Hitting the Target in HER2-Positive Metastatic Colorectal Cancer

Hitting the Target in HER2-Positive Metastatic
Colorectal Cancer
Christopher Lieu, MD
Associate Professor
Associate Director, Clinical Research
University of Colorado Cancer Center

Disclosures
Grants/research support: Merck
i3 Health has mitigated all relevant financial relationships

Learning Objectives
CRC = colorectal cancer; HER2 = human epidermal growth factor receptor 2.
Distinguish actionable targets that can inform personalized care plans
in CRC
Evaluate practice guidelines on treatment combinations and
sequences for patients with metastatic CRC
Appraise emerging efficacy and safety data on novel targeted
therapies for patients with HER2-positive metastatic CRC
Assess strategies for optimizing the safety and tolerability of novel
targeted therapies for HER2-positive metastatic CRC

Metastatic CRC (mCRC):
Epidemiology and Clinical
Burden

Introduction to mCRC
OS = overall survival.
Sung et al, 2021; Siegel et al, 2022; ACS, 2020; SEER, 2022; Väyrynen et al, 2020; Baran et al, 2018.
CRC is the third most common type of cancer diagnosed worldwide.
Almost 150,000 new cases and more than 50,000 deaths from CRC
are reported each year in the United States
In recent decades, the overall incidence of CRC has decreased
among older adults due to screening and lifestyle factors. At the same
time, incidence is increasing among younger adults
The 5-year relative OS rate for patients with mCRC is ~15%
Approximately 33% of patients with CRC will develop metastases at
either presentation or follow-up

Overview of
Guideline-Recommended
Treatment Options

mCRC Treatment Flow
NCCN = National Comprehensive Cancer Network; FOLFOX = leucovorin/fluorouracil/oxaliplatin; FOLFIRI = leucovorin/fluorouracil/irinotecan;
CAPEOX = capecitabine/oxaliplatin; FOLFIRINOX = leucovorin/fluorouracil/irinotecan/oxaliplatin; VEGF = vascular endothelial growth factor;
EGFR = epidermal growth factor receptor; MSI-H = microsatellite instability–high; dMMR = deficient mismatch repair;
BRAF = v-Raf murine sarcoma viral oncogene homolog B.
NCCN, 2023.
NCCN Colon Cancer Guidelines
First-Line Regimens
• FOLFOX, FOLFIRI, CAPEOX, or FOLFIRINOX ± anti–VEGF-EGFR
• Nivolumab ± ipilimumab or pembrolizumab (MSI-H/dMMR)
Second-Line Regimens
• Chemotherapy ± anti-VEGF/EGFR (dependent on first-line treatment)
• Encorafenib + anti-EGFR (BRAF v600E)
• Trastuzumab + pertuzumab, lapatinib, or tucatinib; trastuzumab deruxtecan (HER2-amplified)
• Pembrolizumab, nivolumab ± ipilimumab, or dostarlimab (MSI-H/dMMR)
Third-Line Regimens and Beyond
• Pembrolizumab, nivolumab ± ipilimumab, or dostarlimab (MSI-H/dMMR)
• Regorafenib
• Chemotherapy ± anti-VEGF/EGFR
• Trastuzumab + tucatinib, pertuzumab, or lapatinib, or trastuzumab deruxtecan (HER2-amplified)

Genomic Markers in CRC
RAS = rat sarcoma virus; PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN = phosphatase and tensin homolog;
MET = MET proto-oncogene; amp = amplification; POLE = DNA polymerase epsilon catalytic subunit; Tx = treatment; PD-1 = programmed cell death protein 1;
PD-L1 = programmed death ligand 1; MEK = mitogen-activated protein kinase.
Dienstmann et al, 2018.
8%
26%
8%
2%
2%
2%
1%
2%
2%
1%
45%
RAS mutation ±
PIK3CA/PTEN mutation
BRAF V600E
Kinase
inhibitor
MET inhibitor
Anti-HER2 Tx
Anti–PD-1/PD-L1
BRAF inhibitor + anti-EGFR ± MEK inhibitor
PIK3CA/PTEN mutation
Wild type
Anti-EGFR therapies

Special Considerations in the
First-Line Setting: Anti-EGFR in
the First-Line Setting,
Immunotherapy in MSI-H mCRC

aAdjuvant fluoropyrimidine monotherapy allowed if completed >6 months before enrollment.
bUntil disease progression, unacceptable toxicity, withdrawal of consent, investigator’s judgment, or curative intent resection.
cPrimary tumor in descending colon, sigmoid colon, rectosigmoid, and rectum.
1L = first-line; WT = wild type; SOC = standard of care; ECOG = Eastern Cooperative Oncology Group; PS = performance status;
mFOLFOX6 = modified FOLFOX6; PFS = progression-free survival; RR = response rate; DOR = duration of response; R0 = no residual tumor.
Yoshino et al, 2022; Clinicaltrials.gov, 2022.
Phase 3, Randomized, Open-Label, Multicenter Study (NCT02394795)
EGFR Inhibitor vs VEGF Inhibitor With SOC
1L RAS WT mCRC: Trial Design
Patients With RAS WT
mCRC
• Unresectable disease
• No prior chemotherapya
• Aged 20-79 years
• ECOG PS 0-1
• ≥1 evaluable lesion
• Adequate organ
function
• Life expectancy ≥3
months
N=823
Panitumumab +
mFOLFOX6
b
Bevacizumab +
mFOLFOX6
b
Primary End Point
• OS: left-sidedc population; if
significant, analyzed in overall
population
Secondary End Points
• PSF, RR, DOR, R0 resection:
left-sidedc and overall populations
• Safety: all treated patients
Stratification Factors
• Institution
• Age 20-64 vs 65-79 years
• Liver metastases present vs absent
R
1:1
PARADIGM: Panitumumab + mFOLFOX6

