Key Presentations from the 2022 ASCO Annual Meeting:

Breast Cancer Issue

Angela DeMichele, MD, MSCE

Jill & Alan Miller Endowed Chair in Breast Cancer Excellence
Professor of Medicine
Co-Director, 2-PREVENT Translational Center of Excellence
Co-Leader Breast Cancer Program, Abramson Cancer Center
University of Pennsylvania

17 June 2022
 DESTINY-Breast04 (Modi, et al.)
HER- DESTINY-Breast03 (Hamilton, et al.)
Directed
Therapy ILD from T-DXd (Kish, et al.)

Patritumab ph 1/2 (Krop, et al.)

HER2CLIMB-04 TPS

HER2CLIMB-05 TPS
 DESTINY-Breast04

Trastuzumab deruxtecan (T-DXd)

vs treatment of physician’s choice in patients with
HER2-low unresectable and/or metastatic breast cancer:
Results of DESTINY-Breast04, a randomized, phase 3 study
Shanu Modi Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, USA
June 5, 2022

Additional authors: William Jacot, Toshinari Yamashita, Joo Hyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani,
Naoto Ueno, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Xiaojia Wang, Binghe Xu, Dhiraj Gambhire,
Lotus Yung, Gerold Meinhardt, Yibin Wang, Nadia Harbeck, David Cameron
On behalf of the DESTINY-Breast04 investigators

Shanu Modi, MD
4 DESTINY-
Breast04

T-DXd MOA, Bystander Effect, and Rationale for Targeting HER2-low mBC
T-DXd1,2 Neighborin
g Tumor
T-DXd
Cell
binds to
HER2 Tumor Cell
Tumor
cell
death
8:1 drug-to-
antibody T-DXd
Highly potent ratio internalized
Topoisomeras
topoisomerase I Cleavable linker e I inhibitor
inhibitor enters nucleus Membrane-
payload Linker permeable
cleaved, payload
releasing results in
topoisomeras bystander
e I inhibitor effect
Internalization of T-DXd leads to release of the DXd
payload and subsequent cell death in the target tumor cell T-DXd HER2 protein
and neighboring tumor cells through the bystander Topoisomerase I inhibitor
effect1,2 payload Adapted with permission from Modi S, et al. J Clin Oncol 2020;38:1887-96. CC BY ND 4.0.

• Results from a phase 1b study has reported efficacy of T-DXd in heavily pre-treated patients (N = 54) with HER2-low mBC with a mPFS of 11.1 months and an ORR: 37.0%3

HER2, human epidermal growth factor receptor 2; MOA, mechanism of action; mBC, metastatic breast cancer; mPFS, median progression-free survival; ORR, objective response rate; T-DXd, trastuzumab deruxtecan.
1. Nakada T, et al. Chem Pharm Bull. 2019;67:173-85. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22:5097-108. 3. Modi S, et al. J Clin Oncol 2020;38:1887-96.

Shanu Modi, MD
5 DESTINY-
Breast04

DESTINY-Breast04: First Randomized Phase 3 Study of T-DXd for

HER2-low mBC
An open-label, multicenter study (NCT03734029)

T-DXd

5.4 mg/kg Q3W

Patientsa (n = 373) Primary endpoint
• HER2-low (IHC 1+ vs IHC • PFS by BICR (HR+)
2+/ISH−), unresectable, HR+ ≈
and/or mBC treated with 1-2 R 480
2:1 Key secondary
prior lines of chemotherapy in HR− ≈ 60
TPC endpointsd
the metastatic setting Capecitabine, eribulin,
• PFS by BICR (all patients)
• HR+ disease considered gemcitabine,
paclitaxel, nab- • OS (HR+ and all patients)
endocrine refractory paclitaxelc
(n = 184)
Stratification factors
• Centrally assessed HER2 statusb (IHC 1+ vs IHC 2+/ISH−)
• 1 vs 2 prior lines of chemotherapy
• HR+ (with vs without prior treatment with CDK4/6 inhibitor) vs HR−

