HER2-positive mBC Research Articles

Health Care Resource Utilization and Costs for Metastatic Breast Cancer Patients Newly Treated with Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Agents

IntroductionHER2-positive metastatic breast cancer (mBC) is an incurable disease associated with years of chronic therapy and excess cost. HER2-targeted therapies have shown survival benefit for early-stage and mBC; however, the economic impact of these therapies has not been fully assessed. We evaluated health care resource use (HCRU) and costs of mBC patients treated with HER2-targeted therapy. MethodsThis was a retrospective cohort study using the IQVIA Real-World Data Adjudicated Claims Database (July 1, 2014 to July 31, 2019). Female patients aged ≥18 years with mBC who initiated HER2-targeted therapy in the prior year were identified. The index date was the initiation date of the HER2-targeted agent, after which patients were required to have ≥12 months of follow-up. Annual and cumulative all-cause and BC-related costs (2019 USD) and annual BC-related HCRU were computed in years 1, 2, and 3 following the index date. ResultsFollowing the initiation of HER2-targeted therapy, the mean annual total all-cause costs per patient in years 1 (n = 423), 2 (n = 357), and 3 (n = 166) were $320,892 (SD: $224,343), $235,159 (SD: $185,287), and $226,254 (SD: $197,901), respectively. The mean annual total BC-related costs were $240,048 (SD: $151,230), $175,631 (SD: $148,058), and $165,506 (SD: $159,374) in years 1, 2, and 3, respectively. A major portion of BC-related costs were costs associated with HER2-targeted treatment. The 3-year cumulative all-cause and BC-related total costs were $769,573 (SD: $456,920) and $624,455 (SD: $401,319), respectively. ConclusionTreatment of HER2-positive mBC is a substantial economic burden. A potential approach to minimizing cost and HCRU is to prevent recurrence.

Real-World Analysis of the Efficacy and Safety of a Novel Irreversible HER2 Tyrosine Kinase Inhibitor Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer.

BackgroundAs a novel irreversible pan-ErbB inhibitor recently approved in China, pyrotinib has exhibited promising anticancer efficacy and acceptable safety profile in HER2-positive metastatic breast cancer (mBC). The aim of this retrospective study was to estimate the efficacy and safety of pyrotinib treatment in Chinese mBC patients.MethodsWe retrospectively reviewed the real-world clinicopathological and treatment data of HER2-positive mBC patients receiving pyrotinib-based treatment from August 2018 to July 2019 in Qilu Hospital of Shandong University and other medical centers of Shandong Province in China.ResultsA total of 64 patients treated with pyrotinib were included for analysis, and the median follow-up duration was 260 days (interquartile range, 199.0 to 339.0 days). Fifty-nine (92.2%) patients had been previously treated with trastuzumab and/or T-DM1, while 11 (17.2%) patients had been exposed to lapatinib. The objective response rate (ORR) of all patients was 73.4%, and the disease control rate (DCR) was 98.4%, with a clinical benefit rate (CBR) of 87.5%. Patients with exposure to lapatinib responded well to pyrotinib-based treatment, although the ORR was significantly lower compared with that of patients without exposure to lapatinib (44.1% vs 77.5%, p=0.037). Previous lapatinib exposure was negatively associated with the objective response of pyrotinib treatment (odds ratio [OR]=0.248, 95% confidence interval [CI] 0.063–0.970, p=0.045). The median progression-free survival (mPFS) for patients with previous lapatinib exposure and patients with visceral metastasis was 299 days (95% CI 240.1–357.9 days) and 359 days (95% CI 258.3–459.7 days), respectively. But the mPFS of the whole cohort has not been reached until the cut-off date. Cox multivariate analysis revealed that only visceral metastasis was an independent predictor of significantly shorter PFS (p=0.041) but not previous exposure to lapatinib (p=0.092). Diarrhea (28.1%), hand-foot syndrome (17.2%), and neutropenia (9.4%) were the most common grade 3 adverse events associated with pyrotinib treatment.ConclusionPyrotinib is highly beneficial to HER2-positive metastatic breast cancer patients, even in patients with previous lapatinib exposure. Pyrotinib is a feasible replacement of lapatinib in combination with chemotherapeutic drugs or as a monotherapy. Adverse effects are tolerable and easily manageable.

289P A retrospective population-based observational study in metastatic HER2-positive breast cancer patients in Denmark previously treated with T-DM1

Current Danish guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab with one of several chemotherapeutic agents for 3rd line or later treatments. This study aims to describe treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a Danish real-world setting.

