Lalgoritmo terapeutico oggi: L algoritmo terapeutico oggi: fattori - - PowerPoint PPT Presentation

La medicina personalizzata nel carcinoma del colon retto metastatico tra realtà e aspettative future metastatico tra realtà e aspettative future Pisa, 11 dicembre 2018

L’algoritmo terapeutico oggi: L algoritmo terapeutico oggi: fattori clinici e molecolari

Chiara Cremolini Chiara Cremolini University of Pisa Azienda Ospedaliero-Universitaria Pisana p

1st line treatment of mCRC: ESMO/ Pan- Asian consensus guidelines 1° - Patient 2° T 2° - Treatment intent 2 Treatment intent

/ 3° - RAS/ BRAF 4° - Primary location

Yoshino et al., Ann Oncol ‘18

1st line treatment of mCRC: ESMO/ Pan- Asian consensus guidelines 1° - Patient 2° T 2° - Treatment intent 2 Treatment intent

/ 3° - RAS/ BRAF 4° - Primary location

Yoshino et al., Ann Oncol ‘18

1° 1° - Patient Patient 2° 2° - RAS/ BRAF RAS/ BRAF 3° - Tumor location

Cremolini et al, Nat Rev Clin Oncol ‘17

FOLFOXIRI + bev provides consistent efficacy results…

FOIB1 n=57 TRIBE2 n=252 OPAL3 n=97 STEAM4 n=93 MOMA5 n=232* CHARTA6 n=125 QUATTRO7 n=69 JACCRO CC-118 n=62** n=62**

Response rate

77% 65% 64% 60% 63% 70% 72% 76%

Disease t l t

100% 90% 87% 91% 91% N/A 99% NA

control rate Median PFS, mos

13.1 12.3 11.1 11.9 9.5 12.0 13.3 11.5

Median OS

T N t N t

Median OS, mos

30.9 29.8 32.2 34.0 Too early 28.0 Not reached Not reached

• 1. Masi et al. Lancet Oncol 2010; 2. Cremolini et al. Lancet Oncol 2015

3 S i l B J C 2015 4 B d ll l ASCO GI 2017

*>70% patients with RAS or BRAF mutation ** only RAS mutant

• 3. Stein et al. Br J Cancer 2015; 4. Bendell et al. ASCO GI 2017
• 5. Falcone et al. ESMO 2016; 6. Schmoll et al. ASCO 2017
• 7. Yamazaki et al. JSCO 2017; 8. Miyamoto et sl. JSCO 2017

Highlights 2018

Another TRIBE: why? Another TRIBE: why?

• Not a “simple” confirmation of TRIBE

Not a simple confirmation of TRIBE (triplet + bev vs doublet + bev) T t FAQ b t f t

• To answer two FAQs about upfront

FOLFOXIRI/ bev:

• is it better than the pre- planned

sequential exposure to the same agents?

• are treatments after progression

feasible and efficacious?

TRIBE2: Study design

FOLFOX + bev*

PD1

5FU/bev

FOLFIRI + bev*

PD2

5FU/bev

Arm A

R

5FU/bev 5FU/bev

R 1:1

FOLFOXIRI FOLFOXIRI

PD2

Arm B

FOLFOXIRI + bev*

5FU/bev

PD1

FOLFOXIRI + bev*

5FU/bev

PD2

Arm B

Progression Free Survival 2

* Up to 8 cycles

Cremolini et al, ESMO ‘18

Primary endpoint: Progression Free Survival 2

Median follow up = 22.8 mos Arm A N = 340 Arm B N = 339 Events N (%) 235 (69%) 188 (55%) Events, N (%) 235 (69%) 188 (55%)

