[Skip to Content]
[Skip to Content Landing]
Figure.
Kaplan-Meier Estimates of Progression-Free and Overall Survival
Kaplan-Meier Estimates of Progression-Free and Overall Survival

T-DM1 indicates trastuzumab emtansine. Shaded areas (A and C) indicate 95% CIs.

Table 1.  
Treatment Schema
Treatment Schema
Table 2.  
Baseline Characteristics for 45 Patients
Baseline Characteristics for 45 Patients
Table 3.  
Efficacy at 3 Months for 44 Patientsa
Efficacy at 3 Months for 44 Patientsa
Table 4.  
Adverse Eventsa
Adverse Eventsa
1.
Slamon  DJ, Clark  GM, Wong  SG, Levin  WJ, Ullrich  A, McGuire  WL.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.  Science. 1987;235(4785):177-182. doi:10.1126/science.3798106PubMedGoogle ScholarCrossref
2.
Agus  DB, Akita  RW, Fox  WD,  et al.  Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth.  Cancer Cell. 2002;2(2):127-137. doi:10.1016/S1535-6108(02)00097-1PubMedGoogle ScholarCrossref
3.
Cho  HS, Mason  K, Ramyar  KX,  et al.  Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.  Nature. 2003;421(6924):756-760. doi:10.1038/nature01392PubMedGoogle ScholarCrossref
4.
Franklin  MC, Carey  KD, Vajdos  FF, Leahy  DJ, de Vos  AM, Sliwkowski  MX.  Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.  Cancer Cell. 2004;5(4):317-328. doi:10.1016/S1535-6108(04)00083-2PubMedGoogle ScholarCrossref
5.
Baselga  J, Cortés  J, Kim  SB,  et al; CLEOPATRA Study Group.  Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.  N Engl J Med. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216PubMedGoogle ScholarCrossref
6.
Dang  C, Iyengar  N, Datko  F,  et al.  Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.  J Clin Oncol. 2015;33(5):442-447. doi:10.1200/JCO.2014.57.1745PubMedGoogle ScholarCrossref
7.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer, version 2. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed October 24, 2019.
8.
Urruticoechea  A, Rizwanullah  M, Im  SA,  et al.  Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy.  J Clin Oncol. 2017;35(26):3030-3038. doi:10.1200/JCO.2016.70.6267PubMedGoogle ScholarCrossref
9.
Cortés  J, Fumoleau  P, Bianchi  GV,  et al.  Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer.  J Clin Oncol. 2012;30(14):1594-1600. doi:10.1200/JCO.2011.37.4207PubMedGoogle ScholarCrossref
10.
Krop  IE, Kim  SB, González-Martín  A,  et al; TH3RESA Study Collaborators.  Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.  Lancet Oncol. 2014;15(7):689-699. doi:10.1016/S1470-2045(14)70178-0PubMedGoogle ScholarCrossref
11.
Blackwell  KL, Burstein  HJ, Storniolo  AM,  et al.  Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.  J Clin Oncol. 2010;28(7):1124-1130. doi:10.1200/JCO.2008.21.4437PubMedGoogle ScholarCrossref
12.
Eisenhauer  EA, Therasse  P, Bogaerts  J,  et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026PubMedGoogle ScholarCrossref
13.
Wahl  RL, Jacene  H, Kasamon  Y, Lodge  MA.  From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors.  J Nucl Med. 2009;50(suppl 1):122S-150S.PubMedGoogle ScholarCrossref
14.
Simon  R.  Optimal two-stage designs for phase II clinical trials.  Control Clin Trials. 1989;10(1):1-10. doi:10.1016/0197-2456(89)90015-9PubMedGoogle ScholarCrossref
15.
Yu  AF, Manrique  C, Pun  S,  et al.  Cardiac safety of paclitaxel plus trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer.  Oncologist. 2016;21(4):418-424. doi:10.1634/theoncologist.2015-0321PubMedGoogle ScholarCrossref
16.
Verma  S, Miles  D, Gianni  L,  et al; EMILIA Study Group.  Trastuzumab emtansine for HER2-positive advanced breast cancer.  N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124PubMedGoogle ScholarCrossref
17.
Giordano  SH, Temin  S, Chandarlapaty  S,  et al.  Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update.  J Clin Oncol. 2018;36(26):2736-2740. doi:10.1200/JCO.2018.79.2697PubMedGoogle ScholarCrossref
18.
Diéras  V, Miles  D, Verma  S,  et al.  Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.  Lancet Oncol. 2017;18(6):732-742. doi:10.1016/S1470-2045(17)30312-1PubMedGoogle ScholarCrossref
19.
Perez  EA, Barrios  C, Eiermann  W,  et al.  Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE Study.  J Clin Oncol. 2017;35(2):141-148.PubMedGoogle ScholarCrossref
20.
Argolo  DF, Singh  J, Smyth  L,  et al. Trastuzumab and pertuzumab-based versus other therapy as second-line therapy in HER2-positive metastatic breast cancer: a retrospective study from singe center. Paper presented at: American Society of Clinical Oncology Annual Meeting; June 5, 2015; Chicago, IL.
21.
Swain  SM, Baselga  J, Kim  SB,  et al; CLEOPATRA Study Group.  Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.  N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513PubMedGoogle ScholarCrossref
22.
ClinicalTrials.gov. A study to evaluate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with human epidermal growth factor-2 (HER2) positive locally advanced or metastatic breast cancer (BC) who received prior trastuzumab and taxane based therapy (KATE2). https://clinicaltrials.gov/ct2/show/NCT02924883. Accessed October 21, 2019.
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    Oncology
    November 27, 2019

    Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial

    Author Affiliations
    • 1Memorial Sloan Kettering Cancer Center, New York, New York
    • 2Weill Cornell Medicine, New York, New York
    JAMA Netw Open. 2019;2(11):e1916211. doi:10.1001/jamanetworkopen.2019.16211
    Key Points español 中文 (chinese)

    Question  Is dual anti–human epidermal growth factor receptor 2 (ERBB2, formerly HER2) therapy with trastuzumab and pertuzumab effective after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer?

    Findings  In this phase 2 clinical trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month progression free survival rate of 73.3%. Treatment was well tolerated with no occurrences of symptomatic left ventricular systolic dysfunction.

    Meaning  In this study, dual anti-ERBB2 therapy with trastuzumab and pertuzumab after prior pertuzumab exposure was active and well tolerated.

    Abstract

    Importance  Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)–positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown.

    Objective  To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer.

    Design, Setting, and Participants  This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019.

    Intervention  Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks.

    Main Outcomes and Measures  The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival.

    Results  A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction.

    Conclusions and Relevance  In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit.

    Trial Registration  ClinicalTrials.gov identifier: NCT02252887

    Introduction

    Human epidermal growth factor receptor 2 (ERBB2, formerly HER2) is a proto-oncogene that encodes the 185-kDa ERBB2 protein, a transmembrane tyrosine kinase receptor that is a member of the human epidermal growth factor receptor family. Human epidermal growth factor receptor 2, which is involved in the regulation of cell growth and survival, is amplified in 15% to 20% of invasive breast carcinomas and confers shortened progression-free survival (PFS) and overall survival (OS) compared with other breast tumors.1 Activation of ERBB signaling is dependent on homodimerization or heterodimerization, with the ERBB2-ERBB3 dimer as the most potent inducer of cell proliferation.2 Clinical outcomes for patients with ERBB2-positive breast cancer have significantly improved with the development of ERBB2-targeted therapies. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain IV of ERBB2 and thereby limits its activation.3 Pertuzumab, also a monoclonal antibody, disrupts ERBB2 dimerization via binding of the extracellular domain II of ERBB2, thereby inhibiting ligand-activated signaling with other growth factor receptors.4 Together, trastuzumab and pertuzumab synergistically inhibit tumor growth through their complementary mechanisms of action.4

    In the frontline setting, standard treatment of patients with ERBB2-positive metastatic breast cancer includes the combination of taxane chemotherapy with trastuzumab and pertuzumab.5,6 This approach was established by pivotal data from the randomized phase 3 Clinical Evaluation of Trastuzumab and Pertuzumab (CLEOPATRA) trial,5 which demonstrated improvements in both PFS and OS in patients treated with docetaxel, trastuzumab, and pertuzumab on a 3-week schedule. Our group reported similar findings in a phase 2 study6 evaluating the combination of weekly paclitaxel with trastuzumab and pertuzumab. The use of either docetaxel or weekly paclitaxel with trastuzumab and pertuzumab for first-line treatment of patients with ERBB2-positive metastatic breast cancer is endorsed by the National Comprehensive Cancer Network guidelines.7