PARADIGM: Panitumumab + mFOLFOX6 (cont.)
CI = confidence interval; HR = hazard ratio; pan = panitumumab; bev = bevacizumab.
Yoshino et al, 2022; Watanabe et al, 2023.
No new safety signals observed
Acneiform rash (panitumumab 74.8%; bevacizumab 3.2%); peripheral neuropathy (panitumumab
70.8%; bevacizumab 73.7%); stomatitis (panitumumab 61.6%; bevacizumab 73.7%) in left-sided
population
Overall Survival

ctDNA = circulating tumor DNA; KRAS = Kirsten rat sarcoma viral oncogene homolog; ECD = extracellular domain;
NRAS = neuroblastoma RAS viral oncogene homolog; RET = rearranged during transfection; NTRK = neurotrophic tyrosine receptor kinase;
ALK = anaplastic lymphoma kinase; mOS = median OS.
Shitara et al, 2023.
Biomarker Analyses
Gene Alteration Frequency (n=733)
Survival in the Overall Population Analyzed for ctDNA
PARADIGM: Panitumumab + mFOLFOX6 (cont.)
In hyperselected patients with no gene alterations, OS was longer with pan vs bev, regardless of primary tumor
sidedness
In patients with any gene alterations, OS was similar or shorter with pan vs bev, regardless of primary tumor sidedness
Negative hyperselection using ctDNA analysis rather than tumor sidedness may identify patients for 1L pan over bev

KEYNOTE-177: Pembrolizumab
PCR = polymerase chain reaction; IHC = immunohistochemistry; RECIST = Response Evaluation Criteria in Solid Tumors; Q3W = every 3 weeks;
IV = intravenously; Q2W = every 2 weeks; BICR = blinded independent central review; ORR = overall response rate; HRQOL = health-related quality of life;
PD = progressive disease.
André et al, 2020; Shiu et al, 2021.
Study Design (NCT02563002)
Key Eligibility Criteria
• MSI-H (PCR)/dMMR (IHC) stage IV CRC
• Treatment-naive
• ECOG PS 0 or 1
• Measurable disease by RECIST v1.1
Pembrolizumab 200 mg Q3W for up to 35 cycles
Investigator-choice chemotherapy
mFOLFOX IV Q2W
or mFOLFOX6 + bevacizumab IV Q2W
or mFOLFOX6 + cetuximab IV Q2W
or FOLFIRI IV Q2W
or FOLFIRI + bevacizumab IV Q2W
or FOLFIRI + cetuximab IV Q2W
Optional crossover to
pembrolizumab 200 mg Q3W for up
to 35 cycles for patients with
centrally verified PD by RECIST v1.1,
central review
Until unacceptable
toxicity, disease
progression, or
patient/physician
withdrawal decision
Safety and
survival
follow-up
Primary End Points
• PFS per RECIST v1.1, BICR
• OS
• ORR per RECISTS v1.1, BICR
• Safety
Exploratory end points
• PFS2
• HRQOL
Tumor response assessed at Week 9 and
Q9W thereafter per RECIST v1.1 by BICR
R
1:1

KEYNOTE-177: Pembrolizumab (cont.)
Pembro = pembrolizumab; chemo = chemotherapy.
Shiu et al, 2021.
Progression-Free Survival
Response Rate:
Pembro = 45.1%
Chemo = 33.1%

KEYNOTE-177: Pembrolizumab (cont.)
TRAEs = treatment-related adverse events.
Shiu et al, 2021.
Grade ≥3 TRAEs: 22% for pembrolizumab, 66% for chemo
Overall Survival
Effective crossover rate =
60%

Take-Home Points
RAF = rapidly accelerated fibrosarcoma.
NCCN, 2023.
Strongly consider first-line anti-EGFR therapy in combination
with chemotherapy in all RAS/RAF wild-type, left-sided mCRC
Immunotherapy is the treatment of choice in the first-line
treatment of MSI-H mCRC
Early biomarker testing in mCRC is critical for appropriate
treatment selection

Diagnostic Workup and
Biomarker Testing

Targeted and Single-Gene Sequencing
Vacante et al, 2018; Turano et al, 2019; NCCN, 2023.
Advantages
Relatively quick turnaround
In-house testing sometimes available
Disadvantages Limited set of genes and alterations tested
Exhaustion of limited tissue samples
Targeted gene sequencing panels are useful tools for analyzing
specific mutations in each sample

