Nuevos tratamientos en cáncer de mama

HER-2, secuencia terapéutica.

Mariana Chávez Mac Gregor MD, MSc.

Professor, Health Services Research Department
Professor, Breast Medical Oncology Departments
The University of Texas MD Anderson Cancer Center
 Disclosures
• Consulting/Advisory Board: Pfizer, Novartis, AstraZeneca,
Lilly, Genentech/Roche, Exact Sciences, Merck, Daiichi
Sankyo
• Participating in Data Safety Monitoring Board: AstraZeneca,
Genentech
Her2-amplified breast cancer
• 20% invasive breast cancers.
• Poor prognosis
• Tumors more likely to be high grade and to have lymph
node involvement.

Hudis, NEJM 2007;357:39-51.

 Drugs approved by the FDA for the treatment of MBC
1990-2009 2000-2019 2020-
Paclitaxel 1994 Lapatinib 2010 Neratinib 2020
Paclitaxel 1994 Eribulin 2011 Sacituzumab 2020
Goserelin 1995 Everolimus 2012 Tucatinib 2020
Anastrozole 1995 Pertuzumab 2012 Pembrolizumab 2020
Docetaxel 1996 TDM1 2013 Margetuximab 2020
Capecitabine 1998 Palbociclib 2015 Elacestrant 2023
Trastuzumab 1998 Ribociclib 2017
Exemestane 1999 Abemaciclib 2017
Fulvestrant 2002 Olaparib 2018
Gemcitabine 2004 Talazoparib 2018
AB-Paclitaxel 2005 Atezolizumab 2019
Ixabepilone 2005 Alpelisib 2019
Bevacizumab 2008 T-Deruxtecan 2019
 HER2 Targeted Drugs

Trastuzumab
Pertuzumab
Margetuximab TDM1
T-Deruxtecan

Lapatinib
Neratinib
Tucatinib
 CLEOPATRA: Phase III Study of Trastuzumab
+ Pertuzumab in HER2+ MBC:
n=406 PD
Placebo + trastuzumab

Patients with Docetaxel*

HER2-positive MBC ≥6 cycles recommended
centrally confirmed
(N = 808) PD
Pertuzumab + trastuzumab

Docetaxel*
≥6 cycles recommended

• Randomization was stratified by geographic region and prior treatment status

• Prior (neo)adjuvant systemic breast cancer chemotherapy including trastuzumab and/or taxanes allowed if
followed by a disease-free interval of ≥12 months
• Study dosing q3w:
− Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance
− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
− Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
* <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion
Overall survival 20 years ago…

HR = 0.80
1.0 p = 0.046

Probability of survival
0.8
25.1 months (20%)
0.6

0.4 20.3 months

0.2 H + CT
CT
0
0 5 15 25 35
Time (months)

H, trastuzumab; CT, chemotherapy

Slamon et al.Slamon
N Englet al. NEJM 2001
J Med 2001
Primary endpoint: Independently assessed PFS

∆ = 6.1 months
100
Ptz + T + D: median 18.5 months

Progression-free survival (%)

90
Pla + T + D: median 12.4 months
80
70
60
50
40
HR = 0.62
30 95% CI 0.51‒0.75
20 p<0.0001
10
0
0 5 10 15 20 25 30 35 40

n at risk
Time (months)
Ptz + T + D 402 345 267 139 83 32 10 0 0
Pla + T + D 406 311 209 93 42 17 7 0 0
Stratified byT,prior
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; treatment status and region
trastuzumab
Baselga, NEJM 2012.
 Final OS Analysis
Median follow-up 50 months (range 0–70 months)
100 Ptz + T + D
90
Pla + T + D
80
70
60
OS (%)

50
40
30 HR 0.68
20 95% CI = 0.56, 0.84 40.8 Δ 15.7 56.5
10 p = 0.0002 months months months
0
0 10 20 30 40 50 60 70
Time (months)
n at risk
Ptz + T + D 402 371 318 268 226 104 28 1
Pla + T + D 406 350 289 230 179 91 23 0

ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.

