Future drugs for patients not tolerating or progressing ... · Future drugs for patients not...

Future drugs for patients not tolerating or

progressing under Sorafenib

Fabio Piscaglia

Internal Medicine

University of Bologna, Italy

[email protected]

DICHIARAZIONE DI CONFLITTO DI INTERESSI ULTIMI 2 ANNI

Fabio Piscaglia

• Bayer (speaker and advisory board fee)

• Bracco (speaker fee)

• Eisai (advisory board)

• Esaote (research grants)

PER QUALI PAZIENTI I FARMACI DOPO SORAFENIB?CONDIZIONI ALLA SOSPENSIONE DI SORAFENIB

Quali pazienti stanno attualmente andando nei trial di 2a linea e quali potremo trattare in futuro nella pratica clinica?

Reig M, Hepatology 2013;58, 2023-2031

Per trial arruolabili 19%, nella vita reale almeno 50%

POSSIBILI TARGET FARMACEUTICI IN RELAZIONE AI MECCANISMI DI CANCEROGENESI

Hanahan & Weinberg, Cell 2013, 144:646-674

Hallmarks consolidati



Hallmarks consolidatiTarget dei TKI anti-angiogenici (es. Sorafenib)



Hallmarks consolidatiTarget dei TKI anti-fattori di crescita

MET is the only known tyrosine kinase receptor for hepatocyte-growth factor (HGF) and is involved in cancer progression and metastasis



Regorafenib

Tivantinib



Cell 2013, 144:646-674

Hallmarks di recente identificazione



Cell 2013, 144:646-674

Hallmarks di recente identificazione

Target non utili per terapie oncologiche

2015 2019

Apatinibvs placebo In 2nd line HCC

Q3 2019 data readout

2016

Regorafenib in 2 nd-lineHCC (RESORCE)

Q2 2016

Nivolumab in 2 nd-line HCC(extend ph I/II to 500) Q4 2018 data readout

(could be earlier)

Pembrolizumab in 2 nd-line HCC (KEYNOTE-240)Q4 2018 data readout

2018

Y90 +/- Nexavar ® in HCC (SORAMIC)

~ 1H 2016 recruitment ? 2018 data readout

Y90 vs TACE in advanced HCC


Nivolumab vs Nexavar ®

in 1 st -line HCCQ2 2018 data readout

Donafenib vs Nexavar ®

In 1st line HCC Q3 2019 data readout

1L Competitor data

2L Competitor data

Nexavar® data

2017

Cabozantinibin 2 nd-line HCC


Ramucirumabin 2 nd-line HCC (REACH II)


Tivantinib in 2 nd-line(METIV-HCC)


Lenvatinib vs Nexavar ® in 1st-line (REFLEX)


HCC - Evolving Systemic Therapy Landscape

Ramuricumab in 2 nd line in HCC (LY3009806)




LENVATINIBDONAFENIBAPATINIB

Lenvatinib (Lenvima, Eisai, Inc.)

BID, twice daily; HCC, hepatocellular carcinoma; NCI-CTCAE, National Cancer Institute Common Toxicity Criteria for Adverse Events; PO, orally

Ganten TM, et al. Presented at the 2014 European Society of Medical Oncology(ESMO) meeting. Poster 5545

Dosing Trial RR-DTC

Patients

2

Plus Pembrolizumab in selected solid tumours1a/2

Plus Everolimus in advanced or mRCC1

In anaplastic thyroid cancer2

Refractory to gemcitabine-based unresectablebiliary tract cancer2

Refractory, unresectable Stage III/IV melanoma2

Phase

• MOA: multi-targed, TKI that inhibits VEGFR-1, 2, 3; FGFR-1, 2, 3, and 4; PDGFR-alpha, KIT, and RET

• Administered: orally

• Approved indications: progressive radioactive-iodine refractory DTC

Meccanismo di azione simile a Sorafenib e Regorafenib. Difficle prevedere se gli eventi avversi siano così diversi da permettere trattamento a chi non tollera Sorafenib. Attualmente non in valutazione in seconda linea

Lenvatinib (Lenvima, Eisai, Inc.)multi-targed, TKI that inhibits VEGFR-1, 2, 3; FGFR-1, 2, 3, and 4;

PDGFR-alpha, KIT and RET. Oral.

