Chair and Presenter, Prof Eric Van Cutsem, MD, PhD, and Scott Kopetz, MD, PhD, prepared useful Practice Aids pertaining to colorectal cancer for this CME/MOC/NCPD activity titled “Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: Navigating Practicalities in the Era of Molecularly Defined Care.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD information, and to apply for credit, please visit us at https://bit.ly/3aSSAtm. CME/MOC/NCPD credit will be available until November 13, 2022.
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Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: Navigating Practicalities in the Era of Molecularly Defined Care
1. Clinician Guide to Resources for Colorectal Cancer
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
Organization URL Focus/Available Resources
Resources
for
Clinicians
Resources
for
Patients
American Cancer Society https://www.cancer.org
• Research resources
• Cancer statistics
• Treatment tools
American Cancer Society https://www.cancer.org
• Patient advocacy
• Educational materials
• Tools to navigate treatment
Colon Cancer Coalition https://coloncancercoalition.org
• Events (“Get Your Rear in Gear”)
• Educational materials
• Patient and survivor stories
Livestrong Foundation https://www.livestrong.org
• Cancer support services
• Community programs
• Resource guides
Colorectal Cancer Alliance https://www.ccalliance.org
• Buddy Program Helpline
• Patient Navigator Program
• Patient and family support group chat
• Blue Hope Nation, an online support community
• Clinical trial finder
• Never Too Young (resources for younger patients)
• Financial resources
Fight Colorectal Cancer https://fightcolorectalcancer.org
• Research
• Advocacy
Fight Colorectal Cancer https://fightcolorectalcancer.org
• Educational information
• Resource library Webinars
• Resources for caregivers
• Clinical trial resources
National Comprehensive
Cancer Network Guidelines
• Treatment planning guides
• Cancer treatment discussion support
• Survivorship overview
https://www.nccn.org/patientresources/patient-resources/
guidelines-for-patients
National Cancer Institute https://www.cancer.gov; https://www.cancer.gov/types/
colorectal; https://www.cancer.gov/types/liver
• Patient guides on types of cancer, treatment, and coping with cancer
National Cancer Institute
https://www.cancer.gov; https://www.cancer.gov/types/
colorectal/hp; https://www.cancer.gov/types/liver/hp
• Research funding
• Clinical trials
• Scientific meetings
National Colorectal
Cancer RoundTable
https://nccrt.org
• Promotes early detection and screening
• Resources for organizations and clinicians to promote screening
National Comprehensive
Cancer Network Guidelines
https://www.nccn.org/guidelines
• Diagnosis guidelines
• Therapy guidance
• Evidence Blocks
2. Colorectal Cancer: Current and Emerging Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
Selected Clinical Trials
NCT Number
NCT05004350
Encorafenib + cetuximab vs
irinotecan/cetuximab or
FOLFIRI/cetuximab
BRAF V600E–mutant
metastatic CRC
Phase 2,
not yet recruiting
NAUTICALCRC
NCT03693170
Encorafenib + binimetinib
+ cetuximab
BRAF V600E–mutant
metastatic CRC
Phase 2; active,
not recruiting
ANCHOR CRC
NCT04607421
Encorafenib + cetuximab ± CT
vs standard of care therapy with
a safety lead-in of encorafenib +
cetuximab + CT
Previously untreated
BRAF V600E–mutant
metastatic CRC
Phase 3, recruiting
BREAKWATER
NCT04673955 Encorafenib + cetuximab
BRAF V600E–mutant
metastatic CRC
Recruiting
BERING CRC
Study Title Condition Regimen Phase/
Recruitment Status
Encorafenib/Cetuximab
NCT Number
NCT03524820
NCT03446157
NCT04515394
NCT01910610
NCT02713373
Cetuximab
Cetuximab + palbociclib
Colorectal neoplasms
FOLFIRI/cetuximab, followed by
oxaliplatin-based CT with
bevacizumab vs
