Colorectal Cancer Research & Treatment News - recap from the May 2014 ASCO conference

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Dr. Cathy Eng delivers updates on current trials and studies impacting the treatment of colon and rectal cancer.

Dr. Cathy Eng delivers updates on current trials and studies impacting the treatment of colon and rectal cancer.

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  • 1. Welcome to Fight Colorectal Cancer’s & Colon Cancer Alliance joint Webinar Research News: Make Sure You Know the Latest News About CRC Research and Treatment Our webinar will begin shortly.
  • 2. ABOUT THE COLON CANCER ALLIANCE Our mission is to knock colon cancer out of the top three cancer killers. We are doing this by championing prevention, funding cutting-edge research and providing the highest quality patient support services. In 2013, the Colon Cancer Alliance:
  • 3. Today’s Webinar: 1. Today’s Speaker: Cathy Eng, M.D. @CathyEngMD 2. Archived Webinars: FightColorectalCancer.org/Webinars 3. AFTER THE WEBINAR: expect an email with links to the material. Also a survey on how we did, receive a Blue Star pin when completed 4. Ask a question in the panel on the RIGHT SIDE of your screen 5. Follow along via Twitter – use the hashtag #CRCWebinar
  • 4. Introducing Patient Resource Guide Download Fight Colorectal Cancer’s new patient resource guide, Your Guide in the Fight. Created for those recently diagnosed with Stage III or Stage IV colorectal cancer, this FREE publication is available at fightcolorectalcancer.org/guideinthefight. This 65-page workbook provides readers with comprehensive information on diagnosis interpretation, detailed treatment options and future planning.
  • 5. Funding Science Established in 2006, our Lisa Fund has raised hundreds of thousands of dollars to directly support the innovative research in treating late-stage colorectal cancer. 100% of the funds donated go directly to Late-stage colorectal cancer research. Learn more or donate: FightColorectalCancer.org/LisaFund
  • 6. Disclaimer The information and services provided by Fight Colorectal Cancer are for general informational purposes only. The information and services are not intended to be substitutes for professional medical advice, diagnoses, or treatment. If you are ill, or suspect that you are ill, see a doctor immediately. In an emergency, call 911 or go to the nearest emergency room. Fight Colorectal Cancer never recommends or endorses any specific physicians, products or treatments for any condition.
  • 7. Speaker Cathy Eng, M.D. Associate Professor in the Department of Gastrointestinal (GI) Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Dr. Eng received her medical degree from Hahnemann University School of Medicine in Philadelphia, PA Dr. Eng is board certified in internal medicine and medical oncology. Twitter: @CathyEngMD
  • 8. Department of GI Medical Oncology CURRENT DEVELOPMENTS 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 July 16, 2014
  • 9. 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.
  • 10. 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
  • 11. 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
  • 12. 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 .
  • 13. UPDATES IN FIRST-LINE TREATMENT: ANTI- VEGF THERAPY
  • 14. TRIBE Phase III Study Design Falcone A. ASCO 2013. Abstract 3505. Patients • Unresectable mCRC • No prior mCRC treatment • Adjuvant oxali-containing chemotherapy allowed if >12 mo between tx and relapse Treat to progression FOLFIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) 1:1 Randomization FOLFOXIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance)
  • 15. TRIBE: PFS (ITT Population) Falcone A. ASCO 2013. Abstract 3505.
  • 16. TRIBE: Secondary Endpoint (OS) Falcone A. ASCO 2013. Abstract 3505.
  • 17. TRIBE: Secondary Endpoints Endpoint FOLFIRI + Bev (n=256) FOLFOXIRI + Bev (n=252) P Value Response rate 53% 65% 0.006 Complete response 3% 5% Partial response 50% 60% R0 secondary surgery All patients 12% 15% 0.327 Liver-only subgroup 28% 32% 0.823 Overall survival 25.8 months 31.0 months Unstratified hazard ratio (HR): 0.83 (0.66- 1.05) 0.125 Stratified HR: 0.78 (0.63-1.00) 0.054 Falcone A. ASCO 2013. Abstract 3505.
