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Innovazione e personalizzazione:
come i nuovi farmaci cambiano la strategia
terapeutica. GLI AGGIORNAMENTI
Colon Retto
Alessio Cogoni
UOC Oncologia
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Median Survival Increases With Increased Lines of Therapy
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Proportional Impact on Magnitude of OS Benefit Achieved Across Lines of Therapy
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A classical case of mCRC in 2019
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The Luxury of So Many Options: How Do We Personalize Therapy?
la krisis, momento cruciale in cui il massimo disequilibrio del corpo si trasforma nell’inizio della guarigione. La natura da sola non è capace, però, di superare le fasi più critiche e le malattie più tenaci: diventa indispensabile l’arte del medico.
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The Luxury of So Many Options: How Do We Personalize Therapy?
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The Luxury of So Many Options: How Do We Personalize Therapy?
Annals of Oncology, Volume 29, Issue 1, January 2018, Pages 44–70
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Current Major Research Trends in Metastatic Colorectal Cancer
Intensification of therapy: the triplets
Individualization of therapy: new molecular predictive factors and new drugs
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Current Major Research Trends in Metastatic Colorectal Cancer
Intensification of therapy: the triplets
Individualization of therapy: new molecular predictive factors and new drugs
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TRIBE-2 Trial
Cremolini et al, ESMO GI / WCGIC 2019
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TRIBE-2 Trial
Cremolini et al, ESMO GI / WCGIC 2019
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TRIBE-2 Trial
Cremolini et al, ESMO GI / WCGIC 2019
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TRIBE-2 Trial
Lower rates of per-protocol second-line treatment with FOLFOXIRI + bev → FOLFOXIRI + bev (59%) vs FOLFOX + bev → FOLFIRI + bev (78%)
Per-Protocol Second-line PFS Se
con
d-l
ine
PFS
(%
)
Mos Patients at Risk, n FOLFOXIRI + bev
FOLFIRI + bev
100
80
60
40
20
0
0 5 10 15 20 25
129 195
88 107
27 28
6 9
3 1
1 1
Cremolini et al, ESMO GI / WCGIC 2019
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TRIBE-2 Trial
Cremolini et al, ESMO GI / WCGIC 2019
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TRIBE-2 Trial
Cremolini et al, ESMO GI / WCGIC 2019
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VISNU-1 Trial
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VISNU-1 Trial
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VISNU-1 Trial
Sastre, et al. ASCO 2019
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VOLFI Trial
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VOLFI Trial
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Current Major Research Trends in Metastatic Colorectal Cancer
Intensification of therapy: the triplets
Individualization of therapy: new molecular predictive factors and new drugs
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Molecular Landscape in CRC
BRAF V600E (8-10%)
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BEACON CRC Trial
Kopetz. NEJM. 2019
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BEACON CRC Trial
Kopetz. NEJM. 2019
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BEACON CRC Trial
Kopetz. NEJM. 2019
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BEACON CRC Trial
Kopetz. NEJM. 2019
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BEACON CRC Trial
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BEACON CRC Trial
Kopetz. NEJM. 2019
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BEACON CRC Trial
Kopetz. NEJM. 2019
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Molecular Landscape in CRC
MSI (4-5%)
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Immunotherapy: Pembrolizumab
MK-3475-016
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Immunotherapy: Nivolumab±Ipilimumab
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Immunotherapy: Nivolumab±Ipilimumab
Andre et al ASCO GI 2018 Overman et al JCO 2018
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Immunotherapy: Nivolumab±Ipilimumab
Lenz et al, ESMO 2018
1st line
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Immunotherapy: Nivolumab±Ipilimumab
Chalabi et al, ESMO 2018
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Immunotherapy: Nivolumab±Ipilimumab
Chalabi et al, ESMO 2018
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Immunotherapy + Chemotherapy
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Immunotherapy + Chemotherapy
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Immunotherapy in MSS
CCTG CO.26
Chen et al, ASCO 2019
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Immunotherapy in MSS
Chen et al, ASCO 2019
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Immunotherapy in MSS
Regorafenib
Level 1: 80 mg/day
21 on 7 days off
+
Nivolumab 3 mg/kg q2w
Regorafenib
Level 2: 120 mg/day
21 on 7 days off
+
Nivolumab 3 mg/kg q2w
Regorafenib
Level 3: 160 mg/day
21 on 7 days off
+
Nivolumab 3 mg/kg q2w Colorectal cancer
Gastric cancer
Total 36 cases
N=3~6
N=3~6 N=3~6
DOSE ESCALATION COHORT: 3+3 design
EXPANSION COHORT
REGONIVO (EPOC 1603)
Fukuoka et al, ASCO 2019
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Immunotherapy in MSS
Ch
ange
fro
m b
asel
ine
(%) COLORECTAL CANCER
ORR (36%)
(33% with MSS pts)
MSI-H (all other patients were MSS) Time since first dosing (weeks)
Ch
ange
fro
m b
asel
ine
(%)
PD SD PR CR
Fukuoka et al, ASCO 2019
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Immunotherapy in MSS
Adverse events, N (%) All
n=50 Regorafenib 80 mg
n=22
All grades Grade≥3 All grades Grade≥3
All events 50 (100) 20 (40) 22 (100) 6 (27)
Palmar-plantar erythrodysesthesia 35 (70) 5 (10) 13 (59) 0 (0)
Hypertension 24 (48) 2 (4) 10 (46) 2 (9)
Fatigue 23 (46) 0 (0) 10 (46) 0 (0)
Rash 21 (42) 6 (12) 8 (36) 0 (0)
Fever 20 (40) 0 (0) 8 (36) 0 (0)
Proteinuria 15 (30) 6 (12) 5 (23) 2 (9)
Liver dysfunction 14 (28) 3 (6) 5 (23) 2 (9)
Oral mucositis 11 (22) 0 (0) 3 (14) 0 (0)
Diarrhea 11 (22) 1 (2) 5 (23) 0 (0)
Decreased appetite 11 (22) 0 (0) 6 (27) 0 (0)
Hyperthyroidism 6 (12) 0 (0) 4 (18) 0 (0)
Hypothyroidism 6 (12) 0 (0) 4 (18) 0 (0)
Hoarseness 5 (10) 0 (0) 4 (18) 0 (0)
Platelet count decreased 5 (10) 1 (2) 0 (0) 0 (0)
Phase III is about to start!!! Fukuoka et al, ASCO 2019
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Immunotherapy in MSS
ImBlaze 370
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Immunotherapy in MSS
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Molecular Landscape in CRC
HER2 (5 %)
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HERACLES-A
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MyPathway
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MOUNTAINEER
Strickler et al, ESMO 2019
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HERACLES-B
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HERACLES-B
Sartore-Bianchi et al et al, ESMO 2019
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Molecular Landscape in CRC
NTRK (0,5-1%)
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TRK Fusion Inhibitors
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Larotrectinib
Lassen U et al, ESMO 2018
Adult Trial (ph I) + NAVIGATE (ph II) + SCOUT (ph I/II Pediat)
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Entrectinib
Demetri et al, ESMO 2018
STARTRK2 (ph II) + STARTRK1 (ph I) + ALKA-372-001 (ph I)
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Conclusions
The treatment algorithm for mCRC have not changed in the last five years (apart from introduction of sidedness as a choice driver)
Continuum of care, the sequential exposure to all available treatments, is still the SOC
Chemotherapy triplets + biologics are gaining weight, but the best target population is unclear
Personalized medicine allows to tailor very small subgroups of patients who can benefit of target drugs with sometimes preliminary but outstanding evidences of activity