Carcinoma colorettale: personalizzazione del trattamento

Transcription

1 33 Incontro Oncologico del Triveneto Padova, Aprile 2017 Carcinoma colorettale: personalizzazione del trattamento Fotios Loupakis, MD PhD U.O.C. Oncologia Medica 1 Dipartimento di Oncologia Clinica e Sperimentale Istituto Oncologico Veneto IRCCS, Padova Regione del Veneto

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3 Case 1 Age 80 ECOG PS=1 (asthenia, no major comorbidities) Synch presentation colonic mass hepatic flexure, 2 small liver lesions and multiple lung metastases (max 1 cm) CAPE + BEV

4 Case 2 Age 55 ECOG PS=0 Synch presentation colonic mass hepatic flexure, 5 large liver lesions (diameter up to 8 cm) FOLFOXIRI + BEV

5 we are in 2017.is that it?

6 RAS WT RAS MUT

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8 Right vs Left Cetuximab vs Bevacizumab Adapted from Lenz et al., ESMO 2016

9 PATIENT: age, fitness, personal motivation Appropriate for Combo? YES NO NO Appropriate for Triplet? YES Fluorop. + bev (or personalized tx) RAS/BRAF YES Previous oxa- adj? MUT W T NO Primary Tumor Location RIGHT LEFT Doublet + bev Doublet + anti-egfr Triplet + bev

10 Ok, you didn t move that much.what about the future?

11 MSI-H mcrc RAS wild-type 50% RAS mutations 50% MSI-H 5%

12 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

13 Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142 Michael J. Overman, 1 Sara Lonardi, 2 Francesco Leone, 3 Ray McDermott, 4 Michael A. Morse, 5 Ka Yeung Mark Wong, 6 Bart Neyns, 7 Joseph L. Leach, 8 Pilar Garcia-Alfonso, 9 James J. Lee, 10 Andrew Hill, 11 Heinz-Josef Lenz, 12 Jayesh Desai, 13 Rebecca A. Moss, 14 Z. Alexander Cao, 14 Jean-Marie Ledeine, 15 Hao Tang, 14 Scott Kopetz, 1,a Thierry André 16,a 1 MD Anderson Cancer Center, Houston, TX, USA; 2 Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy; 3 Candiolo Cancer Institute FPO-IRCCS, University of Torino School of Medicine, Torino, Italy; 4 St. Vincent s University Hospital, Dublin, Ireland; 5 Duke University Medical Center, Durham, NC, USA; 6 The University of Sydney, Sydney Medical School, Sydney, Australia; 7 Universitair Ziekenhuis Brussel, Brussels, Belgium; 8 Allina Health System, Minneapolis, MN, USA; 9 Hospital General Universitario Gregorio Marañón, Madrid, Spain; 10 University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; 11 Tasman Oncology Research Pty Ltd, Southport, Queensland, Australia; 12 USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 13 Royal Melbourne Hospital, Victoria, Australia; 14 Bristol-Myers Squibb, Princeton, NJ, USA; 15 Bristol-Myers Squibb, Braine-l Alleud, Belgium; 16 Hôpital Saint Antoine, AP-HP, Paris, France a Co-senior authors. Presented by: Dr Michael J. Overman

14 Study Design Stage 1 a Stage 2 b Patients Nivolumab 3 mg/kg Q2W 74 patients were treated in monotherapy stages 1 and 2 Histologically confirmed metastatic/recurrent CRC dmmr/msi-h per local laboratory 1 prior line of therapy Nivolumab 3 mg/kg Q2W Stage 1 c Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses Stage 2 d Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses Then nivolumab 3 mg/kg Q2W Then nivolumab 3 mg/kg Q2W Primary endpoint: ORR per investigator assessment Secondary endpoint: ORR per blinded independent central review (BICR) Other endpoints: PFS, OS, biomarkers, safety and tolerability Q2W, every 2 weeks; Q3W, every 3 weeks. a Enrollment complete; b Opened based on an adequate ORR (CR + PR) in patients with centrally confirmed MSI-H CRC treated in mstage 1; c Opened despite an adequate ORR in mstage 1 to proceed to mstage2; d Opened based on an adequate ORR in cstage 1. Presented by: Dr Michael J. Overman