OPTIMOX/bevacizumab,
followed by irinotecan-based
CT with bevacizumab, followed
by anti-EGFR mAb with or
without irinotecan
Cetuximab + pembrolizumab
Metastatic CRC
Metastatic CRC
Tepotinib + cetuximab
Metastatic CRC
Metastatic CRC that cannot
be removed by surgery
Phase 2, recruiting
Phase 2, recruiting
Phase 2, recruiting
Phase 3, recruiting
Phase 1/2; active,
not recruiting
Cetuximab Therapy for Third-Line
Rechallenge in Metastatic Colorectal Cancer
Palbociclib and Cetuximab in
Metastatic Colorectal Cancer
PERSPECTIVE
STRATEGIC-1
Cetuximab and Pembrolizumab in Treating Patients
With Colorectal Cancer That Is Metastatic or
Cannot Be Removed by Surgery
Study Title Condition Regimen
Phase/
Recruitment Status
Cetuximab
3. Colorectal Cancer: Current and Emerging Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
Selected Clinical Trials
NCT03658772
NCT04991948
MSI-stable CRC
Unresectable metastatic CRC
Grapiprant + pembrolizumab
CYAD-101 with FOLFOX infusion
administered concurrently
followed by pembrolizumab
Phase 1, recruiting
Phase 1,
not yet recruiting
Grapiprant and Pembrolizumab in Patients With
Advanced or Progressive MSS Colorectal Cancer
Phase 1b Study to Evaluate the Addition of
a Pembrolizumab Treatment After Treatment With
CYAD-101 With a FOLFOX Preconditioning
in Metastatic Colorectal Cancer Patients
NCT Number Study Title Condition Regimen
Phase/
Recruitment Status
NCT03374254
NCT02437071
Pembrolizumab + binimetinib
vs pembrolizumab +
mFOLFOX7 vs pembrolizumab
+ mFOLFOX7 + binimetinib vs
pembrolizumab + FOLFIRI vs
pembrolizumab + FOLFIRI +
binimetinib
Pembrolizumab + radiotherapy
vs pembrolizumab + ablation
Metastatic CRC
Metastatic CRC
Phase 1; active,
not recruiting
Phase 2; active,
not recruiting
MK-3475-651
Assess the Efficacy of Pembrolizumab
Plus Radiotherapy or Ablation in
Metastatic Colorectal Cancer Patients
NCT04854434 Selinexor ± pembrolizumab
Metastatic CRC Phase 2, recruiting
A Study to Evaluate the Safety and Efficacy of
Selinexor With or Without Pembrolizumab Versus
Standard of Care in Previously Treated Metastatic
Colorectal Cancer With RAS Mutations
Pembrolizumab
NCT Number
NCT03520946
Ramucirumab + TAS102 vs
TAS102
CT-refractory advanced
metastatic CRC
Phase 3, recruiting
RAMTAS
NCT03798626
Metastatic colorectal,
gastroesophageal,
and renal cancers
Phase 1, recruiting
Gevokizumab With Standard of Care Anticancer
Therapies for Metastatic Colorectal,
Gastroesophageal, and Renal Cancers
Gevokizumab + modified
FOLFOX6 + bevacizumab
(first-line tx); gevokizumab +
FOLFIRI + bevacizumab
(second-line tx)
Study Title Condition Regimen Phase/
Recruitment Status
Ramucirumab
4. Colorectal Cancer: Current and Emerging Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
Selected Clinical Trials
NCT Number
NCT04776148
Lenvatinib + pembrolizumab
vs regorafenib or TAS102
Metastatic CRC Phase 3, recruiting
LEAP-017
NCT04965870 TAS102
CT-refractory metastatic CRC Recruiting
RETRO-TAS
NCT04073615 TAS102 ± rivoceranib
Metastatic CRC Phase 1/2, recruiting
Phase 1b/2 Study of Rivoceranib and
Trifluridine/Tipiracil for Metastatic
Colorectal Cancer
NCT04511039 TAS102 + talazoparib
Locally advanced or
metastatic CRC or
gastroesophageal cancer
Phase 1, recruiting
Trifluridine/Tipiracil and Talazoparib for the
Treatment of Patients With Locally Advanced or
Metastatic Colorectal or Gastroesophageal Cancer
NCT03223779 TAS102 + radiation therapy
Hepatic metastases from CRC Phase 1/2, recruiting
Study of TAS-102 Plus Radiation Therapy for the
Treatment of the Liver in Patients With Hepatic
Metastases From Colorectal Cancer
NCT04737187 TAS102 ± bevacizumab
Refractory metastatic CRC Phase 3, recruiting
SUNLIGHT
Study Title Condition Regimen
Phase/
Recruitment Status
TAS102
NCT03635021 CRC Phase 3, recruiting
CR-SEQUENCE
