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Exploring Novel Treatment Strategies for Metastatic Colorectal Cancer

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Exploring Novel Treatment Strategies for Metastatic Colorectal Cancer

  1. 1. Exploring Novel Treatment Strategies for Metastatic Colorectal Cancer Jaffer A. Ajani, MD Professor of Medicine MD Anderson Cancer Center
  2. 2. Disclosures Dr. Ajani has no relevant financial relationships to disclose
  3. 3. Pretest
  4. 4. Learning Objectives Distinguish predictive and prognostic markers that can refine individualized treatment of metastatic CRC Apply current and emerging data on novel therapies in clinical management of metastatic CRC Appraise recent data on novel combination and sequential treatment strategies for patients with metastatic CRC
  5. 5. CRC: Incidence and Mortality Keller et al, 2020.
  6. 6. Proportion of CRC Cases Associated With Sporadic and Hereditary Factors Keum & Giovannucci, 2019.
  7. 7. Trends in Colonoscopy Prevalence and CRC Incidence Rates Siegel et al, 2020.
  8. 8. Incidence and Mortality by Gender Siegel et al, 2020.
  9. 9. Factors That Increase/Decrease CRC Risk Keum & Giovannucci, 2019.
  10. 10. New Cases and Deaths by Age, 2020 aDeaths for colon and rectal cancers are combined because a large number of rectal cancer deaths are misclassified as colon. Siegel et al, 2020.
  11. 11. Early-Onset CRC Is Increasing Siegel et al, 2020.
  12. 12. CRC at Different Stages Kuipers et al, 2015.
  13. 13. Two Independent Pathways Can Lead to CRC Kuipers et al, 2015.
  14. 14. Common Genetic and Epigenetic Alterations Kuipers et al, 2015. Tumor Suppressors
  15. 15. Common Genetic and Epigenetic Alterations Kuipers et al, 2015. Tumor Suppressors (cont.)
  16. 16. Common Genetic and Epigenetic Alterations Kuipers et al, 2015. Proto-Oncogenes
  17. 17. Common Genetic and Epigenetic Alterations Kuipers et al, 2015. Proto-Oncogenes (cont.)
  18. 18. MSI-H Is Associated With High Mutation Rates and Immune Activation MSI-H = microsatellite instability-high. Vogelstein et al, 2013. MSI-high tumor: Anti-CD3 Ab
  19. 19. Immunotherapy in Hypermutated Metastatic CRC aComplete/partial response according to RECIST version 1.1 bComplete/partial response or stable disease according to RECIST version 1.1 cSame clinical study. ORR = overall response rate; DCR = disease control rate; NA = not applicable; MSS = microsatellite stable; HNPCC = hereditary nonpolyposis colorectal cancer; dMMR = mismatch repair deficient. Sveen et al, 2019; Lipson et al, 2013; Le et al, 2015; Le et al, 2017; Overman et al, 2017; Gong et al, 2017; Fabrizio et al, 2018.
  20. 20. Immunotherapy in Hypermutated Metastatic CRC: Combination Therapies aComplete/partial response according to RECIST version 1.1 bComplete/partial response or stable disease according to RECIST version 1.1 cSame clinical study. Sveen et al, 2019; Overman et al, 2018; Lenz et al, 2018; Hochster et al, 2017.
  21. 21. Neoadjuvant Immunotherapy in Early-Stage CRC Chalabi et al, 2020. Study Design
  22. 22. Neoadjuvant Immunotherapy in Early-Stage CRC Chalabi et al, 2020. Patient Characteristics
  23. 23. Neoadjuvant Immunotherapy in Early-Stage CRC Chalabi et al, 2020. Pathological Response
  24. 24. Neoadjuvant Immunotherapy in Early-Stage CRC Chalabi et al, 2020. Pathological Response (cont.)
  25. 25. Neoadjuvant Immunotherapy in Early-Stage CRC Chalabi et al, 2020. Changes in IFN-γ, CXCL13, and TLSs
  26. 26. Neoadjuvant Immunotherapy in Early-Stage CRC Chalabi et al, 2020. Changes in TCR clonality, CD8/PDL-1+ cells, CD8+ cells, PD-L1
  27. 27. Sidedness of CRC and Molecular Biology Keum & Giovannucci, 2019.
  28. 28. Impact of Primary Tumor Location on Survival Venook et al, 2016. CALGB/SWOG 80405 Trial Side N (Events) Median OS (mos) 95% CI Left 732 (550) 33.3 31.4–35.7 Right 293 (242) 19.4 16.7–23.6 HR = 1.55 (95% CI, 1.32–1.82); P<0.0001
  29. 29. Sidedness Is Prognostic aAdjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior radiotherapy, age, sex, synchronous disease, in-place primary, and liver metastases. Venook et al, 2016. CALGB/SWOG 80405 Trial KRAS wt N = 1025 Right 1° Median OS (mos) Left 1° Median OS (mos) Hazard Ratio 95% CI (R vs L adjusteda) P-value (adjusteda) All patients 19.4 33.3 1.55 1.32–1.82 <0.0001 Cetux 16.7 36.0 1.87 1.48–2.32 <0.0001 Bev 24.2 31.4 1.32 1.05–1.65 0.01
  30. 30. CRYSTAL: FOLFIRI ± Cetuximab Tejpar et al, 2017. Progression-Free Survival
  31. 31. CRYSTAL: FOLFIRI ± Cetuximab Tejpar et al, 2017. Overall Survival
  32. 32. PRIME: FOLFOX ± Panitumumab Boeckx et al, 2017.
