CRC Case Closed Presentation.pdf

Case Closed: Utilizing Biomarkers
in the Management of Metastatic
Colorectal Cancer
Presented by:
Benny Johnson, DO
Assistant Professor, GI Medical Oncology
The University of Texas
MD Anderson Cancer Center

Guidelines for
Biomarker Testing
Case Closed: Utilizing Biomarkers in the
Management of Metastatic Colorectal Cancer

Case 1
u 45-year-old male presents with 4-month history of
abdominal pain and GI bleeding
u He was found to have a sigmoid colon mass on
colonoscopy, biopsy proven for moderately
differentiated adenocarcinoma
u CT CAP reveals bilateral pulmonary nodules and
bulky liver metastases
u He is treatment naïve and presents to your clinic
to establish care
u What is the necessary molecular testing that
should be ordered at this time?
CT CAP, computed tomography chest abdomen pelvis; GI, gastrointestinal.

Case 1 Poll Question
a. KRAS, BRAFV600E, MMR/MSI
b. All RAS (KRAS, NRAS) testing, BRAFV600E
MMR/MSI
c. All RAS testing, BRAFV600E, MMR/MSI, HER2
amplification
d. All RAS testing, BRAFV600E, MMR/MSI, HER2
amplification and gene fusion testing

2011: actionability of CRC
genomic profiling
KRAS mutations
KRAS mt
KRAS wt
Anti-EGFR antibodies
KRASG12C
KRASnon-G12C
NRAS mutations
BRAF mutation
BRAFV600E
BRAFnon-V600E
KRAS/NRAS/BRAF
wild-type
MSS/pMMR
MSI-H/dMMR
Her2/neu amplifications
NTRK or RET fusions
High
TMB
POLE, POLD
mutations
G12C inhibitors + anti-EGFR
(soon)
Anti-EGFR antibodies
Encorafenib
+
cetuximab
Pembrolizumab (frontline),
Nivolumab + ipilimumab
(frontline, refractory)
Trastuzumab + pertuzumab
Trastuzumab deruxtecan
Tucatinb + trastuzumab (soon)
Larotrectinib or entrectinib // RET kinase inhibitors
Genomic
features
MMR status
CNA/
amplifications
Fusions/
translocations
Anti–PD-1
antibodies
Mutation burden
2022: actionability of CRC
genomic profiling
Precision
Oncology
mCRC
mCRC Is Not One Disease!

NCCN 2022 Guideline Recommendations
for Molecular Profiling in CRC
u Determination of tumor gene status for KRAS/NRAS and BRAF
mutations, as well as HER2 amplifications and MSI/MMR status (if
not previously done), are recommended for patients with mCRC
u Testing may be carried out for individual genes or as part of an
NGS panel, although no specific methodology is recommended
u NGS panels have the advantage of being able to pick up rare
and actionable genetic alterations, such as neurotrophic tyrosine
receptor kinase (NTRK) fusions
MSI/MMR, microsatellite instability/mismatch-repair; NGS, next-generation sequencing.
NCCN, 2022.

Role of NGS Panel Testing in CRC
u NGS Testing vs Single Gene Testing?
u NCCN Guidelines:
u All patients with mCRC should have tumor tissue genotyped for RAS (KRAS and
NRAS) and BRAF mutations individually or as part of NGS panel
Decision analysis for upfront NGS
vs single gene or hotspot testing
Tissue vs blood testing?
PD-L1, EGFR, ALK, ROS1, BRAF, MET, HER2, RET, NTRK
cfDNA, cell-free DNA; GENIE, Genomics Evidence Neoplasia Information Exchange; NHS/HPFS, Nurses Health Study/Health Professionals Follow-up Study;
NSCLC, non-small cell lung cancer; TCGA, The Cancer Genome Atlas.
NCCN, 2022; Pennell et al, 2018; Strickler et al, 2018.

ctDNA Is an Option for Upfront Molecular
Testing in mCRC
u Avoids invasive biopsies with quick turnaround time with current assays
~7-14 days! Can identify ACTIONABLE ALTERATIONS that impact frontline
decisions for patients
u Frequencies of genomic alterations detected in cfDNA were comparable
to those observed in 3 independent tissue-based CRC sequencing
compendia
u First examples of how large-scale genomic profiling of cfDNA from
patients with CRC can detect genomic alterations at frequencies
comparable to those observed by direct tumor sequencing
u Sequencing of cfDNA also generated insights into tumor heterogeneity
and therapeutic resistance and identified novel EGFR ectodomain
mutations
cfDNA, cell-free DNA; ctDNA, circulating tumor DNA.
Strickler et al, 2018.