Comprehensive Genomic Profiling
TMB = tumor mutational burden.
Vacante et al, 2018; NCCN, 2023.
Comprehensive genomic profiling is a next-generation
sequencing approach that uses a single assay to assess
hundreds of genes including relevant cancer biomarkers
Advantages
Large number of genes and alterations tested
Ability to obtain TMB and MSI
May guide clinical trial enrollment
Disadvantages
Usually requires a send-out test
More time-consuming to obtain results
Expensive

Liquid Biopsy and ctDNA
Osumi et al, 2019; NCCN, 2023.
Collection of blood sample to
test for relevant biomarkers
to inform patient
management
Most commonly applied to the collection of
peripheral blood for analysis of cell-free ctDNA
Advantages
Can obtain results in the absence of tissue availability
May be more reflective of real-time molecular changes
Disadvantages
Panel of genes tested is typically smaller
Dependent on the presence of detectable
ctDNA
May not fulfill clinical trial eligibility criteria

Challenges in Biomarker Testing
Mendelaar et al, 2021; NCCN, 2023.
Rapidly evolving and increasingly complex field
Relevant biomarkers are rapidly evolving in each disease type
Some alterations have promising data, but no FDA-approved
therapies yet (eg, KRAS G12C)
Biomarkers that cross multiple tumor types
Positive example: MSI-H and NTRK fusions
Negative example: PD-L1 established in multiple tumor types but NOT
mCRC
Testing turnaround time

Biomarker Testing and
Clinical Features of HER2-
Amplified mCRC

Testing for HER2 Amplification
NGS = next-generation sequencing; FISH = fluorescence in situ hybridization.
NCCN, 2023; Ross et al, 2018; Siena et al, 2018.
Screening Type IHC or FISH
Individual or Panel Genomic
Sequencing (NGS)
Directly tests for a…
 HER2 protein overexpression
and amplification
 HER2 amplification
Read as a…
 IHC: 3+ staining in >50% of cells is read
as positive, while 2+ is equivocal and
reflexive FISH testing is recommended
 FISH: HER2:CEP17 ratio ≥2 in >50% of
cells is read as positive
 Genetic sequencing
Potential
disadvantages
 May not identify mutated HER2, such as
short variants that are functionally
active but do not bind the staining
antibody
 May not be optimized for mCRC
 May not identify promoter region
or other driver mutations that
cause overexpression without
increasing
copy number
 Testing turnaround time
 More expensive than IHC

HER2 as a Target in Metastatic CRC
RTK = receptor tyrosine kinase; ERBB2 = erythroblastic oncogene B 2; HER = human epidermal growth factor receptor; PI3K = phosphoinositide 3-kinase;
TDM1 = trastuzumab emtansine; TDxD = trastuzumab deruxtecan.
Image modified from Gradishar, 2012.
Hynes & Lane, 2005.
HER2 is an RTK encoded by ERBB2
HER2 heterodimerizes with other
ligand-bound HER family
members
HER2-HER3 heterodimer is a
potent driver of PI3K signaling
Multiple therapies target HER2
and/or HER2 heterodimers

Prevalence of HER2 Amplification in CRC
Dataset Patients (n) HER2 Amp Rate
Genie Cohort v12.1 137,166 2.3%
Foundation Medicine 5,127 3.0%
Caris Life Sciences 1,226 3.8%
TCGA 224 3.1%
TCGA = The Cancer Genome Atlas.
AACR, 2023; Bose et al, 2016; Arguello et al, 2014; TCGA, 2012

HER2 in Metastatic CRC
Wang et al, 2020; Richman et al, 2016.
Higher incidence in the left colon
Not mutually exclusive with RAS or
BRAF mutations
Associated with lung and brain
metastases
No evidence that HER2 impacts
response to chemotherapy
Possible resistance mechanism to
EGFR antibodies
Clinical and Molecular Features

HER2 in Metastatic CRC (cont.)
Bekaii-Saab et al, 2022.
Worse Outcomes HER2-Positive mCRC With Anti-EGFR Therapy?
Meta-Analysis of Anti-EGFR Treatment in Patients With RAS WT
HER2-Positive vs HER-Negative mCRC
Overall:
Heterogeneity
PFS ORR
Overall:
Heterogeneity:

Take-Home Points
NCCN, 2023; Ross et al, 2018; Siena et al, 2018; Wang et al, 2020; Richman et al, 2016.
Next-generation sequencing will identify a vast majority of HER-
positive mCRC
IHC/FISH will have faster turnaround times
HER2 positivity is enriched in left-sided, RAS/RAF wild-type
mCRC
Concern about anti-EGFR resistance in HER2-positive mCRC

Novel Targeted Therapies in
HER2-Positive Metastatic
CRC: Mechanisms of Action,
Efficacy, and Safety

Common Themes Across Multiple Studies
Sartore-Bianchi et al, 2016; Tosi et al, 2020; Meric-Berstam et al, 2019; Strickler et al, 2022a.
Dual inhibition with trastuzumab appears critical for response
Response rates are significantly higher than what would be
expected in a heavily-pretreated population
Very few randomized studies
Toxicity appears manageable
No response if concurrent RAS mutation

