• Non ci sono risultati.

Terapie innovative ed evidenze scientifiche

N/A
N/A
Protected

Academic year: 2022

Condividi "Terapie innovative ed evidenze scientifiche"

Copied!
25
0
0

Testo completo

(1)

TERAPIE INNOVATIVE ED EVIDENZE SCIENTIFICHE

Federica Morano

Fondazione IRCCS Istituto Nazionale dei Tumori

Milano

(2)

More than 1,000 ongoing I-O combination trials

EVOLVING SIENCE AND BIOMARKERS PARADIGM

(3)

Overman et al, J Clin Oncol 2018

WHAT HAVE WE LEARNED SO FAR?

(4)

PRIMARY RESISTANCE TO PD-1 BLOCKADE?

Shin et al, Cancer Discov 2017

HLA processing and JACK 1-2 Loss Of Function mutations

Data set: 16 MSI-H mCRC

pts treated with

pembrolizumab

(5)

PRIMARY RESISTANCE TO PD-1 BLOCKADE?

Grasso et al, Cancer Discov 2018

WNT signaling and immune-related genes

and pathway mutated in combined 1,211

CRC cases

(6)

Cohen et al, JAMA Oncol 2018

MSI misdiagnosis?

38 pts

MSI-high/dMMR* mCRC treated with immunotx

3 out of 5 pts

who experienced PRIMARY RESISTANCE had MSS/pMMR tumours at central review

*per local assessment by means of IHC or PCR methods

(7)

Shrock et al, Ann Oncol ‘19

TMB and response to checkpoint inhib in MSI-H mCRC

*Optimal cut-point range between 37 and 41 mt/Mb

*

22 pts treated with immunotherapy (19 pembro alone)

TMB appears to be an important independent biomarker within MSI-H mCRC to stratify

patients for likelihood of response to immunotherapy

(8)

Marisa et al, JNCI ‘18

MSI-H mCRC and Immune Chekpoint (ICK) Expression

(9)

Qualitative analysis of tumor mutations (missense vs “indels”)

HIGH MSI SENSOR SCORE = MORE INDELS MUT (more immunogenic)

Mandal et al, Science ‘19

MSI-H INTENSITY

(10)

6004 CRCs

5702 (95%) MSS 302 (5%)

MSI-high

5538 (97%) TMB-low

164 (3%) TMB-high

1 (0.3%) TMB-low

301 (99.7%) TMB-high

Fabrizio et al, J Gastroint Oncol ‘18

BEYOND MSI-H: TMB-high in MSS tumors

(11)

TOMORROW’S MISSION

To bring immunotherapy to MSS CRC!

(12)

As cancer therapies evolve, the cancer survival curve continues to change

I-O therapies have a low tumour response rate in the short term, but over time they mostly show a plateau in the tail of the

survival curve. This demonstrates long-term survival

Chemotherapy Targeted therapy Time

I-O + biomarker/I-O/other MoA combination

Sur vi val

Precision medicine

I-O monotherapy

WHAT CAN WE LEARN FROM THE OTHERS?

(13)

Chen et al, ASCO GI ’19

CO.26 STUDY: Durvalumab + Tremelimumab vs BSC

OS PFS

(14)

Adapted from Kim et al, Ann Oncol ’16 Hedge et al., Clin Cancer Res 2016

MEK inhibitors

Checkpoint inhibitors

BRINGING IMMUNOTHERAPY TO MSS mCRC

(15)

• Unresectable locally advanced or metastatic CRC

• Received ≥ 2 prior regimens of cytotoxic chemotherapy for metastatic disease

• ECOG PS 0-1

• MSI-H capped at 5% Regorafenib 160 mg oral 21/7 days

Atezolizumab 840 mg IV q2w + cobimetinib 60 mg oral 21/7 days

Atezolizumab 1200 mg IV q3w

R 2:1:1

Loss of cl in ica l b e n e fi t

Bendell et al, ESMO WCGI ‘18

IMBlaze370 (COTEZO) study design

Atezo + cobi (n = 183)

Atezo (n = 90)

Rego (n = 90) Median OS, mo

(95% CI)

8.9 (7.00, 10.61)

7.1 (6.05, 10.05)

8.5 (6.41, 10.71) HR vs rego

(95% CI)

1.00 (0.73, 1.38)

1.19

(0.83, 1.71) N/A

P value

0.9871 0.3360

a

N/A

12-mo OS, % 38.5% 27.2% 36.6%

(16)