Case 1 Review
u 45-year-old male presents with 4-month history of
abdominal pain and GI bleeding
u He was found to have a sigmoid colon mass on
colonoscopy, biopsy proven for moderately
differentiated adenocarcinoma
u CT CAP reveals bilateral pulmonary nodules and
bulky liver metastases
u He is treatment naïve and presents to your clinic
to establish care

Case 1 Poll Question Review
a. KRAS, BRAFV600E, MMR/MSI
b. All RAS (KRAS, NRAS) testing, BRAFV600E
MMR/MSI
c. All RAS testing, BRAFV600E, MMR/MSI, HER2
amplification
d. All RAS testing, BRAFV600E, MMR/MSI, HER2
amplification and gene fusion testing

HER2-Positive mCRC

Case 2
u A 54-year-old female with RAS/RAF wild type
metastatic sigmoid cancer presents to your clinic
for a second opinion
u She was previously treated with
FOLFOX/bevacizumab, followed by
FOLFIRI/bevacizumab and developed PD
u You realize she has never been screened for HER2
amplification and obtain IHC testing
u The patient is found to have HER2 IHC 3+
u What is the next best treatment for this patient?
FOLFOX, folinic acid/fluorouracil/oxaliplatin; FOLFIRI, folinic acid/5-fluorouacil/irinotecan; IHC, immunohistochemistry;
PD, progressive disease.

a. FOLFIRI/cetuximab
b. Irinotecan/cetuximab
c. Trastuzumab + lapatinib OR trastuzumab +
pertuzumab OR traztuzumab deruxtecan
d. FOLFOXIRI/trastuzumab
FOLFOXIRI, folinic acid/fluorouracil/oxaliplatin/irinotecan.

HER2 Biomarker for Metastatic CRC: NOT Prognostic
• Trastuzumab + Lapatinib
• Trastuzumab + Pertuzumab
• Traztuzumab Deruxtecan
NCCN Guidelines 1.2022
OS, overall survival.
Bertotti et al, 2011; Richman et al, 2016; NCCN, 2022.
QUASAR Stage II/III
N=1914
FOCUS frontline metastatic
N=888

HER2 Biomarker for Metastatic CRC:
YES Predictive for Lack of Anti-EGFR Benefit
CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival.
Raghav et al, 2019.
N=77

HER2 Targeting in Refractory mCRC:
Trastuzumab + Pertuzumab
MyPathway: n=57; ORR 32%
CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Meric-Bernstam et al, 2019.

Trastuzumab + Pertuzumab (cont.)
MyPathway: n=57; ORR 32%
Meric-Bernstam et al, 2019.

Trastuzumab + Lapatinib
Sartore-Bianchi et al, 2016.
HERACLES-A: n=27; ORR 30%

Trastuzumab + Lapatinib (cont.)
Sartore-Bianchi et al, 2016.
HERACLES-A: n=27; ORR 30%

Cohort A N RR
IHC3+ 40 57.5%
IHC2+/ISH+ 13 7.7%
ICR, independent central review; IHC, immunohistochemistry; ISH, in situ hybridization; NE, not estimable; q3w, every 3 weeks; RR, response rate.
Yoshino et al, 2021; Siena et al, 2021.
DESTINY-CRC01:
Trastuzumab Deruxtecan
u 6.4 mg/kg dose q3w (higher than breast cancer dose; same as gastric/lung)
u All RAS/BRAF V600E wild-type tumors
u Prior HER2 allowed (16 pts in cohort A) but re-testing of HER2 required (same efficacy as no prior HER2 tx)

Interstitial Lung Disease Toxicity
u Grade 5 ILDs:
u In the 3 fatal cases adjudicated as drug-related ILD, onset was from
9 days to 120 days (median: 22 days) and death occurred 6 to 19
days after diagnosis (median: 6 days)
u Adjudicated drug-related ILDs:
u Median time to adjudicated onset was 61.0
days (range 9-165 days)
u 8 of 8 patients received corticosteroids
u 4 patients with grade 2 recovered and 1
patient with grade 3 did not recover (later
died due to disease progression)
u Median time from adjudicated onset date to
initiation of steroid treatment in the 8 ILD cases
was 3.5 days (range 0-50)
ILD, interstitial lung disease.
Yoshino et al, 2021; Siena et al, 2021.