  • 18. TRIBE: Grade ≥3 Adverse Events Patients, % FOLFIRI + Bev (n=254) FOLFOXIRI + Bev (n=250) P Value Serious adverse events (AEs) 19.7 20.4 NR Fatal AEs 3.5 2.8 NR Treatment-related deaths 1.6 2.4 NR Early deaths (<60 days from randomization) 2.3 3.2 NR Diarrhea 11 19 0.012* Stomatitis 4 9 0.048* Neutropenia 20 50 <0.001* Febrile neutropenia 6 9 0.315 Neurotoxicity 0 5 <0.001* Falcone A. ASCO 2013. Abstract 3505.
  • 19. The Role of Bevacizumab Maintenance Therapy: Chronicity of Treating Unresectable Disease
  • 20. CAIRO3: Study Design  Primary endpoint: PFS2 (PFS after re-introduction of bevacizumab + XELOX)  Secondary endpoints: PFS1, OS, TT2PD, ORR, safety  Upon PD1, 60% of patients received bevacizumab + XELOX in arm A and 47% in arm B Koopman, et al.ASCO GI2014. Abstract LBA388 Previously untreated mCRC (n=558) R bevacizumab + XELOX (x6) CR PR SD bevacizumab + capecitabine (n=279) Observation (n=279) bevacizumab + XELOX (n=168) PD2PD1 PFS2 PFS1 TT2PD ArmA ArmB bevacizumab + XELOX (n=132) PD2PD1 Median follow-up 48 months (cut-off 060114)
  • 21. CAIRO3: median PFS1 Koopman,et al. ASCO GI 2014.AbstractLBA388 0 6 12 18 24 30 36 PFS1estimate 1.0 0.8 0.6 0.4 0.2 0 279 84 18 10 7 6 5 Time (months) Observation Maintenance Stratified HR (95% CI) p-value Median 4.1 months 8.5 months 0.43 (0.36‒0.52) <0.0001 No. at risk: 278 173 96 53 36 18 10 4.1 8.5 Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months)
  • 22. CAIRO3: median PFS2 (primary endpoint) Koopman,et al. ASCO GI 2014.AbstractLBA388 8.5 11.7 PFS2estimate 1.0 0.8 0.6 0.4 0.2 0 Time (months) No. at risk: 0 6 12 18 24 30 36 Observation Maintenance Stratified HR (95% CI) p-value Median 8.5 months 11.7 months 0.67 (0.56‒0.81) <0.0001 Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months) PFS2 = PFS1 for pts in whom bevacizumab + capecitabine is not reintroduced after PFS1 for any reason 279 182 101 37 16 12 7 278 206 136 76 46 26 13
  • 23. CAIRO3: OS Koopman,et al. ASCO GI 2014.AbstractLBA388 18.1 21.6 0Sestimate 1.0 0.8 0.6 0.4 0.2 0 Time (months) No. at risk: 0 6 12 18 24 30 36 279 251 198 131 89 61 35 Observation Maintenance Stratified HR (95% CI) p-value Median 18.1 months 21.6 months 0.89 (0.73‒1.07) 0.22 278 258 206 159 112 72 39 Median duration of follow-up 48 months Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months)
  • 24. Impact of Currently Approved Molecular Markers
  • 25. Biomarker Development  Review of Definitions:  Prognostic marker Independent of treatment May impact surveillance  Predictive marker Impacts type of treatment provided
  • 26. Molecular Markers for Anti-VEGF  None identified and validated:  Bevacizumab  Aflibercept  Regorafenib  Anti-EGFR Therapy  Predictive: KRAS/NRAS  Prognostic: BRAF
  • 27. 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
  • 28. 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
  • 29. 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.
