Il disegno e la conduzione delle sperimentazioni cliniche nell’era dell’oncologia di precisione: cosa sta cambiando?

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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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UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY

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

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Key-words: TIME

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Key-words: EFFICIENCY

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Key-words: COOPERATION

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

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

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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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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”

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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.

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Disegno “expansion platform”

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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 Oncomine

^TM

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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UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY 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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UNIVERSITY OF TORINO – DEPARTMENT OF ONCOLOGY 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”

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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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