Anti-HER2 antibody prolongs overall survival disproportionally more than progression-free survival in HER2-Positive metastatic breast cancer patients

BackgroundThis meta-analysis aimed to test the hypothesis that the HER2-positive metastatic breast cancer (mBC) patients treated with anti-HER2 antibodies in trial intervention arms have a greater prolongation of overall survival (OS) than of progression-free survival (PFS) and this extra-prolongation of median survival time in OS relates specifically to the anti-HER2 antibody. MethodsThe NCBI/Pubmed and Cochrane databases were searched systematically for HER2-positive or mBC trials published in English during January 1999–November 2017. Treatment arms with shorter PFS were considered as the “control” arm, whereas those with longer PFS as the “test” arm. The between-treatment drug differences were grouped into nine categories. Groups with or without anti-HER2 antibodies were pooled respectively for comparisons. The interrelationships between PFS and OS hazard ratios (HRs) and median survival time differences were investigated by conducting fixed-effects and mixed-effects linear meta-regression analyses. ResultsTwenty-eight trials (10,928 patients) from 438 articles were collected, and four with missing data were excluded in meta-regression analysis. Overall median PFS (HR = 0.73, 95% CI: 0.68–0.78) and median OS (HR = 0.82, 95% CI: 0.77–0.87) weakly favored the longer PFS arm with a weak correlation between the PFS and OS HRs. However, the between-treatment drug difference was anti-HER2 antibody, the absolute increment in median OS time was double that of median PFS time (p < 0.001) and linearly correlated, which was not found with any non-anti-HER2 antibody drug differences. ConclusionsAnti-HER2 antibody in patients with HER2-positive mBC prolonged OS more than PFS and mandates further investigation.

The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial

In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2‐positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond

ABSTRACT Introduction Despite the substantial improvements made in human epidermal growth factor receptor 2 (HER2)–targeted therapies since the approval of trastuzumab more than 20 years ago, there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation in other solid tumors, including non–small cell lung cancer, colorectal cancer, and HER2-low tumors. Areas covered The current treatment and investigational landscape of HER2-positive and HER2-low metastatic BC (mBC) and the preclinical and clinical trials investigating T-DXd. To identify relevant literature, a search was performed on English-language publications and congress abstracts. Expert opinion T-DXd is likely to become the standard of care for second-line treatment of HER2-positive mBC, and it may play a role in the treatment of hormone receptor–positive and triple-negative mBC with HER2-low expression. Because it was recently approved in the United States and Japan to treat HER2-positive metastatic GC, it holds promise for the treatment of other HER2-positive solid tumors, including colorectal cancer, non–small cell lung cancer, and HER2-low BC.

Zanidatamab, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

TPS2656 Background: Zanidatamab is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action including enhanced binding, clustering, receptor internalization and downregulation; this results in inhibition of ligand-dependent and -independent proliferation and potent activation of antibody-dependent cellular cytotoxicity. Zanidatamab monotherapy is well tolerated and has shown promising anti-tumor activity in patients (pts) with pre-treated advanced HER2-positive cancers, and was well tolerated in a Phase I trial (NCT02892123). Tislelizumab is an investigational anti-programmed death-1 (PD-1) antibody engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, which is a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. Tislelizumab is well tolerated and has anti-tumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. The highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort Phase 1B/2 study (NCT04276493) is designed to evaluate zanidatamab as a first-line therapy with chemotherapy in pts with HER2-positive metastatic breast cancer (mBC; cohort 1) or with chemotherapy + tislelizumab in pts with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). Weight-based dosing (cohorts 1a and 2a) and flat dosing (cohorts 1b and 2b) regimens of zanidatamab are being investigated. In cohort 1 (n = 20), pts with treatment-naïve HER2-positive (IHC3+ or ISH amplified) mBC will receive intravenous (IV) zanidatamab 30 mg/kg (cohort 1a) or 1800 mg (cohort 1b), plus IV docetaxel 75 mg/m2 once every 3 weeks (Q3W). In cohort 2 (n = 30), treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive IV zanidatamab 30 mg/kg (cohort 2a), or 1800 mg (pts &lt; 70kg; cohort 2b) or 2400 mg (pts ≥ 70kg; cohort 2b), plus IV tislelizumab 200 mg and chemotherapy (CAPOX regimen: oral capecitabine 1000 mg/m2 twice daily [days 1–14] and IV oxaliplatin 130 mg/m2 [day 1]) Q3W. For cohort 2 there is a six pt safety lead-in phase, followed by dose expansion after approval by the safety monitoring committee. Primary endpoints are the safety profile and objective response rate. Secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: NCT02892123.