R

• A multicenter, randomized, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) vs Nexavar ® in 1L treatment of patients with unresectable HCC

• 145 centers: Belgium (3); France (14); Germany (9); Italy (7); Poland (3); Russian Federation (5); Spain (5); United Kingdom (6)

954

Primary endpoint:• OS

Main secondary endpoints:• PFS

• TTP, ORR, HRQoL

Select patient criteria:• Unresectable HCC

per AASLD*

• Child-Pugh class A

• ECOG PS 0-1

• No prior systemic therapy for HCC

Lenvatinib12 mg (or 8 mg) QD

Nexavar ®

400 mg PO BID

Until PD orunacceptable

toxicity

1:1

*AASLD criteria, including cirrhosis of any etiology or with chronic hepatitis B or C infection criteria.

1L, first-line; AASLD, American Association for the Study of Liver Diseases; ECOG PS, Eastern Cooperative Oncology Group performance status; QD, once a day; BID, twice a day; OS, overall survival; PFS, progression-free survival; TTP, time to progression; ORR, objective response rate; HRQoL, health-related quality of life.

https://clinicaltrials.gov/ct2/show/NCT01761266

• Study start date: March 2013• Estimated primary completion date: April 2016• This study is ongoing, but no more recruiting participants

Arruolamento chiuso. In attesa dei dati definitivi di sopravvivenza fine 2016

R

• A multicenter, randomized, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) vs Nexavar ® in 1L treatment of patients with unresectable HCC

• 145 centers: Belgium (3); France (14); Germany (9); Italy (7); Poland (3); Russian Federation (5); Spain (5); United Kingdom (6)

954



• TTP, ORR, HRQoL


per AASLD*


• ECOG PS 0-1

• No prior systemic therapy for HCC

Lenvatinib12 mg (or 8 mg) QD

Nexavar ®

400 mg PO BID


toxicity

1:1


1L, first-line; AASLD, American Association for the Study of Liver Diseases; ECOG PS, Eastern Cooperative Oncology Group performance status; QD, once a day; BID, twice a day; OS, overall survival; PFS, progression-free survival; TTP, time to progression; ORR, objective response rate; HRQoL, health-related quality of life.


• Study start date: March 2013• Estimated primary completion date: April 2016• This study is ongoing, but no more recruiting participants

Arruolamento chiuso. In attesa dei dati definitivi di sopravvivenza fine 2016Meccanismo di azione simile a Sorafenib. Difficle pre vedere che gli eventi

avversi siano così diversi da permettere trattament o a chi non tollera Sorafenib. Attualmente non in valutazione in seconda linea

Lenvatinib (Lenvima, Eisai, Inc.)multi-targed, TKI that inhibits VEGFR-1, 2, 3; FGFR-1, 2, 3, and 4;

PDGFR-alpha, KIT and RET. Oral.

DONAFENIB in studio in prima linea vs SORAFENIB

APATINIB in studio in seconda linea vs Placebo

Tutti studi all-comers(non selezione molecolare dei pazienti)


Hanahan & Weinberg, Cell 2013, 144:646-674RAMUCIRUMAB

RAMUCIRUMABRecombinant IgG1 monoclonal Ab inhibiting VEGF-R2. Intravenous

Zhu AX, Lancet Oncol 2015;16:859-870

AFP >400 AFP <400

Phase-3: Ramucirumab vs Placebo in 2nd line HCC progressing on Sorafenib with AFP>400



TIVANTINIB

highly selective MET inhibitor . Also displays cytotoxic activity via molecular mechanisms that are independent from its ability to bind MET. Administrated orally

Tivantinib – METIV-HCC (NCT01755767)

Tivantinib For Second-line Treatment of Advanced He patocellular Carcinoma: A Randomised, Placebo-controlled Phase 2 Study

Santoro et al, Lancet Oncology 2013;14:55-63

Unchanged OS in c-MET (-)Unchanged TTP in c-MET (-)

HR: 0.38 (95% CI: 0.18-0.81) Log Rank: P=0.01

Median OS Patients Events

Tivantinib 7.2 mos 22 17

Placebo* 3.8 mos 15 15

Santoro et al, Lancet Oncology 2013;14:55-63

Improved OS in c-MET (+)Improved TTP in c-MET (+)

Tivantinib For Second-line Treatment of Advanced He patocellular Carcinoma: A Randomised, Placebo-controlled Phase 2 Study

