Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS
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Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS

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Dr. Cathy Eng's presentation regarding biomarkers. Explaining why colon and rectal cancer patients should undergo testing for KRAS, NRAS and other tumor tests.

Dr. Cathy Eng's presentation regarding biomarkers. Explaining why colon and rectal cancer patients should undergo testing for KRAS, NRAS and other tumor tests.

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    Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS Presentation Transcript

    • Department of GI Medical Oncology ALPHABET SOUP: MAKING SENSE OF KRAS, BRAF, RAS AND OTHER BIOMARKERS IN METASTATIC COLORECTAL CANCER Cathy Eng, M.D., F.A.C.P. Associate Professor Associate Medical Director, Colorectal Center Director of Network Clinical Research, GI Med Oncology Co-Chairman, SWOG Rectal Subcommittee April 23, 2014
    • Cancers of the Colon and Rectum International Statistics Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014 Incidence Mortality 1.2 Million 609,000 Worldwide per annum USA (2014) Incidence Mortality 136,830 50,310 Colorectal cancer is the 3rd most common cancer in men and the 2nd in women.
    • Advances in the Treatment of Metastatic Colorectal Cancer 1980 1985 1990 1995 2000 2005 Therapeutic concepts Palliative CT Neoadjuvant CT Capecitabine Oxaliplatin Cetuximab Bevacizumab Irinotecan 5-FU Panitumumab Targeted therapies { 5-FU = 5-fluorouracil; CT = chemotherapy. {Cytotoxic chemotherapies Ras OS: 20M OS: 32 months Aflibercept Regorafenib
    • 15.6 20.3 19.9 21.3 23.1 28 17.6 19.2 0 5 10 15 20 25 30 First-Line Bevacizumab in mCRC: Overall Survival *P<0.001; †P = 0.0769. 1. Hurwitz H et al. N Engl J Med. 2004;350:2335-2342; 2. Saltz LB et al. J Clin Oncol. 2008;26:2013-2019; 3. Fuchs C et al. J Clin Oncol. 2007;25:4779-4786; 4. Fuchs C et al. J Clin Oncol. 2008;26:689-690; OS(months) * NO169662 AVF2107g1 BICC-C3,4
    • Approved Anti-VEGF Agents Antiangiogenic agent Description Target Approval Bevacizumab Recombinant humanized monoclonal antibody VEGF-A 1st-line mCRC1,2: •FDA 2004 •EMEA 2005 2nd-line mCRC1: •FDA 2006, 2013 Aflibercept Fully human fusion protein VEGF-A VEGF-B PIGF 2nd-line mCRC3,4: •FDA 2012 •EMEA 2013, •TGA 2013 Regorafinib Small molecule TKI VEGFR-1,2 & 3 PDGFR-b, TIE-2, FGFR-1, Ret, Kit, & Raf kinases Salvage5,6: •FDA 2012 •CHMP 2013 •TGA 2013 CHMP, Committee for Health and Medicine Products; EMEA, European Medicines Agency; FDA, United States Federal Drug Administration, FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; PlGF, placental growth factor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor .
    • Biomarker Development  Review of Definitions:  Prognostic marker  Independent of treatment  May impact surveillance  Predictive marker  Impacts type of treatment provided
    • Molecular Markers for Anti-VEGF  None identified and validated:  Bevacizumab  Aflibercept  Regorafenib  Anti-EGFR Therapy  Predictive: KRAS/NRAS  Prognostic: BRAF
    • Current Molecular Markers
    • KRAS  Proto-oncogene  First globally utilized predictive marker for the treatment of MCRC when considering anti-EGFR therapy  30%-50% of all patients  MT (exon 2): codons 12, 13, 61, and rarely 146  KRAS WT does = efficacy of therapy nor does it indicate duration of response
    • Copyright © American Society of Clinical Oncology Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007 Cetuximab and K-ras modulate signaling through the epidermal growth factor receptor (EGFR) pathway
    • BRAF MT  Serine-threonine kinase belong to the RAF family  Mutation also leads to constitutive activation  V600E accounts for 90% of mutations  Found in < 10 % of all CRC patients  Associated with hypermethylation of CpG island.  Mutually exclusive with KRAS MT  Prognostic but NOT predictive  All studies insufficiently powered to provide sufficient data to determine use of anti-EGFR therapy based on BRAF status.