BICR, blinded independent central review; CDK, cyclin-dependent kinase; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; OS, overall
survival; PFS, progression-free survival; Q3W, every three weeks; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician’s choice.
a If patients had HR+ mBC, prior endocrine therapy was required. b Performed on adequate archived or recent tumor biopsy per ASCO/CAP guidelines using the VENTANA HER2/neu (4B5) investigational use only [IUO] Assay system. cTPC was

administered accordingly to the label. dOther secondary endpoints included ORR (BICR and investigator), DOR (BICR), PFS (investigator), and safety; efficacy in the HR− cohort was an exploratory endpoint.

Shanu Modi, MD
DESTINY-Breast04 Summary and Implications

• Significant, clinically important

improvement in PFS and OS
• MBC, tumors with Her2 1+ or 2+
expression by IHC
• Heavily pre-treated population
• Every subgroup benefited
• Neutropenia, N/V most common
AEs
• ILD in 12%; Grade 3 in 5/371
(0.9%) Grade 5 in 3/371 (0.8%)
• New standard in a population in
whom there are few good options
• Caveats: Testing, toxicity, cost
Trastuzumab Deruxtecan vs Trastuzumab Emtansine in Patients With HER2-Positive Unresectable and/or Metastatic Breast Cancer: Safety Follow-up of the Randomized, Phase 3 Study
DESTINY-Breast03

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Expanded Safety Review of T-DXd in D-03 (Hamilton, Abstract 1000)

• Fatigue about the same frequency

• Earlier with T-DXd
• More alopecia, nausea and
vomiting with T-DXd
 • “Real world data” from a physician survey and
chart review 8/17/21 – 9/16/21
• Cardinal Health Oncology Provider Extended
Network
• Included patients who received at least 4
months of T-DXd (n=149)

ILD Experience:
ACTIVITY • 4/149 patients had ILD - - lower than in
rwORR (CR+ PR) 74.5% clinical trials
• All cases diagnosed at 5.4 mg/kg
rwDCR (CR+PR+SD) 85.9%
• Occurred within first 5 cycles
Time to response (median) 2.7 months • All diagnosed with grade 2 symptoms and
Duration of response (median) 9.7 months CT scan
• Steroid treatment recommendations were
not consistently followed
Results From the Phase 1/2 Study <br />of Patritumab Deruxtecan, a <br />HER3-Directed Antibody-Drug Conjugate (ADC), in Patients With HER3-Expressing Metastatic Breast Cancer

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Phase 1/2 Trial of Patritumab Deruxtecan in Her3-Expressing MBC

HR+/Her2- TNBC Her2+

Liver or lung 90% 64% 85%

# Prior lines 6 (2-13) 2 (1-13) 5.5 (2-11)

Phase 1/2 Trial of Patritumab Deruxtecan in Her3-Expressing MBC
 Tucatinib: HER2CLIMB-04 and HER2CLIMB-05
• HER2CLIMB-04:
• Phase 2, single arm trial
• Tucatinib + T-DXd in patients with and without brain mets
• 1 Endpoint: clinical ORR Primary endpoint

• HER2CLIMB-05
• Phase 3, placebo controlled
• CLEOPATRA-type design
• Tucatinib/Trastuzumab/Pertuzumab maintenance therapy
Triple Negative Keynote 522 (Pusztai et al.)
Breast Cancer
ASCENT (Bardia et al.)

NeoSTAR (Spring et al.)

PARP inhibitor resistance (Dombrowski et al.)