    In the second-line setting, the randomized phase 3 PHEREXA trial8 evaluated the combination of capecitabine with trastuzumab and pertuzumab vs capecitabine with trastuzumab alone. While the addition of pertuzumab in the second-line setting was not associated with a significant gain in PFS, an 8-month increase in OS was reported, although the trial was underpowered to evaluate this end point. Other trials have demonstrated median PFS of approximately 3 to 4 months for patients treated with trastuzumab and chemotherapy-based regimens after 2 or more prior lines of therapy.9-11 Based on these historical data, we aimed to determine the 3-month and median PFS rates of dual anti-ERBB2 therapy, including pertuzumab and trastuzumab, given with chemotherapy among patients previously exposed to pertuzumab. Accordingly, we conducted a phase 2 trial of gemcitabine with pertuzumab and trastuzumab in patients with ERBB2-positive metastatic breast cancer in the second-line setting and beyond.

    Methods
    Study Population and Design

    This was a single-center, phase 2 trial in which all patients were enrolled from the Memorial Sloan Kettering Cancer Center. Eligible patients had ERBB2-positive metastatic breast cancer and prior treatment with pertuzumab-based therapy. We defined ERBB2 positivity as 3+ by immunohistochemistry stain or amplified by fluorescent in situ hybridization with an ERBB2 to CEP17 ratio of 2.0 or greater. Additional eligibility criteria included being 18 years or older, having an Eastern Cooperative Oncology Group performance status of 0 to 1, having measurable or nonmeasurable disease, having had up to 3 prior chemotherapy regimens in the metastatic setting, having adequate organ function, and having baseline left ventricular ejection fraction (LVEF) of 50% or greater, measured by echocardiogram, within 4 weeks before enrollment. Patients may have had pertuzumab-based therapy in the neoadjuvant or adjuvant setting. Patients with treated brain metastasis who were stable for 2 or more months before enrollment were included. Patients were excluded if they had a history of cardiac morbidities (eg, unstable angina, myocardial infarction, congestive heart failure, or uncontrolled ventricular arrhythmias) within 12 months of enrollment or any grade 3 or higher toxic response to prior trastuzumab or pertuzumab. This trial was approved by the institutional review board of the Memorial Sloan Kettering Cancer Center, and all participants provided written informed consent prior to enrollment. Reporting of this trial is in accordance with Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The clinical trial protocol is available as Supplement 1.

    Treatment

    Patients received gemcitabine at 1200 mg/m2 on days 1 and 8 of a 21-day cycle and trastuzumab (8-mg/kg loading dose, then 6 mg/kg) plus pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks, all given intravenously (Table 1). Each cycle spanned 3 weeks and included gemcitabine with trastuzumab and pertuzumab given on day 1 and gemcitabine alone on day 8. After 3 months of therapy, if patients were deemed to be progression free, gemcitabine could be held at the discretion of the treating physician, and patients were maintained with antibodies alone. Treatment was continued until progression of disease or unacceptable toxic effects.

    Treatment Modifications

    For grade 3 or greater toxic effects, gemcitabine was held until the adverse event (AE) improved to grade 2 or less. Up to 3 consecutive weeks of treatment delay was allowed for recovery. On improvement and reinitiation of treatment, the gemcitabine dose was reduced. A maximum of 2 dose reductions were permitted (ie, from 1200 mg/m2 to 1000 mg/m2 and from 1000 mg/m2 to 800 mg/m2; later amended to 1000 mg/m2 to 800 mg/m2 and from 800 mg/m2 to 600 mg/m2). For trastuzumab and pertuzumab, treatment was held for significant asymptomatic LVEF decline (ie, 10%-15% decline to <50%, or ≥10% decline from baseline) or New York Heart Association class III to class IV heart failure. Treatment with the anti-ERBB2 antibodies could be restarted if repeated echocardiogram showed LVEF recovery within 3 weeks. Trastuzumab or pertuzumab dose reductions were not permitted.

    Clinical Assessments

    Response to therapy was evaluated with serial computed tomography scan of the chest, abdomen, and pelvis every 3 months during study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.12 Patients also received optional fludeoxyglucose F 18 positron emission tomography–computed tomography scans every 3 months, and an exploratory end point was to evaluate response by Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) version 1.0.13 A complete blood cell count was obtained before each chemotherapy dose. Patients were seen once per cycle, with comprehensive chemistry laboratory assessments performed every cycle. Monitoring for LVEF occurred at baseline and every 3 months within 3 months after treatment completion by echocardiogram or multigated acquisition study. Monitoring for AEs occurred continuously, and toxic effects were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0.