  • 30. NRAS  Resembles Kras  Oncogene  < 5% of all mCRC  Mutations in codons 12, 13, 61, 117 and 146  Usually codon 61  Mutually exclusive with KRAS
  • 31. Front-line chemotherapy with anti-EGFR therapy
  • 32. 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
  • 33. 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.
  • 34. 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.
  • 35. Revised PRIME Consort Diagram Douillard et al: NEJM, 2013
  • 36. 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
  • 37. PFS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS Oliner KS. ASCO 2013. Abstract 3511.
  • 38. OS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS Oliner KS. ASCO 2013. Abstract 3511.
  • 39. PRIME: Summary and Clinical Implications  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.
  • 40. Treatment choice: Front line chemotherapy with anti-EGFR therapy or anti-VEGF therapy?
  • 41. PEAK Phase II Study Design Schwarzberg et al: JCO, 2014. Patients • mCRC • KRAS wild-type • ECOG PS 0-2 • 1st line therapy; prior adjuvant chemotherapy allowed if completed >6 mo before inclusion • N=285 Primary Endpoint: PFS 1:1 Randomization FOLFIRI + Bevacizumab (Bev: 5 mg/kg every 2 weeks) FOLFIRI + Panitumumab
  • 42. 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
  • 43. 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
  • 44. 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)
  • 45. 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.
  • 46. FIRE-3: Progression Free Survival Stintzing S. ASCO 2013. Abstract LBA3506
  • 47. FIRE-3: Overall Survival Heinemann V. ASCO 2013. Abstract LBA3506.
  • 48. 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
  • 49. 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.
  • 50. 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
  • 51. FIRE-3 Update: Overall Survival by All-RAS MutationStatus 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.
  • 52. FIRE-3: Summary and Clinical Implications  Current data limitations  No central assessment of response  OS data continues to mature  Practical impact  EGFR antibodies added to FOLFIRI can be considered a viable option in first-line, KRAS wild- type mCRC Heinemann V. ASCO 2013. Abstract LBA3506.
  • 53. CALGB/SWOG 80405: PHASE III TRIAL OF FOLFIRI OR FOLFOX WITH BEVACIZUMAB OR CETUXIMAB FOR PATIENTS W/ KRAS WILD TYPE UNTREATED METASTATIC ADENOCARCINOMA OF THE COLON OR RECTUM A Venook, D Niedzwiecki, HJ Lenz, F Innocenti, M Mahoney, B O’Neil, J Shaw, B Polite, H Hochster, R Goldberg, R Mayer, R Schilsky, M Bertagnolli, C Blanke ALLIANCE and SWOG
  • 54. CALGB / SWOG 80405: FINAL DESIGN N = 1140 1° Endpoint: Overall Survival Chemo + Cetuximab Chemo + Bevacizumab mCRC 1st-line KRAS wild type (codons 12,13) STRATA: FOLFOX/FOLFIRI Prior adjuvant Prior XRT FOLFIRI or FOLFOX MD choice
  • 55. CALGB/SWOG 80405: Eligibility Criteria • Untreated Metastatic CRC • Tumor KRAS wild type codons 12 & 13 • > 12 months since adjuvant therapy • ECOG 0-1 • Preserved organ function AT ENROLLMENT • CHOOSE: FOLFOX or FOLFIRI • INTENT: Palliative or Part of strategy to resect all metastases
  • 56. CALGB/SWOG 80405: Statistics  Assumption: OS: 22 mos to 27.5 mos Δ 5.5 months  90% power to detect HR of 0.80 (2-sided α=0.05) ACCRUAL GOAL = 1140 (1137)  Estimate 326 eligible pre-amendment (333) KRAS wild type, single biologic arm  Estimate 814 post-amendment (804) Actual
  • 57. CALGB/SWOG 80405: Overall Survival Arm N (Events) OS (m) Median 95% CI Chemo + Cetux 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2 P=0.34 HR 0.925 (0.78-1.09)