HERACLES: Trastuzumab + Lapatinib
QW = every week; PO = orally; QD = every day; ddPCR = droplet digital PCR.
Sartore-Bianchi et al, 2016.
Primary End Point
• ORR (RECIST 1.1 with central
independent radiological review)
• PFS, safety
Translational
• HER2 ctDNA in plasma (ddPCR); HER2
ectodomain in serum (ELISA); NGS in
tissue and plasma in de novo resistant
patients and upon PD
• Patients histologically
diagnosed with metastatic
CRC not amenable to
surgery
• HER2-positive, KRAS exon
2 WT
• Prior fluoropyrimidines,
irinotecan, oxaliplatin,
cetuximab, or
panitumumab; prior
bevacizumab, aflibercept
or regorafenib allowed
but not mandatory
• PS 0-1
Trastuzumab IV 4 mg/kg load
and then 2 mg/QW
Lapatinib PO 1,000 mg/QD
PD

HERACLES: Trastuzumab + Lapatinib (cont.)
CR = complete response.
Sartore-Bianchi et al, 2016; Tosi et al, 2020.
7 years of follow-up
32 patients evaluable
ORR = 28% with 1 patient
with 7-year CR
Median PFS = 4.7 months
Median OS = 10.0 months
Grade 3 AEs 22%: fatigue,
rash, increased bilirubin; no
grade 4/5
HER2-Positive mCRC Radiographic Response HER2 IHC score 3+
HER2 IHC score 2+

MyPathway: Pertuzumab + Trastuzumab
Meric-Bernstam et al, 2021.
Phase 2a Multiple Basket Study: HER2-Positive Solid Tumors
• HER2-altereda tumors
• Aged ≥18 years
• Measurable lesions per RECIST v1.1
• ECOG PS ≤2
• No satisfactory alternative treatment
options
• Tissue-agnostic enrollment
Key Exclusion Criteria
• Primary tumor type with FDA-
approved indication for trastuzumab
and/or pertuzumab
• Prior HER2-targeted treatment
Analysis in patients with HER2
amplification and/or overexpression
N=258
Pertuzumab 840 mg loading dose, then
420 mg IV Q3W
+
Trastuzumab 8 mg/kg loading dose,
then 6 mg/kg IV Q3W
Re-evaluate every 2 cycles (6 weeks) for
24 weeks, then every 4 cycles (12 weeks)
Treatment until disease progression or
unacceptable toxicity
Colorectal n=84
Biliary n=40
NSCLC n=27
Uterine n=23
Urothelial n=22
Salivary n=18
Ovarian n=12
Pancreas n=10
Other n=22

MyPathway: Pertuzumab + Trastuzumab (cont.)
PR = partial response; SD = stable disease.
Patients with objective response: 32% (18/57) (95% CI: 20-45)
Median PFS: 2.9 months (all); 5.3 months KRAS WT
Most common TRAEs: diarrhea, fatigue, and nausea
HER2-Positive mCRC

MyPathway: Pertuzumab + Trastuzumab (cont.)
Anti-HER2 Therapy Is Ineffective in Setting of a KRAS Mutation
Only 1 response seen in the
KRAS-mutated cohort

MOUNTAINEER: Tucatinib + Trastuzumab
2L = second-line; BID = twice daily; C = cycle; D = day; cORR = confirmed ORR.
Strickler et al, 2022a.
Tucatinib, an Oral Selective Small Molecule Inhibitor of HER2 Receptor
Study Design: Phase 2 Trial in mCRC
 ≥2L mCRC
 HER2-positive per
local IHC/ISH/NGS
testing
 RAS WT
 Measurable disease
per RECIST v1.1
 Prior
fluoropyrimidines,
oxaliplatin,
irinotecan, and anti-
VEGF mAb
Cohort B (n=41)
Tucatinib 300 mg PO BID +
trastuzumab 6 mg/kg Q3W
(loading dose 8 mg/kg
C1D1)
Cohort C (n=31)
Tucatinib 300 mg PO BID
Cohort A (n=45)
Tucatinib 300 mg PO BID +
trastuzumab 6 mg/kg Q3W
(loading dose 8 mg/kg
C1D1)
Expansion
End Points: Efficacy
Assessed in patients who received any amount of
study treatment and had HER2-positive tumors
1. Primary: cORR in Cohorts A+B (RECIST v1.1. BICR)
2. Secondary:
 Cohorts A+B: DOR per BICR, PFS per BICR, OS
 Cohort C: ORR by 12 weeks of treatment per
BICR
(pre-crossover)
3. Prespecified:
 DCR for pre- and post-crossover patients
 cORR per BICR for post-crossover patients
Safety presented in pre- and post-crossover patients
who received any amount of study treatment
Patients treated with tucatinib monotherapy were allowed to cross over and receive tucatinib and trastuzumab if they
experienced radiographic progression at any time point or if they had not achieved a PR or CR by Week 12
Data cutoff: March 28, 2022
R