    Statistical Analysis

    The primary end point of this study was the proportion of patients who were progression free at 3 months or later. Progression-free survival events included disease progression or death, whichever occurred first. The study was powered on the basis of a binary end point of the proportion of patients who were progression free at 3 months. For the primary intention-to-treat analysis, evaluable patients included all study participants who received at least 1 full dose of therapy. A target rate of 70% or higher was selected as the promising progression-free rate at 3 months, while the null rate of 50% was based on evidence from 3 prior studies involving more than 900 patients with ERBB2-positive metastatic breast cancer treated in the second-line setting or beyond, in which median PFS was 3 to 4 months.9-11 A Simon optimal 2-stage design was used to evaluate the efficacy of this regimen.14 This design required a total of 45 patients and assumed a 10% type I and type II error rate. The type I error was 1-sided, and secondary analyses were conducted at a 2-sided type I error of 5%. In the first stage, 21 patients were enrolled. Accrual to the second stage was contingent on 12 or more patients in the first stage being alive and progression free at 3 months. At the end of the study, if 27 or more patients were alive and progression free 3 months after the initiation of therapy, the regimen would be considered a success and deemed worthy of further study. The Kaplan-Meier method was used to calculate PFS estimates. A secondary end point was OS, which was estimated using the Kaplan-Meier method. Additional secondary end points included safety, tolerability, and assessment of biomarkers (not presented in this article). An exploratory end point was to evaluate response by PERCIST (not presented in this article). Adverse events with frequencies of 25% or greater were summarized by percentage. We incorporated a stopping rule to ensure cardiac safety. Cardiac events were defined as symptomatic left ventricular systolic dysfunction (LVSD; deaths and nondeaths), non-LVSD cardiac death, or probable cardiac death.15 A cardiac event rate of 4% or less and an asymptomatic LVEF decline (of ≥10% from baseline to <50%) rate of 20% or less were considered acceptable. Data were analyzed between January 2019 and March 2019. All analyses were conducted using SAS statistical software version 9.2 (SAS Institute) and R version 3.5.0 (R Project for Statistical Computing).

    Results
    Study Population

    A total of 45 patients were enrolled from March 2015 to April 2017. Baseline characteristics are presented in Table 2. The median (range) age was 57.1 (31.7-77.2) years. At initiation of study treatment, 38 patients (84%) had visceral disease, and 7 (16%) had nonvisceral disease. Measurable disease was present in 30 patients (67%), and 15 (33%) had nonmeasurable disease. A total of 33 patients (73%) had estrogen receptor–positive and/or progesterone receptor–positive disease. Metastatic disease was present at the time of breast cancer diagnosis in 20 patients (44%). Overall, 22 patients (49%) had received 1 prior line of chemotherapy in the metastatic setting, 17 (38%) received 2 prior lines, and 6 (13%) received 3 prior lines. Notably, 22 patients (49%) received prior trastuzumab emtansine (T-DM1).

    Efficacy

    Of the 45 enrolled patients, 1 was not evaluable because she received concurrent endocrine therapy with study treatment. Accordingly, 44 patients were included in efficacy analyses (eFigure in Supplement 2). At a median (range) follow-up period of 27.6 (8.3-36.0) months, the 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). The 3-month PFS was 73.9% (95% CI, 58.0%-94.2%) in patients who had not received prior T-DM1 and 72.7% (95% CI, 56.3%-93.9%) in those who received prior T-DM1. Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months) (Figure, A); it was 5.6 months (95% CI, 5.1-11.0 months) for those without prior T-DM1 treatment and 5.5 months (95% CI, 5.4-8.2 months) for those who received prior T-DM1 (Figure, B). The 3-month OS rate was 100%, and median OS was not reached (Figure, C). In terms of clinical benefit, 1 patient (2%) had a complete response, 9 (20%) had a partial response, and 23 (52%) had stable disease (Table 3).