Ladiratuzumab/pembro TPS
Event-free Survival by Residual Cancer Burden After Neoadjuvant Pembrolizumab + Chemotherapy vs Placebo + Chemotherapy for Early-Stage TNBC: Exploratory Analysis From
KEYNOTE-522

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KEYNOTE-522 Study Design (NCT03036488)

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KEYNOTE-522 Outcomes by RCB
‣ RCB: A more granular outcome measure than pCR
• Differentiates outcomes by different amounts of residual disease (RCB 1, 2 or 3)
• Strongly associated with EFS (I-SPY and Pooled analyses)
‣ KEYNOTE 522 prespecified this analysis
• 784 in Pembro arm; 390 in Placebo arm
• Median follow up 39.1 months at this analysis

‣ Results
• Fewer Pembro patients than placebo in RCB 1, 2 and 3, showing shift toward better RCB by Pembro
• Minimal EFS benefit to Pembro arm in RCB 0 or 1
• Better EFS with Pembro in RCB-2
• All RCB-3 do terribly, but without Pembro, especially terrible
• Conclusion: EFS benefit to Pembro regardless of extent of disease response
Poster 1071: Sacituzumab Govitecan vs Treatment of Physician's Choice in
Patients With Previously Treated Metastatic Triple-Negative Breast Cancer:
Final Data From the Phase 3 ASCENT Study
Bardia et al.

Primary
Endpoint
ASCENT Trial Final Analysis
‣ 1 case of > grade 2 ILD in Sacituzumab arm
‣ Final results reported in both the brain met negative (BM-neg) and ITT analyses

BM Neg (n=468) ITT (n=529)

Median PFS 5.6 vs. 1.7 months 4.8 vs. 1.7 months
(HR 0.39) (HR 0.41)
Median OS 12.1 vs. 6.7 months 11.8 vs. 6.9 months
(HR 0.48) (HR 0.51)
OS at 24 months 22.4% vs. 5.2% 20.5% vs. 5.5%
CBR 45% vs. 9% 40% vs. 8%
Median duration of 6.3 vs. 3.6 months 6.3 vs. 3.6 months
response

‣ Confirms superior outcomes and tolerability in 2L or greater setting

Phase 2 study of response-guided neoadjuvant sacituzumab govitecan
(IMMU-132) in patients with localized triple-negative breast cancer: results
from the NeoSTAR trial.
Spring et al.
 NeoSTAR Results
‣ pCR rate to SG alone: 30% (15/50)
• No discontinuation for progression
‣ Radiologic response rate to SG alone: 42%
(21/50)
‣ High pCR rate in BRCAmut + (but only 8 pts)
‣ Only grade 4 AE was neutropenia
‣ High levels (>50%) low grade nausea, fatigue,
alopecia
• No discontinuation for toxicity

‣ Conclusion: ”proof of principal” for larger trials and

combination therapies
ASCO 2022
Abstract 1096
‣ Goal: identify patients carrying DNA damage
repair (DDR) gene mutations who may be
particularly sensitive to PARP inhibitors
‣ Approach:
• Whole exome DNA sequencing and concurrent
RNA sequencing with germline subtraction
• Population: n=1213 patients, no clear
description of ascertainment strategy
Results
‣ Of 1,213 BC patients, 273 (22.5%) had clinically-
actionable mutations in DDR genes including 74 (6.1%)
having BRCA1/2 mutations and 37 with mutations in
multiple (≥2) DDR genes DDR gene mutations were less
common in HER2+ cancers (n=31, 15.0%) compared to
HER2-HR+ (n=175, 23.4%) or TNBC (n=53, 27.0%) (p<0.01)
‣ The overall frequencies of DDR gene mutations were similar
across patient ages, though BRCA1/2 mutations were more
common, and non-BRCA1/2 less common, in patients
<40 years old (Chi square, p<0.05; Figure 2).
‣ Across subtypes, four DDR genes were found in 23% of BC
patients: PTEN (6.5%), ARID1A (4.7%), BRCA2 (3.2%), and
BRCA1 (3.0%); other DDR genes were in <1% of patients
‣ For the 74 patients with BRCA1/2 mutations, 12 (6.2%)
carried other repair gene mutations (9 of 36 BRCA1; 4 of
39 BRCA2; 1 patient carried mutations in both BRCA genes).
Rationale:
• LIV-1- linked to
Vedotin will induce
inflammation
through cell death
(standard cytotoxic
mechanism)
• Draws inflammatory
cells into tumor
• Make tumor more
responsive to ICI?
 TROPiCS-02 (Rugo et al)

PALOMA-2 (Finn et al.)