MOUNTAINEER: Tucatinib + Trastuzumab (cont.)
a2 patients did not have HER2-positive disease as specified per protocol and were excluded.
b1 patient discontinued before receiving treatment.
cTreatments used in adjuvant/neoadjuvant setting are counted as 1 line. Data cutoff: March 28, 2022.
Key Patient Baseline Characteristics
Characteristics
Tucatinib +
Trastuzumab
Cohorts A+B (n=84)
a
Tucatinib Monotherapy
Cohort C (n=30)
b
Median age (range), years 55.0 (24-77) 59.5 (29-75)
Sex, n (%)
Male 51 (60.7%) 15 (50.0%)
Female 33 (39.3%) 15 (50.0%)
ECOG PS, n (%)
0 50 (59.5%) 17 (56.7%)
1 31 (36.9%) 13 (43.3%)
2 3 (3.6%) 0
Primary tumor site, n (%)
Left colon and rectum 71 (84.5%) 27 (90.0%)
All other primaries 13 (15.5%) 3 (10.0%)
Transverse colon 7 (8.3%) 0
Right colon 5 (6.0%) 3 (10.0%)
Multiple/overlapping sites 1 (1.2%) 0
Patients with liver metastases at study entry, n (%) 54 (64.3%) 15 (50.0%)
Patients with lung metastases at study entry, n (%) 59 (70.2%) 20 (66.7%)
Prior lines of systemic therapy in any setting, median (range)
c
3 (1-6) 2 (1-5)

Efficacy Outcomes
Responses
Tucatinib +
Trastuzumab
Cohorts A+B
(n=84)
Tucatinib
Monotherapy Cohort
C (n=30)
Tucatinib +
Trastuzumab
Post-Crossover
(n=28)
Best overall
response per
BICR, n (%)
CR 3 (3.6%) 0 0
PR 29 (34.5%) 1 (3.3%) 5 (17.9%)
SD 28 (33.3%) 23 (76.7%) 18 (64.3%)
PD 22 (26.2%) 4 (13.3%) 5 (17.9%)
Not available 2 (2.4%) 2 (6.7%) 0
ORR per BICR, % (95% CI) 38.1% (27.7-49.3) 3.3% (0.1-17.2) 17.9% (6.1-36.9)
DCR per BICR, n (%) 60 (71.4%) 24 (80.0%) 23 (82.1%)

IQR = interquartile range.
Strickler et al, 2022b.
PFS and OS
Progression-Free Survival per BICR Overall Survival
Median follow-up for Cohorts A+B was 20.7 months (IQR: 11.7, 39.0)
Tucatinib +
Trastuzumab
Events
Median
PFS
95% CI
Cohorts A+B 59/84
8.2
months
4.2-10.3
Tucatinib +
Trastuzumab
Events
Median
OS
95% CI
Cohorts A+B 38/84
24.1
months
20.3-36.7

AE = adverse event; TEAE = treatment-emergent AE; SAE = adverse event.
Safety Summary
TEAEs, n (%)
Tucatinib +
Trastuzumab
Cohorts A+B
(n=86)
Tucatinib
Monotherapy Cohort
C
(n=30)
Tucatinib +
Trastuzumab
Post-Crossover
(n=28)
Any grade AEs 82 (95.3%) 28 (93.3%) 23 (82.1%)
Grade ≥3 AEs 33 (38.4%) 8 (26.7%) 6 (21.4%)
SAEs 19 (22.1%) 3 (10.0%) 2 (7.1%)
AEs leading to tucatinib
discontinuation
5 (5.8%) 0 2 (7.1%)
Deaths due to AEs 0 0 0
Most common AEs
Diarrhea 55 (64.0%) 10 (33.3%) 10 (35.7%)
Abdominal pain 13 (15.1%) 6 (20.0%) 3 (10.7%)
Fatigue 38 (44.2%) 6 (20.0%) 3 (10.7%)

Management of Diarrhea With Tucatinib
Tukysa® prescribing information, 2020.
Diarrhea is an expected side effect of tucatinib, though most
cases are mild
Prophylactic antidiarrheal medication is not typically needed
Patients should have loperamide available that can be started at
the onset of diarrhea
Based on the severity of the diarrhea, interrupt dose, then dose
reduce or permanently discontinue tucatinib