CI, confidence interval; Pla, placebo; Ptz, pertuzumab. Swain S, et al. ESMO 2014
 EMILIA Study Design (TDM4370g)
HER2-positive LABC or
MBC (N=980) T-DM1
PD
3.6 mg/kg q3w IV
• Prior taxane and
trastuzumab 1:1
• Progression on Capecitabine
metastatic treatment or 1000 mg/m 2 PO bid, days 1–14, q3w
within 6 months of + PD
adjuvant treatment Lapatinib
1250 mg/day PO qd

• Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC,
presence of visceral disease
• Primary endpoints: PFS by independent review, OS, and safety
• Key secondary endpoints: PFS by investigator, ORR, DOR
• Statistical considerations: Hierarchical statistical analysis was performed in pre-specified sequential
order: PFS by independent review → OS → secondary endpoints
− PFS analysis: 90% power to detect HR=0.75; 2-sided alpha 5%
Verma, NEJM, 2012
− OS analyses: 80% power to detect HR=0.80; 2-sided alpha 5%
 Progression-Free Survival
(Independent Review)
1.0 Median No. of
(months) events
Cap + Lap 6.4 304
0.8
Proportion progression-free
T-DM1 9.6 265
Stratified HR=0.650 (95% CI, 0.55, 0.77)
P<0.0001
0.6

0.4

0.2

0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Time (months)
No. at risk by independent review:
Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0
T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Verma, NEJM, 2012

Unstratified HR=0.66 (P<0.0001).
 Overall Survival
Median (months) No. of events
Cap + Lap 25.1 182
T-DM1 30.9 149
1.0 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006
85.2% Efficacy stopping boundary P=0.0037 or HR=0.727
0.8
78.4%
Proportion surviving

64.7%
0.6

51.8%
0.4

0.2

0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
No. at risk: Time (months)
Cap + Lap 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4
T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). Verma, NEJM, 2012
 ASCO Guidelines
Advanced HER2+ BC
With brain mets ER+ or PR + and HER2+
First-line
HER2 targeted therapy
Local therapy (surgery; (trastuzumab, pertuzumab and
whole brain taxane)
radiotherapy, HER2 therapy + chemo
stereotactic Progression Endocrine therapy +
radiosurgery) and trastuzumab or
Second-line lapatinib
systemic therapy HER2 targeted therapy
T-DM1
Progression

Third-line
T-DM1 or pertuzumab if not previously given;
Capecitabine/lapatinib; Lapatinib/trastuzumab;
trastuzumab/chemotherapy

Giordano et al., J Clin Oncol 2014;32(19):2078-99.

Ramakrishna et al., J Clin Oncol 2014;32(19):2100-8.
 Trastuzumab Deruxtecan (DS-8201)

Trastuzumab deruxtecan is an ADC Payload MOA:

• A humanized anti-HER2 IgG1 mAb with the same topoisomerase I inhibitor
amino acid sequence as trastuzumab High potency of payload
• A topoisomerase I inhibitor payload, an exatecan
High drug to antibody ratio ≈ 8
derivative
Payload with short systemic half-
• A tetrapeptide-based cleavable linker life
Stable linker-payload

Tumor-selective cleavable linker

Tetrapeptide-Based Cleavable Linker

Membrane-permeable payload

Topoisomerase I Inhibitor
payload
(DXd)

Deruxtecan
Trastuzumab
 ADC Characteristic Differences Between T-DXd and T-DM1

Trastuzumab T-DXd1-4,a ADC Attributes T-DM13-5

Trastuzumab
deruxtecan emtansine
Topoisomerase I
(T-DXd)1 Payload MoA Anti-microtubule (T-DM1)5
inhibitor

~8:1 Drug-to-antibody ratio ~3.5:1

Tumor-selective cleavable
Yes No
linker?
Evidence of bystander
Yes No
anti-tumor effect?

aThe clinical relevance of these features is under investigation.