    • NRAS  Resembles Kras  Oncogene  < 5% of all mCRC  Mutations in codons 12, 13, 61, 117 and 146  Usually codon 61  Mutually exclusive with KRAS
    • Front-line chemotherapy with anti-EGFR therapy
    • Update on PRIME Study Phase III Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. Patients • Previously untreated mCRC • Fluorouracil-based adjuvant chemotherapy allowed if PD occurred ≥6 mo after completion; no oxaliplatin • Tumor tissue from primary tumor or metastasis available for biomarker analysis • ECOG PS 0-2 • N=1183 Primary endpoint: PFS Panitumumab 6.0 mg/kg q 2 wk FOLFOX4 q 2 wk 1:1 Randomization FOLFOX4 q 2 wk
    • Distribution of mutations in mCRC RAS wt ~50% KRAS mt (exon 2) ~40% KRAS mt (non exon 2 KRAS mt) & NRAS mt ~10% Rare KRAS Mutations NRAS Mutations Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.
    • PRIME Biomarker Analysis: Analysis of KRAS/NRAS and BRAF Mutations RAS and BRAF Status FOLFOX4 Alone Panitumumab + FOLFOX4 KRAS exon 2 (codon 12/13) WT MT 331 219 325 221 WT KRAS exon 2 tumors tested for RAS and BRAF (n = 321) (n = 320) WT KRAS exon 2/MT other RAS, n (%) 57 (18) 51 (16) KRAS exon 3 (codon 61), n (%) WT MT Failure 306 (95) 14 (4) 1 (0) 308 (96) 10 (3) 2 (1) KRAS exon 4 (codons 117/146), n (%) WT MT Failure 296 (92) 15 (5) 10 (3) 288 (90) 21 (7) 11 (3) NRAS exon 2 (codons 12/13), n (%) WT MT Failure 307 (96) 14 (4) 0 (0) 308 (96) 8 (3) 4 (1) NRAS exon 3 (codon 61), n (%) WT MT Failure 305 (95) 14 (4) 2 (1) 305 (95) 12 (4) 3 (1) NRAS exon 4 (codons 117/146), n (%) WT MT Failure 313 (98) 0 (0) 8 (2) 316 (99) 0 (0) 4 (1) BRAF exon 15 (codon 600), n (%) WT MT Failure 280 (87) 29 (9) 12 (4) 286 (89) 24 (8) 10 (3) Oliner J, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3511. Oliner J, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 2275.
    • Revised PRIME Consort Diagram Douillard et al: NEJM, 2013
    • PRIME: Progression-free survival in patients with (A) Original wild-type (WT) KRAS, (B) Updated All WT RAS, Overall survival in patients with (C) Original WT KRAS and (D) All WT KRAS Douillard J et al. JCO 2010;28:4697-4705; NEJM, 2013 ©2010 by American Society of Clinical Oncology D B
    • PFS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS Oliner KS. ASCO 2013. Abstract 3511.
    • OS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS Oliner KS. ASCO 2013. Abstract 3511.
    • PRIME: Summaryand ClinicalImplications  About 17% of patients with mCRC harbor mutations beyond KRAS exon 2 mutations  Excluding patients with RAS mutations identifies patients more likely to benefit from anti-EGFR therapy.  Practical interpretation: until an all-RAS test becomes available, EGFR monoclonal antibodies have the potential to be detrimental in patients who may harbor an unrecognized RAS mutation when administered with oxaliplatin-based chemotherapy regimens Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.
    • Treatment choice: Front line chemotherapy with anti-EGFR therapy or anti-VEGF therapy?
