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 ° 2 ° - Treatment 2 T Treatment intent 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 ° 2 ° - Treatment 2 T Treatment intent 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… JACCRO FOIB 1 TRIBE 2 OPAL 3 STEAM 4 MOMA 5 CHARTA 6 QUATTRO 7 CC-11 8 n=57 n=252 n=97 n=93 n=232* n=125 n=69 n=62** n=62** Response rate 77% 65% 64% 60% 63% 70% 72% 76% Disease 100% 90% 87% 91% 91% N/A 99% NA control rate t l t Median PFS, 13.1 12.3 11.1 11.9 9.5 12.0 13.3 11.5 mos Median OS Median OS, Too T N t Not N t Not 30.9 29.8 32.2 34.0 28.0 mos early reached reached *>70% patients with RAS or BRAF mutation ** only RAS mutant 1. Masi et al. Lancet Oncol 2010; 2. Cremolini et al. Lancet Oncol 2015 3 S 3. Stein et al. Br J Cancer 2015; 4. Bendell et al. ASCO GI 2017 i l B J C 2015 4 B d ll l 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 To answer two FAQs about upfront t FAQ b t f t 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 + FOLFIRI + Arm A PD1 PD2 bev* bev* 5FU/bev 5FU/bev 5FU/bev 5FU/bev R R 1:1 FOLFOXIRI FOLFOXIRI FOLFOXIRI FOLFOXIRI Arm B Arm B PD2 PD2 PD1 + bev* + bev* 5FU/bev 5FU/bev Progression Free Survival 2 * Up to 8 cycles Cremolini et al, ESMO ‘18
Primary endpoint: Progression Free Survival 2 Median follow up = 22.8 Arm A Arm B mos N = 340 N = 339 235 (69%) 235 (69%) 188 (55%) 188 (55%) Events, N (%) Events N (%) 16.2 18.9 Median PFS2, mos HR = 0.69 [95% CI: 0.57 ‐ 0.83] p<0.001
1st line - Safety Profile FOLFOX + FOLFOXIRI + G3/4 adverse events, bev bev p p % patients N = 336 N = 336 0.140 Nausea 3 6 Vomiting 2 3 0.419 Diarrhea 5 17 <0.001 0.299 Stomatitis 3 5 Neutropenia 21 50 <0.001 Febrile neutropenia 3 7 0.050 0.505 Neurotoxicity 1 2 Asthenia 6 7 0.633 Hypertension 10 7 0.223 Venous 0.204 6 4 thromboembolism Cremolini et al, ESMO ‘18
1st line – RECIST Response Rate FOLFOX + FOLFOXIRI + bev bev OR [95%CI], p N = 340 N = 339 Best Response, % Complete Response 4% 3% Partial Response 46% 58% 1.55 [1.14-2.10] Response Rate 50% 61% p=0.005 St bl Stable Disease Di 40% 40% 31% 31% Progressive Disease 7% 4% Not Assessed 3% 4% Cremolini et al, ESMO ‘18
1st line - Progression Free Survival Median follow up = 22.8 FOLFOX + bev FOLFOXIRI + bev mos N = 340 N = 339 288 (85%) ( ) 261 (77%) ( ) Events, N (%) Events, N (%) Median 1 st 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 1 ° 1 ° - “ “precision oncology” i i l ” Patient Patient is here? 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 Molecular markers Clinical considerations
The relative weight of our drivers in subsequent lines Molecular markers Clinical considerations considerations
2nd- line after chemo + bev in wt patients RAS and BRAF wt subgroup (N=73) Progression ‐ Free Survival Overall Survival 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 Trifluridine/ idi / Regorafenib 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 Carlotta, 2018 Chiara, 2015
From negative selection to negative hyper- selection PRESSING Panel HER2 amplification or mutations lifi ti t ti • HER2 • 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
pos pos HER2 HER2 neg neg 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* RAS and BRAF wild-type* * * * patients clearly RESISTANT to patients clearly SENSITIVE to anti-EGFRs ti EGFR anti-EGFRs N=47 N=47 * * 0/47 MSI hi h 0/47 MSI-high 8/47 (17%) MSI hi h 8/47 (17%) 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
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