1. Nakada T et al. Chem Pharm Bull (Tokyo). 2019;67:173-85. 2. Ogitani Y et al. Clin Cancer Res. 2016;22:5097-108. 3. Trail PA et al. Pharmacol Ther. 2018;181:126-42.
4. Ogitani Y et al. Cancer Sci. 2016;107:1039-46. 5. LoRusso PM et al. Clin Cancer Res. 2011;17:6437-47.
 DESTINY-Breast01 Study Design:
An Open-Label, Multicenter, Phase 2 Study
Population
PART 1 PART 2
• ≥18 years of age
• Unresectable and/or PK Stage Dose-Finding Stage Continuation Stage
(n=65) (n=54) (n=134)
metastatic BC
• HER2-positive
T-DM1 5.4 mg/kg
(centrally confirmed on R
Resistant/Refractory 1:1:1 (n=22)
archival tissue) (n=249)
5.4 mg/kg
(n=28) PART 2a
• Prior T-DM1 6.4 mg/kg R
5.4 mg/kg
(n=22) 1:1
• Excluded patients with 6.4 mg/kg (n=130)
(n=26)
history of significant 7.4 mg/kg
(n=21)
ILD
T-DM1 PART 2b
• Stable, treated brain
Intolerant 5.4 mg/kg
metastases were (n=4) (n=4)
allowed
184 patients
enrolled at 5.4 mg/kg

Data Cutoff: August 1, 2019

Endpoints • 79 patients (42.9%) are ongoing
• 105 patients (57.1%) discontinued, primarily for progressive disease
• Primary: confirmed ORR by independent central (28.8%)
imaging facility review per RECIST v1.1
• Secondary: investigator-assessed ORR, DCR, DOR, CBR,
PFS, OS, PK and safety
Modi S, NEJM 2019
 Best Change in Tumor Size

Confirmed ORR: 60.9% (11 CRs)

Stable Disease: 36.4%
Modi S, NEJM 2019
 Progression-Free Survival

Median: 16.4 months

(95% CI, 12.7-NE)

• Median follow-up, 11.1 months (range, 0.7-19.9 months)

• Median PFS in the 24 patients with brain metastases was 18.1 months (95% CI, 6.7-18.1
months) Modi S, NEJM 2019
 Progress Has Been Made in HER2+ mBC
Trastuzumab + pertuzumab + taxane, • mBC 1L standard of care was established in the CLEOPATRA trial 1,2
Standard of Carea

1L
CLEOPATRA: mPFS = 18.7 months1

• EMILIA trial established T-DM1 as 2L+ standard of care

• In the changing treatment landscape, more recent clinical trials and
T-DM1, EMILIA:
2L+ real-world studies have demonstrated mPFS outcomes with T-DM1
mPFS = 9.6 mo3
in the range of 6-7 months2,4-7
• mPFS for T-DM1 in the randomized KATE2 was 6.8 months (2020)4

T-DXd • T-DXd demonstrated robust activity in a 3L+ phase 2 single arm

3L+
DESTINY-Breast01: mPFS = 16.4 months8 study, leading to regulatory approvals globally2,8

Given these data, T-DXd was evaluated in a head-to-head trial

versus T-DM1 in previously treated HER2+ mBC

aNot intended for cross-trial comparison.

1 . Swain SM et al. N Engl J Med. 2015;372:724-34. 2. Perez J et al. Expert Opin Biol Ther. 2021;21:811-24. 3. Verma
S et al. N Engl J Med. 2012;367:1783-91. 4. Emens LA et al. Lancet Oncol. 2020;21:1283-95.
5. Daniels et al. Breast. 2021;58:106-12. 6. Lupichuk S et al. Breast Cancer (Auckl). 2019;13:1178223419879429. 7. Vici P et al. Oncotarget. 2017;8:56921-56931. 8. Modi S et al. Presented at San Antonio Breast
Cancer Symposium 2020; December 8-11, 2020; San Antonio, TX, USA. Poster PD3-06.
 San Antonio Breast Cancer Symposium – December 6-10, 2022

DESTINY-B02: Randomized, Phase 3, open label, multicenter study

Krop I, et al SABCS 2022

This presentation is the intellectual property of the presenter. Contact mchavez1@mdanderson.org for permission to reprint a nd/or distribute.
DESTINY-B02: Primary Endpoint PFS by BICR