DESTINY-CRC01: Trastuzumab Deruxtecan
aA futility monitoring was done after ≥20 patients in Cohort A had 12 weeks of follow-up to inform opening of Cohorts B and C.
bORR was based on RECIST v1.1 in all cohorts.
cData presented are from the full analysis set.
Yoshino et all, 2022; Siena et al, 2021.
Open-Label, Phase 2 Trial: Study Design
Primary analysis
(data cutoff:
August 9, 2019)
Primary End Point
 ORRb (cohort A)
 ORRb (cohorts B and C)
 PFS
 OS
 DOR
 DCR
 Safety and tolerability
Final analysis
(data base lock:
December 28, 2020)
Patient Disposition at Final Analysisc
 No patients remain on treatment
 At the end of the study, median follow-up was 62.4 weeks for Cohort
A, 27.0 weeks for Cohort B, and 16.9 weeks for Cohort C
Primary Analysis of Cohort A2
 Results yielded promising antitumor activity and a manageable
safety profile
 The median follow-up was 27.1 weeks at data cutoff
 Unresectable and/or mCRC
 HER2-expressing (central
confirmation)
 RAS/BRAF V600E WT
 ≥2 prior regimens
 Prior anti-HER2 treatment
allowed
 Excluded patients with a
history of or
current/suspected
interstitial lung disease
Cohort A:
HER2-positive
(IHC 3+ or IHC 2+/ISH) n=53
Cohort B
a
:
HER2 IHC 2+/ISH–
n=15
Cohort C
a
:
HER2 IHC 1+
n=18
6.4 mg/kg dose of T-DXd Q3W
(all cohorts)

DESTINY-CRC01: T-DXd (cont.)
aLeft: rectum, sigmoidal, descending; right: cecum, ascending, transverse. bBy local assessment. c1patient in Cohort A had an NRAS mutation;
1 patient in Cohort B was not examined. d1 patient in Cohort C was not examined. eBy central assessment. Sums may not total 100% due to rounding.
f1 patient was nonevaluable for ISH testing.
Yoshino et al, 2022; Yoshino et al, 2021.
Patient Baseline Characteristics
HER2 IHC3+ or
IHC2+/ISH+
Cohort A (n=53)
HER2 IHC2+/ISH-
Cohort B (n=15)
HER2 IHC1+
Cohort C (n=18)
Overall
(N=86)
Age, median (range),
years
57.0 (27-79) 62.0 (37-78) 58.5 (43-79) 58.5 (27-79)
Female, % 52.8% 33.3% 38.9% 46.5%
Sum of target lesions,
median, cm
8.1 8.1 10.2 9.0
Primary tumor site, %
a
Left 88.6% 93.3% 94.4% 90.7%
Right 11.4% 6.7% 5.6% 9.3%
RAS WT, %
b,c
98.1% 93.3% 100% 97.7%
BRAF V6600E WT, %
b,d
100% 100% 94.4% 98.8%
HER2 status, %
e
IHC 3+ 75.5% 0 0 46.5%
IHC 2+ 24.5% 100% 0 32.6%
IHC 1+ 0 0 100% 20.9%
ISH+ 98.1%
f
0 22.2% 65.1%
ISH- 0 100% 77.8% 33.7%

aBy local assessment.
Patient Baseline Characteristics
HER2 IHC3+ or
IHC2+/ISH+
Cohort A (n=53)
HER2 IHC2+/ISH-
Cohort B (n=15)
HER2 IHC1+
Cohort C (n=18)
Overall
(N=86)
Microsatellite status, %
a
Microsatellite stable 81.1% 93.3% 66.7% 80.2%
Unknown 18.9% 6.7% 33.3% 19.8%
Prior treatment, %
Irinotecan 100% 100% 100% 100%
Fluorouracil/
capecitabine
100% / 54.7% 93.3% / 46.7% 100% / 55.6% 98.8% / 53.5%
Oxaliplatin 100% 93.3% 100% 98.8%
Cetuximab or
panitumumab
100% 100% 94.4% 98.8%
Bevacizumab 75.5% 73.3% 83.3% 76.7%
Prior anti-HER2 agents 30.2% 0 0 18.6%
Median prior regimens for metastatic disease: 4 (range: 2-11)

aPatients were missing postbaseline scans.
NE = not evaluable.
Efficacy
HER2 IHC3+ or
IHC2+/ISH+
Cohort A
(n=53)
HER2 IHC2+/ISH-
Cohort B
(n=15)
HER2 IHC1+
Cohort C
(n=18)
Confirmed ORR by ICR, % (n) [95% CI] 45.3% (24) [31.6-59.6] 0 [0.0-21.8] 0 [0.0-18.5]
CR 0 0 0
PR 45.3% (24) 0 0
SD 37.7% (20) 60% (9) 22.2% (4)
PD 9.4% (5) 33% (5) 55.6% (10)
Not evaluable
a
7.5% (4) 6.7% (1) 22.2% (4)
Disease control rate, % (95% CI) 83.0% (70.2-91.9) 60.0% (32.3-83.7) 22.2% (6.4-47.6)
Duration of response, median (95% CI),
months
7.0 (5.8-9.5) NE (NE-NE) NE (NE-NE)
Treatment duration, median (95% CI),
months
5.1 (3.9-7.6) 2.1 (1.4-2.6) 1.4 (1.3-1.5)

