ciascun

farmaco che dimostra evidenza in fase II

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Disegno “expansion platform”

“Holistic approach”

Catenacci DV. Mol Oncol. 2015 May;9(5):967-96.

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Holistic approach: the SHIVa trial

Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.

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Holistic approach: the SHIVa trial

• Open-label, randomised, controlled phase 2 trial

• 8 French academic centres

• Adult patients with any kind of metastatic solid tumour

refractory to standard of care

• The molecular profile of each patient's tumour was

established with a mandatory biopsy of a metastatic

tumour and large-scale genomic testing.

Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.

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Holistic approach: the SHIVa trial

• Included only patients for whom a molecular alteration

was identified within one of three molecular pathways

(hormone receptor, PI3K/AKT/mTOR, RAF/MEK),

which could be matched to one of ten regimens including

11 available molecularly targeted agents (erlotinib,

lapatinib plus trastuzumab, sorafenib, imatinib,

dasatinib, vemurafenib, everolimus, abiraterone,

letrozole, tamoxifen).

• Patients randomly assigned (1:1) to receive a matched

molecularly targeted agent (experimental group) or

treatment at physician's choice (control group).

Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.

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The SHIVa trial

Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.

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Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.

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The SHIVa trial

Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.

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The SHIVa trial

"So far, no evidence from randomised clinical trial supports

the use of molecularly targeted agents outside their

indications on the basis of tumour molecular profiling"

"Our findings suggest that off-label use of molecularly

targeted agents outside their indications should be

discouraged, and enrolment into clinical trials encouraged,"

Le Tourneau C,

Institut Curie, Paris, France

https://www.medscape.com/viewarticle/851399

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Conclusions

Traditionally, trials were designed to investigate 1 drug at a time in homogeneous patient populations.

New trial designs have the potential: - To accelerate efforts to identify effective treatments, tailored to specific subgroups of patients, for challenging diseases - To evaluate multiple treatments, in heterogeneous patient populations, with the possibility to add new treatments in the future and eliminate investigational treatments lacking efficacy.

To realize this approach, continuous teamwork and innovation in statistical methodology, clinical trial logistics and coordination are mandatory.

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“Per qualsiasi dubbio…”