MOUNTAINEER: Open-Label, Phase 2 Study of Tucatinib
Combined with Trastuzumab for HER2-Positive mCRC
BICR, blinded independent central review; cORR, confirmed overall response rate; DOR, duration of response; RECIST, response
evaluation criteria in solid tumors.
Strickler et al, 2022; NCT03043313.
N=40
N=30
ORR 38 %
DOR 12.4 mo
mPFS 8.2 mo
mOS 24.1 mo
N=84

Landscape of Anti-HER2 Therapy in mCRC
AB, antibody; ADC, antibody-drug conjugate; Col. Am. Path., College of American Pathologists;
TDM1, trastuzumab emtansine; TKI, tyrosine kinase inhibitor; TTZ, trastuzumab; TTZ-D, trastuzumab deruxtecan.
Yoshino et al, 2021; Siena et al, 2021; Sartore-Bianchi et al, 2016; Meric-Bernstam et al, 2019; Nakamura et al, 2019; Sartore-
Bianchi et al, 2020; Strickler et al, 2019; Strickler et al, 2021.
Treatment
Combination
Strategy Pts HER2 Criteria ORR PFS (mo) OS (mo)
DESTINY CRC01 ADC 53
Col. Am.
Path.
45.3% 6.9 15.5
TTZ-Lapatinib AB+TKI 27 HERACLES 30% 5.4 14
TTZ-Pertuzumab AB+AB 57
Col. Am.
Path.
32% 2.9 11.4
TTZ-Pertuzumab AB+AB 19
Col. Am.
Path.
35% 4 -
Pertz-TDM1 AB+ADC 31 HERACLES 10% 4.1 -
TTZ-Tucatinib AB+TKI 26
Col. Am.
Path.
52% 8.1 18.7
Worse than TTZ-D
Better than TTZ-D

Case 2 Review
u A 54-year-old female with RAS/RAF wild type
metastatic sigmoid cancer presents to your clinic
for a second opinion
u She was previously treated with
FOLFOX/bevacizumab, followed by
FOLFIRI/bevacizumab and developed PD
u You realize she has never been screened for HER2
amplification and obtain IHC testing
u The patient is found to have HER2 IHC 3+
IHC, immunohistochemistry ; PD, progressive disease.

b. Irinotecan/cetuximab
c. Trastuzumab + lapatinib OR trastuzumab +
pertuzumab OR traztuzumab deruxtecan
d. FOLFOXIRI/trastuzumab

NTRK Fusion-Positive mCRC

Case 3
u 82-year-old female with a sporadic (MLH1
hypermethylation, BRAFV600E wt) MSI-H mCRC
u Received upfront pembrolizumab and had frank
progression of disease on her first restaging scan
u She has an excellent performance status
u Expanded molecular profiling with gene fusion
testing revealed an NTRK1 fusion
u What is your next best step regarding
management?
MSI-H, microsatellite instability-high; wt, wild-type.

management?
a. Re-challenge FOLFOX/bevacizumab
b. Nivolumab
c. Larotrectinib or entrectinib
d. FOLFIRI/bevacizumab

NTRK Fusions and CRC
u NTRK are genes that encode the
tropomyosin receptor kinase (Trk)
family, comprised of three
transmembrane proteins, TrkA,
TrkB, and TrkC receptors, which
are encoded by the NTRK1,
NTRK2, and NTRK3 genes,
respectively
u The signal transduction
pathways activated by these
receptors are associated with
proliferation, differentiation, and
survival in normal and neoplastic
neuronal cells
u Estimated prevalence of NTRK
gene fusions in CRC ~ 0.2-1%
Okamura et al, 2018; Amatu et al, 2016; Gatalica et al, 2019.

Incidence of Fusions Increase in MSI-H in CRC
MSS, microsatellite stable; TMB-L/-I/-H, tumor mutational burden-low/-
intermediate/-high.
Madison et al, 2018; Marsoni, 2018.
Foundation Medicine, tumor/ctDNA
21,879 CRC specimens
NO fusion
YES fusion
• Fusion rate: 0.6%
• 42% of fusions in MSI-H pts
Kinase Cases % MSI-H
ALK 14 14
BRAF 23 17
RET 22 45
NTRK1 22 86
NTRK3 3 100
FGFR2 3 100
RET, BRAF, NTRK1, ALK, EGFR, FGFR3,
FGFR1, ROS1, RAF1, FGFR2, NTRK3,
PDGFRB, MET, NTRK2