Adapted from Kim et al, Ann Oncol ’16 Hedge et al., Clin Cancer Res 2016

MEK inhibitors

Checkpoint inhibitors

BRINGING IMMUNOTHERAPY TO MSS mCRC

Bevacizumab

(17)

Grothey et al, ESMO Congress 2018

MODUL STUDY – 5FU + ATEZO + BEV ARM

PFS – primary endpoint

(18)

Adapted from Kim et al, Ann Oncol ’16 Hedge et al., Clin Cancer Res 2016

MEK inhibitors

Checkpoint inhibitors

BRINGING IMMUNOTHERAPY TO MSS mCRC

Bevacizumab + 5FU

Chemotherapy

(19)

Motz et al, Nature Rev Immunol ’11

Inhibition of T-reg cell

Inhibition of myeloid-derived suppressor cells

Maturation of dendritic cells

Inhibition of myeloid-derived suppressor cells

Increase in CD8+ tumor-infiltrating lymphocytes

Immunogenic-cell death (ICD)

Bevacizumab Chemotherapy

Galluzzi et al, Nature Rev Drug Discover 2012; Terme et al, Canc Res 2012 Duffy et al, Ann Oncol 2014; Smyth et al, Nat Rev Clin Oncol 2016

Combining chemo, bev and PD-(L)-1 inhib

(20)

R 1:2

mCRC pts 1st line Unresectable

N=201 pts

FOLFOXIRI+bev

(up to max 8 cycles)

FOLFOXIRI+bev+atezo

(up to max 8 cycles)

5FU/LV +Bev

5FU/LV +Bev +Atezo

PD

INDUCTION MAINTENANCE

Phase II random

Stratification factors:

• Center

• PS 0 vs 1-2;

• primary tumor location (R vs L or rectum);

• Previous adjuvant CT

Primary endpoint: PFS

A rm A A rm B

PD-L1 inhib + triplet + Bev: ATEZOTRIBE trial

(21)

Adapted from Kim et al, Ann Oncol ’16 Hedge et al., Clin Cancer Res 2016

MEK inhibitors

Checkpoint inhibitors

BRINGING IMMUNOTHERAPY TO MSS mCRC

Chemotherapy

Alkylating agents

Bevacizumab +

5FU

(22)

Iatrogenic switch to instable tumor under CT pressure

Germano et al, Nature ‘17

Acquired resistance to TMZ

TMB-high/MSI-like

(23)

PD

C1 C2

CT Scan:

mCRC patients

• ECOG PS 0-1

• ≥ 2 prior lines of treatment for advanced disease Centrally confirmed:

• MSS

• Negative IHC for MGMT

• MGMT methylation

I P I

- TMZ: temozolomide 150 mg/sqm daily on days 1-5, every 4 weeks.

- NIVO: nivolumab 480 mg i.v. every 4 weeks.

- IPI: ipilimumab 1 mg/Kg i.v. every 8 weeks.

27 patients with benefit from TMZ

enrolled

C1 C2 C3

CR PR SD

PD

OUT OF STUDY

Rebiopsy (optional)

T M Z T

M Z

T M

Z T

M Z

T M Z N I V O

N I V O

N I V O I

P i

I P i

MAYA STUDY

(24)

Courtesy of Salvatore Siena and Silvia Marsoni I

P I

ARETHUSA TRIAL

(25)

federica.morano@istitutotumori.mi.it

Riferimenti

Documenti correlati

Intracoronary bone marrow derived progenitor cells in acute myocardial infarction.. Lunde K, Solheim S, Aakhus S,

Quando simili esperimenti di doppia IF venivano eseguiti utilizzando K20 ed anticorpo anti-T12, le immagini sovrapposte documentavano una colocalizzazione di ZNF9 e T12, che è

Nel presente lavoro di tesi è stato quindi verificato se nel panello, ottenuto dalla spremitura a freddo dei semi di lino, si mantenessero le caratteristiche

The structure of the paper is as follows: in Section 2, we give an overview of the molecular line surveys used to assign radial velocities to the clumps and describe the

acknowledges support by the National Aeronautics and Space Administration through the TESS Guest Investigator Program (80NSSC18K1585) and by the National Science

Remarkably low genetic variation but high population differentiation in the climbing perch, Anabas testudineus (Anabantidae), based on the mtDNA control region. Length-weight

3 Centre for Astrophysics Research, School of Physics, Astronomy and Mathematics, University of Hertfordshire, College Lane, Hat- field AL10 9AB, UK. 4 ASTRON, the Netherlands

Tuttavia, valutando il campione dello studio per mezzo dello strumento di spettro SCI-PSY, che include non solo sintomi tipici positivi come deliri e