Available Therapeutic Options for the Management of HER2-Positive - - PowerPoint PPT Presentation

Adam M Brufsky, MD, PhD Professor of Medicine Co-Director, Comprehensive Breast Cancer Center UPMC Hillman Cancer Center Associate Division Chief Division of Hematology/Oncology Department of Medicine University of Pittsburgh Pittsburgh, Pennsylvania

Available Therapeutic Options for the Management of HER2-Positive Metastatic Breast Cancer

Case Presentation: Dr Hurvitz

• 62 yo woman diagnosed 9 years ago with stage II ER/PR negative, HER2+

breast cancer, s/p adjuvant AC-TH; diagnosed with metasatatic breast cancer to liver (same biomarkers) 3 years ago, treated with THPàHP with CR in liver. 8 months ago develops headaches, scans show 7 lesions in CNS. No extracranial disease.

• Question: In addition to local (RT/SRS) therapy, what systemic treatment do you

recommend?

• Continue HP
• Continue HP, add neratinib
• Neratinib/capecitabine
• Lapatinib/capecitabine
• Trastuzumab/capecitabine/tucatinib

Case Presentation: Prof Piccart-Gebhart

37 y old premenopausal pt (year 2013)

6 cm mass

• Unremarkable past and familial medical Hx/

2 months after the delivery of a baby boy

• Physical exam: no hypertension, BMI<25, LVEF>65%
• Pathology: ductal invasive carcinoma

grade 2 RO+ RPg+ HER2 3+ FISH+

• PET-CT scan: « de novo » metastatic disease with

liver, lung, bone involvement

Case Presentation: Prof Piccart-Gebhart

Sequential treatments : 2013 → 2018

T-DM1 X 3 cycles P.D. EC X 7 cycles P.R. SURGERY Tamoxifen Trastuzumab

Zoledronic acid

X 3 months P.D. Docetaxel + Trastuzumab + Pertuzumab X 8 months P.D. +

• ne cerebellar

lesion Mastectomy + axill. Dissection + bilateral oophorectomy Stereotactic RT

Lapatinib + Cape (1 month) Lapatinib + Trastuzumab (2 months) Trastuzumab + Cape (3 months) Trastuzumab + Eribulin (x 6 cycles) Trastuzumab Carboplatin Gemcitabine (3 months) Trastuzumab + Pegylated Liposomal Doxorubicin (2 months) P.D.

& new brain lesion 2nd Stereotactic RT

P.D. P.D. P.D. P.D.

• utside

brain

Toxicity +++

RCB 3

P.D. Palliative care

Letrozole + Neratinib

Response for 10 months !

Baseline FDG PET HER2 PET FDG PET post 3 T-DM1 cycles

Adam M Brufsky, MD, PhD Professor of Medicine Co-Director, Comprehensive Breast Cancer Center UPMC Hillman Cancer Center Associate Division Chief Division of Hematology/Oncology Department of Medicine University of Pittsburgh Pittsburgh, Pennsylvania

Available Therapeutic Options for the Management of HER2-Positive Metastatic Breast Cancer

Disclosures

Consulting Agreements Agendia Inc, Amgen Inc, AstraZeneca Pharmaceuticals LP, bioTheranostics Inc, Celgene Corporation, Daiichi Sankyo Inc, Eisai Inc, Genentech, Lilly, Novartis, Pfizer Inc, Puma Biotechnology Inc, Sandoz Inc, a Novartis Division

SystHERs: Characteristics of De Novo vs Recurrent HER2-Positive mBC

Characteristic De Novo (n = 487) Recurrent (n = 490) P-Value Median Age at Diagnosis, years 55 58 <0.001 Hormone Receptor Status <0.001 ER- and/or PR-positive 65.1% 75.1% ER- and/or PR-negative 34.9% 24.9% Selected Metastatic Sites Bone 57.1% 45.9% <0.001 Liver 41.9% 33.1% 0.005 Lung 29.6% 33.9% 0.15 CNS 4.3% 13.5% <0.001

Tripathy D et al. The Oncologist 2019;24:1-9.

SystHERs: First-Line Systemic Treatment

Treatment De Novo (n = 487) Recurrent (n = 490) Pts treated with 1st-line therapy for mBC 97.9% 96.1% Pts treated with 1st-line HER2-targeted therapy for mBC 96.7% 92.2% Trastuzumab use 95.7% 85.9% Pertuzumab use 77.8% 68.6% Pts treated with any 1st-line chemotherapy for mBC 89.7% 80.0% Most common regimen: Pertuzumab/trastuzumab/taxane ± ET 73.3% 59.8%

Tripathy D et al. The Oncologist 2019;24:1-9.