  • 58. CALGB/SWOG 80405: Progression-Free Survival (Investigator Determined) Arm N (Events) PFS (m) Median 95% CI Chemo + Bev 559 (498) 10.8 9.7-11.4 Chemo + Cetux 578 (499) 10.4 9.6-11.3 P=0.55 HR 1.04 (0.91 -1.17)
  • 59. CALGB/SWOG 80405: Overall Survival FOLFOX Subgroup Arm N (Events) OS (m) Median 95% CI FOLFOX + Cetux 426 (277) 30.1 26.6-34.8 FOLFOX + Bev 409 (290) 26.9 24.7–30.0 P=0.09 HR 0.9 (0.7-1.0)
  • 60. CALGB/SWOG 80405: Overall Survival FOLFIRI Subgroup Arm N(Events) OS (m) Median 95% CI FOLFIRI + Bev 150 (81) 33.4 27.3-41.3 FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2 P=0.28 HR 1.2 (0.9-1.6)
  • 61. CALGB/SWOG 80405: Grade 3-4 Toxicities Toxicity Chemo + Bev N = 534 (%) Chemo +Cetux N = 547 (%) Total Grade 3 278 (52) 295 (54) Hematologic 142 (26.6) 150 (27.4) Non-Hem 234 (43.8) 259 (47.3) Total Grade 4 66 (12.4) 75 (13.7) Total Grade 5 7 (1.3) 3 (0.5) Neuropathy Gr ≥ 3 71 (14) 68 (12) Rash Gr 3 0 40 (7) Diarrhea Gr ≥ 3 45 (8) 59 (11) Hypertension Gr ≥ 3 35 (7) 3 (1) GI Events Gr ≥ 3 10 (2) 2 (0.5)
  • 62. CALGB/SWOG 80405: Data Pending  Response Rate  Duration of therapy / dose intensity  Analysis special subsets:  Patients rendered NED  Patients recur after adjuvant therapy  Details 2nd and later treatments  Concordance KRAS analysis: local v. central
  • 63. Anti-EGFR versus Bevacizumab Trials FIRE CALGB/SWOG 80405 PEAK Number of patients 592 1137 285 Chemotherapy backbone FOLFIRI FOLFOX or FOLFIRI FOLFOX Primary endpoint Response rate Overall survival PFS Anti-EGFR Cetuximab Cetuximab Panitumumab KRAS selection Codon 12/13 Codon 12/13 Codon 12/13 Expanded RAS available to date Yes No Yes Response rate (anti-EGFR v anti- VEGF; %) 62 v 58 N/A 58 v 54 Median PFS (anti-EGFR v anti-VEGF; months) 10.0 v 10.3 10.4 v 10.8 10.9 v 10.1 Median Overall survival (anti-EGFR v anti-VEGF; months) 28.7 v 25.0 * 29.9 v 29.0 34.2 v 24.3 * * Statistically significant
  • 64. 2nd line Anti-Angiogenic Options
  • 65. ML18147 (TML): Continuing Bevacizumab Beyond Progression  A randomized, open-label phase III intergroup study Standard second-line CT (oxaliplatin or irinotecan based) until PD (n = 411) BEV 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD (n = 409) Progressive mCRC after BEV + standard first-line CT (either oxaliplatin or irinotecan based) (n = 820) Bennouna J, et al. Lancet Oncol. 2013;14:29-37. Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS (≤ 9 or > 9 mos), time from last BEV dose (≤ 42 or > 42 days), ECOG PS at baseline (0/1 or 2) Primary endpoint: OS
  • 66. ML18147 (TML): Continuing Bevacizumab Beyond Progression Increases OS (ITT) OS(%) Mos CT (n = 410) BEV + CT (n = 409) 100 80 60 40 20 0 0 6 12 18 24 30 36 42 48 9.8 mos 11.2 mos Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062) Stratified† HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211) *Primary analysis method. †Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS (≤ 9 mos, > 9 mos), time from last dose of BEV (≤ 42 days, > 42 days), ECOG PS at baseline (0, ≥ 1). Bennouna J, et al. Lancet Oncol. 2013;14:29-37. 100 80 60 40 20 0 PFS(%) 0 6 12 18 24 30 36 42 Mos Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P < .0001) Stratified† HR: 0.67 (95% CI: 0.58- 0.78; log-rank P < .0001) 4.1mo 5.7 mo
  • 67. Aflibercept (VEGF-Trap)  Fully human fusion protein and soluble recombinant decoy VEGF receptor consisting of  VEGFR-1 Ig domain 2  VEGFR-2 Ig domain 3  Human IgG1 Fc  Stronger binding than bevacizumab  Blocks VEGF and PlGF  t1/2: ~ 17 days The Structure of VEGF Trap 1 2 3 4 5 6 7 1 2 3 4 5 6 7 VEGF Trap Kd = 0.5 pM Fc VEGFR-1 Kd 10-30 pM VEGFR-2 Kd 100-300 pM Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398.