FOLFOX + panitumumab
followed by FOLFIRI +
bevacizumab vs FOLFOX +
bevacizumab followed by
FOLFIRI + panitumumab
NCT Number Study Title Condition Regimen
Phase/
Recruitment Status
Bevacizumab
5. Colorectal Cancer: Current and Emerging Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
Selected Clinical Trials
NCT Number
NCT02301962 Panitumumab
Metastatic CRC Phase 4, recruiting
Phase IV Panitumumab Study in Indian Subjects
With Metastatic Colorectal Cancer
NCT03043950 Panitumumab
RAS wild-type metastatic CRC Active, not recruiting
VALIDATE
NCT03751176 FOLFIRI ± panitumumab
RAS wild-type metastatic CRC
Phase 2; active,
not recruiting
BEYOND
NCT03584711 FOLFOX + panitumumab
Metastatic CRC Phase 2, recruiting
OPTIPRIME
NCT01328171 FOLFOXIRI ± panitumumab
Nonresectable, RAS wild-type
metastatic CRC
Phase 2; active,
not recruiting
VOLFI
NCT01312857 Panitumumab
Resected, RAS wild-type
metastatic CRC
Phase 2; active,
not recruiting
Study of Hepatic Arterial Infusion With
Intravenous Irinotecan, 5-FU, and Leucovorin
With or Without Panitumumab, in Patients With
Wild-Type RAS Who Have Resected Hepatic
Metastases From Colorectal Cancer
NCT01991873 Maintenance CT ± panitumumab
RAS wild-type metastatic CRC
Phase 2; active,
not recruiting
PanaMa
Study Title Condition Regimen
Phase/
Recruitment Status
Panitumumab
6. Current Clinical Guidelines for Therapy Selection
and Molecular Testing in mCRC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
NCCN Clinical Practice Guidelines: First-Line Therapies for Colon Cancer1
Patient Appropriate for Intensive Therapy?
See subsequent therapy
See subsequent therapy
Yes No
NCCN Clinical Practice Guidelines: Second- and Third-Line Therapies for Colon Cancer1
• FOLFOX ± bevacizumab
• CAPEOX ± bevacizumab
• FOLFOX + cetuximab or panitumumab (KRAS/NRAS/BRAF WT
and left-sided tumors only)
• FOLFIRI ± bevacizumab
• FOLFIRI + cetuximab or panitumumab (KRAS/NRAS/BRAF WT
and left-sided tumors only)
• FOLFOXIRI ± bevacizumab
• Pembrolizumab or nivolumab ± ipilimumab (dMMR/MSI-H only)
• FOLFIRI or irinotecan
• FOLFIRI + bevacizumab (preferred) or ziv-aflibercept or
ramucirumab
• Irinotecan + bevacizumab (preferred) or ziv-aflibercept or
ramucirumab
or
• FOLFIRI + cetuximab or panitumumab
(KRAS/NRAS/BRAF WT only)
• Irinotecan + cetuximab or panitumumab
(KRAS/NRAS/BRAF WT only)
• Encorafenib + cetuximab or panitumumab (BRAF V600
mutation positive)
or
• Nivolumab ± ipilimumab or pembrolizumab
(dMMR/MSI-H only)
• Trastuzumab + (pertuzumab or lapatinib) or trastuzumab
deruxtecan (HER2-amplified and RAS and BRAF WT)
• Irinotecan + (cetuximab or panitumumab) (KRAS/NRAS/BRAF WT
only)
• Regorafenib
• Trifluridine + tipiracil ± bevacizumab
• Nivolumab ± ipilimumab or pembrolizumab (dMMR/MSI-H only)
• Trastuzumab + (pertuzumab or lapatinib) or trastuzumab deruxtecan
(HER2-amplified and RAS and BRAF WT)
• Regorafenib
• Trifluridine + tipiracil ± bevacizumab
• Nivolumab ± ipilimumab or pembrolizumab (dMMR/MSI-H only)
• Trastuzumab + (pertuzumab or lapatinib) or trastuzumab deruxtecan
(HER2-amplified and RAS and BRAF WT)
• Infusional 5-FU ± leucovorin ± bevacizumab
• Capecitabine ± bevacizumab
• Cetuximab or panitumumab (category 2B) (KRAS/NRAS/BRAF WT and
left-sided tumors only)
• Nivolumab or pembrolizumab (dMMR/MSI-H only)
• Nivolumab + ipilimumab (dMMR/MSI-H only) (category 2B)
• Trastuzumab + (pertuzumab or lapatinib) or trastuzumab deruxtecan
(HER2-amplified and RAS and BRAF WT)
Previous
oxaliplatin-based
therapy
without
irinotecan
See subsequent therapy
7. Current Clinical Guidelines for Therapy Selection
and Molecular Testing in mCRC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
Integrating New Clinical Data Into the CRC Treatment Algorithm
What if it’s right-sided MSI-H or BRAF V600E–mutant CRC?