Estrogen
MAINTAIN (Kalinsky, et al.)
Receptor
Positive Breast FAKTION (Jones et al.)
Cancer
I-SPY HR+/Her2- Molecular Subtypes
(Huppert et al.)

Oncotype ER low (Giordano et al.)

SET 2,3 in CALGB-9741 (Metzger et al.)

 LBA1001

Primary Results From TROPiCS-02: A Randomized

Phase 3 Study of Sacituzumab Govitecan Vs
Treatment of Physician’s Choice in Patients With
Hormone Receptor-Positive/HER2-Negative
Advanced Breast Cancer
Hope S. Rugo,1 Aditya Bardia,2 Frederik Marmé,3 Javier Cortes,4 Peter Schmid,5 Delphine Loirat,6 Olivier Trédan,7 Eva Ciruelos,8 Florence Dalenc,9
Patricia Gómez Pardo,10 Komal L. Jhaveri,11 Rosemary Delaney,12 Olivia Fu,12 Lanjia Lin,12 Wendy Verret,12 Sara M. Tolaney13
1Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; 2Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard
Medical School, Boston, MA, USA; 3Medical Faculty Mannheim, Heidelberg University, University Hospital Mannheim, Heidelberg, Germany; 4Medical Oncology Department, International Breast Cancer Center,
Quironsalud Group, Madrid & Barcelona, Spain, Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain; 5Barts Cancer Institute, Queen Mary University of
London, London, United Kingdom; 6Institut Curie, Medical Oncology Department and D3i, Paris, France; 7Medical Oncology Department, Centre Léon Bérard, Lyon, France; 8Medical Oncology, Hospital Universitario
12 de Octubre, Madrid, Spain; 9Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France; 10Hospital Universitari Vall D'Hebron, Barcelona, Spain; 11Memorial Sloan-Kettering Cancer Center, New York, NY, USA;
12Department of Clinical Development, Gilead Sciences Inc, Foster City, CA, USA; 13Department of Global Patient Safety, Gilead Sciences Inc, Foster City, CA, USA; 14Department of Biostatistics, Gilead Sciences Inc,

Foster City, CA, USA; 15Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Speaker: Hope S. Rugo

Hope S. Rugo, MD
TROPiCS-02 Design and Patient Population

‣ Rationale
• TROP-2 expressed in
80% of all BC
‣ 92% power to detect
PFS HR 0.70
‣ Stopped after this first
IA for OS

• 95% had visceral disease at study entry

• Most with liver disease
• 86% had prior metastatic ET
• All had prior CDK4/6 inhibitor
• 60% had < 12 months response to this
TROPiCS-02 Results

‣ Absolute difference in PFS only 1.5 months

‣ No overall survival benefit (13.9 months vs. 12.3 months, HR 0.84, NS)
‣ CBR 34% vs. 22%
‣ Sacituzumab had slightly better QOL but both arms had high toxicity
Overall Survival (OS) With First-Line Palbociclib Plus Letrozole (PAL+LET) Versus Placebo Plus Letrozole (PBO+LET) in Women With Estrogen Receptor–Positive/Human Epidermal
Growth Factor Receptor 2–Negative Advanced Breast Cancer (ER+/HER2− ABC): Analyses From PALOMA-2

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PALOMA-2 Overall Survival Analysis

• OS was a secondary endpoint. Trial not powered for this.