Incidence of Fusions Increase in MSI-H in CRC (cont.)
Fu et al, 2020.
• Intestinal cancer MSI-H vs MSS fusion Odds Ratio: 22
• MSS fusion: 0.2%
• MSI-H fusion: 7.85%
3DMed NGS tumor/nml blood,
20,296 solid tumor specimens
4,891 CRC specimens
RET, ALK, ROS1, FGFR, NTRK

Fusions in mCRC and RAS/RAF Status and MLH1 Methylation
• 2,314 CRC: 21 Fusions (0.4% of pMMR/MSS and 5% of dMMR/MSI-H)
• all in RAS/RAF wild-type patients
• 0.9% of pMMR/MSS RAS/RAF wt
• 15% of dMMR/MSI-H RAS/RAF wt
• 42% of dMMR/MSI-H, RAS/RAF wt and MLH1 hypermethylation
dMMR, mismatch-repair deficient; pMMR, mismatch-repair proficient.
Cocco et al, 2019; Sato et al, 2018.
• 162 MSI-H CRC: 10% Fusion rate
• 55% of dMMR/MSI-H, RAS/RAF wt and MLH1 hypermethylation

‘Precision’ in Fusion Testing Algorithms in mCRC
Incidence and molecular characteristics support limiting testing for NTRK
fusions to CRC pts with wild-type KRAS, NRAS, and BRAF with sporadic MSI-H
dMMR, mismatch-repair deficient; pMMR, mismatch-repair proficient.
Cocco et al, 2019; Solomon et al, 2019.

NTRK Fusions and mCRC: 2 FDA Approved Targeted Agents
Larotrectinib
N=159
Drilon et al, 2018; Hong et al, 2020; Doebele et al, 2020.
RR 79%
Entrectinib
N=54
RR 57%
3 CRC patients
8 CRC patients

Case 3 Review
u 82-year-old female with a sporadic (MLH1
hypermethylation, BRAFV600E wt) MSI-H mCRC
u Received upfront pembrolizumab and had frank
progression of disease on her first restaging scan
u She has an excellent performance status
u Expanded molecular profiling with gene fusion
testing revealed an NTRK1 fusion
management?

management?
a. Re-challenge FOLFOX/bevacizumab
b. Nivolumab
c. Larotrectinib or entrectinib
d. FOLFIRI/bevacizumab

BRAFV600E Mutant mCRC

Case 4
u 35-year-old male with no medical history presented
to local ED in 4/2016 with abdominal pain
u Surgery for gallbladder removal revealed a large
transverse colon mass with diffuse omental implants
u Biopsy positive for adenocarcinoma (CK7-, CK20+,
CDX2+) consistent with colon primary
u Pathology significant for a microsatellite stable,
BRAFV600E mutated tumor
u The patient presents with a large bowel obstruction,
eventually started on FOLFOXIRI chemotherapy,
with some initial clinical improvement
u After 6 cycles of chemotherapy, reimaging showed progressive disease
u What is the best next treatment?

b. Encorafenib/binimetinib/cetuximab
c. Cetuximab or panitumumab
d. Encorafenib/cetuximab

“BRAF Mutations”: BRAFV600E Is Associated with Poor OS &
Unique Clinical Presentation
LNs, lymph nodes.
Yaeger et al, 2018; Modest et al 2016; Morris et al, 2014.

BRAFV600E as a Therapeutic Target in Cancer
u Activated BRAF perpetuates MAPK activity,
leading to cell cycle progression and tumor
cell proliferation.
u BRAF inhibitors have activity in metastatic
- melanoma (RR 34-53%)
- NSCLC (RR 42%)
- papillary thyroid cancer (RR 29%)
- refr. hairy cell leukemia (RR 85-100%)
u BRAF + MEK targeted therapies have activity
in
- metastatic melanoma (RR 64-69%)
- metastatic NSCLC (RR 67%)
Can we utilize a similar approach in BRAFV600E metastatic colorectal cancer?
RR, response rate.
McArthur et al, 2014; Ribas et al, 2014; Falchook et al, 2015; Tiacci et al, 2015; Hyman et al, 2015.