    • PEAK: Randomized Phase II (KRAS WT) FOLFOX/Pmab (N=142) FOLFOX/Bev (N=143) Median PFS (95% CI) 10.9 (9.4-13.0) 10.1 (9.0-12.6) Median OS (95% CI) 34.2 (26.6-NR) 24.3 (21.0-29.2) ORR (95% CI) 58 (49-66) 54 (45-62)] Subsequent therapy: Anti EGFR 21% 38% Anti-VEGF 40% 24% Schwarzberg et al: JCO 2014
    • PEAK: Randomized Phase II (KRAS WT and rare RAS WT) FOLFOX/Pmab (N=88) FOLFOX/Bev (N=82) Median PFS (95% CI) 13.0 (10.9-15.1) 9.5 (9.0-12.7) Median OS (95% CI) 41.3 (28.8-41.3) 28.9 (23.9-31.3) ORR (95% CI) 64 (52.7-73.6) 61 (49-71.2) Subsequent therapy: Anti EGFR 22% 37% Anti-VEGF 40% 33% Schwarzberg et al: JCO 2014
    • FIRE-3 Phase III Study Design Heinemann V. ASCO 2013. Abstract LBA3506. Patients • mCRC • KRAS wild-type • ECOG PS 0-2 • 1st line therapy; prior adjuvant chemotherapy allowed if completed >6 mo before inclusion • N=592 Primary Endpoint: Response Rate FOLFIRI + Cetuximab (Cetuximab: 400 mg/m2 loading dose; 250 mg/m2 weekly) 1:1 Randomization FOLFIRI + Bevacizumab (Bev: 5 mg/kg every 2 weeks)
    • FIRE-3: Overall Response Rate Endpoint FOLFIRI + Cetuximab FOLFIRI + Bevacizumab OR P Value ORR, intent-to-treat (ITT) population (N=592) 62.0% 58.0% 1.18 (0.85-1.64) 0.183 Complete response 4.4% 1.4% Partial response 57.6% 56.6% Stable disease 17.5% 28.8% Progressive disease 7.1% 5.4% Not evaluable 13.1% 7.8% ORR, Evaluable (N=526) 72.2% 63.1% 1.52 (1.05-2.19) 0.017 Heinemann V. ASCO 2013. Abstract LBA3506.
    • FIRE-3: Progression Free Survival Stintzing S. ASCO 2013. Abstract LBA3506
    • FIRE-3: Overall Survival Heinemann V. ASCO 2013. Abstract LBA3506.
    • Consort FIRE-3 Diagram N=592 KRAS exon 2 wild-type ITT population N=407 (69%) RAS evaluable population N=65 (16%) ‘New’ RAS mutant N=342 RAS wild-type N= 171 FOLFIRI + Cetuximab N= 34 FOLFIRI Cetuximab N= 171 FOLFIRI + Bevacizumab N= 31 FOLFIRI + Bevacizumab N=752 mCRC 1st-line unselected patients N=58 FOLFIRI + Cetuximab N=55 FOLFIRI + Bevacizumab N=113 KRAS exon 2 mutant population* KRAS unknown= 30 No treatment= 13 No treatment KRAS mt = 4 Stinzing et al: ESMO, 2013
    • KRAS Wildtype Exon 2 Additional Subsets ? ? ? EXON 1 EXON 2 EXON 3 EXON 4 EXON 2 EXON 3 EXON 4 KRAS NRAS 12 13 12 13 61 146 59 61 117 146 wt ? ? EXON 1 EXON 15EXON 11BRAF 600 ? ? Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
    • Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 91/171 (53.2%) 33.1 24.5 – 39.4 ― FOLFIRI + Bevacizumab 110/171 (64.3%) 25.6 22.7 – 28.6 HR 0.70 (95% CI: 0.53 – 0.92) p (log-rank)= 0.011 FIRE-3: Overall survival RAS* all wild-type 0.0 12 24 36 48 60 72 months since start of treatment 171 171 No. at risk 128 127 71 68 39 26 20 9 6 1 0.75 1.0 0.50 0.25 0.0 Probabilityofsurvival Δ = 7.5 months * KRAS and NRAS exon 2, 3 and 4 wild-typeStinzing et al: ESMO, 2013
    • FIRE-3 Update:Overall Survival by All-RASMutationStatus Study Population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab HR P Value ITT (N=592) 28.7 months 25.0 months 0.77 0.017 RAS WT (n=342) 33.1 months 25.6 months 0.70 0.011 RAS MT (n=65) 16.4 months 20.6 months 1.20 0.57 BRAF MT (n=48) 12.3 months 13.7 months 0.87 0.65 Stintzing S. European Cancer Conference 2013. Abstract LBA17.