PFS and OS

Yoshino et al, 2021.
TEAEs in ≥20% of Patients
HER2 IHC3+ or
IHC2+/ISH+
Cohort A
(n=53)
HER2
IHC2+/ISH-
Cohort B
(n=15)
HER2 IHC1+
Cohort C
(n=18)
Overall
(N =86)
n (%) Any Grade Any Grade Any Grade Any Grade Grade ≥3
Patients with any TEAE 53 (100%) 15 (100%) 18 (100%) 86 (100%) 56 (65.1%)
Nausea 37 (69.8%) 9 (60.0%) 7 (38.9%) 53 (61.6%) 5 (5.8%)
Anemia 21 (39.6%) 4 (26.7%) 6 (33.3%) 31 (36.0%) 12 (14.0%)
Fatigue 21 (39.6%) 7 (46.7%) 3 (16.7%) 31 (36.0%) 1 (1.2%)
Decreased appetite 18 (34.0%) 5 (33.3%) 7 (38.9%) 30 (34.9%) 0
Platelet count decreased 17 (32.1%) 4 (26.7%) 7 (38.9%) 28 (32.6%) 8 (9.3%)
Vomiting 23 (43.4%) 3 (20.0%) 1 (5.6%) 27 (31.4%) 1 (1.2%)
Neutrophil count
decreased
20 (37.7%) 2 (13.3%) 4 (22.2%) 26 (30.2%) 19 (22.1%)
Diarrhea 19 (35.8%) 0 4 (22.2%) 23 (26.7%) 1 (1.2%)

ILD = interstitial lung disease.
Yoshino et al, 2022; Yoshino et al, 2021; Enhertu® prescribing information, 2022.
Adjudicated drug-related ILDs
Median time to adjudicated onset date was 61.0 days
(range: 9-165 days)
8 of 8 patients with grade ≥2 ILD received corticosteroids
4 patients with grade 2 recovered, 1 patient with grade 3
did not recover (later died due to disease progression),
and 3 patients died due to ILD
Grade 5 ILDs
In the 3 fatal cases adjudicated as drug-related ILD, onset was
from 9-120 days (median: 22 days), and death occurred 6-19 days
after diagnosis (median: 6 days)
Primary cause of death was ILD in all 3 patients
AE of Special Interest: Interstitial Lung Disease
As of July 3, 2020, new ILD/pneumonitis guidelines recommend to monitor
for symptoms, interrupt or discontinue T-DXd, conduct imaging (as
clinically indicated), and start steroids as soon as ILD is suspected
All Patients
(N=86)
n (%)
Grade 1 0
Grade 2 4 (4.7%)
Grade 3 1 (1.2%)
Grade 4 0
Grade 5 3 (3.5%)
Any grade/total 8 (9.3%)

Management of T-DXd Interstitial Lung Disease
Enhertu® prescribing information, 2022.
Consider corticosteroid
treatment (eg, ≥0.5 mg/kg per
day prednisolone or
equivalent)
Interrupt T-DXd until resolved
to Grade 0, then:
If resolved in ≤28 days from
date of onset, maintain dose
If resolved in >28 days from
date of onset, reduce dose 1
level
Dose level -1 = 6.4 mg/kg
Dose level -2 = 5.4 mg/kg
Promptly initiate systemic
corticosteroid treatment (eg,
≥1 mg/kg per day
prednisolone or equivalent)
Continue for ≥14 days
followed by gradual taper for
≥4 weeks
Permanently discontinue T-
DXd in patients who are
diagnosed with any
symptomatic ILD/pneumonitis
Asymptomatic ILD/Pneumonitis
(Grade 1)
Symptomatic ILD/Pneumonitis
(Grade ≥2)

MOUNTAINEER-03: Tucatinib/Trastuzumab/mFOLFOX6
aStratification: primary tumor sidedness, liver metastases.
bLevoleucovorin may be given in place of leucovorin.
cTime from randomization to disease progression on next-line treatment or death from any cause.
INV = investigator; PK = pharmacokinetics; PROs = patient-reported outcomes.
Bekaii-Saab et al, 2023; Clinicaltrials.gov, 2023a.
Global, Randomized, Open-Label, Phase 3 Trial
(n≈400)
 HER2-positive 1L
mCRC assessed by
central IHC/ISH
testing
 RAS WT
 Measurable disease
per RECIST v1.1
 ECOG PS 0-1
 Treated,
asymptomatic brain
metastases permitted
Tucatinib +
trastuzumab +
mFOLFOX6b
(n≈200)
mFOLFOX6b ±
bevacizumab or
cetuximab
(n≈200)
End Points
Primary
 PFS per RECIST v1.1 (BICR)
Secondary
 OS
 Confirmed ORR per RECIST
v1.1
 PFS per RECIST v1.1 (INV)
 DOR
 PFS2c
 Safety
 PK
 PROs
Ra