15 Response and Disease Control ORR, n (%) 20 (27.0) Best overall response, n (%) CR PR SD PD 2 (2.7) 18 (24.3) 28 (37.8) 20 (27.0) Presented by: Dr Michael J. Overman

16 C h a n g e i n S u m o f T a r g e t L e s i o n s S i z e ( % ) a Change in Tumor Burden b b O n On treatment T r e a t m e n t O f f T r e a t m e n t Off treatment CR or CPR o m p l e t e o r P a r t i a l First occurrence R e s o p o n sof e new lesion F i r s t O c c u r r e n c e o f N e w C h a n g e T r u n c a t e d t o % W e e k s a Patients evaluated as dmmr/msi-h by local laboratory. Tumor evaluations by investigator assessment. b Change truncated to 100%. Presented by: Dr Michael J. Overman

17 Progression-Free Survival 100 PFS per Investigator Probability of PFS (%) a Median [95% CI], months 12-month rate [95% CI], % PFS per BICR 12-month rate [95% CI], % 9.6 [4.3, NE] 48.4 [33.6, 61.7] 45.6 [32.2, 58.1] Months No. at risk BICR, blinded independent central review; NE, not estimable. a Patients evaluated as dmmr/msi-h by local laboratory. PFS assessed by investigators. Presented by: Dr Michael J. Overman

18 Overall Survival Median OS [95% CI], months 12-month OS rate [95% CI], % NR [17.1, NE] 73.8 [59.8, 83.5] Probability of Survival (%) a Months No. at risk NR, not reached. a Patients evaluated as dmmr/msi-h by local laboratory. Presented by: Dr Michael J. Overman

19 Investigator-Assessed Best Change in Target Lesion Size (%) Reduction in Target Lesion Size Regardless of PD-L1 Expression Tumor PD-L1 Expression 1% < 1% Presented by: Dr Michael J. Overman

20 Investigator-Assessed Best Change in Target Lesion Size (%) Investigator-Assessed Best Change in Target Lesion Size (%) Reduction in Target Lesion Size Regardless of BRAF Mutation Status and Lynch Syndrome BRAF Mutation Status Clinical History of Lynch Syndrome Mutant Wild type + Confirmed CR/PR Yes No + Confirmed CR/PR Presented by: Dr Michael J. Overman

21 ONLY MSI-H? (3-5%)

22 Clinical activity and safety of cobimetinib and atezolizumab in colorectal cancer Presented By Johanna Bendell at 2016 ASCO Annual Meeting

23 Slide 3 Presented By Johanna Bendell at 2016 ASCO Annual Meeting

24 PD-L1 and MEK Inhibition: A Rational Combination Presented By Johanna Bendell at 2016 ASCO Annual Meeting

25 Efficacy: Change in Tumor Burden Presented By Johanna Bendell at 2016 ASCO Annual Meeting

26 Efficacy: Change in Tumor Burden Over Time Presented By Johanna Bendell at 2016 ASCO Annual Meeting

27 WHAT ELSE?

28 BRAF mutation What else? RAS/BRAF wild-type 40% 10% RAS mutations 50% MSI 5%

29 Strong Prognostic Value in mcrc Richamn S et al, J Clin Oncol 09

30 Treatment: what do current guidelines say? adapted from Van Cutsem et al, Ann Oncol 16

31 What if we hit the target?

32 Monotherapy Kopetz et al, J Clin Oncol 15

33 Let s make it easy... anti-egfrs: not enough... anti-braf single-agent : not enough... What about doublets? adapted from Clarke C, JGO 15