  • 68. EFC10262: VELOUR Phase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept) Stratification factors: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) 1:1 mCRC after failure of an oxaliplatin based regimen R 600 pts Aflibercept 4 mg/kg IV + FOLFIRI q 2 weeks 600 pts Placebo + FOLFIRI q 2 weeks 68 30% of patients had prior BEV Primary endpoint: OSPI: Allegra et al
  • 69. VELOUR Study: Survival Results Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. OS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032) Placebo/FOLFIRI Median: 12.06 mos Aflibercept/FOLFIRI Median: 13.50 mos PFS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 Stratified HR: 0.758 (95% CI: 0.661- 0.869; log-rank P < .0001) Placebo/FOLFIRI Median: 4.67 mos Aflibercept/FOLFIRI Median: 6.90 mos
  • 70. Overall Survival: Stratified by Previous Bevacizumab; ITT Population Tabernero J, et al. Eur J Cancer. 2013;[Epub ahead of print]. OS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 33 36 39 HR: 0.862 (95.34% CI: 0.673-1.104) Placebo/FOLFIRI Median: 11.7 mos Aflibercept/FOLFIRI Median: 12.5 mos Pts at Risk, n Placebo AFL 187 186 170 178 138 150 115 121 81 89 54 59 37 36 22 22 13 13 Previous Bevacizumab OS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 33 36 39 HR: 0.788 (95.34% CI: 0.699-0.927) Placebo/FOLFIRI Median: 12.4 mos Aflibercept/FOLFIRI Median: 13.9 mos Pts at Risk, n Placebo AFL 427 426 403 388 347 348 286 295 205 222 139 157 94 112 65 82 38 62 No Previous Bevacizumab
  • 71. Treatment of heavily pretreated metastatic colorectal cancer
  • 72. Regorafenib (BAY 73-4506), an oral multikinase inhibitor targeting multiple tumor pathways1-3 1. Wilhelm SM et al. Int J Cancer 2011. 2. Mross K et al. Clin Cancer Research 2012. 3. Strumberg D et al. Expert Opin Invest Drugs 2012. Biochemical activity Regorafenib IC50 mean ± SD nmol/l (n) VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF-1 2.5 ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAFV600E 19 ± 6 (6) Regorafenib Sorafenib
  • 73. Randomized Phase III Regorafenib (BAY 73-4506) vs. BSC (CORRECT Trial)  Multitargeted TKI of VEGFR-2, TIE-2  90% powered to detect a 33.3% % (HR=0.75; regorafenib/placebo) difference in OS  Primary endpoint: OS  Secondary endpoints: PFS and RR R Placebo PO QD Cycle = 28 Days  Patients with refractory mCRC  N= 760 Regorafenib 160 mg QD x 21 days Grothey et al: Lancet. 2013 Jan 26;381(9863):303-12
  • 74. CORRECT: OS (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) Grothey et al: Lancet. 2013 Jan 26;381(9863):303-12
  • 75. Phase III TAS-102 (RECOURSE) Patients • Pretreated mCRC • ECOG PS 0-1 • N=800 Primary endpoint: OS TAS-102 2:1 Randomization Placebo Yoshino et al: World GI Congress, 2014
  • 76. RECOURSE RESULTS:  Improved median OS was 7.1 months for TAS-102 vs. 5.3 months for placebo (hazard ratio 0.68).  TAS-102 also improved PFS compared to placebo (hazard ratio 0.48), which was a secondary endpoint.  Likely submitted for expedited FDA approval Yoshino et al: World GI Congress, 2014
  • 77. Should all RAS WT patients receive anti-EGFR therapy front-line?