    Treatment Exposure

    The median (range) duration of study treatment was 20.8 (1.6-35.6) months for all enrolled patients. The median (range) number of study treatment cycles per patient was 8 (3-37). The median (range) number of cycles of gemcitabine exposure was 8 (3-31). Initial gemcitabine recommended dose was 1200 mg/m2, which was delivered to 5 patients. Owing to significant toxic effects, described in the next section, the study was amended to deliver gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks; this was also the median dose intensity. The median (range) number of cycles of dual-antibody exposure was 8 (3-37).

    Toxic Effects Profile and Cardiac Safety

    Within the first 3 months of the study, 5 patients required gemcitabine dose reduction (4 patients because of grade 3 neutropenia and 1 patient because of grade 3 vomiting). Accordingly, the study was amended to lower the initial dose of gemcitabine from 1200 mg/m2 to 1000 mg/m2. At this dose, gemcitabine with trastuzumab and pertuzumab was well tolerated with no unexpected AEs (Table 4). Grade 3 or higher AEs included neutropenia (23 patients [51%]), anemia (6 patients [13%]), alanine aminotransferase level elevation (2 patients [4%]), aspartate transaminase level elevation (1 patient [2%]), fatigue (1 patient [2%]), thrombocytopenia (1 patient [2%]), diarrhea (1 patient [2%]), and nausea (1 patient [2%]). Notably, the incidence of febrile neutropenia was 0%.

    Regarding cardiac safety, median LVEF was preserved throughout. No patients experienced protocol-defined cardiac events (symptomatic LVSD). The median (range) LVEF was 60% (52%-80%) at baseline and 61% (45%-70%) at 3 months. One patient (2%) with no known cardiac history had an asymptomatic LVEF decline. She met the eligibility criteria for study enrollment with an LVEF of 57% at baseline. At 3 months, her LVEF decreased to 45%, at which point dual-antibody therapy was held. A repeated echocardiogram was performed 2 weeks later, which showed that her LVEF had recovered to 58% and dual-antibody therapy was resumed. A follow-up echocardiogram 4 weeks later showed preserved LVEF at 55%.

    Discussion

    In this study of gemcitabine given with dual anti-ERBB2 antibody therapy for the treatment of ERBB2-positive metastatic breast cancer among patients previously treated with pertuzumab-based therapy, the Kaplan-Meier 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). This study met its primary end point and prespecified definition of success: a promising 3-month PFS rate of at least 70%. Thus, this trial demonstrated encouraging activity of dual anti-ERBB2 therapy with gemcitabine in the second-line setting and beyond.

    Nearly half of patients in this study received T-DM1 after disease progression on first-line treatment with taxane plus dual anti-ERBB2 therapy. Currently, T-DM1 is a standard second-line treatment based on the EMILIA study16 and endorsed by American Society of Clinical Oncology guidelines17 for systemic therapy in patients with ERBB2-positive metastatic breast cancer. The EMILIA trial, a randomized phase 3 study,16 demonstrated improved PFS (9.6 vs 6.4 months) and OS (29.9 vs 25.9 months) with T-DM1 compared with the combination of lapatinib plus capecitabine.18 With the negative results of the first-line MARIANNE study,19 T-DM1 remains a standard option in the second-line setting. However, our data encourage further study of reexposure to trastuzumab plus pertuzumab beyond progression from prior treatment with this dual-antibody therapy. Retrospective data from our institution add additional support.20 Argolo et al20 reported that trastuzumab and pertuzumab–based combinations in the second-line setting were associated with a median PFS of 10.3 months (95% CI, 5.9-16.3 months) vs 5.3 months (95% CI, 3.0-6.6 months) in patients treated with regimens that did not include pertuzumab (P = .03). In contrast, the PHEREXA trial8 demonstrated no significant PFS difference between capecitabine with trastuzumab plus pertuzumab vs capecitabine with trastuzumab alone for second-line treatment (9.0 vs 11.1 months; hazard ratio, 0.82; 95% CI, 0.65-1.02; P = .07). However, OS was 28.1 vs 36.1 months, favoring the pertuzumab-containing arm (HR, 0.68; 95% CI, 0.51-0.90). Although underpowered to evaluate OS, the signal of OS benefit in this study was consistent with the greater OS than PFS benefit with dual-antibody therapy in the CLEOPATRA study.21 Other trials are currently testing novel therapeutic strategies in the second-line setting. For example, in the phase 2 KATE2 trial,22 which evaluated the efficacy and safety of T-DM1 combined with atezolizumab, an anti–programmed death-ligand 1 antibody, vs T-DM1 combined with a placebo, there was no PFS benefit in the atezolizumab arm, and OS data are not yet mature. In addition to immunotherapy, other novel ERBB2-directed therapies include small-molecule tyrosine kinase inhibitors (eg, neratinib, afatinib, tucatinib, pyrotinib), antibody-drug conjugates, and bispecific antibodies. An important future direction will be to compare the efficacy of these emerging therapeutics with dual-antibody therapy (ie, pertuzumab plus trastuzumab) and with standard second-line T-DM1.