34 anti-egfrs + BRAF inhib doublets Combination N RR Ref Panitumumab Vemurafenib Cetuximab Vemurafenib Cetuximab Encorafenib Panitumumab Dabrafenib 15 13% 27 4% 50 22% Yaeger et al, J Clin Oncol 15 Hyman et al, N Engl J Med 15 Tabernero et al, ESMO WCGIC % Atreya et al, ASCO 15

35 When doublets are not enough...

36 Rational TRIPLET combinations Adapted from Korphaisarn et al, The Cancer Journal 16

37 Triplets: available data Strategy Combination N RR Ref BRAFi anti-egfr MEKi Panitumumab dabrafenib trametinib 35 26% Atreya et al, ASCO 15 BRAFi anti-egfr chemotherapy Cetuximab vemurafenib irinotecan 17 35% Hong et al, ASCO 15 BRAFi anti-egfr Pi3KCAi Cetuximab encorafenib alpelisib 52 27% Tabernero et al, ESMO WCGIC 16

38 Median Overall Survival, mo...looks promising, doesn t it? ,1 12, , ,7 4,3 4,1 2 0 CETUX + chemo CETUX + chemo FOLFIRI FOLFIRI panitumumab 3 CETUX + chemo CETUX + irinotecan Triplet Enco-Cet- regimen Alpelisib Doublet regimen 2nd line+ n=24 2nd line+ n=12 2nd line n=23 2nd line n=22 2nd line+ n=8 2nd line+ n=13 2nd line+ n=52 adapted from Tabernero et al, ESMO WCGIC 16

39 ...let s give it a try!

40 this challenge... is a tough one Barras D et al, Clin Cancer Res 16

41 We re not there in the clinic yet, but gene amplification of EGFR, KRAS, and mutant BRAF acquired mutations in KRAS, EGFR, and MAP2K1 Oddo et al, Cancer Res 16 gene amplification of MET effectiveness of MET-inhibition Pietrantonio et al, Cancer Discovery 16

42 OOOOOPS...

43 The BRAF /MSI-H association Keep the adjuvant distinct from the metastatic setting Around 1/3 of BRAF mutant mcrc are MSI-H Around 1/3 of MSI-H are BRAF mutant BRAF mutation drives the poor prognosis of mcrc MSI-H Don t ask me about the predictive role of MSI status to BRAF target strategies nor about the predictive role of BRAF status to immunotherapy. Goldstein J et al, Ann Oncol 14 Venderbosch S et al, Clin Cancer Res 14

44 Let me add a final piece of confusion Rectal Non mucinous No peritoneal spread Cremolini et al, Ann Oncol 16 Left-sided Low Grade No peritoneal spread Jones et al, ASCO Annual Meeting 16

45 BRAF mutation Going deeper. HER-2 3% RAS/BRA F wild-type 40% 10% RAS mutations 50% MSI 5%

46 anti-her2: real results! Sartore Bianchi et al, Lancet Oncology 16

47 BRAF mutation Going to the superrare! TRK/ROS/ALK/RET HER-2 3% Rearrangem RAS/BRA F wild-type RAS mutations 40% 10% MSI 5% 50%

48 Entrectinib Rolfo et al, Expert Opin Investig Drugs 2015

49 1 Entrectinib 75 year-old female 3 prior therapies, ECOG PS 0 mcrc with NTRK1 fusion entrectinib 1600 mg/m 2 Schedule A Mar 2014 Apr 2014 Co Entrectinib was relapsed or refra harboring NTRK alterations. A BSA-based R mg/m 2 QD, whic with complete tu models. Exploration o ongoing. Pharmacokineti increases from Among patients inhibitor-naïve N 10/11 (91%) pat exhibited object with durable res These prelimina development of 014 Copies of this poster o personal use and may permission from ASCO De Braud et al, ASCO Annual Meeting 15

50 StarTRK-2 * *any line of therapy Primary endpoint: Overall Response Rate

51 See you in 2018

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