医学交流课件：2017 NCCN Guidelines update for colorectal Cancer and advances in care

1、AL B BENSON III, MD, FACP, FASCOPROFESSOR OF MEDICINEASSOCIATE DIRECTOR OF CLINICAL INVESTIGATIONSROBERT H LURIE COMPREHENSIVE CANCER CENTER OFNORTHWESTERN MEDICINEJ Clin Oncol. 1992CALGB/SWOG 80405meta-analysis 1992 80405 results Venook et al, 2014. 20002005200820092010 Capecitabine Oxaliplatin Cet

2、uximabIrinotecan5-FUPanitumumabTargeted therapiesBevacizumabKRAS5-FU, fluorouracil.National Cancer Institute, 2014; Van Cutsem et al, J Clin Oncol. 2012;30(28):3499-3506; Grothey et al, Ther Adv Med Oncol. 2012;4(6):301-319; Sridharan et al, Oncology (Williston Park). 2014;28(2):110-118; FDA Approve

3、d Drugs; FDA News Release; Lonsurf prescribing information.AfliberceptRegorafenibRamucirumabTrifluridine/tipiracilMetastatic Colon Cancer: Some Challenges High Response Rates and prolonged survival (some subsets mOS 36 mos)have changed landscape Sequence of therapy What combinations Selection of sur

4、gical patients Selection of liver directed therapy patients Role of molecular/genomic profiling/selection Immunotherapy combinationsDOI: 10.1200/JCO.2009.23.4450 Journal of Clinical Oncology 28, no. 3 (January 2010) 493-508. RCTs comparing hepatic resection to RFA for resectable hepatic colorectal m

5、etastases RTCs documenting the safety and efficacy of RFA. RFA versus hepatic resection for oligometastatic hepatic colorectal metastases Systemic chemotherapy versus RFA plus systemic therapy for liver-predominant CRHM Conversion chemotherapy as an approach for patients who have unresectable tumors

6、 but have limited liver disease The role of RFA for patients who have progressed after all standard systemic options but have remaining liver disease Role of cytoreductive RFA A registry study Which approach to RFA (open, laparoscopic, or percutaneous) is most appropriate Optimal periprocedural and

7、post procedural imaging modalities and timing Technical studies to improve the technology to enhance utility of RFA RFA compared to other liver-directed treatment optionsPeter Gibbs (1), Volker Heinemann, Navesh K. Sharma, Michael P. N. Findlay, Jens Ricke, Val Gebski, Mark Van Buskirk, Guy A. van H

8、azel, on behalf of the SIRFLOX Study Group(1) The Royal Melbourne Hospital, Melbourne, Australia Gibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-0615The combination of chemotherapy plus a biologic is standard first-line therapy for mCRC treated w

9、ith palliative intentLiver metastases are the dominant site of disease in mCRC and the dominant cause of deathSeveral decade history of evolving liver-directed therapies (HAC, cTACE, DEB-TACE, ablation, SBRT, SIRT) No large Phase III RCTs to date, therefore uncertain clinical utilitySIRFLOX is the f

10、irst large Phase III RCT of a liver-directed therapyGibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-06151. ANZ: Australia, New Zealand; AP: Asia Pacific; EME: Europe & Middle East; UK: United Kingdom; US: United States2. FOLFOX-based (+ biolo

11、gic) vs. FOLFOX-based (+ biologic) + SIRT Study NameStudy DesignGeographic Region (1)Recruitment CompletedPatients RecruitedOS Data ExpectedSIRFLOXRCT (2)ANZ, EME, US April 2013530FOXFIRERCT (2)UK November 2014364FOXFIRE GlobalRCT (2)ANZ, AP, EME, US January 2015209Total accrual 1,1032017Gibbs P et

12、al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-0615ANZ: Australia, New Zealand; AP: Asia Pacific; EME: Europe & Middle East; US: United States Prospective open-label RCTPrimary endpoint: Progression-Free SurvivalANZ: 280 (53%) EME:191 (36%) US: 59 (11%

13、)1. Bevacizumab allowed at investigators discretion, per institutional practiceGibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.Stratified by Presence of extra-hepatic metastases Degree of liver involvement Intended use of bevacizumab InstitutionRandomize