    Our study demonstrated promising activity of dual-antibody therapy after prior exposure in the second-line setting and beyond. Notably, 49% of patients received T-DM1 prior to enrollment in this study. After exposure to pertuzumab and T-DM1, treatment practices vary and typically comprise chemotherapy combined with trastuzumab.17 In a small study of 29 patients, Cortés et al9 reported that the median PFS of dual-antibody therapy after disease progression on pertuzumab monotherapy was 4.4 months (80% CI, 1.5-7.3 months).9 In a heavily pretreated population of 602 patients enrolled in the TH3RESA trial,10 median PFS with treatment of physician’s choice (typically trastuzumab plus chemotherapy) was 3.3 months (95% CI, 2.9-4.1 months). Similarly, Blackwell et al11 reported a median PFS of 3 months in nearly 300 patients treated with trastuzumab and lapatinib after disease progression on trastuzumab-based regimens. Thus, in these 3 studies of more than 900 patients, the median PFS was approximately 3 to 4 months with standard options in the second-line setting and beyond. Although no direct cross-trial comparisons can be made, the median PFS of 5.5 months in the current study is encouraging.

    Gemcitabine (at 1000 mg/m2) given with trastuzumab and pertuzumab was well tolerated. The most common grade 3 to 4 AEs were neutropenia and anemia, consistent with the known toxic profile of gemcitabine. Despite these toxic effects, median gemcitabine dose intensity was 1000 mg/m2, indicating that delivery of the full dose was feasible. Notably, the incidence of febrile neutropenia and grade 3 to 4 diarrhea were 0%. No patients experienced clinical heart failure (ie, symptomatic LVSD), and no patients withdrew from the study because of asymptomatic LVEF decline. One patient experienced asymptomatic LVEF decline, which recovered after antibody treatment was delayed, and treatment was resumed without further incident. Similar to trials in the first-line setting,5,6 the addition of pertuzumab did not increase cardiac toxic effects.

    Limitations and Strengths

    This study has limitations. One limitation is its single-arm design; however, historical data were used to inform the efficacy target. Furthermore, this is a single-center study, and larger randomized clinical trials are needed. The study was strengthened by use of a single chemotherapeutic agent (ie, gemcitabine). Blood was collected throughout the study, and potential biomarkers of response will be reported separately. Additionally, an imaging substudy comparing response assessed by RECIST vs PERCIST criteria will be reported separately.

    Conclusions

    This phase 2 clinical trial demonstrated promising efficacy and confirmed the tolerability and safety profile of gemcitabine with trastuzumab and pertuzumab for the treatment of ERBB2-positive metastatic breast cancer in the second-line setting and beyond. To our knowledge, this is the first study to show promising efficacy of a pertuzumab-containing regimen after prior exposure to pertuzumab. Our findings support the advancement of phase 3 trials comparing the efficacy of regimens containing trastuzumab and pertuzumab with standard and novel ERBB2-directed treatment in patients previously treated with this dual-antibody combination.

    Back to top
    Article Information

    Accepted for Publication: October 4, 2019.

    Published: November 27, 2019. doi:10.1001/jamanetworkopen.2019.16211

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Iyengar NM et al. JAMA Network Open.

    Corresponding Author: Neil M. Iyengar, MD, Memorial Sloan Kettering Cancer Center, 300 E 66th St, Office 823, New York, NY 10065 (iyengarn@mskcc.org).

    Author Contributions: Drs Iyengar and Dang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Iyengar, Smyth, Traina, Fornier, Goldfarb, Patil, Jochelson, Hudis.

    Acquisition, analysis, or interpretation of data: Iyengar, Lake, Gucalp, Singh, Traina, DeFusco, Fornier, Goldfarb, Jhaveri, Modi, Troso-Sandoval, Patil, Ulaner, Norton, Hudis, Dang.