Krop I, et al SABCS 2022

DESTINY-B02: OS

Krop I, et al SABCS 2022

 DESTINY-B03: Updated Analysis
Randomized, open-label, multicenter study (NCT03529110)
Primary endpoint
• PFS (BICR)
Key secondary
T-DXd endpoint
5.4 mg/kg Q3W • OSc
Patients (N = 524) (n = 261)
Secondary
• Unresectable or metastatic HER2-positivea
breast cancer endpoints
R
• Previously treated with trastuzumab and a 1:1 • ORR (BICR and
taxane in metastatic or (neo)adjuvant setting investigator)
with recurrence within 6 months of therapyb T-DM1 • DoR (BICR)
3.6 mg/kg Q3W
• Safety
(n = 263)
Stratification factors
• Hormone receptor status The prespecified OS interim analysis was planned with 153 events.d
• Prior treatment with pertuzumab At the time of data cutoff (July 25, 2022), 169 OS events were observed and the
P value to achieve statistical significance was 0.013
• History of visceral disease
BICR, blinded independent central review; DoR, duration of response; HER2, human epidermal growth factor receptor 2; IHC, imm unohistochemistry; ISH, in situ hybridization; ORR, objective response rate; OS, overall survival; PFS, progression-free
survival; Q3W, every 3 weeks; R, randomization; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.
a
HER2 IHC 3+ or IHC 2+/ISH+ based on central confirmation. bProgression during or within 6 months after completing adjuvant therapy involving trastuzumab and a taxane. c80% powered at 2-sided significance level of 5%. dInformation fraction of 61%, with
a P value boundary to reach statistical significance of 0.008. The P value was recalculated based on the actual OS events at the data cutoff.

Hurvitz S, et al SABCS 2022

 Baseline Characteristics and Prior Therapies
T-DXd T-DM1
Characteristic (n = 261) (n = 263)
HER2 status (IHCa), n (%)
3+ 234 (89.7) 232 (88.2)
2+ (ISH positive) 25 (9.6) 30 (11.4)
1+ | Not evaluable 1 (0.4) | 1 (0.4) 0 | 1 (0.4)
ECOG PSb, n (%)
0 | 1 154 (59.0) | 106 (40.6) 175 (66.5) | 87 (33.1)

Hormone receptor status, n (%)

Positive | Negative 131 (50.2) | 130 (49.8) 134 (51.0) | 129 (49.0)

History of brain metastases, n (%)

Yes | No 62 (23.8) | 199 (76.2) 52 (19.8) | 211 (80.2)

Brain metastases at baselinec, n (%)2

Yes | No 43 (16.5) | 218 (83.5) 39 (14.8) | 224 (85.2)

Visceral disease, n (%)

Yes | No 184 (70.5) | 77 (29.5) 185 (70.3) | 78 (29.7)

aHER2 status was evaluated by immunohistochemical analysis at a central laboratory. HER2 ISH positive refers to positive resul ts on in situ hybridization. HER2 status was not able to be evaluated for 1 patient in each treatment group. bECOG status
was missing for 1 patient in each treatment group. c Patients with BM at baseline is the patient population analysis presented in the Hurvitz et al presentation at SABCS 2021.
1. Cortés J et al. N Engl J Med. 2022;386:1143-1154. 2. Hurvitz SA et al. Presented at: San Antonio Breast Cancer Symposium 2021; December 7-10, 2021; San Antonio, TX, USA. Presentation GS3-01.
 Baseline Characteristics and Prior Therapies
T-DXd T-DM1
Characteristic (n = 261) (n = 263)
Previous treatment for mBC, n (%)
No 21 (8.0) 29 (11.0)
Yes 240 (92.0) 234 (89.0)
Lines of previous therapy in the context of metastatic disease (includes
patients with rapid progression as one line of treatment)a, n (%)
Median (range) 1 (0-16) 2 (0-14)
0 2 (0.8) 3 (1.1)
1 130 (49.8) 123 (46.8)
2 56 (21.5) 65 (24.7)
3 35 (13.4) 35 (13.3)
4 15 (5.7) 19 (7.2)
≥5 23 (8.8) 18 (6.8)
Previous cancer therapyb, n (%)
Trastuzumab 260 (99.6) 262 (99.6)
Pertuzumab 162 (62.1) 158 (60.1)
Taxane 260 (99.6) 262 (99.6)
Other anti-HER2 antibody 42 (16.1) 38 (14.4)
Anti-HER2 TKI 42 (16.1) 36 (13.7)
Other anti-HER2 antibody or ADC 2 (0.8) 3 (1.1)
Hormone therapy 109 (41.8) 112 (42.6)
Other systemic therapy 260 (99.6) 262 (99.6)
a
Patients who had had rapid progression (i.e., progression that had occurred within 6 months after receipt of neoadjuvant or adjuvant therapy or within 12 months after receipt of a neoadjuvant or adjuvant pertuzumab -containing regimen) were
considered to have had one line of previous therapy. Lines of previous therapy did not include endocrine therapy. bAll patients received at least 1 previous cancer therapy. One patient who had previously received T-DM1 treatment was enrolled in
error in the T-DXd arm.
1. Cortés J et al. N Engl J Med. 2022;386:1143-1154. 2. Hurvitz SA et al. Presented at: San Antonio Breast Cancer Symposium 2021; December 7 -10, 2021; San Antonio, TX, USA. Presentation GS3-01.
 San Antonio Breast Cancer Symposium – December 6-10, 2022