14、d1:1n = 530 Eligible patients Non-resectable liver-only or liver-dominant mCRC No prior chemo for advanced disease WHO performance status 01 mFOLFOX6 (+ bevacizumab) (1) SIRT n = 263 enrolled n = 267 enrolled mFOLFOX6 (+ bevacizumab) (1)118-EUA-06151. Bevacizumab allowed at investigators discretion,

15、 per institutional practice. 2. Work-up procedure at Day (D) -14 to D-3 prior to SIRT; SIR-Spheres Y-90 resin microspheres administered on either D3 or D4, of either Cycle 1 or Cycle 2.Treatment arm: mFOLFOX6 (+ bevacizumab) (1) + SIRT (2)Work up for SIRTPreparationOn day -14 to -3Control arm: mFOLF

16、OX6 (+ bevacizumab) (1)Cycle 1BevOX = 85 mg/m2Cycle 2Cycle 3Cycle 4FOLFOXBevOX = 85 mg/m2FOLFOXBevOX = 85 mg/m2FOLFOXBevOX = 85 mg/m2FOLFOXOX = 60 mg/m2OX = 60 mg/m2OX = 60 mg/m2BevOX = 85 mg/m2Cycle 2Cycle 3Cycle 4Cycle 1FOLFOXFOLFOXFOLFOXFOLFOXSIRTOn day 3 or 4Gibbs P et al. Presented at 2015 ASCO

17、 Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-0615CharacteristicFOLFOX (+ bev)(n = 263)FOLFOX (+ bev) + SIRT(n = 267)Age, years, median (range)63 (23 89)63 (28 81)SexFemale Male 88 (34%) 174 (66%) 85 (32%) 182 (68%)WHO performance 0 status1175 (67%) 87 (33%)176 (66%) 90 (34%)Extra

18、-hepatic metastases104 (40%)108 (40%)Primary tumor not removed121 (46%)119 (45%)Synchronous metastases233 (89%)241 (90%)Gibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-0615nEvents Median FOLFOX (+ bev)26322510.2 monthsFOLFOX (+ bev) + SIRT2672171

19、0.7 months HR: 0.93 (95% CI: 0.771.12), p=0.430.000.250.500.751.0001224364860Proportion Not ProgressingTime from Randomization (months)Number at riskFOLFOX 263 96 29 9 5 2 FOLFOX + SIRT267 106 33 11 5 2Gibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-

20、EUA-0615Probability of Hepatic Progression0.00.7nMedianFOLFOX (+ bev)26312.6 monthsFOLFOX (+ bev) + SIRT26720.5 monthsHR: 0.69 (95% CI: 0.550.90), p=0.002 01224364860Time from Randomization (months)Number at riskFOLFOX 263 96 29 9 5 2 FOLFOX + SIRT267 106 33 11 5 27.9 month improve

21、ment in median PFS in the liver31% reduction in risk of disease progression in the liverGibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-0615Liver metastases are the dominant site of disease in mCRC and the dominant cause of deathThe addition of S

22、IRT, using Y-90 resin microspheres, to FOLFOX-based first-line chemotherapy in patients with liver-dominant metastases: Did not improve overall PFS, but achieved A 7.9 month improvement in median PFS in the liver, representing a 31% reduction in risk of disease progression in the liver HR: 0.69; p=0

23、.002 with No negative impact on duration of systemic therapy, and Had toxicities that were acceptable and as predictedGibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.118-EUA-0615NT4%3%6%4%40%EXON 1EXON 2EXON 3EXON 4EXON 2EXON 3EXON 4KRASNRAS12 1312 13611

24、4659 61117 146EXON 1EXON 15EXON 11BRAF600NT8%117NT, not testedDouillard et al, 2013.17% additional mutations inKRAS and NRAS !mab:40mg mi.v. 120mininitial dose250 mg/m2i.v. 60minq 1wBevacizumab: 5 mg/kgi.v. 30-90minq 2w/0iFOLFIRI+CetuximabFOLFIRI + BevacizumabBevacizumab: 5 mg/kgiv 30-90 minevery 2

25、wkmCRCFirst-line therapy KRAS wild-typeN = 592Cetuximab:400 mg/m2iv 120 mininitial dose250 mg/m2iv 60 minevery 1 wkPrimary objective: overall response rate (inv assessed)Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%)284 e