BRAF Inhibition: Monotherapy Unsuccessful in mCRC
u Preclinical studies in BRAF mutant CRC
cell line models suggested activity with
vemurafenib
u Vemurafenib in Patients With Metastatic
BRAF-Mutated Colorectal Cancer: phase
2 pilot study
u 21 patients treated, 1 patient had a
confirmed partial response (RR 5%;
95% CI, 1% to 24%) and 7 other
patients had stable disease by RECIST
criteria
u mPFS: 2.1 mos
u mOS: 7.7 mos
u Drastically different than malignant
melanoma
Kopetz et al, 2015.

Resistance Mechanisms to Targeted Therapy in
BRAFV600E mCRC
RAS
RAF
MEK
ERK
DNA
PI3K
AKT
PTEN
• Cell Motility
• Metastasis
• Angiogenesis
• Proliferation
• Cell Survival
BRAF-inhibitor
EGFR
EGFR
Anti-EGFR mAb
MEK-inhibitor
-
KRAS/EGFR
amplifications
-MEK, RAS
mutations
mAb, monoclonal antibody.
Ahronian et al, 2015.

SWOG 1406: VIC Regimen vs Cetuximab/Irinotecan
BID, twice daily; q2w, every 2 weeks; VIC, vemurafenib, irinotecan, cetuximab.
Kopetz et al, 2021.
Treatment refractory,
BRAFV600E, RASWT
metastatic CRC
Irinotecan +
cetuximab
Irinotecan +
cetuximab +
vemurafenib
N=100 (1:1 randomization)
Vemurafenib 960 mg BID
Irinotecan 180 mg/m2 q2w
Cetuximab 500 mg/m2 q2w
(Optional Crossover
at progression)
1st clinical
improvement
demonstrated
for patients with
BRAFV600E mCRC!
PFS
Primary objective was met!

BEACON Phase 3: Does MEK Inhibition with
BRAF + Anti-EGFR Therapy Improve Survival?
Kopetz et al, 2019.
Treatment refractory,
BRAFV600E, RASWT
metastatic CRC
Irinotecan +
cetuximab
Encorafenib
+ cetuximab
+ binimetinib
N=665 (1:1:1 randomization)
Encorafenib 300 mg daily
Binimetinib 45 mg twice daily
Cetuximab 2500 mg/m2 every week
Primary endpoint: OS of triplet arm vs control
Encorafenib
+ cetuximab
ORR 26%*
ORR 20%*
ORR 2%
*denotes statistical significance relative to control arm

BEACON Phase 3: Survival Outcomes
No OS difference between
encorafenib/cetuximab vs
encorafenib/cetuximab/
binimetinib
Encorafenib + cetuximab
became FDA approved 4/2020!
Primary Endpoints Met:
1. ORR (26.1% vs. 1.9%, p<0.001)
2. OS (Median 9.0 months vs. 5.4 months, [HR 0.52,
95% CI (0.39-0.70), p<0.0001]
Kopetz et al, 2019; Kopetz et al, 2020.

Kopetz et al Corcoran et al Yaeger et al Van Geel et al Kopetz et al Corcoran et al Kopetz et al
ORR (%) 5 12 13 18 16 21 20 (27)
PFS
(months)
2.1 3.5 3.2 4.2 4.4 4.2 4.3 (4.5)
OS
(months)
7.7 -- 7.6 -- -- 9.1 9.3 (9.3)
The Pathway to Precision Therapy for BRAFV600E Mutant mCRC
Encorafenib +
cetuximab
Dabrafenib +
panitumumab
+ trametinib
Vemurafenib
+ cetuximab
+ irinotecan
Encorafenib +
cetuximab +
alpelisib
Vemurafenib
+
panitumumab
Dabrafenib +
Trametinib
Vemurafenib
monotherapy
Monotherapy Doublet Regimens Triplet Regimens
FDA
approved
2015 2017 2018 2020
Kopetz et al, 2015; Corcoran et al, 2015; Yaeger et al, 2015; van Geel et al, 2017; Corcoran et al, 2018; Kopetz et al 2019;
Johnson & Kopetz, 2020.

