TERAPIE INNOVATIVE ED EVIDENZE SCIENTIFICHE
Federica Morano
Fondazione IRCCS Istituto Nazionale dei Tumori
Milano
More than 1,000 ongoing I-O combination trials
EVOLVING SIENCE AND BIOMARKERS PARADIGM
Overman et al, J Clin Oncol 2018
WHAT HAVE WE LEARNED SO FAR?
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
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
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
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
Marisa et al, JNCI ‘18
MSI-H mCRC and Immune Chekpoint (ICK) Expression
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
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
TOMORROW’S MISSION
To bring immunotherapy to MSS CRC!
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?
Chen et al, ASCO GI ’19
CO.26 STUDY: Durvalumab + Tremelimumab vs BSC
OS PFS
Adapted from Kim et al, Ann Oncol ’16 Hedge et al., Clin Cancer Res 2016
MEK inhibitors
Checkpoint inhibitors
BRINGING IMMUNOTHERAPY TO MSS mCRC
• 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
aN/A
12-mo OS, % 38.5% 27.2% 36.6%
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
Grothey et al, ESMO Congress 2018
MODUL STUDY – 5FU + ATEZO + BEV ARM
PFS – primary endpoint
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
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
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
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
Iatrogenic switch to instable tumor under CT pressure
Germano et al, Nature ‘17
Acquired resistance to TMZ
TMB-high/MSI-like
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
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T M Z N I V O
N I V O
N I V O I
P i
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MAYA STUDY
Courtesy of Salvatore Siena and Silvia Marsoni I
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