1L
recommendation
3L
recommendation
2L
recommendation
What if the tumor progresses on 2L therapy?
What if the tumor progresses on previous therapy?
Pembrolizumab or nivolumab ± ipilimumab (dMMR/MSI-H only)
Encorafenib/cetuximab + binimetinib triplet (BRAF V600E only)
Cytotoxic treatment + bevacizumab/anti-EGFR antibody
TAS102 + bevacizumab
Regorafenib
FOLFIRI + bevacizumab (preferred) or ziv-aflibercept or ramucirumab
FOLFOX + bevacizumab
FOLFIRI/irinotecan + cetuximab or panitumumab
Encorafenib + cetuximab or panitumumab (BRAF V600 mutation)
Supported by KEYNOTE-177, CheckMate -142, CALGB/SWOG 80405, ANCHOR CRC2-6
Supported by RECOURSE, REARRANGE10,11
Supported by BEACON CRC, CheckMate -142, GARNET2,7-9
David presents with asymptomatic
mCRC with wild-type KRAS and NRAS
• Aged 63 years
• CBC: Hb 11 g/dL; PLT 172 x 109
/L
• 4 cm retroperitoneal lymphadenopathy
• ECOG PS 1
8. Current Clinical Guidelines for Therapy Selection
and Molecular Testing in mCRC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
NCCN Clinical Practice Guidelines for Molecular Testing in CRC
All patients diagnosed with CRC should be tested for the following mutations
NCCN Guidelines: Microsatellite Instability or Mismatch Repair Testing1
RAS mutations
• NRAS
• KRAS
BRAF
dMMR/
MSI-H status
Universal mismatch repair (MMR)a
or microsatellite instability (MSI)
testing is recommended in all
newly diagnosed patients with
colon cancer
MMR or MSI testing should be
performed only in CLIA-approved
laboratories
Testing for MSI may be
accomplished by PCR or a
validated NGS panel—the latter
especially in patients with
metastatic disease who require
genotyping of RAS and BRAF
The presence of BRAF V600E
mutation or MLH1 promoter
methylation is consistent with
sporadic cancer
Abnormal MLH1 IHC should be
followed by tumor testing for
BRAF V600E mutation or MLH1
promoter methylation
IHC refers to staining tumor
tissue for protein expression of
the 4 MMR genes known to be
mutated in LS (MLH1, MSH2,
MSH6, and PMS2)
a
IHC for MMR and DNA analysis for MSI are different assays
and measure different biological effects caused by deficient
MMR function.
9. Current Clinical Guidelines for Therapy Selection
and Molecular Testing in mCRC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JEN40
1. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. Version 3.2021. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. 2. Andre T et al. 2021 American Society of Clinical Oncology Annual Meeting (ASCO 2021). Abstract 3500. 3. Lenz H-J et al. ASCO
2020. Abstract 4040. 4. Venook A et al. European Society for Medical Oncology Congress 2016 (ESMO 2016). Oral presentation. 5. Van Cutsem E et al. ESMO World Congress on Gastrointestinal Cancer 2021 (ESMO World GI 2021). Abstract O-10. 6. https://clinicaltrials.gov/ct2/show/
NCT03693170. 7. Kopetz S, Van Cutsem E et al. N Engl J Med. 2019;381:1632-1643. 8. https://clinicaltrials.gov/ct2/show/NCT02928224. 9. Berton D et al. ASCO 2021. Abstract 2564. 10. Mayer RJ et al. N Engl J Med. 2015;372:1909-1919. 11. Argilés G et al. ESMO World GI 2019. Abstract
O-026. 12. Van Cutsem E et al. Ann Oncol. 2016;27:1386-1422.
Many Drivers for First-Line Treatment Are Also Valid in Later Line12
Patient and treatment characteristics become even more relevant in later lines
Genetic Mutations Affect Treatment Selection1
Patients with RAS mutations do not respond to anti-EGFR agents
Patients with BRAF V600E mutations respond poorly to anti-EGFR agents unless given with a BRAF inhibitor
Checkpoint inhibitors are effective for dMMR/MSI-H tumors
Tumor Characteristics Patient Characteristics Treatment Characteristics
• Clinical presentation
– Tumor burden
– Tumor localization
• Tumor biology
• RAS mutation status
• BRAF mutation status
• Age
• Performance status
• Organ function
• Comorbidities; patient attitude,
expectation, and preference
• Toxicity profile
• Flexibility of treatment
administration
• Socioeconomic factors
• Quality of life