AIOM GIOVANI Perugia, Luglio 2017

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1 AIOM GIOVANI 2017 Perugia, Luglio 2017 Scelta delle linee successive nel paziente RAS e BRAF wild-type con particolare accento su nuovi bersagli terapeutici Francesca Battaglin U.O.C. Oncologia Medica 1 Dipartimento di Oncologia Clinica e Sperimentale Istituto Oncologico Veneto IRCCS, Padova Tutor: Dr. Antonio Galvano Regione del Veneto

2 Not all patients receive a second-line therapy An example: FIRE-3: subsequent lines of treatment FOLFIRI + Cetuximab N= 297 FOLFIRI + Bevacizumab N= 295 p Any 2nd-line therapy, % nd-line beva, % nd-line anti-egfr, % Heinemann H et Al, Lancet Oncology 2013

3 Impact of second-line CT on OS Modest et Al JCO 2015 ESMO guidelines 2016

4 Facing a progressing mcrc patient Patients conditions and motivation First-line treatment: a. What did he get? b. How did he tolerate it? c. Did he benefit? Treatment goal

5 Which second-line treatment? WHICH CHEMO? WHICH BIOLOGIC? BOTTOM-LINE: - Few data available in a real world setting - Most indications derived from: a) subgroup analyses; b) indirect comparisons

6 Which chemo? Standard is to SWITCH chemo! Tournigand et al, J Clin Oncol 2004

7 Which second-line treatment after FOLFOXIRI (+bev)? FOLFIRI + bev FOLFOXIRI + bev Progression-free survival probability I N D U C T I O N MA I N T E N FOLFOXIRI + bev 5-FU only + bev 6 mos median OXALIPLATIN and IRINOTECAN-free interval 0 6 mos 6 12 mos F-up time (months)

8 Next effort: TRIBE-2 trial FOLFOX + bev* 5FU/bev PD1 FOLFIRI + bev* 5FU/bev PD2 R 1:1 FOLFOXIRI + bev* 5FU/bev PD1 FOLFOXIRI + bev* 5FU/bev PD2 *all repeated for 8 cycles (4 months) followed by maintenance with 5FU/bev until PD Primary endpoint: Progression-free survival 2

9 Which second-line treatment? WHICH BIOLOGIC? After BEV After anti-egfr Bevacizumab Aflibercept (+ FOLFIRI) [Ramucirumab (+ FOLFIRI)] Anti-EGFR Bevacizumab Aflibercept (+ FOLFIRI) [Ramucirumab (+ FOLFIRI)] Anti-EGFR?

10 Angiogenesis inhibition in second-line

11 Second-line anti-vegf in RAS WT Wirapati et al, ASCO Annual Meeting 2017

12 How to choose the right antiangiogenic drugs? Bevacizumab beyond PD OS PFS RR AEs Early PD Bev Iri I Line Aflibercept Ramucirumab NA How can we choose? CT back-bone Treatment goal Toxicity profile Economic costs Need of predictive biomarkers!!!

13 Second line anti-egfr Study (drug) EPIC (Cet) No molec selection PICCOLO (Pani) KRAS wt (cod 12, 13, 61) PICCOLO (Pani) All wt OS (HR) HR=0.98 p=0.71 HR=1.01 p=0.91 HR=0.92

14 Panitumumab after PD on Bev Study 1186 mcrc pts PD after 1stline fluorobased CT R FOLFIRI FOLFIRI+Pan ORR and PFS, not in OS OS: KRAS wt subgroup receiving 1 st -line bev Peeters et al, Ann Oncol 2014

15 A direct comparison: the SPIRITT study 182 KRAS wt mcrc pts PD after at least 4 cycles of FOLFOX/XELOX Bev R FOLFIRI+Bev FOLFIRI+Pan Phase II study Hecht et al, ASCO GI 2013

16 Still a chance 6% of patients receiving 2 nd -line chemo+cet conversion to resectability Adam et al, J Clin Oncol 2007

