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(1)

personalizzazione:

come i nuovi farmaci cambiano la strategia

terapeutica.

GLI AGGIORNAMENTI

Colon Retto

Alessio Cogoni

UOC Oncologia

(2)
(3)

Lines of Therapy

(4)

Benefit Achieved Across Lines of Therapy

(5)

A classical case of mCRC in 2019

(6)
(7)

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.

(8)

We Personalize Therapy?

(9)

We Personalize Therapy?

Annals of Oncology, Volume 29, Issue 1, January 2018, Pages 44–70

(10)

Metastatic Colorectal Cancer

 Intensification of therapy: the triplets

 Individualization of therapy: new molecular predictive

factors and new drugs

(11)

Metastatic Colorectal Cancer

 Intensification of therapy: the triplets

Individualization of therapy: new molecular predictive

factors and new drugs

(12)

TRIBE-2 Trial

Cremolini et al, ESMO GI / WCGIC 2019

(13)

TRIBE-2 Trial

Cremolini et al, ESMO GI / WCGIC 2019

(14)

TRIBE-2 Trial

Cremolini et al, ESMO GI / WCGIC 2019

(15)

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

Second-line PFS (%)

Patients at Risk, n Mos 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

(16)

TRIBE-2 Trial

Cremolini et al, ESMO GI / WCGIC 2019

(17)

TRIBE-2 Trial

Cremolini et al, ESMO GI / WCGIC 2019

(18)

VISNU-1 Trial

(19)

VISNU-1 Trial

(20)

VISNU-1 Trial

Sastre, et al. ASCO 2019

(21)

VOLFI Trial

(22)

VOLFI Trial

(23)

Metastatic Colorectal Cancer

Intensification of therapy: the triplets

 Individualization of therapy: new molecular predictive

factors and new drugs

(24)

Molecular Landscape in CRC

BRAF V600E (8-10%)

(25)

BEACON CRC Trial

Kopetz. NEJM. 2019

(26)

BEACON CRC Trial

Kopetz. NEJM. 2019

(27)

BEACON CRC Trial

Kopetz. NEJM. 2019

(28)

BEACON CRC Trial

Kopetz. NEJM. 2019

(29)

BEACON CRC Trial

(30)

BEACON CRC Trial

Kopetz. NEJM. 2019

(31)

BEACON CRC Trial

Kopetz. NEJM. 2019

(32)

Molecular Landscape in CRC

MSI (4-5%)

(33)

Immunotherapy: Pembrolizumab

MK-3475-016

(34)

Immunotherapy: Nivolumab±Ipilimumab

(35)

Immunotherapy: Nivolumab±Ipilimumab

Andre et al ASCO GI 2018 Overman et al JCO 2018

(36)

Immunotherapy: Nivolumab±Ipilimumab

Lenz et al, ESMO 2018

1st line

(37)

Immunotherapy: Nivolumab±Ipilimumab

Chalabi et al, ESMO 2018

(38)

Immunotherapy: Nivolumab±Ipilimumab

Chalabi et al, ESMO 2018

(39)

Immunotherapy + Chemotherapy

(40)

Immunotherapy + Chemotherapy

(41)

Immunotherapy in MSS

CCTG CO.26

Chen et al, ASCO 2019

(42)

Immunotherapy in MSS

Chen et al, ASCO 2019

(43)

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

(44)

Immunotherapy in MSS

Change from baseline (%) COLORECTAL CANCER ORR (36%) (33% with MSS pts)

MSI-H (all other patients were MSS)

Time since first dosing (weeks)

Change from baseline (%)

PD SD PR CR

Fukuoka et al, ASCO 2019

(45)

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

(46)

Immunotherapy in MSS

ImBlaze 370

(47)

Immunotherapy in MSS

(48)

Molecular Landscape in CRC

HER2 (5 %)

(49)

HERACLES-A

(50)

MyPathway

(51)

MOUNTAINEER

Strickler et al, ESMO 2019

(52)

HERACLES-B

(53)

HERACLES-B

Sartore-Bianchi et al et al, ESMO 2019

(54)

Molecular Landscape in CRC

NTRK (0,5-1%)

(55)

TRK Fusion Inhibitors

(56)

Larotrectinib

Lassen U et al, ESMO 2018

Adult Trial (ph I) + NAVIGATE (ph II) + SCOUT (ph I/II Pediat)

(57)

Entrectinib

Demetri et al, ESMO 2018

STARTRK2 (ph II) + STARTRK1 (ph I) + ALKA-372-001 (ph I)

(58)

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

(59)

Grazie

alessio.cogoni@aousassari.it

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