• A phase III , randomized, double-blind study of tivantinib (ARQ 197) in subjects with c-MET diagnostic-high inoperable HCC treated with one prior systemic therapy

• 113 centers: Europe (79)

• C-Met high status on tumor tissue always to be confirmed centrally in double testing

• Study start date: December 2012• Estimated study completion date: June 2017• Estimated primary completion date: March 2017

• Enrolment concluded and follow up is ongoing. Final analysis still to be performed

N=368


Main secondary endpoints:• PFS• Safety

Select patient criteria:• Histologically confirmed

HCC inoperable and not eligible for local treatment

• MET diagnostic-high tissue

• At least 4 weeks of one prior Nexavar® treatment

• ECOG PS 0-1

PlaceboPO BID

1:1

Tivantinib120 mg PO BID(240 mg/day)

Tivantinib – METIV-HCC (NCT01755767)

ECOG PS, Eastern Cooperative Oncology Group performance status; PO, orally; BID, twice a day.


R Until PD orunacceptable

toxicity



CABOZANTINIB

R

• A phase III, randomized (1:1), double-blind , controlled study of cabozantinib (XL184) vs placebo in subjects with HCC who have received prior Nexavar ®

• 102 centers: Europe (43); United Kingdom (5)

N=760



• ORR

Select patient criteria:• HCC that has progressed

following 1-2 systemic treatments

• Received prior Nexavar®

• ECOG PS 0-1


1:1

Cabozantinib – CELESTIAL (NCT01908426)

ECOG PS, Eastern Cooperative Oncology Group performance status; PO, orally; QD, once daily; PD, progressive disease; PFS, progression-free survival; ORR, objective response rate.


Cabozantinib60 mg tablet PO QD

Placebo PO QD

• Study start date: August 2013• Estimated primary completion date: October 2016

• This study is currently recruiting participants


toxicity

• tyrosine kinase inhibitor inhibits the action of VEGFR-1, -2, -3; RET, and MET

Sia 2a che ulteriore lineaTripla azione



NIVOLUMABIPILIMUMABTREMELIMUMAB

NIVOLUMAB

human IgG4 anti-PD-1 monoclonal antibody. Inhibitory ligand blocking antibody (blocks the interaction between PD-1 and PD-L1/PD-L2,1) against the programmed death; allows the immune system to attack the tumor as an example of immune checkpoint blockade. Intravenous infusion. Approved indications: US treatment of melanoma (Dec 2014); EU metastatic melanoma as a monotherapy (Apr 2015)

MHC

PD-L1

PD-1

PD-1

T-cellreceptor

PD-L2

T cell

NFκB

Other

PI3K

Tumor cell

IFNγ

IFNγR

Shp-2

Nivolumab

1.Topalian SL, et al. N Engl J Med. 2012;366:2443-2454

Nivolumab Phase 1/2. Maximal Change in Target Lesions From Baseline

120

100

80

60

40

20

0

-20

-40

-60

-80

-100

Patients (N = 40) †

Cha

nge

in T

arge

t Les

ion

Fro

m B

asel

ine,

%

Uninfected

HCV

HBV

Confirmed response*

* ** * * *

* *†2 uninfected patients not shown: 1 had disease progression before the first assessment; 1 had a maximal change of +23%‡Patient with resolved HCV infection

‡

AB. El-Khoueiry,1 et al. Presented at ASCO Annual meeting 2015. Abstract LBA 101

Phase 1/2 Safety and Antitumor Activity of Nivoluma b in Patients With Advanced Hepatocellular Carcinoma (HCC): CA209-040

AB. El-Khoueiry,1 et al. Presented at ASCO Annual meeting 2015. Abstract LBA 101

Protocol ongoing. Currently expansion phase:1L randomized Nivolumab 3mg/kg vs Sorafenib (open randomization)Infusion once a week for 3 weeks out of 4

2L different combined dosages (Nivolumab ± Ipilimumab) (Phase I/II).

NIVOLUMAB ( ± IPILIMUMAB in 2L)

NIVOLUMAB

R

• A randomized, multi-center phase III study of nivolumab vs Nexavar® as first-line treatment in patients with advanced HCC

• 103 centers: Belgium (3); Czech Republic (2); France (8); Germany (5); Poland (3); Spain (4); United Kingdom (4)

• Study start date: November 2015• Estimated primary completion date: June 2019

• This study is currently recruiting participants

N=726

Primary endpoint:• TTP• OS

Main secondary endpoints:• PFS• ORR• Programmed death L1

expression

Select patient criteria:• Histologically confirmed,

unresectable, advanced HCC

• Not eligible for LRT

• ECOG PS 0-1


1:1

Nivolumab3 mg/kg IV2,*

Nexavar ®

400 mg PO BID

*3 mg/kg IV dose is based on Phase 1/II study findings. BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenously; LRT, locoregional therapy; PO, orally; PD, progressive disease; PFS, progression-free survival; ORR, objective response rate.