    Drafting of the manuscript: Iyengar, Smyth, Patil.

    Critical revision of the manuscript for important intellectual content: Iyengar, Lake, Gucalp, Singh, Traina, DeFusco, Fornier, Goldfarb, Jhaveri, Modi, Troso-Sandoval, Patil, Ulaner, Jochelson, Norton, Hudis, Dang.

    Statistical analysis: Patil.

    Obtained funding: Iyengar, Hudis.

    Administrative, technical, or material support: Gucalp, Singh, Traina, Fornier, Modi, Ulaner, Hudis.

    Supervision: Iyengar, Norton, Hudis, Dang.

    Conflict of Interest Disclosures: Dr Iyengar reported receiving personal fees from Novartis outside the submitted work. Dr Smyth reported receiving grants and personal fees from Roche/Genentech and AstraZeneca and personal fees from Puma Biotechnology and Pfizer outside the submitted work. Dr Gucalp reported receiving funding to her institution for clinical trial and salary support from Pfizer, Innocrin Pharmaceuticals, Merck, Novartis, Roche, OncoTherapy Science, Zenith Pharmaceuticals, and BioAtla; serving on the Pfizer advisory board; developing an internal podcast for Pfizer on male breast cancer; and serving as a consultant and steering committee member for Innocrin Pharmaceuticals outside the submitted work. Dr Traina reported receiving honoraria and research fees from Roche and Daiichi Sankyo and receiving honoraria from Puma Biotechnology for serving on the advisory board outside the submitted work. Dr DeFusco reported owning shares in Amgen. Dr Goldfarb reported receiving grants from Sprout Pharmaceuticals and Paxman; personal fees from Procter and Gamble, Sermonix Pharmaceuticals, and AMAG Pharmaceuticals; and nonfinancial support from TherapeuticsMD outside the submitted work. Dr Jhaveri reported receiving personal fees from Genentech during the conduct of the study; receiving personal fees for serving as a consultant and/or on the advisory boards of Pfizer, AstraZeneca, Novartis, Taiho Oncology, Spectrum Pharmaceuticals, Juno Therapeutics, ADC Therapeutics, and Synthon; and receiving funding to her institution from Novartis, Pfizer, Genentech, Zymeworks, Eli Lilly and Co, Novita Pharmaceuticals, and Debiopharm. Dr Modi reported participating in the speakers bureau for Genentech and serving on the advisory boards for Daiichi Sankyo, Novartis, GlaxoSmithKline, and MacroGenetics outside the submitted work. Dr Hudis reported serving as chief executive officer of the American Society of Clinical Oncology starting in June 2016. Dr Dang reported serving on the advisory boards of Eli Lilly and Co, Daiichi Sankyo, and Puma Biotechnology during the conduct of the study and receiving grants from Puma Biotechnology and Roche/Genetech outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported by a grant from the Breast Cancer Research Foundation to Dr Iyengar, a grant from the Conquer Cancer Foundation of the American Society of Clinical Oncology to Dr Iyengar, a grant from Genentech/Roche to Dr Dang, a grant from the Kat’s Ribbon of Hope Breast Cancer Foundation to Dr Iyengar, and core grant P30 CA008748 from the Memorial Sloan Kettering Cancer Center.

    Role of the Funder/Sponsor: Genentech/Roche had approval of the manuscript. All other funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: This article was presented at the Annual Meeting of the American Society of Clinical Oncology; June 4, 2017; Chicago, Illinois; and the Annual Meeting of the European Society of Medical Oncology; September 10, 2017; Madrid, Spain.