DESTINY-B03: Updated Primary Endpoint –PFS by BICR

mPFS was ~4X longer for T-DXd compared with T-DM1 T-DXd T-DM1
Progression-Free Survival Probability, %

100
Median 28.8 6.8
T-DXd: 75.2% (95% CI, 69.3-80.2) (95% CI), (22.4-37.9) (5.6-8.2)
80 T-DM1: 33.9% (95% CI, 27.7-40.2) months
HR 0.33 (95% CI, 0.26-0.43)
T-DXd: 53.7% (95% CI, 46.8-60.1)
T-DM1: 26.4% (95% CI, 20.5-32.6) P < 0.000001a,b
60

40

20
Censor
T-DXd (n = 261)
T-DM1 (n = 263)
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
Time, months
T-DXd 261 256 250 244 240 225 216 207 205 191 176 173 167 154 146 140 134 131 130 125 123 117 113 107 99 96 90 82 73 64 55 41 32 28 23 20 18 13 7 5 4 2 1 0

T-DM1 263 253 201 164 156 134 111 99 96 81 69 67 63 58 54 51 49 49 47 47 42 41 39 37 36 32 28 27 22 19 15 14 8 7 6 4 2 2 2 1 1 1 1 1 1 0

Hurvitz S, et al SABCS 2022

This presentation is the intellectual property of the presenter. Contact mchavez1@mdanderson.org for permission to reprint a nd/or distribute.
 DESTINY-B03: OS
T-DXd T-DM1
T-DXd: 94.1% (95% CI, 90.4-96.4) Median NR NR
T-DM1: 86.0% (95% CI, 81.1-89.8)
100 (95% CI), (40.5-NE) (34.0-NE)
T-DXd: 77.4% (95% CI, 71.7-82.1) months
Overall Survival Probability ,%

T-DM1: 69.9% (95% CI, 63.7-75.2)

HR 0.64 (95% CI, 0.47-0.87)
80
P 0.0037a,b

60

40

Anti-cancer therapies in post trial setting:

• T-DXd arm: 64/182 (35.2%) received T-
20
DM1
Censor • T-DM1 arm: 42/243 (17.3%) received T-DXd
T-DXd (n = 261)
T-DM1 (n = 263)
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

Time, months
T-DXd 218 213 211 206 201 200 196 193 187 182 173 156 142 124 109 91 73 64 51 44 38 30 22 18 11 9 7 6 1 1 1 0