• There is a lot of missing data, as patients were lost to follow up
• Authors removed these patients from analysis set instead of censoring at last follow up
• Also lack of info on the “crossover” – that is, patients who subsequently got another CDK4/6
inhibitor
• Planned analysis: Combine data with PALOMA-1 to increase sample size
 Results – PALOMA-2 OS Analysis
‣ N=666 (2:1 randomization)
Palbo arm Placebo arm
Missing survival data 13% 21%
Deaths 62% 60%
Median OS (ITT) 53.9 months 51.2 months HR 0.96
Median OS 51.8 months 46.8 months HR 0.93
(Combined with P1)
DFI>12 months 64 months 44.6 months HR 0.74 (.55 - .98)

• Unclear why this is different from Ribociclib, which has shown OS benefit in first line.
Sample size issue should have been the same in other trials
Was LOS an issue? Crossover?
• All CDK 4/6 inhibitors have shown OS benefit in second line
• With PALLAS and PENELOPE trials also negative, begs question of which drug is best option
A randomized phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition in patients with
unresectable or metastatic hormone receptor positive, HER2 negative breast cancer:<br />MAINTAIN Trial

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MAINTAIN Trial
‣ Randomized, placebo-
controlled phase II
‣ N=170
• 120 evaluable patients
provided 80% power to
detect a 3-month PFS
difference (1-sided alpha
0.025)
‣ <20% in both arms had prior
chemotherapy
‣ Most had palbo in prior line
‣ 60% had visceral mets
MAINTAIN Trial Results
‣ Met primary endpoint
• But difference was 2.53 months
• Patients on ET alone arm did
particularly poorly regardless of
drug used, as seen in other
studies
‣ No issues with tolerability
‣ Mutation biomarkers
• 42% had an ESR1 mut
• Tracked with CCND1 and FGFR1
amps
• ESR-1 WT did better with
continuation of CDK4/6 inhibitor
• Was that also in part due to the
other CDK-related mutations?
Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION):<br />Overall
survival and updated progression-free survival data with expanded biomarker analysis

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FAKTION: trial design<br />

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FAKTION: Fulvestrant + capivasertib/placebo OS analysis

‣ Primary endpoint (updated from 2020,

about the same):
• Doubled PFS. 10.3 vs. 4.8 months,
• HR 0.58, p=0.004
‣ Overall survival endpoint (now mature)
• Median OS 29.3 months vs. 23.4
months
• HR 0.66, p=0.035
‣ New assessment of biomarkers
representing PI3K/AKT pathway analysis
• Used NGS, pyrosequencing
‣ Benefits are primarily seen in the
pathway altered group
Pathologic Complete Response (pCR) Rates for HR+/HER2- Breast Cancer by Molecular Subtype in the I-SPY2 Trial

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I-SPY2 study design

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 I-SPY pCR rates by molecular subtypes in HR+/Her2- BrCa

‣ 8 investigational arms included in this analysis

• T-AC control, Veliparib/Carbo, Neratinib,
MK2206, AMG386, Ganitumab, Ganetespib,
Pembrolizumab
‣ Analyzed by Mammaprint score (Hi1 or Hi2),
BluePrint (Basal, Luminal), Response
Predictive Subtype (RPS; HR/Her2, immune,
DNA repair, basal/luminal markers)
Case series of patients with ER+ disease
• Tumor expression of ER was 1 – 10%
• Dx’d 8/11 – 8/20
• Sent Oncotype DX

• N=38, All received chemotherapy

• No patients had an RS<21

• 94.7% had RS>25

• At median follow up 40 months, 3 recurrences

• 3-year RFS 97% (96.9 – 97.1)
Measurement of endocrine activity (SET2,3) related to prognosis and prediction of benefit from dose-dense (DD) chemotherapy in estrogen receptor-positive (ER+) cancer: CALGB 9741
(Alliance)

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SET 2,3 in CALGB 9741
Goal: To determine the prognostic and predictive benefit
of the SET 2,3 index in dose-dense vs. conventional dose
chemotherapy

Results:
- High SET 2,3 Prognostic for DFS (HR 0.47 (95% CI
0.35 – 0.64)
- Independent of ROR-PT

- High SET 2, 3 Prognostic for OS (HR 0.38, 95% CI

0.27-0.54)

- Low SET 2,3 Independently predictive of benefit of

dose-dense chemotherapy
- Interaction term significant 0.098