17 Bevacizumab after PD on Cetuximab FIRE-3 trial Heinemann et al, ASCO Annual Meeting 2013

18 Ciardiello et al, Ann Oncol 2016 Cetuximab beyond PD? GOIM CAPRI trial FOLFOX 340 mcrc pts KRAS exon 2 wt FOLFIRI + Cet PD R 1:1 Primary endpoint: PFS FOLFOX+ Cet

19 FIRST-LINE SECOND-LINE Angiogenesis inhibitors Anti-EGFR - Bevacizumab - Aflibercept - Ramucirumab - Panitumumab - Cetuximab THIRD/FOURTH LINE - Cetuximab/Panitumumab - Regorafenib - TAS Rechallenge CONTINUUM OF CARE early integration of SIMULTANEOUS CARE

20 CORRECT trial: primary endpoint Regorafenib mos = 6.4 mos Placebo mos = 5.0 mos HR=0.77 (95%CI ) p= Grothey et al, Lancet 2013

21 Regorafenib: open issues Predictive markers New response parameters (other than RECIST) Adverse event management / Dose reduction?

22 TAS-102: the RECOURSE trial About 20% rego-pretreated mos 7.1 vs 5.3 months

23 RECOURSE trial: safety profile Lab abnormalities, % TAS-102 (n=533) Placebo (n=265) All Gr Gr 3 Gr 4 All Gr Gr 3 Gr 4 Leukopenia Anemia Neutropenia Lymphocytopenia Thrombocytopenia TAS-102 (n=533) Placebo (n=265) Adverse events, % All Gr Gr 3 Gr 4 All Gr Gr 3 Gr 4 Febrile neutropenia Yoshino et al, WCGIC 2014

24 TAS 102: open issues Predictive markers Drug availability

25 Regorafenib vs TAS-102: the REGOTAS Study Fukuoka et al, ASCO Annual Meeting 2017

26 Rechallenge with EGFR Inhibitors: pooled data from the PRIME and PEAK Studies Median OS after rechallenge of 14.2 mo Siena et al, WCGIC 2017

27 The CRICKET Study First line irinotecan based CT + Cetux Second line oxa-based CT + Bev Iri-Cetux Primary endpoint: ORR Secondary endpoints: PFS, OS, Toxicity rate Rossini et al, WCGIC 2017

28 BRAF mutation BRAF mutation How targeted are we? Going deeper. RAS/BRAF wild-type 40% 10% RAS mutations 50% HER-2 3% RAS/BRA F wild-type RAS mutations 40% 10% 50% MSI 5%

29 anti-her2: real results! Sartore Bianchi et al, Lancet Oncology 2016

30 HERACLES results: PFS by HER2 gene copy number HERACLES study: PFS Sartore-Bianchi A et al. Lancet Oncol 2016

31 Immunotherapy: the rising star Type of response MSI (n=10) MSS (n=18) Complete Response 0% 0% Partial Response 40% 0% Objective Response Rate 40% 0% Disease Control Rate 90% 11% Modified from Le et al, N Eng J Med 2015

32 Pembrolizumab PFS results: MSI-H vs non-msi-h Presented By Dung Le at ASCO Annual Meeting 2016

33 Phase 2 CheckMate 142 Study Design APC T-cell Interaction Tumor Microenvironment Activation (cytokine secretion, lysis, proliferation, migration to tumor) MHC TCR Dendritic +++ cell B7 CD B7 CTLA anti-ctla-4 T cell TCR MHC T cell +++ Tumor cell PD-1 PD-L1 --- anti-pd-1 PD-1 PD-L2 --- anti-pd-1 CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab) Andre et al, ASCO Annual Meeting 2017

34 Phase 2 CheckMate 142: Investigator-Assessed Overall Response Rate Andre et al, ASCO Annual Meeting 2017

35 Phase 2 CheckMate 142: Nivo +Ipi PFS and OS Andre et al, ASCO Annual Meeting 2017

36 Future prospectives: where are we going? Liquid biopsy Primary and acquired resistance, dynamic clonal evolution Anti-EGFR Rechallenge The CHRONOS Study New strategies to overcome secondary resistance Panitumumab+MEK inhibitor (NCT ) Cetuximab+MET inhibitor (NCT ) SYM004 (NCT )

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