T-DM1 191 186 183 179 172 169 167 164 164 158 140 129 117 106 90 70 59 45 41 38 27 20 15 8 7 4 3 3 1 1 0
HR, hazard ratio; mOS, median overall survival; NE, not estimable; NR, not reached; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.
There were 19 patients (7.3%) treated with T-DXd and 28 patients (10.6%) treated with T-DM1 who were lost to follow-up.
aThe P value for overall survival crossed the prespecified boundary (P = 0.013) and was statistically significant. bTwo-sided from stratified log-rank test.
Hurvitz S, et al SABCS 2022
 PFS KM Curves for Patients With and Without BM
Brain Metastases at Baseline No Brain Metastases at Baseline
T-DXd T-DM1 T-DXd T-DM1
mPFS (95% CI), 15.0 3.0 mPFS (95% CI), NE 7.1
mo (12.5-22.2) (2.8-5.8) mo (22.2-NE) (5.6-9.7)
12-mo PFS rate 72.0 20.9 12-mo PFS rate 76.5 36.4
(95% CI), % (55.0-83.5) (8.7-36.6) (95% CI), % (70.0-81.8) (29.4-43.4)
HR (95% CI) 0.25 (0.13-0.45) HR (95% CI) 0.30 (0.22-0.40)

Time, Time,
months months

At data cutoff, in patients with BMs at baseline, PD was observed: At data cutoff, in patients without BMs at baseline, PD was observed:
• In 21/43 treated with T-DXd versus 27/39 with T-DM1 • In 63/218 treated with T-DXd versus 128/224 with T-DM1
• In the brain in 9/21 treated with T-DXd versus 11/27 with T-DM1 • In the brain in 4/63 treated with T-DXd versus 1/128 with T-DM1

Hurvitz SA et al. Presented at: San Antonio Breast Cancer Symposium 2021; December 7 -10, 2021; San
Antonio, TX, USA. Presentation GS3-01.
28
Adverse Events of Special Interest

n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade

Adjudicated as drug-related ILD/pneumonitis, n (%)
T-DXd (n = 257) 7 (2.7) 18 (7.0) 2 (0.8) 0 0 27 (10.5)
T-DM1 (n = 261) 4 (1.5) 1 (0.4) 0 0 0 5 (1.9)
LVEF, n (%)

T-DXd (n = 257) 1 (0.4)a 6 (2.3)b 0 0 0 7 (2.7)

T-DM1 (n = 261) 0 1 (0.4)b 0 0 0 1 (0.4)

• There were no grade 4 or 5 adjudicated drug-related ILD/pneumonitis events observed and 93% of events
with T-DXd were low grade (grade 1/2)

aLeft
ventricular dysfunction. bDecreased ejection fraction.
LVEF, left-ventricular ejection fraction.
CNS activity?
 HER2CLIMB Trial Design
Tucatinib + Trastuzumab + Capecitabine
Key Eligibility Criteria (21-day cycle)
• HER2+ metastatic breast cancer N=410
• Prior treatment with trastuzumab, Tucatinib 300 mg PO BID
pertuzumab, and T-DM1 +
Trastuzumab 6 mg/kg Q3W (loading dose 8 mg/kg C1D1)
• ECOG performance status 0 or 1
+
• Brain MRI at baseline Capecitabine 1000 mg/m2 PO BID (Days 1-14)
R*
• Previously treated stable brain (2:1)
metastases
Placebo + Trastuzumab + Capecitabine
• Untreated brain metastases not needing (21-day cycle)
immediate local therapy
• Previously treated progressing brain Placebo
metastases not needing immediate local +
therapy N=202 Trastuzumab 6 mg/kg Q3W (loading dose 8 mg/kg C1D1)
• No evidence of brain metastases +
Capecitabine 1000 mg/m2 PO BID (Days 1-14)
*Stratification factors: presence of brain metastases https://clinicaltrials.gov/ct2/show/NCT02614794
(yes/no), ECOG status (0 or 1), and region (US or Canada
or rest of world)

Murthy R, NEJM 2019

Progression-Free Survival in the Primary Endpoint
Population

Murthy R, NEJM 2019

PFS among patients with brain metastases

Murthy R, NEJM 2019

Overall Survival in the Primary Endpoint
Population

Murthy R, NEJM 2019

HER2+
BEYOND…
NALA Study Design

Saura C, J Clin Oncol 2020

NALA: PFS

1y-PFS: 29% vs. 15%

ORR: 33% vs 27% (p=.120)
Median DOR: 8.5 mo vs. 5.6 mo (HR: 0.50, p=0.004)