Study Schema
Safety Lead-in Phase 3
Encorafenib + Cetuximab + mFOLFOX6
N=30
Encorafenib + Cetuximab + FOLFIRI
N=30
Doses:
Encorafenib 300 mg PO QD
Cetuximab 500 mg/m2 IV Q2W
FOLFOX full doses IV Q2W
FOLFIRI full doses IV Q2W
Arm A**
Encorafenib + Cetuximab
N=290
Randomize
1:1:1*
Arm B**
Encorafenib + Cetuximab + FOLFOX
or FOLFIRIβ
N=290
Control Arm§
Physicians Choice: FOLFOX, FOLFIRI,
FOLFOXIRI, CAPOX, all +/- anti-VEGF
antibody
N=290
• Patients with BRAF V600E mutant, MSS/pMMR mCRC and no prior
systemic therapy in the metastatic setting
• Patients with BRAF V600E mutant,
MSS/pMMR mCRC with 0 -1 prior
regimens in the metastatic setting
1° ENDPOINTS
• PFS (BICR) Arm A v. Control
AND
• PFS (BICR) Arm B v. Control
(BICR-blinded independent central review)
KEY 2° ENDPOINTS
• OS Arm A v. Control
AND
• OS Arm B v. Control
*Stratified by: ECOG PS 0 v. 1, Region US/Canada v. Europe v. ROW
**Same dosing as SLI; βFOLFOX or FOLFIRI based on SLI results; § No crossover
ENDPOINTS
• Incidence of DLTs, Adverse events,
dose modifications/discontinuations
due to AEs
• PK including drug-drug interactions FOLFOX: Folinic acid (leucovorin), Fluorouracil (5-FU)- infusional, Oxaliplatin
FOLFIRI: Folinic acid (leucovorin), Fluorouracil (5-FU)- infusional, Irinotecan
CAPOX: Capecitabine, Oxaliplatin
FOLFOXIRI: Folinic acid (leucovorin), Fluorouracil (5-FU), Oxaliplatin, Irinotecan
BREAKWATER: Moving BRAF + EGFR to the Frontline?
AEs, adverse events; ECOG PS, Eastern Cooperative Oncology Group performance status; DLT, dose-limiting toxicities; PO,
orally; QD, daily; ROW, rest of world; SLI, safety lead-in.

Case 4 Review
u 35-year-old male with no medical history presented
to local ED in 4/2016 with abdominal pain
u Surgery for gallbladder removal revealed a large
transverse colon mass with diffuse omental implants
u Biopsy positive for adenocarcinoma (CK7-, CK20+,
CDX2+) consistent with colon primary
u Pathology significant for a microsatellite stable,
BRAFV600E mutated tumor
u The patient presents with a large bowel obstruction,
eventually started on FOLFOXIRI chemotherapy,
with some initial clinical improvement
u After 6 cycles of chemotherapy, reimaging showed progressive disease

b. Encorafenib/binimetinib/cetuximab
c. Cetuximab or panitumumab
d. Encorafenib/cetuximab

MSI-H/dMMR mCRC

Case 5
u A 44-year-old female presents with a 4-month
history of weight loss, anemia and abdominal pain
u CT CAP reveals a transverse colon mass with lung,
liver and retroperitoneal nodal metastases.
u Colonoscopy confirms a mass in the transverse
colon biopsy proven for poorly differentiated
mucinous adenocarcinoma
u IHC testing reveals loss of MLH1 and PMS2
consistent with deficient mismatch repair status
(dMMR)
u What therapy do you offer in the frontline setting?

a. Pembrolizumab or nivolumab alone or in
combination with ipilimumab; referral for genetic
testing
b. FOLFOXIRI/bevacizumab; referral for genetic
testing
c. FOLFOX/bevacizumab; referral for genetic
testing
d. 5-FU/bevacizumab; referral for genetic testing
5-FU, fluorouracil; FOLFOX, folinic acid/fluorouracil/oxaliplatin;
FOLFOXIRI, folinic acid/fluorouacil/oxaliplatin/irinotecan.

MSI-H/dMMR CRC
u Prevalence: 4-5% of mCRC
u Clinical features: Right sided
primary, lymphocytic infiltrates,
poorly differentiated, good
prognosis in early stages
u Etiology:
u Germline MMR = Lynch syndrome
u Sporadic MSI-H via MLH1
hypermethylation or biallelic
alterations
Loss of MMR Protein Expression
Variation in microsatellite length
1000s of mutations
Martin et al, 2010.

MSI-H/dMMR Biomarker for mCRC
2L/3L
u Pembrolizumab FDA approved 5/2017 for “MSI-H or dMMR” tumors
u dMMR CRC: progressed following treatment with 5-FU, oxaliplatin, and
irinotecan
u Solid tumors: progressed following prior treatment and who have no
satisfactory alternate treatment options
u Nivolumab FDA approved 7/2017 for ”MSI-H or dMMR” CRC
u progressed following treatment with 5-FU, oxaliplatin, and irinotecan
u Nivolumab/ipilimumab FDA approved 7/2018 for “MSI-H or dMMR”
CRC
u progressed following treatment with 5-FU, oxaliplatin, and irinotecan
Frontline
u Pembrolizumab FDA approved 6/2020 for first line MSI-H/dMMR CRC
u For treatment naïve mCRC patients
2L, second line; 3L, third line.
NCCN, 2022.