    • FIRE-3: Summary and Clinical Implications  Current data limitations  No central assessment of response  OS data continues to mature  Duration of second and subsequent lines of therapy not reported  Practical impact  EGFR antibodies added to FOLFIRI can be considered a viable option in first-line, KRAS wild- type mCRC  Next steps  CALGB 80405 data (in 2014) may clarify results Heinemann V. ASCO 2013. Abstract LBA3506.
    • Should all RAS WT patients receive anti-EGFR therapy front-line?
    • New EPOC Study: Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC  Original EPOC study showed 8% PFS benefit to addition of neoadjuvant FOLFOX to surgery in mCRC patients with operable liver metastases[1]  New EPOC study evaluated addition of cetuximab to standard neoadjuvant chemotherapy in mCRC[2]  Primary endpoint: PFS  Secondary endpoints: OS, preop response, pathologic resection status, periop safety, QoL, cost-effectiveness Patients with resectable KRAS WT mCRC with liver mets (N = 621) Neoadjuvant Chemotherapy* (randomized n = 134; primary analysis n = 116) Neoadjuvant Chemotherapy* + Cetuximab (randomized n = 137; N = 117) 1. Nordlinger G, et al. Lancet. 2008. 2. Primrose JN, et al. ASCO 2013. Abstract 3504. *CAPOX, OxMdG, IrMdG
    • New EPOC: Neoadjuvant Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC: PFS  Median PFS significantly worse with cetuximab: 14.1 months vs 20.5 months with chemotherapy alone  Study stopped at predefined futility analysis  Immature data, but more events unlikely to change result Primrose JN, et al. ASCO 2013. Abstract 3504. Proportionprogressionfree 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 Time to progression or death (months) HR: 1.49 (95% CI: 1.04-2.12); P = .030 Number at risk Chemo alone Chemo + Cetuximab 116 117 89 87 65 54 38 24 23 15 12 5 5 3 2 2 1 1 1 0 0 0 Chemo alone Chemo + cetuximab
    • Why did the new EPOCH study fail?  KRAS is a predictive marker of potential benefit for the use of EGFR inhibition.  Cetuximab does not have a role in the adjuvant setting  N0147: FOLFOX +/- cetuximab failed to demonstrate an improvement in DFS in stage III colon cancer  3-yr DFS: 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98–1.49; P=.08)  Is it the combination of FOLFOX and cetuximab? Alberts et al: JAMA. Apr 4, 2012; 307(13): 1383–1393.
    • Upcoming: Liver-Only Trials
    • BOS-2 (EORTC 40091): Phase II KRAS WT Resectable Liver Mets R A N D O M I Z E FOLFOX • First-line mCRC • N=360 FOLFOX + bevacizumab FOLFOX + panitumumab Study amended: Wild-type KRAS tumors only Primary Endpoint: PFS http://www.clinicaltrials.gov/ct2/show/NCT01508000?term=BOS-2&rank=1
    • BOS -3 (EORTC-1207) Phase II/III Study Design (Pending) http://www.clinicaltrials.gov/ct2/show/NCT01646554?term=BOS-2&rank=2 Patients • mCRC • KRAS MT • ECOG PS 0-1 • 1st line therapy; prior adjuvant chemotherapy allowed if completed >12 mo before inclusion Primary endpoint: PFS FOLFOX + Aflibercept (Aflibercept: 4 mg/m2) 1:1 Randomization FOLFOX
    • CALGB/SWOG 80405: Results: ASCO 2014 R A N D O M I Z E FOLFOX or FOLFIRI* + cetuximab • First-line mCRC • Amended accrual; N=2300 wild-type patients FOLFOX or FOLFIRI* + cetuximab + bevacizumab FOLFOX or FOLFIRI* + bevacizumab Study amended: Wild-type KRAS tumors only Primary endpoint: OS
    • SWOG 1406: BRAF MT mCRC PI: S Kopetz
    • Conclusions:  All RAS WT tumor types may provide more benefit in OS if an anti-EGFR therapy is provided in the front-line setting.  Provision of anti-EGFR therapy in the setting of a RAS MT can be detrimental  Many institutions utilize outside sites for tissue processing  Not all codons are identified  Need a readily available panel with all RAS mutations