DESTINY-CRC02: Trastuzumab Deruxtecan
aIf clinically indicated. bStratification: ECOG PS 0-1, HER2 status: IHC3+ or IHC2+/ISH+, RAS status (WT vs mutant).
HEOR = heath economics and outcomes research.
Raghav et al, 2021; Clinicaltrials.gov, 2023b.
Global, Randomized, 2-Arm, 2-Stage, Phase 2 Trial
(n≈120
planned)
 Patients with HER2-
overexpressing (IHC3+ or
IHC2+/ISH+) unresectable,
recurrent, or metastatic CRC
 Previous treatment with
chemotherapy, anti-EGFR
therapy (if RAS WT), anti-VEGF
therapy, and anti–PD-L1
therapy (if tumor
is MSI-high/dMMR or TMB-
high)a
 Prior anti-HER2 therapy
allowed
 RAS WT or mutant
 BRAF WT
 ECOG PS 0 or 1
Arm 1
T-DXd
5.4 mg/kg Q3W
(n=40)
Arm 2
T-DXd
6.4 mg/kg Q3W
(n=40)
Primary End Point
 Confirmed ORR by
RECIST v1.1 (BICR)
 ORR per RECIST v1.1
(INV)
 DOR
 DCR
 CBR
 PFS
 OS
 Safety
 PK
 Immunogenicity
 HEOR
Rb
T-DXd
5.4 mg/kg Q3W
(n=40)
Stage 1 Stage 2

HER2-Targeted Therapies: Patients With Advanced or
mCRC
LVEF = left ventricle ejection fraction.
Tosi et al, 2020; Meric-Bernstam et al, 2019; Meric-Berstam et al, 2021; Sartore-Bianchi et al, 2020; Siena et al, 2021; Yoshino et al, 2022; Strickler et al, 2022b.
Recent Data
Regimen Trial (n), Year ORR
PFS,
month
s
OS,
months
Most Common
Grade ≥3 AEs
Trastuzumab +
lapatinib
HERACLES-A
(n=32), 2016
28% 4.7 10.0
Fatigue: 16%
Decreased LVEF: 6%
Trastuzumab +
pertuzumab
MyPathway
(n=84; 57 evaluable), 2019
32% 2.9 11.5
Hypokalemia: 5%
Abdominal pain: 5%
Pertuzumab and
T-DM1
HERACLES-B
(n=31), 2020
9.7% 4.1
Not
reported
Thrombocytopenia: 7%
Trastuzumab
deruxtecan
DESTINY-CRC01
(N=78; 53 HER2-positive),
2021
45.3% 6.9 15.5
Neutropenia: 22%
Anemia: 14%
Tucatinib +
trastuzumab
MOUNTAINEER
(n=117; 84 Cohorts A+B),
2022
38.1% 8.2 24.1
Hypertension: 7%
Diarrhea: 3.5%

Case Explorations: Applying
Emerging Evidence in the
Management of HER2-
Positive Metastatic CRC

Case Study: Ms. KR
PMH = past medical history; chemoXRT = chemoradiation; LAR = laparoscopy.
51-year-old female with no PMH is diagnosed with mid-rectal
adenocarcinoma with no evidence of metastasis, staged
cT3N1aM0
Undergoes total neoadjuvant therapy with chemoXRT with
concurrent capecitabine followed by 8 cycles of FOLFOX
chemotherapy
LAR successfully completed revealing ypT3N0M0 disease,
ostomy reversal completed at Week 6

Case Study: Ms. KR (cont.)
CT = computed tomography; MSS = microsatellite-stable.
Image courtesy of Dr. Christopher Lieu.
Initial restaging CT at 3
months reveals bilateral
pulmonary nodules
concerning for metastatic
disease
Molecular testing is
performed
Molecular testing results:
KRAS/NRAS/BRAF wild-type
HER2 amplification by FISH
MSS, TMB-low

a. FOLFOX and bevacizumab
b. FOLFIRI and bevacizumab
c. FOLFIRI and cetuximab
d. Trastuzumab and pertuzumab
e. Trastuzumab and tucatinib
f. Trastuzumab deruxtecan
What Treatment Option Would You Select at This Time?

Image courtesy of Dr. Christopher Lieu.
Anti-HER2 therapy is declined
by insurance because patient
has not technically had “first-
line therapy” in the metastatic
setting
She is initiated on FOLFIRI and
bevacizumab every 2 weeks
Restaging studies at 2 months
reveals progression of disease
in the lungs

a. FOLFOX and bevacizumab
b. FOLFIRI and cetuximab
c. Trastuzumab and pertuzumab
d. Trastuzumab and tucatinib
e. Trastuzumab deruxtecan

Trastuzumab/tucatinib is initiated
Partial response is observed for 10 months
At 10 months, restaging studies reveal slight progression in the
lungs
ctDNA testing at the time of progression reveals no actionable
alterations

TAS-102 = tipiracil hydrochloride.
a. Trastuzumab and pertuzumab
b. Trastuzumab deruxtecan
c. TAS-102 and bevacizumab
d. Regorafenib
e. Clinical trial enrollment

a. Trastuzumab and pertuzumab
b. Trastuzumab deruxtecan
c. TAS-102 and bevacizumab
d. Regorafenib
e. Clinical trial enrollment

Key Takeaways
Although subsets are relatively small, biomarker-directed therapy
for mCRC is increasing
Early biomarker testing is critical
HER2 positivity is enriched in left-sided, RAS/RAF wild-type
mCRC
May be a resistance mechanism to anti-EGFR–based therapy
Tucatinib in combination with trastuzumab has now received
FDA accelerated approval for patients with HER2-positive mCRC
Sequencing of anti-HER2 therapy is now something all providers
should consider prior to initiation of therapy

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