Landmark Data: dMMR/MSI-H & Pembrolizumab,
Nivolumab, Nivolumab/Ipilimumab
Pembrolizumab
Nivolumab Nivolumab and Ipilimumab
dMMR CRC
N=28
RR 57%
DCR 89%
Le et all, 2015; Overman et al, 2017; Overman et al, 2018; Le et al, 2017; Le et al, 2018.

KEYNOTE 177: Frontline MSI-H mCRC: Primary
Endpoint, Progression Free Survival
Median PFS (16.5 vs.
8.2 months) favoring
Pembrolizumab
HR, 0.60; P=.0002
André et al, 2020.

Overall Survival
Andre et al, 2021.
KEYNOTE 177: Overall Survival - Frontline mCRC
Needed P> 0.0246
60% cross-over
to PD-1
ORR 44%
PD 29%
Pembrolizumab arm:

Lenz et al, 2022.
N=45 pts
ORR 69%, CR 13%
DCR 84%
Follow up >2 yrs
mPFS & mOS
not reached
Response not
limited by KRAS
or BRAF status
Not randomized
data set
NCCN
Guidelines
included for 1L
Checkmate-142: Frontline Nivolumab/Ipilimumab
for MSI-H mCRC - Effective and Durable Responses

Immunotherapy for BRAFV600E, MSI-H mCRC
SOC, standard of care.
Overman MJ et al, 2017; Overman MJ et al, 2017; André et al, 2020.
Nivolumab + ipilimumab:
median PFS: not reached
Nivolumab :
median PFS: 14.3 months
MSI-H, BRAFV600E
CRC
Nivolumab
Nivolumab +
ipilimumab
Response rate 25% 54%
Disease control
rate
75% 79%
Immune checkpoint blockade is a safe and effective option
for MSI-H, BRAFV600E metastatic CRC, even in frontline.
KN 177:
Pembrolizumab
vs. SOC
Chemotherapy
Pembrolizumab:
median PFS: 16.5 months
HR 0.59

Case 5 Review
u A 44-year-old female presents with a 4-month
history of weight loss, anemia and abdominal pain
u CT CAP reveals a transverse colon mass with lung,
liver and retroperitoneal nodal metastases.
u Colonoscopy confirms a mass in the transverse
colon biopsy proven for poorly differentiated
mucinous adenocarcinoma
u IHC testing reveals loss of MLH1 and PMS2
consistent with deficient mismatch repair status
(dMMR)

a. Pembrolizumab or nivolumab alone or in
combination with ipilimumab; referral for genetic
testing
b. FOLFOXIRI/bevacizumab; referral for genetic
testing
c. FOLFOX/bevacizumab; referral for genetic
testing
d. 5-FU/bevacizumab; referral for genetic testing

Emerging Targetable
Subsets in CRC

Emerging Targetable Subsets in CRC
u Which of the following mutations or fusions in
metastatic colorectal cancer are being
targeted in clinical trials and therefore
ACTIONABLE today?
a. KRAS G12C
b. RET fusions
c. POLE/POLD1
d. BRAF nonV600
e. NRAS mutations
f. A,B,C,D only

i, inhibitor; I/O, immunotherapy; MDACC, MD Anderson Cancer Center.
Henry et al, 2021.
KRAS G12C CRC Represents a Unique Subtype of mCRC
KRAS G12C represents 3% of mCRC with distinct clinical
outcomes & only modest benefit to SOC
Anti-EGFR + G12Ci &
G12Ci + I/O
combinations
underway

Sotorasib Monotherapy Limited in KRAS G12C CRC
Hong et al, NEJM 2021.
CRC pts: Median duration of SD was 5.4 months
with median PFS at only 4.0 months

Adachi et al, 2020; Akhave et al, 2021.
Innate and adaptive resistance
Adaptive resistance mechanisms to KRAS
G12C inhibitionà

KRAS G12C inhibitors in mCRC: Sotorasib and Adagrasib
Median PFS 6.3m 4m
Awad et al, 2021; Hong et al, 2020; Kim et al, 2020; Amodio et al, 2020.
Challenges of both intrinsic and adaptive resistance
CRC
≈3% of KRAS
mutations in
CRC