Saura C, J Clin Oncol 2020

 Study CP-MGAH22-04 (SOPHIA) Design

MBC HER2+
A rm 1
•≥2 prior anti-HER2
therapies, including Investigator’s
M ar getuximab (15 mg/kg Q 3W)
+ chemother apy
pertuzumab choice of
chemotherapy 1:1 in 3-w eek cy cles
•1-3 prior treatment lines (capecitabine, Randomization
in metastatic setting eribulin, (N=536)
A rm 2
gemcitabine, or
•Prior brain metastasis vinorelbine) T r astuzumab
OK if treated and stable (8 mg/kg loading → 6 mg/kg Q 3W)
+ chemother apy
in 3-w eek cy cles

Sequential • PFS (by CBA; n=257; HR=0.67; α=0.05;

Primary power=90%) Stratification:
Endpoints • Chemotherapy choice
• OS (n=385; HR=0.75; α=0.05; power=80%)
• Prior therapies (≤2 vs >2)
Secondary • PFS (Investigator assessed) • Metastatic sites (≤2 vs >2)
Endpoints • Objective response rate (ORR) by CBA
Tertiary/Explor • ORR (Investigator assessed)
atory Endpoints • Clinical benefit rate (CBR), duration of
response (DoR)
• Safety profile, antidrug antibody
• Effect of CD16A, CD32A, and CD32B on
margetuximab efficacy

Rugo, JAMA Oncol 2021

Primary PFS by Central Review

24% Risk Reduction of Disease Progression

Margetuximab Trastuzumab
+ Chemotherapy + Chemotherapy
(n=266) (n=270)

# of events 130 135

Median PFS 5.8 months 4.9 months

(95% CI) (5.52–6.97) (4.17–5.59)

HR by stratified Cox model, 0.76

(95% CI, 0.59–0.98)
Stratified log-rank P =0.033

Rugo, JAMA Oncol 2021

 San Antonio Breast Cancer Symposium – December 5-9, 2023

HER2CLIMB-02 Study Design

• HER2+ LA/MBC Outcomes
with progression T-DM1 + Tucatinib
after trastuzumab Primary
T-DM1 3.6 mg/kg IV and
and taxane in any • PFS by investigator
tucatinib 300 mg PO BID
settinga assessment per RECIST v1.1
N≈460
• ECOG PS ≤1 R
Key Secondary (hierarchical)
• Previously treated Stratification factors:
1:1
• OS
stable, progressing, • Line of treatment for
• PFS in patients with brain
metastatic disease
or untreated brain (1L vs other)
T-DM1 + Placebo metastases
metastases not • Hormone receptor status • cORR per RECIST v1.1
(positive vs negative) T-DM1 3.6 mg/kg IV and
requiring immediate • Presence or history of brain Placebo PO BID • OS in patients with brain
local therapy metastases (yes vs no) metastases
• ECOG PS (0 vs 1)

The primary analysis for PFS was planned after ≈331 PFS events to provide 90% power for hazard ratio of 0.7 at two -sided alpha level of 0.05.
The first of two interim analysis for OS was planned at the time of the primary PFS analysis, if the PFS result was significa ntly positive.b
NCT03975647. https://www.clinicaltrial s.gov /study/NCT 03975647. Accessed Oct 5, 2023.
a Patients who received prior tucatinib, afatinib, T-DXd, or any investigational anti-HER2, anti-EGFR, or HER2 TKIs were not eligible. Patients who received lapatinib and neratinib were not eligible if the drugs were received within 12 months of starting study
treatment, and patients who received pyrotinib for recurrent or metastatic breast cancer were not eligible. These patients were eligible if the drugs were given for ≤21 days and were discontinued for reasons other than disease progression or severe toxicity.
b Subsequent OS analyses are planned upon 80% and 100% of required events for the final OS analysis.
1L, first-line; BID, twice daily; cORR, confirmed objective response rate; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenously; LA/MBC, locally advanced or metastatic breast cancer; OS, overall survival; PFS, progression-free
survival; PO, orally; R, randomization; RECIST, Response Evaluation Criteria in Solid Tumors; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TKIs, tyrosine kinase inhibitors.
Date of data cutoff: Jun 29, 2023. Patients were enrolled from Oct 8, 2019, to Jun 16, 2022.