SystHERs: Survival Analyses in De Novo and Recurrent HER2-Positive mBC

Tripathy D et al. The Oncologist 2019;24:1-9.

Progression-Free Survival Overall Survival

Metastatic CNS Disease Remains Incurable, Despite Current Treatment Options

Up to 50% of patients with HER2+ MBC will develop brain metastases Lapatinib plus capecitabine is a treatment option for patients with disease that has metastasized to the brain; however, only a fraction of patients respond to therapy Overall response rate of brain metastases was 21.4%, median PFS/time to progression was 4.1 months, and median OS was 11.2 months There is still significant unmet need for patients with CNS metastases T-DM1, trastuzumab, and pertuzumab do not penetrate the CNS under normal conditions

Petrelli et al. Eur J Cancer. 2017;84:141-148.

Hurvitz et al Clin Cancer Res 2019;25:2433-2441

Hurvitz et al Clin Cancer Res 2019;25:2433-2441

SystHERs: Survival Analyses for CNS Mets in HER2-Positive mBC

PFS OS

*FISH+/IHC 3+.

†Confirmed by independently reviewed MRI scan.

Key eligibility

• HER2+ MBC*
• Prior anthracyclines or taxanes
• Any-line therapy
• No CNS metastases†

Evaluable systemic dx Stratification

• Prior trastuzumab
• Prior MBC tx
• 0 vs ≥ 1

R A N D O M I Z E Planned N = 650

Lapatinib 1250 mg/day + Capecitabine 2000 mg/m2/day, days 1-14 q21d Trastuzumab 6 mg/kg IV q21 days + Capecitabine 2500 mg/m2/day, days 1-14 q21d

Pivot X, et al. ESMO 2012. LBA 11.

Phase III CEREBEL: Study Design

Primary Endpoint: CNS metastasis as the site of first relapse Independent Data Monitoring Committee recommended termination of the study: June 2012

CEREBEL: Endpoints

Study Endpoints L + C (n = 251) T + C (n = 250) P Value CNS as first site of progression 8 (3%) 12 (5%) 0.360 Incidence of CNS progression at any time 17 (7%) 15 (6%) 0.865 Median time to first CNS progression 5.7 mo (2-17) 4.4 mo (2-27) Media PFS (ITT) Trastuzumab Naïve 6.6 mo 6.3 mo 8.0 mo 10.9 mo 0.021 NR Median OS 22.7 mo 37.3 mo 0.095 ORR 27% 32% NR

Pivot X, et al. ESMO 2012. LBA 11.

Change From Baseline (%)

–100 –80 –60 –40 –20 20 40 60 80 100 Response by volumetric criteria Response by volumetric criteria –100 – 80 – 60 – 40 – 20 20 40 60 80 100 120 140 Cohort 3A (n=37) Cohort 3B (n=12)

TBCRC 022 Cohort 3A

Primary endpoint – CNS volumetric response

18 responses by volumetric criteria Best CNS volumetric response (n=31)* CNS ORR=49% (95% CI 32–66%)

Cohort 3A: no prior lapatinib

6 patients did not reach first reimaging and were categorized as ‘0’ [3 for toxicity]. ★Patients who also had a CNS response by RANO-BM criteria.

CNS, central nervous system; ORR, objective response rate. Freedman RA et al. J Clin Oncol. 2019 Mar 12.

Response by volumetric criteria CNS ORR=33% (95% CI 10–65%)

Cohort 3B: prior lapatinib

Phase II NEfERT-T Trial

Randomized study of HER2-directed therapy in 1st-line MBC

STUDY OBJECTIVES: Primary: PFS Secondary: ORR, DoR, CBR, frequency and time to symptomatic/progressive CNS metastases, safety

Awada A et al. JAMA Oncol. 2016 Dec 1;2(12).