KRAS G12C Inhibitors in Combination with Anti-EGFR
Is Clinically Active in Refractory KRAS12C-Mutant CRC
NR, not reached.
Klempner et al, 2022; Kuboki et al, 2022.
N=40 pts
sotorasib + panitumumab
ORR 30%, DCR 93%
mPFS 5.7m
mOS NR
N=28 pts
adagrasib + cetuximab
ORR 46%, DCR 100%
mPFS 6.9m
mOS 13.4m

RET Fusions and mCRC: Selpercatinib and Pralsetinib
75
50
25
0
-25
-50
-75
-100
%
Change
from
Baseline
Colon
Rectal Neuroendocrine
Pancreatic
Salivary
Small Intestine
Breast
Carcinoid
Sarcoma Unknown Primary
Ovarian
Selpercatinib RR 44%
9 CRC pts
Pralsetinib
RR 57%
Subbiah, Cassier et al, 2022; Subbiah, Wolf et al, 2022.
2 CRC pts

Vast Majority
of CRC
Hypermutators
are driven by
POLE
POLE/POLD1 Hypermutation in CRC
Campbell et al, 2017; Kim et al, 2013.
N=141
Passenger POLE
Driver POLE
MDACC Experience (NGS in 14,229 patients)
N=454 POLE mutations

Anti–PD-1 Efficacy for POLE (pd) Malignancies
pd, proofreading deficient; pp, proofreading proficient; VUS, variant of unknown significance.
Rousseau et al, 2022.

Median OS for aBRAF 36.1 months
(95% CI, 19.9 to 52.3)
“BRAF Mutations”: Atypical/Non-V600E Mutations à
Distinct Subtype!
Johnson et al, 2019.

KRAS
BRAFm
MEK
ERK
KRAS
BRAFm
MEK
ERK
BRAFm CRAF
EGFR EGFR
Class II Class III
Johnson et al, 2019.
“BRAF Mutations”: Atypical/Non-V600E Mutations à
Distinct Subtype! (cont.)

Yao et al, 2017; Yao et al, 2019; Fontana & Varleri, 2019.
Atypical (Non-V600) BRAF Mutations in mCRC

MAPK Therapy and Atypical (Non-V600) BRAF Mutations
in mCRC
Dankner et al, 2021; Dankner et al, 2022.

Class I (BRAFV600E) Class II (aBRAF nonV600) Class III (aBRAF nonV600)
Structure BRAF monomer BRAF dimers BRAF/CRAF dimers
RTK (EGFR)
Dependency
No No Yes
Kinase activity High High/Intermediate Low
EGFRi sensitivity No Unlikely for monotherapy Likely, but limited duration
Potential
Strategy
BRAFi, EGFRi, +/-
MEKi
RAF dimer inhibitor or paradox
inhibitor; +/- MEKi; ERKi
RAF dimer inhibitor;
SHP2i +MEKi; ERKi
Distinct Signaling + Potential Targetable Approaches aBRAF (Non-V600) mCRC
EGFR
KRAS
BRAFm
MEK
ERK
EGFR
KRAS
BRAFm
MEK
ERK
EGFR
KRAS
BRAFm
MEK
ERK
BRAFm CRAF
Johnson & Kopetz, 2020; Yao et al, 2017; Yao et al, 2019.

Conclusions & Key Takeaways
u Given established and emerging molecular targets in mCRC,
panel-based NGS testing is recommended (tissue- or liquid-
based approved by NCCN)
u HER2 overexpressed mCRC now has multiple active targeted
treatment options
u Fusion yield in mCRC relates to both RAS/RAF wt and MSI-H
status, treatment is active & important to test
u Targeted therapy for BRAFV600E mCRC in the 2L setting is now
standard of care, with ongoing trials to establish its role in
frontline
u PD-1–based immunotherapy is now frontline therapy instead of
chemotherapy for MSI-H mCRC
u KRAS G12C, RET fusions, and POLE all represent exciting
“needle in haystack” emerging/ACTIONABLE targets in mCRC

Thank You for Joining Us!
We are excited to see the impact of this
educational activity on patient care in colorectal
cancer!
In 4 weeks, you will receive a short survey to see if
you’ve been able to implement any of your
intended changes as a result of what you learned
today.
If you have any questions, send us an email:
contact@cmespark.com

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39(15_suppl):3505. DOI:10.1200/JCO.2021.39.15_suppl.3505

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