26、valuable patients per arm needed to achieve 80% power for a one-sided Fishers exact test at an alpha level of 2.5%FOLFIRI: 5-FU: 400 mg/m2 (iv bolus); folinic acid: 400 mg/m2; irinotecan: 180 mg/m2; 5-FU: 2,400 mg/m2 (iv 46 hr)FOLFIRI, fluorouracil, folinic acid, and irinotecan; mCRC, metastatic col

27、orectal cancer.Heinemann et al, 2013.R1:10%4.3%4.9% KRAS WT exon 2 subsetEXON 1EXON 2EXON 3EXON 4EXON 2EXON 3EXON 4KRASNRAS12 1312 136114659 61117 146WT3.8%2%EXON 1EXON 15EXON 11BRAF6000%10%Heinemann et al, 2013.15% additional RAS mutations!Eventsn/N (%)Median(mo)95% CI FOLFIRI + Cetuximab91/171(53.

28、2%)33.124.5-39.4 FOLFIRI + Bevacizumab110/171(64.3%)25.622.7-28.6HR 0.70 (95% CI 0.53-0.92)P (log-rank) = .0110.0122436486072Months Since Start of Treatment171171Number at risk12812771683926209610.751.00.500.250.0Probability of SurvivalMedian = 7.5 moRAS* wild-type: KRAS 61/146; NRAS Exon2, NRAS Exo

29、n3.FOLFIRI, fluorouracil, folinic acid, and irinotecan.Heinemann et al, 2013. Primary endpoint: OS Superiority trial with 90% power to detect an OS HR of 1.25 (2-sided = .05) Secondary endpoints: ORR, PFS, TTF, DOR, and safetyBevacizumab+ FOLFOXor FOLFIRI every 2 wkCetuximab+ FOLFOXor FOLFIRI every

30、2 wkPDPDRandomizedpatients with KRAS WT tumorsUntreated advanced or metastatic CRC(N = 1,142)Approximately70% FOLFOX30% FOLFIRIRe-open: 6/09Closed to accrual: 2/12Patients enrolled: N = 2,334 (total) N = 1,177 (final endpoint) DOR, duration of response; FOLFIRI, fluorouracil, leucovorin, and irinote

31、can; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; H2H, head-to-head; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; TTF, time to treatment failure; WT, wild-type. Bergsland EK (Discussant). ASCO. 2013 (abstr 3504-3506). NCT identifier

32、: NCT00265850. 670/1,137 patients (59%) with KRAS codon 12/13 WT tumors evaluable 621/1,137 analyzed (55%) analyzed 95/621 (15.3%) patients new RAS mutation identified KRAS* NRAS*,1.8%5.9%EXON 3EXON 4EXON 259 614.2%0%EXON 2EXON 3EXON 412 1359 6112 13WT +1.3%2.3%117146117146*Percentages relate to fra

33、ction of RAS evaluable patients with mutations in particular exons.One patient had a mutation at both NRAS Exon1 codon12 and NRAS Exon3 codon 61.WT, wild-type.Lenz H-J, et al. Presented at: ESMO. 2014 (abstr 501O). Overall Survival(All RAS WT FOLFOX Patients)Overall Survival(All RAS WT FOLFIRI Patie

34、nts)ArmN(Events)Median (95% CI)HR(95% CI)PCT + Bevacizumab64(41)35.2(28.3-41.3)1.1(0.7-1.6).7 CT + Cetuximab72(48)32.0(25.6-42.9)ArmN(Events)Median (95% CI)HR(95% CI)PCT + Bevacizumab192(137)29.0(24.0-32.8)0.86(0.6-1.1).2CT + Cetuximab198(129)32.5(26.1-40.4)CT, chemotherapy; FOLFIRI, folinic acid, 5

35、-fluorouracil, and irinotecan; FOLFOX, folinic acid, 5-fluorouracil, and oxaliplatin; FOLFOXIRI, FOLFOX plus irinotecan; HR, hazard ratio; OS, overall survival; WT, wild type.Lenz, et al, 2014. Progression in our understanding of CRC subtypesPresented By David Cunningham Adapted from Bettington, et

36、al. Histopathology 2013;62:367-386.WntOS, overall survival; PFS, progression-free survival.Heinemann et al. J Clin Oncol. 2014;32: abstract 3600. 2014 American Society of Clinical Oncology. Bev, bevacizumab; Cetux, cetuximab; RWD, real-world data.1. Heinemann et al, J Clin Oncol. 2014;32: abstract 3