  • 78. 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
  • 79. 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
  • 80. 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.
  • 81. Upcoming: Liver-Only Trials
  • 82. 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
  • 83. 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
  • 84. Up and Coming: Novel Agents
  • 85. Treat until disease progression or intolerable toxicity • Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1st line platinum/fluoropyrimidine based chemotherapy • Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 of a 28-day cycle N = 330 Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 S C R E E N R A N D O M I Z E Survival and safety follow- up RAINBOW: Gastric Cancer Wilke et al: ASCO GI 2014 1:1
  • 86. RAINBOW: Overall Survival HR (95% CI) = 0.807 (0.678, 0.962) Stratified log rank p-value = 0.0169 RAM + PTX PBO + PTX Patients / Events 330 / 256 335 / 260 Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38) 6-month OS 72% 57% 12-month OS 40% 30% RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0 PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0 No. at risk Censored Δ mOS = 2.3 months
  • 87. Treat until disease progression or intolerable toxicity • Important inclusion criteria: - Progression after 1st line FOLFOX based chemotherapy • Closed to enrollment, results pending FOLFIRI + Ramucirumab 8 mg/kg N = 525 FOLFIRI + Placebo N = 525 S C R E E N R A N D O M I Z E Endpoint: OS Phase III: FOLFIRI +/- Ramucirumab 1:1 http://clinicaltrials.gov/show/NCT01183780, accessed 2/16/14
  • 88. MET/HGF Signaling Pathway Raghav and Eng, Colorectal Cancer, 2012 AMG-102 ARQ-197 MetMab
  • 89. Prior CMET/HGF Agents:  AMG-102:  Randomized phase II study Fulfilled primary endpoint of RR  ARQ-197  Randomized phase II study No difference in PFS  Problems  Cmet expression is not uniformly accepted. Prior studies largely had tumors from the colon or rectum not metastatic site. Higher cmet expression is noted in sites of metastatic disease  Cmet amplification may be a better marker but rare (< 20% of all pts) Van Cutsem, Eng et al: Clin Can Res, June 2014; Eng et al: ASCO, Abs #3508, June 2013
  • 90. Phase II – MetMab ACCOMPLISH Bendell et al: J Clin Oncol 30, 2012 (suppl; abstr TPS3640) Primary Endpoint: PFS Final results: Pending
  • 91. AMG-337: Schema PI’s: Raghav and Eng (MDACC) ETA: Fall 2014  Primary Objectives  Evaluate efficacy of AMG-337 in MET amplified mCRC, refractory to anti-EGFR therapy.  Secondary Objectives:  Evaluate duration of efficacy of AMG-337 in MET amplified mCRC, refractory to prior anti-EGFR therapy, on treatment with AMG-337.  Evaluate survival outcomes in patients with MET amplified mCRC, refractory to prior anti-EGFR therapy, after treatment with AMG-337.  Evaluate safety and toxicity of AMG-337 in patients with mCRC.