  33. 33. PEAK: FOLFOX + Panitumumab vs FOLFOX + Bevacizumab Boeckx et al, 2017.
  34. 34. Metastases and Primary Do Not Always Use the Same Driver Priestley et al, 2019.
  35. 35. Certain Drivers Are Enriched in the Metastases Birkbak & McGranahan, 2020.
  36. 36. Certain Drivers Are Enriched in the Metastases (cont.) Birkbak & McGranahan, 2020.
  37. 37. Copy Number Landscape of Metastatic Cancer Priestley et al, 2019.
  38. 38. Modes of Metastatic Dissemination From the Primary Tumor Birkbak & McGranahan, 2020.
  39. 39. NCCN Guidelines: Suspected or Proven Metastatic Synchronous Adenocarcinoma NCCN, 2020.
  40. 40. KRAS Is a Potential Target Sheridan, 2020.
  41. 41. RAS Inhibition Ryan & Corcoran, 2018.
  42. 42. Agents targeting KRAS under development Keum & Giovannucci, 2019.
  43. 43. KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumor Immunity NSCLC = non-small cell lung cancer, Canon et al, 2019. 2 NSCLC responding to AMG 510
  44. 44. AMG 510 + Anti–PD-1 Increases Inflammatory Storm Canon et al, 2019.
  45. 45. AMG 510 in CRC and Other Solid Tumors Phase 1 Study Fakih et al, 2019. Phase 2 study in CRC is starting to define RR/PFS at MTD
  46. 46. BRAF Mutations: V600E and Atypical/Non-V600E Mutations Yaeger et al, 2018. BRAFV600E 7% Atypical or Non- V600 BRAF mutation 4% BRAF wild type 89%
  47. 47. Guideline Recommendations: Test for BRAF V600E NCCN, 2020; Van Cutsem et al, 2016; Yoshino et al, 2018. NCCN ESMO ESMO Asia BRAFV600E Testing All patients with mCRC should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of an NGS panel Tumor BRAF mutation status should be assessed alongside the assessment of tumor RAS mutational status for prognostic assessment Tumor BRAF mutation status (V600E) should be assessed along side the assessment of tumor RAS mutational status for prognostic assessment
  48. 48. Combination Studies for BRAF-Mutated CRC Kopetz et al, 2015; Falchook et al, 2012; Gomez-Roca et al, 2014; Corcoran et al, 2015; Yeager et al, 2015; Hyman et al, 2015; van Geel et al, 2017; Atreya et al, 2015; Kopetz et al, 2017; Corcoran et al, 2016; Van Cutsem et al, 2019.
  49. 49. Vemurafenib Monotherapy in BRAF-Mutated Tumors Flaherty et al, 2010; Kopetz et al, 2015.
  50. 50. BRAFV600E-Mutated CRC: Vemurafenib/Irinotecan/Cetuximab Hong et al, 2016.
  51. 51. BRAFV600E-Mutated CRC: Encorafenib/Binimetinib/Cetuximab Kopetz et al, 2019. Triplet regimen: encorafenib + binimetinib + cetuximab Doublet regimen: encorafenib + cetuximab Control: cetuximab + irinitecan or cetuximab + FOLFIRI
  52. 52. BRAFV600E-Mutated CRC: Encorafenib/Binimetinib/Cetuximab (cont.) Kopetz et al, 2019.
  53. 53. HER2 Amplification: 4% of CRC Tumors Valtorta et al, 2015. Mutually exclusive with RAS/BRAF mutations Prevalence of 7%-8% of RAS/BRAF wild-type tumors eligible for EGFR inhibitors
  54. 54. Trastuzumab/Pertuzumab in HER2-Amplified CRC wt = wild type; MUT = mutated. Meric-Bernstam et al, 2019. ORR 32% PFS 2.9 mo KRAS wt: 5.7 mo KRAS MUT: 1.4 mo
  55. 55. FDA-Approved Agents Xie et al, 2020. Trifluridine/tipiracil
  56. 56. Biomarker-Driven Treatment of Metastatic CRC Sveen et al, 2019.
  57. 57. Targeted Agents for Metastatic CRC Xie et al, 2020.
  58. 58. Case Study An elderly patient presents with right-sided colon cancer and multiple liver metastases and nodal metastases, poorly differentiated adenocarcinoma. His PS=1. He wants to be treated
  59. 59. Case Study Question 1
  60. 60. Case Study (cont.) This patient turned out to have KRAS WT, BRAF WT, and MSI-H
  61. 61. Case Study Question 2
  62. 62. Dramatic Response to Checkpoint Inhibition Ludford et al, 2020.
  63. 63. Key Takeaways CRC is increasing in younger patients MSI-H CRC can be treated with novel strategies KRAS has become a relevant target BRAF inhibition has produce significant survival advantage Substantially more research is needed to develop even more effective therapies
  64. 64. Posttest
  65. 65. Thank you for joining us! To receive credit, submit an online evaluation at: i3Health.com/colorectal-ASCO20
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