Hurvitz S, et al. SABCS 2023

This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@fredhutch.org for permission to reprint and/or distribute
This presentation is the intellectual property of the presenter. Contact mchavez1@mdanderson.org for permission to reprint a nd/or distribute.
 San Antonio Breast Cancer Symposium – December 5-9, 2023

Progression-Free Survival
T-DM1 + Tucatinib T-DM1 + Placebo PFS in Patients with Brain Metastases
(N=228) (N=235)
# of events 151 182 T-DM1 + Tucatinib T-DM1 + Placebo
Median PFS (N=99) (N=105)
9.5 months (7.4, 10.9) 7.4 months (5.6, 8.1) # of events 70 85
(95% CI)
HR (95% CI): 0.76 (0.61, 0.95) Median PFS
7.8 months (6.7, 10.0) 5.7 months (4.6, 7.5)
P=0.0163 (95% CI)
Confirmed Objective HR (95% CI) a: 0.64 (0.46, 0.89)
Response 42% vs 36.1%

HR, hazard ratio; PFS, progression-free survival; T-DM1, trastuzumab emtansine.

Date of data cutoff: Jun 29, 2023.

Hurvitz S, et al. SABCS 2023

This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@fredhutch.org for permission to reprint and/or distribute
This presentation is the intellectual property of the presenter. Contact mchavez1@mdanderson.org for permission to reprint a nd/or distribute.
 How to incorporate into practice?
• Pertuzumab+ Trastuzumab+Docetaxel- 1st line
• T-DXd- 2nd line for most patients
• 3rd line: TDM1, tucatinib-based combination?

• HER2CLIMB-02: Wait for OS results

• Can be an option for patients with brain metastases
– HER2CLIMB (Tucatinib-Capecitabine-Trastuzumab) vs HER2CLIMB2
(Tucatinib+TDM1)?
– HER2CLIMB required treatment with pertuzumab and TDM1
– What is better to use a combination (Tucatinib + TDM1) or use agents in
sequence?
• Other interesting promising approaches
 AVIATOR Trial (TBCRC 045) – Original Schema
N=100
Vinorelbine + trastuzumab (NH)
• Advanced HER2+ cancer N=20

• Prior trastuzumab,
pertuzumab, and T-DM1 1:2:2 Vinorelbine + trastuzumab + avelumab (NHA)
N=40
• No prior immunotherapy
or vinorelbine
Vinorelbine + trastuzumab + avelumab +
• PD-L1 unselected utomilumab (NHAU)
N=40

CO-PRIMARY OBJECTIVES:
(1) To determine whether vinorelbine/trastuzumab + (2) To determine whether vinorelbine/trastuzumab/avelumab +
avelumab shows improved PFS compared to utomilumab shows improved PFS compared to
vinorelbine/trastuzumab alone (NHA vs NH) vinorelbine/trastuzumab/avelumab alone (NHAU vs NHA)

Waks A, et al. SABCS 2023

NHA vs NH: Progression-free Survival (Co-primary Endpoint)

HR for PFS: 0.53 (90% CI 0.31-0.91), p=0.025

NH (N=18) NHA (N=45)

11.1% 20.0%
ORR
(90% CI 2-31%) (90% CI 11-32%)
15.8 months
mDOR not evaluable
(90% CI 3.6-25.2 mos)

2.0 mos 3.8 mos

p-value is calculated from one-sided stratified log rank test

Waks A, et al. SABCS 2023
 Implications in Practice:
New Algorithm?
First-line
Trastuzumab, pertuzumab and
taxane
Progression

Second-line
T-DXd

Tucatinib
TDM1 Margetuximab
Trastuzumab Neratinib +Lapatinib
+ chemo
Capecitabine

Liposomal Doxorubicin, Chemotherapy + Trastuzumab, Lapatinib + Capecitabine, Lapatinib + Trastuzumab

Approach to therapy for MBC
 Conclusions
• Anti-Her2 therapy is key
– Trastuzumab continues to be the cornerstone
– New drugs
• Improvement of outcomes
– More options and better outcomes for our patients
• Algorithims will continue to change
– How to sequence?
• Magnitud of benefit, OS
• Side effects
• Biomarker studies
– Who really needs it?
– Who benefits from it?
Gracias