37、600. 2. Houts et al, J Clin Oncol. 2016;34: abstract 550.3. Lenz H-J et al, J Clin Oncol. 2016;34: abstract 493. 4. Venook et al, J Clin Oncol. 2016;34: abstract 3504.TreatmentBev-Containing RegimenCetux-Containing RegimenTumor LocationRightLeftRightLeftFIRE-31(n = 39)(n = 127)(n = 30)(n = 137)OS, m

38、o23.028.018.338.3HR (P)0.63 (.038)0.27 (.0001)CALGB 804054(n = 150)(n = 356)(n = 143)(n = 376)OS, mo24.231.416.736.0HR (P)1.32 (.01)1.87 (1,000Sun-exposed melanomas1,000Mismatch repair deficient tumors600Nonsmall cell lung cancers540Colorectal cancers77Pancreatic cancers48Glioblastomas36Medulloblast

39、omas8Respond toImmune CheckpointInhibitorsCourtesy: Luis DiazMSI-H, high levels of microsatellite instability.Courtesy: Axel GrotheyStagePrevalencePrognosis Compared to MSSII15%-20%excellentIII8%-10%sameIV4%-5%same or worseoHypermutated cancers too “deranged” to metastasizeoImmune system can prevent

40、 spreadoBut once a metastatic clone has been selected, same or worse prognosis than MSS MSI-H, high levels of microsatellite instability; MSS, microsatellite stability.The Cancer Genome Atlas, 2012.Dung Le, Jennifer Uram, Hao Wang, Bjarne Bartlett, Holly Kemberling, Aleksandra Eyring, Andrew Skora,

41、Brandon Luber, Nilofer Azad, Daniel Laheru, Barbara Biedrzycki, Ross Donehower, Atif Zaheer, George Fisher, Todd Crocenzi, Steven Duffy, James Lee, Richard Goldberg, Albert de la Chapelle, Minori Koshiji, Feriyl Bhaijee, Thomas Huebner, Ralph Hruban, Laura Wood, Nathan Cuka, Drew Pardoll, Nickolas P

42、apadopoulas, Kenneth Kinzler, Shibin Zhou, Toby Cornish, Janis Taube, James Eshleman, Robert Anders, Bert Vogelstein and Luis Diaz Jr.The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MarylandProvidence Cancer Center, Portland, OregonStanford University School of Medicine, S

43、tanford, CaliforniaBons Secours Cancer Institute, Richmond, VirginiaUniversity of Pittsburgh, Pittsburgh, Pennsylvania Ohio State University Comprehensive Cancer Center, Columbus, OhioMerck & Co., Inc., Kenilworth, New Jerseyo Binding of PD-1 to its ligands PD-L1 and PD-L2 inhibits effector T-ce

44、ll function1o PD-L1 expression on tumor cells and macrophages suppresses immune surveillance, permitting neoplastic growth2o Pembrolizumab is a humanized, IgG4 monoclonal antibody that Binds to PD-1 with high affinity, preventing PD-1 from binding to PD-L1 and PD-L2 Has demonstrated robust antitumor

45、 activity and manageable toxicity in multiple advanced cancersaaApproved by the FDA for the treatment of unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600 mutant, a BRAF inhibitor.PD-1, programmed cell death protein 1; PD-L1, programmed cell death prot

46、ein ligand 1.Le et al, N Engl J Med. 2015;372:2509-2520. 1. Keir et al, Annu Rev Immunol. 2008;26:677-704. 2. Pardoll, Nat Rev Cancer 2012;12:252-264.Colorectal Cancers AntiPD-1 (Pembrolizumab) 10 mg/kg every 2 weeks Here we report and update from the original 13 CRC Cohort A patients reported at AS

47、CO 2015Cohort ADeficient inMismatch Repair(n = 28)Cohort BProficient inMismatch Repair(n = 25)Non-Colorectal CancersCohort CDeficient inMismatch Repair(n = 30)Le et al, J Clin Oncol. 2016;34: abstract 103. CRC, colorectal cancer; MMR, mismatch repair.Le et al, J Clin Oncol. 2016;34: abstract 103. 20

48、16 American Society of Clinical Oncology.CRC, colorectal cancer; MMR, mismatch repair.Le et al, J Clin Oncol. 2016;34: abstract 103. 2016 American Society of Clinical Oncology.MMR-deficient (mPFS = not reached)MMR-proficient (mPFS = 2.3 mo)MMR, mismatch repair; mPFS, median progression-free survival

