Colon cancer: Highlights. Filippo Pietrantonio Istituto Nazionale dei Tumori di Milano

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1 Colon cancer: Highlights Filippo Pietrantonio Istituto Nazionale dei Tumori di Milano

2 Agenda 1) Metastatic colorectal cancer First-line treatment molecularly unselected: FOLFOXIRI-bev (CHARTA trial) Later-line treatment molecularly selected: Irinotecan-cetuximab-vemurafenib in BRAF+ (SWOG S1406 trial) Nivolumab in MSI-high (CheckMate 142 trial) 2) Early stage colorectal cancer Recurrence score in left vs. right (Israelian retrospective data)

3 CHARTA trial

4 CHARTA trial design INDUCTION MAINTENANCE 2 LINE TX Eligibility: 07/2011 FOLFOXbevacizumab Unresectable mcrc ECOG PS 2 Age 18 yo STRATIFICATION BY ESMO GROUPS 1- Initially unresectable, but potentially resectable after conversion 2- Never resectable, symptoms/risk for rapid worsening 3- Never resectable, asymptomatic/slow progression R 12/2014 FOLFOXIRI*- bevacizumab *TRIBE schedule * in frail/elderly pts dose reduction of 25% at 1 cycle (5-FU&CPT11) FU/FA bev cape bev P D Investigator s choice (including reinduction) PRIMARY ENDPOINT: 9 mos P<0.1 (alfa 0.1; beta 0.2) 250 patients Schmoll et al, ASCO GI 17

5 Primary endpoint: progression-free survival FOLFOX-bev (n=121) FOLFOXIRI-bev (n=121) PFS mos 57% 68% p Schmoll et al, ASCO GI 17

6 Overall survival A longer follow up is needed. Schmoll et al, ASCO GI 17

7 FOLFOXIRI + bev: consistent results FOIB 1 TRIBE 2 OPAL 3 STEAM 4 MOMA 5 CHARTA 6 n=57 n=252 n=97 n=93 n=232* n=125 Regimen FOLFOXIRI/ Bev FOLFIRI/Bev +/- Oxa FOLFOXIRI/ Bev FU/Bev maintenance FOLFOXIRI/ Bev vs FOLFIRI/Bev FOLFOXIRI/ Bev Bev ± metroct FOLFOX/Be v ± IRI Response rate 77% 65% 64% 60% 63% 70% Disease control rate 100% 90% 87% 91% 91% N/A Median PFS, months Median OS, months Too early Too early * >70% patients with RAS or BRAF mutation Courtesy of C. Cremolini 1. Masi et al. Lancet Oncol 2010; 2. Cremolini et al. Lancet Oncol Stein et al. Br J Cancer 2015; 4. Bendell et al. ASCO GI Falcone et al. ESMO 2016; 6. Schmoll et al. ASCO GI 2017

8 SWOG S1406 trial

9 Background BRAF-mut is a rare (8%) and aggressive molecular mcrc subtype Anti-EGFRs (w/o chemotherapy) and BRAFi (w/o MEKi) have limited activity Preclinical and early phase 1/2 evidences suggested that anti-egfrs plus BRAFi targeted combinations have a manageable safety profile and encouraging activity Preclinical and early phase 1/2 evidences suggested that the addition of iritotecan to cetuximab-vemurafenib is tolerable and may further increase activity Data from randomized clinical trials were still lacking Hong et al, Cancer Discov 16

10 SWOG S1406 trial design Eligibility: BRAF V600E mcrc (local or central) RAS wt ECOG PS 0-1 Measurable/non-measurable disease One or two prior regimens for mcrc* *Prior irinotecan allowed *Prior anti-egfrs or BRAFi not allowed R Stratified Prior iri Y vs n Irinotecan cetuximab (n=50) Irinotecan cetuximab & vemurafenib (n=49) Vemurafenib 960 mg PO b.i.d. Cetuximab 500 mg/sqm q2 weeks Irinotecan 180 mg/sqm q2 weeks P D Irinotecan cetuximab PLUS vemurafenib CROSSOVER ALLOWED PRIMARY ENDPOINT Progression-free survival SECONDARY ENDPOINTS Safety, OS, ORR in pts with measurable disease Two-sided type 1 error of 5% 90% statistical power Target HR of 0.5: mpfs from 2.4 to 4.8 mos 94 eligible pts needed Kopetz et al, ASCO GI 17

11 Primary endpoint met! Progression-free survival is significantly increased with vem/cet/iri triplet Kopetz et al, ASCO GI 17

12 Secondary endpoints Kopetz et al, ASCO GI 17 A C T I V I T Y ORR (included upr/ucr) IRI-CET (n=45) IRI CET VEMU (n=43) 4% 16% SD 17% 48% PD (included clinical PD) 56% 12% p Acquired resistance S A F E T Y

13 CheckMate 142 trial

14 Background In mcrc, MSI-high status is a rare (4%) and associated with aggressive course and poor response to conventional treatments, independently from BRAF mut MSI-high status is associated with hyper-mutated status and increase in neoantigen load, as well as upregulation of immune check-point signals A previous proof of concept study showed that pembrolizumab was active in MSI-high mcrc and non-colon cancers, but 0% activity was shown for MSS mcrc Angelova, Genome Biology 15; Dung, NEJM 15

15 CheckMate 142 trial design Overamann et al, ASCO GI 17 STAGE 1 MONOTX STAGE 2 MONOTX Eligibility: Histologically confirmed mcrc MSI-H per local testing 1 prior therapy for mcrc 2-stage design Nivolumab 3 mg/kg Q2 weeks Nivolumab 3 mg/kg Q2 weeks Nivolumab 3 mg/kg Ipilimumab 1 mg/kg Q3 weeks x 4 cy Then Nivo 3 mg/kg Q2 weeks STAGE 1 COMBO STAGE 2 COMBO CheckMate 142 is a phase II study investigating the safty and efficacy of nivolumab +- ipilimumab in patients with MSI-H mcrc

16 CheckMate 142: ACTIVITY Overmann et al, ASCO GI 17

17 Looking at potential biomarkers.. Overamann et al, ASCO GI 17 PD-L1 expression Tumor cells Infiltrating cells BRAF mutation Lynch syndrome

18 Looking at survival outcomes.. Overamann et al, ASCO GI 17

19 Safety & QoL.. Overamann et al, ASCO GI 17

20 Agenda 1) Metastatic colorectal cancer First-line treatment molecularly unselected: FOLFOXIRI-bev (CHARTA trial) Later-line treatment molecularly selected: Irinotecan-cetuximab-vemurafenib in BRAF+ (SWOG S1406 trial) Nivolumab in MSI-high (CheckMate 142 trial) 2) Early stage colorectal cancer Recurrence score in left vs. right (Israelian retrospective data)

21 Sidedness matters: <br />Surrogate biomarkers prognosticate early colorectal cancer upon anatomic location Presented By Irit Ben-Aharon at 2017 Gastrointestinal Cancers Symposium

22 Prognostic impact left vs. right patients in 66 studies (stage I IV) HR: 0.82 [95%CI: ], p<0.001 No stage-related differences Petrelli et al, JAMA Oncol 2016

23 Oncotype Dx: a validated prognostic tool

24 Focus on.. Ben Aharon et al, ASCO GI 17 STAGE II, T3N0 MSS: average risk

25 Oncotype Dx and primary tumor location Ben Aharon et al, ASCO GI 17

26 Grazie per l attenzione