1. https://clinicaltrials.gov/ct2/show/NCT02576509. 2. El-Khoueiry AB, et al. J Clin Oncol 2015 (Suppl; Abstr LBA101).


toxicity

TREMELIMUMAB

Sangro, J Hepatol, 2013; 59: 81-88

• Intravenous every 3 months• Pilot study, Only 17 pazient assessed for tumor response• Partial response was 17.6% and disease control rate was 76.4%. • Time to progression was 6.5 Months


Cell 2013, 144:646-674

VACCINATION


Pexa-Vec (JX-594, Polaris)a vaccinia virus engineered to express granulocyte-macrophage colony

stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity

R

• A phase 3 randomized, open-label study to determine whether treatment with vaccinia virus based immunotherapy (Pexa-Vec ) followed by Nexavar ® increases survival compared to Nexavar ® in patients with advanced HCC who have not received prior systemic therapy

• 4 centers: United States (3); New Zealand (1)

• Administration: intratumoural (IT) or intravenous (IV)

• Study start date: October 2015• Estimated study completion date: October 2019• Estimated primary completion date: October 2017• This study is currently recruiting participants

N=600


Secondary endpoints:• TTP

• PFS, ORR, DCR

• Safety


Advanced HCC (i.e., BCLC stage C or B per AASLD criteria*)


• ECOG PS 0-1Nexavar ®

400 mg BID starting Day 1

1:1


BCLC, Barcelona Clinic Liver Cancer; AASLD, American Association for the Study of Liver Diseases; ECOG PS, Eastern Cooperative Oncology Group performance status; IT, intratumoral; PFU, plaque forming units; BID, twice a day; PD, progressive disease; OS, overall survival; PFS, progression-free survival; TTP, time to progression; ORR, objective response rate; DCR, disease control rate.


PexaVec 3, IT injectionsof 1e9 PFUs � Nexavar ®

400 mg BID

P P P SDay 1 Week 2 Week 4 Week 6

Until P

D or

unacceptable toxicity

Attualmente testato solo in 1L quindi i risultati non influenzeranno chi è in progression o intollerante a Sorafenib

Immunoterapia. Studio coreano in adiuvante dopo RF o PEI



Cell 2013, 144:646-674

• A randomized, double-blind, multi-center phase III study of ADI-PEG 20 plus best supportive care (BSC) vs placebo plus BSC in subjects with advanced HCC who have failed prior systemic therapy

• Study start date: July 201173 centers: Italy (10); United Kingdom (10)

• Results presented in abstract form and NEGATIVE (no survival advantage)

N=636


Main secondary endpoints:• TTP• PFS• ORR• Safety and tolerability

Select patient criteria:• Advanced HCC

• Child-Pugh grade B7

• ECOG PS<2

PlaceboIM weekly + BSC

1:1

ADI-PEG 20 + BSC(arginine deiminase with

polyethylene glycol) 18 mg/m2 IM weekly

ADI-PEG 20 (NCT01287585)Arginine deiminase (ADI) formulated with polyethylene glycol (PEG). IM injection

ECOG PS, Eastern Cooperative Oncology Group performance status; IM, intramuscular; PD, progressive disease; OS, overall survival; TTP, time to progression; PFS, progression-free survival; ORR, objective response rate.


R Until PD orunacceptable

toxicity

• ADI degrades arginine, an amino acid crucial to tumor cell metabolism and growth of certain cancers (ie, melanoma, HCC, pancreatic, prostate cancer). Depletion of arginine by ADI from the blood can control tumor growth and even eliminate arginine-requiring cancers without damage to normal tissue cells.