49、.Le et al, J Clin Oncol. 2016;34: abstract 103. 2016 American Society of Clinical Oncology.MMR-deficient(mOS = Not reached)MMR-proficient(mOS = 5.98 mo)MMR, mismatch repair; mOS, median overall survival.Le et al, J Clin Oncol. 2016;34: abstract 103. 2016 American Society of Clinical Oncology.Bosman

50、FT, Carniero F, Hruban, et. al. eds. World Health Organization Classification of Tumours of the Digestive System. Lyon: IARC; 2010.DOI: 10.1200/JCO.2009.23.4450 Journal of Clinical Oncology 28, no. 3 (January 2010) 493-508. Johanna Bendell,1 Tae Won Kim,2 Boon Cher Goh,3 Jeffrey Wallin,4 Do-Youn Oh,

51、5 Sae-Won Han,5 Carrie Lee,6 Matthew D. Hellmann,7 Jayesh Desai,8 Jeremy Lewin,9 Benjamin J. Solomon,10 Laura Q. Chow,11 Wilson H. Miller Jr,12 Justin Gainor,13 Keith Flaherty,13 Jeffrey Infante,1 Meghna Das Thakur,4 Paul Foster,4 Edward Cha,4 Yung-Jue Bang51Sarah Cannon Research Institute/Tennessee

52、 Oncology, Nashville, TN; 2Asan Medical Center, Seoul, South Korea; 3Cancer Science Institute of Singapore, National University of Singapore, Singapore; 4Genentech, Inc., South San Francisco, CA; 5Seoul National University Hospital, Seoul, South Korea; 6UNC Lineberger Comprehensive Cancer Center, Un

53、iversity of North Carolina Chapel Hill, North Carolina; 7Memorial Sloan Kettering Cancer Center, New York, NY; 8Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; 9Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; 10Peter MacCallum Cancer Cen

54、ter, Melbourne, VIC, Australia; 11University of Washington, Seattle, WA; 12Segal Cancer Center and Jewish General Hospital, McGill University, Montreal, QC, Canada; 13Massachusetts General Hospital, Boston, MABendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 201664Bendell J, et al. Cobimet

55、inib and atezolizumab in CRC. ASCO 2016The MAP kinase pathway is one of the most frequently dysregulated pathways in cancer due to hyperactivation by growth factor receptors or activating mutations1Sustained inhibition of RAS, RAF, MEK and ERK signaling may decrease proliferation and induce apoptosi

56、sCobimetinib is a reversible, potent and highly selective inhibitor of MEK1 and MEK2 that has been approved for melanoma Single agent MEK inhibition has shown little activity in mCRC1. Dhillon et al. Oncogene 2007.65Atezolizumab is a humanized engineered mAb that inhibits binding of PD-L1 to its rec

57、eptors PD-1 and B7.1This inhibition can enhance T-cell priming and restore anti-tumor T-cell activityAtezolizumab has demonstrated activity in several tumor types including lung cancer, metastatic urothelial carcinoma, and renal cell carcinoma1-4Response to PD-L1/PD-1 targeting agents in mismatch-re

58、pair proficient CRC (ie MSS) has been lower than seen in other indications51. Herbst et al. Nature 2014. 2. Fehrenbacher et al. Lancet 2016. 3. Rosenberg et al. Lancet 2016. 4. McDermott et al. J Clin Oncol 2016. 5. Le et al. N Engl J Med 2015.Bendell J, et al. Cobimetinib and atezolizumab in CRC. A

59、SCO 201666To examine the possible benefits of MEK inhibition with an anti-PDL1 agent, we evaluated cobimetinib + atezolizumab in patients with advanced solid tumorsMHC, major histocompatibility complex; ND, no drug (vehicle alone).CT26 (KRASmt) CRC models. 1. Ebert et al. Immunity 2016. Bendell J, e

60、t al. Cobimetinib and atezolizumab in CRC. ASCO 2016MEK inhibition alone can result in intratumoral T-cell accumulation and MHC I upregulation, and synergizes with an anti-PDL1 agent to promote durable tumor regression1CD8+ T cell per tumor cellNDMEKiTumor volume (mm3)DayControlAnti-PDL1MEKi (38963)MEKi + anti