  • 92. Other Upcoming/Ongoing Trials  Aflibercept  Different than bevacizumab?  Biomarker study underway (Canada)  Phase I/II: X-TRAP capecitabine + aflibercept, (N=60)  Phase II: Maintenance (N=69)  Phase II Rectal cancer: MDACC (PI’s: Dasari and Eng)  Phase II: Appendiceal CA (PI: Eng)  Phase II: ALIVE-C of FOLFOXIRI +/- Aflibercept (I Chau) in surgically unresectable liver mets  Regorafenib  Biomarkr studies: Korea  Phase II: FOLFOX + Regorafenib (N=54) Primary endpoint: RR (closed to enrollment)  Phase III COAST trial: Maintenance Regorafenib vs. placebo following adjuvant chemotherapy (N=750) Primary endpoint: DFS
  • 93. Rare Population Subsets
  • 94. 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.
  • 95. Single agent BRAF inhibitor in mCRC  Single agent vemurafenib  Refractory mCRC  N=21  1 partial response  Median PFS was 3.7M Kopetz et al: ASCO 2010, Abs #3534
  • 96. TRIBE Phase III Study Design Falcone A. ASCO 2013. Abstract 3505. Patients • Unresectable mCRC • No prior mCRC treatment • Adjuvant oxali-containing chemotherapy allowed if >12 mo between tx and relapse Treat to progression FOLFIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) 1:1 Randomization FOLFOXIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance)
  • 97. MOLECULAR CHARACTERISTICS TRIBE: PFS Subgroup Analyses Falcone A. ASCO 2013. Abstract 3505.
  • 98. 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)
  • 99. FIRE-3 Update: Overall Survival by All-RAS MutationStatus 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. Poor prognostic indicator
  • 100. PHASE 1B STUDY OF VEMURAFENIB IN COMBINATION WITH IRINOTECAN AND CETUXIMAB IN PATIENTS WITH BRAF-MUTATED METASTATIC COLORECTAL CANCER David S. Hong1, Van Morris2, Badi El-Osta1, Siqing Fu1, Michael Overman3, Sarina Piha-Paul1, Bryan Kee3, Ralph Zinner1, David Fogelman3, Imad Shureiqi3, Funda Meric- Bernstam1, Scott Kopetz3 1Investigational Cancer Therapeutics, 2Cancer Medicine-Fellowship, 3Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center
  • 101. Introduction  Vemurafenib (V), an oral kinase inhibitor specific to the mutated V600 isoform of BRAF  FDA approved in melanoma  In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR [Prahallad, 2012].  Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, which is further augmented by irinotecan [Yang 2012].  The safety and efficacy of the combination in patients with BRAF-mutated advanced malignancies have not been studied.
  • 102. Objectives  Primary Objectives  To define the maximum tolerated dose (MTD) of vemurafenib when used in combination with cetuximab and irinotecan  To define the safety profile of this combination  Expansion phase with BRAF (+) KRAS (-) cancers To determine the antitumor activity of this combination in patients with metastatic colorectal cancer (CRC) To determine the antitumor activity of this combination in patients with non-CRC advanced solid malignancies  Secondary Objectives  To evaluate clinical response signals of the combination  To assess pharmacodynamics (PD) profile of the combination Hong et al: ASCO 2014
  • 103. Phase 1, single institution study of vemurafenib with irinotecan and cetuximab • Histologically confirmed metastatic or advanced solid tumors • BRAF V600E mutation • Measurable disease by RECIST 1.1 • ≥ 18 years old • ECOG ≤ 2 • Adequate organ function • Informed consent Key Eligibility Criteria Key Exclusion Criteria • KRAS 12 or 13 mutation • Treatment for tumor control within 3 weeks with investigational drug, 2 weeks with cytotoxic agent given weekly, or 5 half- lives of biological targeted agent • Uncontrolled medical illness • Pregnant, lactating, or breastfeeding Hong et al: ASCO 2014