    References
    1.
    Slamon  DJ, Clark  GM, Wong  SG, Levin  WJ, Ullrich  A, McGuire  WL.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.  Science. 1987;235(4785):177-182. doi:10.1126/science.3798106PubMedGoogle ScholarCrossref
    2.
    Agus  DB, Akita  RW, Fox  WD,  et al.  Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth.  Cancer Cell. 2002;2(2):127-137. doi:10.1016/S1535-6108(02)00097-1PubMedGoogle ScholarCrossref
    3.
    Cho  HS, Mason  K, Ramyar  KX,  et al.  Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.  Nature. 2003;421(6924):756-760. doi:10.1038/nature01392PubMedGoogle ScholarCrossref
    4.
    Franklin  MC, Carey  KD, Vajdos  FF, Leahy  DJ, de Vos  AM, Sliwkowski  MX.  Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.  Cancer Cell. 2004;5(4):317-328. doi:10.1016/S1535-6108(04)00083-2PubMedGoogle ScholarCrossref
    5.
    Baselga  J, Cortés  J, Kim  SB,  et al; CLEOPATRA Study Group.  Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.  N Engl J Med. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216PubMedGoogle ScholarCrossref
    6.
    Dang  C, Iyengar  N, Datko  F,  et al.  Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.  J Clin Oncol. 2015;33(5):442-447. doi:10.1200/JCO.2014.57.1745PubMedGoogle ScholarCrossref
    7.
    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer, version 2. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed October 24, 2019.
    8.
    Urruticoechea  A, Rizwanullah  M, Im  SA,  et al.  Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy.  J Clin Oncol. 2017;35(26):3030-3038. doi:10.1200/JCO.2016.70.6267PubMedGoogle ScholarCrossref
    9.
    Cortés  J, Fumoleau  P, Bianchi  GV,  et al.  Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer.  J Clin Oncol. 2012;30(14):1594-1600. doi:10.1200/JCO.2011.37.4207PubMedGoogle ScholarCrossref
    10.
    Krop  IE, Kim  SB, González-Martín  A,  et al; TH3RESA Study Collaborators.  Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.  Lancet Oncol. 2014;15(7):689-699. doi:10.1016/S1470-2045(14)70178-0PubMedGoogle ScholarCrossref
    11.
    Blackwell  KL, Burstein  HJ, Storniolo  AM,  et al.  Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.  J Clin Oncol. 2010;28(7):1124-1130. doi:10.1200/JCO.2008.21.4437PubMedGoogle ScholarCrossref
    12.
    Eisenhauer  EA, Therasse  P, Bogaerts  J,  et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026PubMedGoogle ScholarCrossref
    13.
    Wahl  RL, Jacene  H, Kasamon  Y, Lodge  MA.  From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors.  J Nucl Med. 2009;50(suppl 1):122S-150S.PubMedGoogle ScholarCrossref
    14.
    Simon  R.  Optimal two-stage designs for phase II clinical trials.  Control Clin Trials. 1989;10(1):1-10. doi:10.1016/0197-2456(89)90015-9PubMedGoogle ScholarCrossref
    15.
    Yu  AF, Manrique  C, Pun  S,  et al.  Cardiac safety of paclitaxel plus trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer.  Oncologist. 2016;21(4):418-424. doi:10.1634/theoncologist.2015-0321PubMedGoogle ScholarCrossref
    16.
    Verma  S, Miles  D, Gianni  L,  et al; EMILIA Study Group.  Trastuzumab emtansine for HER2-positive advanced breast cancer.  N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124PubMedGoogle ScholarCrossref
    17.
    Giordano  SH, Temin  S, Chandarlapaty  S,  et al.  Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update.  J Clin Oncol. 2018;36(26):2736-2740. doi:10.1200/JCO.2018.79.2697PubMedGoogle ScholarCrossref
    18.
    Diéras  V, Miles  D, Verma  S,  et al.  Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.  Lancet Oncol. 2017;18(6):732-742. doi:10.1016/S1470-2045(17)30312-1PubMedGoogle ScholarCrossref
    19.
    Perez  EA, Barrios  C, Eiermann  W,  et al.  Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE Study.  J Clin Oncol. 2017;35(2):141-148.PubMedGoogle ScholarCrossref
    20.
    Argolo  DF, Singh  J, Smyth  L,  et al. Trastuzumab and pertuzumab-based versus other therapy as second-line therapy in HER2-positive metastatic breast cancer: a retrospective study from singe center. Paper presented at: American Society of Clinical Oncology Annual Meeting; June 5, 2015; Chicago, IL.
    21.
    Swain  SM, Baselga  J, Kim  SB,  et al; CLEOPATRA Study Group.  Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.  N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513PubMedGoogle ScholarCrossref
    22.
    ClinicalTrials.gov. A study to evaluate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with human epidermal growth factor-2 (HER2) positive locally advanced or metastatic breast cancer (BC) who received prior trastuzumab and taxane based therapy (KATE2). https://clinicaltrials.gov/ct2/show/NCT02924883. Accessed October 21, 2019.
    ×