PD PD

Previously untreated HER2+ locally recurrent or MBC

• No evidence of primary disease

refractory to trastuzumab or paclitaxel

• No prior therapy for locally recurrent
• r MBC

Neratinib 240 mg/day + Paclitaxel 80 mg/m2 days 1, 8, 15 q28d Trastuzumab 4 mg/kg then 2 mg/kg days 1, 8, 15, 22 q28d + Paclitaxel 80 mg/m2 days 1, 8, 15 q28d

R (1:1)

n=479

NEfERT-T Efficacy

CNS progression is limited with neratinib + paclitaxel

Neratinib treatment effect on both CNS endpoints remained statistically significant after adjusting for the imbalance of baseline CNS metastases (Cox model hazard ratio 0.56, p=0.045; Cochran Mantel-Haenszel p=0.015). Awada A et al. JAMA Oncol. 2016 Dec 1;2(12). N Event Median (95% CI), mo Neratinib + paclitaxel 242 20 Not estimable Trastuzumab + paclitaxel 237 41 Not estimable 4 8 12 16 20 24 28 56 32 36 40 44 48 52 1.0 0.6 0.5 0.8 0.9 0.0 0.7 0.2 0.1 0.4 0.3 242 237 191 196 141 144 102 96 73 70 57 53 45 44 38 35 35 33 22 23 14 14 10 6 3 3 Hazard ratio (95% CI)=0.449 (0.259, 0.780) Log-rank test P-value=0.0036

Free of CNS Progression (%)

Time (months) 32 27

• No. at risk

Neratinib + paclitaxel Trastuzumab + paclitaxel

Phase III NALA study design

Adam Brufsky

Stratification variables

• Number of prior HER2 therapies for MBC
• Disease location
• HR status
• Geographic location

Inclusion criteria

• Metastatic breast cancer (MBC)
• Centrally confirmed HER2+ disease
• ≥2 lines of HER2-directed therapy for MBC
• Asymptomatic and stable brain

metastases permitted Neratinib 240 mg/d + Capecitabine 1500 mg/m2 14/21 d Loperamide (cycle 1)a Lapatinib 1250 mg/d + Capecitabine 2000 mg/m2 14/21 d R (1:1) Follow-up (survival) PD PD Endpoints

• Co-primary: PFS (centrally confirmed) and OS
• Secondary: PFS (local), ORR, DoR, CBR, intervention for

CNS metastases, safety, health outcomes No endocrine therapy permitted

Loperamide 4 mg with first dose of neratinib, followed by 2 mg every 4 h for first 3 d, then loperamide 2 mg every 6–8 h until end of Cycle 1. Thereafter as needed

n=621

Saura C et al. ASCO 2019;Abstract 1002.

307 183 113 69 54 35 20 13 9 7 3 2 2 314 183 82 39 24 9 8 3 2 2 2 2 1 N+C L+C 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33 36

• No. at risk:

Neratinib + Capecitabine Lapatinib + Capecitabine

NALA: Prespecified restricted means analysis – PFS

2.2 months

Mean PFS (months) p-value 8.8 0.0003 6.6

Restriction: 24 months

NALA

Time since randomization (months) PFS probability

Saura C et al. ASCO 2019;Abstract 1002.

CONFIDENTIAL – NOT FOR EXTERNAL DISTRIBUTION INTENDED TO SOLICIT FEEDBACK

OS (co-primary endpoint)

Saura et al. ASCO 2019 presentation. Abstract 1002.

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

Time since randomization (months) OS probability

307 294 275 244 220 182 142 112 82 13 6 2 1 314 303 273 240 208 170 132 107 84 12 8 3 1 N+C L+C

• No. at risk:

64 67 47 47 18 22 15 17 4 4 34 36 28 27

Mean OS (months) Hazard ratio (95% CI) Log-rank p-value 24.0 0.88 (0.72–1.07) 0.2086 22.2

Restriction: 48 months

1.7 months

Neratinib + Capecitabine Lapatinib + Capecitabine

CONFIDENTIAL – NOT FOR EXTERNAL DISTRIBUTION INTENDED TO SOLICIT FEEDBACK

Time to intervention for CNS metastases

Saura et al. ASCO 2019 presentation. Abstract 1002.

100 90 80 70 60 50 40 30 20 10 6 12 18 24 30 36 42 48 54 60

Cumulative incidence (%) Time since randomization (months) Neratinib + Capecitabine Lapatinib + Capecitabine

Overall cumulative incidence (Gray’s test): 22.8% vs 29.2%; p=0.043

Intervention Neratinib + Capecitabine (n=55/307) Lapatinib + Capecitabine (n=75/314) Radiation therapy 11% 15% Surgery/procedure 2% 3% Anticancer medication 1% 1%

Implications for Practice

• Neratinib is likely new SOC for third line HER2

MBC therapy

• Prevents CNS progression as major benefit?
• Await data from tucatinib (SABCS 2019)
• Pyrotinib studies can add to these data