  • 104. Patient baseline characteristics Characteristic N = 12 Age, median (range) 64.8 (42.5- 73.2) Gender Male 7 (58%) Female 5 (42%) Caucasian 12 (100%) ECOG PS 0 1 (8%) 1 10 (83%) 2 1 (8%) Lines of prior therapy, median (range) 2 (1-4) Characteristic N = 12 Site of primary tumor Colon/rectum 11 (92%) Appendix 1 (8%) Prior treatment exposures Irinotecan 8 (67%) Cetuximab 5 (33%) Vemurafenib 1 (8%) Microsatellite status 10 tested MSS 8 (80%) MSI 2 (20%) Hong et al: ASCO 2014
  • 105. Adverse Events by CTCAE version 4.0 Preferred terms Grade 1/2 AEs Grade ≥ 3 AEs Nausea 9 (75%) 0 Anemia 8 (67%) 1 (8%) Diarrhea 8 (67%) 3 (25%) Fatigue 8 (67%) 1 (8%) Rash 8 (67%) 0 Anorexia 6 (50%) 0 Myalgia 5 (42%) 0 Vomiting 5 (42%) 0 Leukopenia 3 (25%) 0 Mucositis 3 (25%) 0 Preferred terms Grade 1/2 AEs Grade ≥ 3 AEs Alopecia 2 (17%) 0 Arthralgia 2 (17%) 1 (8%) Dyspnea 2 (17%) 0 Cramping 1 (8%) 0 Dysgeusia 1 (8%) 0 Fever 1 (8%) 0 GERD 1 (8%) 0 HTN 1 (8%) 0 Hypoalbuminemia 1 (8%) 0 Weight Loss 1 (8%) 0 Hong et al: ASCO 2014
  • 106. Responses by RECIST 1.1 in all restaged patients * Hong et al: ASCO 2014
  • 107. Prior to starting trial End of Cycle 4(1st restaging) 69 y/o male with metastatic BRAFV600E refractory to FOLFOX after first restaging on Vemurafenib+Irinotecan and Cetuximab had a 41% decrease By RECIST1.1 Hong et al: ASCO 2014
  • 108. Months on Study (N=12) Hong et al: ASCO 2014
  • 109. Response to Therapy  12 patients were enrolled onto the study before the 4/15/2014 cutoff for data analysis. 9 are evaluable.  Partial response or stable disease was noted in all 8 patients with colorectal cancer who underwent restaging scans after treatment initiation.  Historic response rates for either vemurafenib or irinotecan+cetuximab in BRAFmut CRC patients are <10%  For the 8 colorectal cancer patients who have undergone restaging, the response rate was 50%.  (95% CI of 16 to 85%) Hong et al: ASCO 2014
  • 110. SWOG S1406: a randomized phase II study of irinotecan and cetuximab with or without vemurafenib in BRAF- mutant metastatic colorectal cancer BRAFV600E-mutated metastatic colorectal cancer 1-2 lines of prior systemic treatment No prior EGFR monoclonal antibody KRAS/NRAS wild-type Arm 1: Irinotecan + Cetuximab Arm 2: Irinotecan + Cetuximab + Vemurafenib R Optional crossover to arm 2 at progression Endpoints Primary: Progression-free survival Secondary: Overall survival ORR by RECIST 1.1 Grade 3/4 Toxicity Target activation June 15 with Central IRB. Open through CTSU for all cooperative groups. PI: Kopetz
  • 111. Is there a role for immunotherapy?
  • 112. Computed Tomographic (CT) Scans of the Chest Showing Tumor Regression in a Metastatic Melanoma Patient Who Received the Concurrent Regimen of Nivolumab and Ipilimumab. WolchokJDetal.NEnglJMed2013;369:122-133.
  • 113. BMS CA209142 study: NCT02060188 MSI-H: MDACC PI - Overman
  • 114. Conclusions:  Many treatment options are available to patients but limitations remain for KRAS MT patients.  Controversy remains whether all RAS WT tumor types may have more benefit for OS if an anti- EGFR therapy is provided in the front-line setting.  However, provision of anti-EGFR therapy in the setting of a RAS MT can be detrimental  Many institutions utilize outside sites for tissue processing  Need a readily available panel with all RAS mutations  With categorization based on molecular marker analysis, it is likely more “rare” subgroups will be identified.
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