Drug Target Selection % Patients Phase

Ramucirumab VEGFR2 AFP>400 44 III

Refametinib MEK RAS mutations

<5 II

Tivantinib MET MET-high 48 III

MSC2156119J MET MET-high 48 I/II

BLU-554 FGFR4 FGF19 6 FGFR4 Amp

I/II

RO5137382 Glypican-3 Glypican-3 II

Terapia su bersaglio




<5 II




I/II



Selezione su liquid biopsy (prelievo).Studio terminato con insufficiente arruolamento




<5 II




I/II



Regorafenib – RESORCE (NCT01774344)

Eur J Cancer, 2013;49:3412-3419

Best individual patient response Regorafenib. Studio concluso di fase 2 in HCC

• A randomized, double-blind, placebo-controlled, multicenter phase 3 study of regorafenib in patients with advanced HCC who have progressed on Nexavar ® treatment

• 178 centers: Austria (3), Belgium (2), Czech Republic (3), France (21), Germany (14), Hungary (4), Italy (19), Netherlands (3), Spain (12), Switzerland (3), United Kingdom (5)


Secondary endpoints:• TTP• PFS• ORR• DCR

Stratification: Geographical region, ECOG PS, AFP levels, EHS/MVI

Regorafenib160 mg PO QD (3 weeks

on, 1 week off) + BSC(4 weeks/cycle)

Placebo QD(3 weeks on, 1 week off) + BSC (4 weeks/cycle)

ST

RA

TIF

ICA

TIO

NN

=57

3R

AN

DO

MIZ

AT

ION

2:

1

Select patient criteria:• Advanced, unresectable

HCC per AASLD


• ECOG PS 0-1

• Failed Nexavar®

• Tolerated Nexavar®


Inclusion criterion: Sorafenib terminated <4 weeks


Data will be presented for the first time end of Ju ne

Possible reasons for the success:

- Refined stratification , not only geography but also ECOG PS, AFP levels, EHS/MVI- Inclusion criteria : patients tolerant to Sorafenib and having terminated it by no longer

than 4 weeks and with documented radiological progression

Exclusion of slow progressors and of “practical” first liners (patients with early discontinuation of Sorafenib due to adverse events).

Press release

I risultati dello studio RESORCE avranno importanti implicazioni per il disegno delle future sperimentazioni:

- Regorafenib dovrebbe diventare reference standard d i paragone per gli studi di 2L trials

- Lo studio RESORCE ci ha insegnato che i pazienti de bbono essere stratificati meglio all’inclusione per tipologia e tempistica di progressione.

- Disegnare sperimentazioni per pazienti poco tollera nti al Sorafenib diventerà più difficile (richiede molti centri).

- Se qualcuno degli studi di 2L in corso prima dell’u scita di Regorafenib per HCC risulterà positivo sarà complesso decidere quale sia il trattamento di riferimento per la pratica clinica o negli studi

Il futuro delle terapie farmacologiche


- La variabilità del decorso dell’HCC non è ancora be n compresa (forse anche per le limitate conoscenze molecolari / istologiche) e questo può impattare il disegno dei trial

- Non ci sono all’orizzonte farmaci che verosimilment e andranno bene per TUTTI i pazienti con HCC (all-comers)

- Le strategie terapeutiche in campo oncologico si st anno diversificando rispetto alla sola terapia antiangio genica e si disegnano studi “arricchiti” per caratteristiche mo lecolari

- In futuro possibili vaccini individualizzati?

- Pressochè tutte le nuove sperimentazioni richiedono campioni di tessuto per escludere forme miste / colangioCa e so prattutto per cercare marcatori di risposta (meglio biopsia recen te)


L’evoluzione delle terapie dell’HCC richiederà :

- Centri che gesticano bene gli eventi avversi da Reg orafenib

- Capacità organizzative (imaging, biopsie, visite, a rchiviazione dati in CRF elettroniche) all’altezza dei trial di 2L vs Regorafenib 3L

- La nuova normativa Italiana a seguito di quella Eur opea richiede ora regole molto stringenti per accreditamente stud i Fase 1 (in vigore da luglio 2016)

Pertanto sarà sempre più importante l’interazione co n o l’affidamento a centri di riferimento

Grazie per l’attenzione

[email protected]

NB: il documento con le ”RACCOMANDAZIONI MULTISOCIETARIE ITALIANE(AISF, AIOM, IT-IHBPA, SIC, SIRM, SITO) PER LA GESTIONE CLINICA INTEGRATA DEL PAZIENTE CON EPATOCARCINOMA” sarà

accessibile e scaricabile dai siti delle società scientifiche entro l’estate 2016www.webaisf.org

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