Median PFS2, mos

16.2 18.9

HR = 0.69 [95% CI: 0.57‐0.83] p<0.001

1st line - Safety Profile

G3/4 adverse events,

FOLFOX + bev FOLFOXIRI + bev p

% patients

N = 336 N = 336 p Nausea

3 6 0.140

Vomiting

2 3 0.419

Diarrhea

5 17 <0.001

Stomatitis

3 5 0.299

Neutropenia

21 50 <0.001

Febrile neutropenia

3 7 0.050

Neurotoxicity

1 2 0.505

Asthenia

6 7 0.633

Hypertension

10 7 0.223

Venous thromboembolism

6 4 0.204

Cremolini et al, ESMO ‘18

1st line – RECIST Response Rate

FOLFOX + FOLFOXIRI +

Best Response, %

bev N = 340 bev N = 339 OR [95%CI], p Complete Response 4% 3% Partial Response 46% 58%

Response Rate 50% 61%

1.55 [1.14-2.10] p=0.005

St bl Di 40% 31% Stable Disease 40% 31% Progressive Disease 7% 4% Not Assessed 3% 4%

Cremolini et al, ESMO ‘18

1st line - Progression Free Survival

Median follow up = 22.8 mos FOLFOX + bev N = 340 FOLFOXIRI + bev N = 339 Events, N (%) 288 (85%) 261 (77%) Events, N (%) ( ) ( )

Median 1st PFS, mos

9.9 12.0

HR = 0.73 [95% CI: 0.62‐0.87] p<0.001

Cremolini et al, ESMO ‘18

How much “ i i l ”

1° 1° -

“precision oncology” is here?

Patient Patient 2° 2° - RAS/ BRAF RAS/ BRAF 3° - Tumor location

Cremolini et al, Nat Rev Clin Oncol ‘17

Primary tumor location: molecular background

The relative weight of our drivers in the first- line setting

Clinical Molecular markers considerations

The relative weight of our drivers in subsequent lines

Molecular markers Clinical considerations considerations

2nd- line after chemo + bev in wt patients

Progression‐Free Survival Overall Survival RAS and BRAF wt subgroup (N=73)

Median PFS: 8.2 vs 5.7 mos Median OS: 21.1 vs 12.6 mos P=0.10 P=0.37

Bennouna et al., JAMA Oncology ‘18

Later lines of therapy

Phase III options T ifl idi / Regorafenib Trifluridine/ Tipiracil

Molecular landscape of mCRC

RAS mut Wild- type BRAF V600E mut MSI BRAF non V600 mu BRAF non V600 mu PIK3CA/ PTEN mut MET amplification HER2 amplification Gene fusions POLE mut

Chiara, 2015 Carlotta, 2018

From negative selection to negative hyper- selection

PRESSING Panel HER2 lifi ti t ti

• HER2 amplification or mutations
• MET amplification
• ALK/ROS1/NTRKs and RET fusions
• PI3K/PTEN/Akt and MAPKs pathways’ activating
• PI3K/PTEN/Akt and MAPKs pathways’ activating

mutations Cremolini et al, Ann Oncol ‘17

HER2: steps towards practice

Figure1- Forest plot showingHER2associationwithresistancetoanti-EGFRtreatm ent acrosstreatm ent lines

Sartore Bianchi et al, ASCO GI ‘18 – submitted

HER2: steps towards practice

HER2 HER2 neg neg pos pos pos pos

Predictive impact (anti- EGFRs)

Retrospective subgroup analysis of CALGB80405 (doublets + bev vs doublets + cetuximab) ( )

Innocenti et al, ASCO ‘17

Predictive impact (anti- EGFRs)

Case-control PRESSING study

* * * *

RAS and BRAF wild-type* patients clearly RESISTANT to ti EGFR RAS and BRAF wild-type* patients clearly SENSITIVE to anti-EGFRs N=47 anti-EGFRs N=47

* *

8/47 (17%) MSI hi h 0/47 MSI hi h 8/47 (17%) MSI-high 0/47 MSI-high

6/8 (75%) associated with other genomic alterations predictive of genomic alterations predictive of intrinsic resistance

Cremolini et al, Ann Oncol ‘17

The “best” negative hyperselection for anti- EGFRs

RAS mut Wild- type BRAF V600E mut MSI BRAF non V600 mut PIK3CA/ PTEN mut MET amplification HER2 amplification Gene fusions POLE mut