Systematic Review: Economic Evaluation of Treatment for Human Epithelial Growth Factor Receptor 2-positive Metastatic Breast Cancer from a National Health Insurance Perspective

Background: Economic evaluation is often held from the societal perspective. Even it is important, as the therapy affects greatly to the patients’ life in society, economic evaluation from the payer perspective, is as important as it may help National Health Insurance (NHI) as the payer avert budget deficit as was observed in Indonesia. Unfortunately economic evaluation from the payer’s perspective is very rare to be done. This article compiles and reviews research articles of economic evaluation of therapy for human epithelial growth factor receptor 2-positive metastatic Breast Cancer (mBC) as an alternative to trastuzumab therapy, which has recently been removed from Indonesia’s National Health Insurance coverage. Methods: The literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and PICO methodology (Population, Intervention, Comparison, and Outcome). Relevant articles were retrieved from online biomedical databases Scopus, PubMed, ScienceDirect, and SAGE Journals. Quality appraisal was performed using a standardized checklist which consisted of items in the CHEC checklist. Results: A total of six articles pertaining to economic evaluation of therapy for HER2-positive mBC from the NHI perspective (period: 2008–2018) were reviewed. Trastuzumab+chemotherapy showed the longest overall survival (OS, 37.8 months) with Progression-free Survival (PFS) of 12.7 months. Trastuzumab+docetaxel as 1st line therapy were associated with the longest PFS (19 months) with a total cost of US$ 12,732. With respect to therapy sequence, 1st line, trastuzumab+pertuzumab+docetaxel; 2nd line, trastuzumab+emtansine ; and 3rd line, lapatinib+capecitabine was associated with the highest quality-adjusted life year (QALY; 1.81) but also the highest total cost and incremental cost (US$360,880 and US$197,250, respectively). The sequence of 1st line, trastuzumab/docetaxel; 2nd line, T-DM1; and 3rd line, trastuzumab/lapatinib was associated the lowest QALY (1.27) but was the most cost-effective (total cost: $158,293). Lapatinib+capecitabine as 2nd line therapy and exemestane monotherapy were associated with the lowest total cost (US$3,190). Conclusion: Lapatinib+capecitabine as 2nd line therapy and exemestane monotherapy show potential as alternatives to trastuzumab therapy for HER-2 positive mBC.

Exploring the concepts and practices of advanced breast cancer treatment: a narrative review.

ObjectiveTo explore the concepts and practices of advanced breast cancer treatment.BackgroundMetastatic breast cancer (MBC) has become a chronic disease, with a median overall survival (OS) of around 3 years and a 5-year survival rate of about 25%. OS are strongly associated with the best available care, which consists of not only application of guidelines, but also multidisciplinary specialized care, the most efficacious medicines, and so on. Advanced breast cancer (ABC) Guidelines are the most important and authoritative guidelines for MBC.MethodsIn this review, we demonstrate the history and evolution of the global ABC Guidelines. Since 2015, Chinese multidisciplinary experts have drafted guidelines for clinical diagnosis and treatment of MBC. All of these ABC guidelines describe specialized therapeutic principles for different subtypes MBC in detail. Encouragingly, we have found that some special subtypes are hopeful of being cured, such as HER-2 positive patients with low tumor burden or HR-positive (HR+) MBC with non-visceral metastasis. In our opinion, the definition of cure of MBC is that MBC patients achieve CR and remain for more than five years after systemic treatment, including those with local therapy. Consequently, we also have conducted some researches and meaningful explorations in different subtypes of MBC. In HER2 positive MBC, our study revealed that regular HER2 circulating extracellular domain (ECD) assay can provide the real-time monitoring of tumor burden and prediction of poor outcome, and may present an important opportunity to reassess HER2 status. In HR+ MBC, we suggested that hormone therapy (HT) maintenance is the priority choice for HR+/HER2− MBC after first-line combined chemotherapy. Besides, our real-world study revealed that fulvestrant combined with ovarian suppression was an active option for premenopausal HR+/HER2- MBC. And also, we observed that everolimus (low-dose) combined with hormone therapy was still effective for HR+/HER2− MBC. For mTNBC patients, we found that THA and endostatin exhibited potential efficacy and was well tolerated in pretreated patients.ConclusionsOur concepts and practices will contribute to the design of relevant clinical research and accumulation of evidence, and cure of MBC is promising.

Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study

PurposeIntravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC.MethodsIn this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy.ResultsAt clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%.ConclusionsSafety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies.Trial registrationNCT02402712

Abstract PS10-08: Tucatinib potentiates the activity of the antibody-drug conjugate T-DM1 in preclinical models of HER2-positive breast cancer

Abstract Background: Tucatinib is an orally administered, reversible, highly specific HER2 tyrosine kinase inhibitor recently approved by the FDA in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer (mBC), including patients with brain metastases, that have failed at least one anti-HER2 regimen in the metastatic setting. In a phase IB clinical trial, tucatinib in combination with the HER2-targeted antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) was well tolerated and demonstrated activity in heavily pre-pretreated patients with HER2-positive mBC (NCT01983501; Borges VF et al., 2018). We previously presented preclinical data that tucatinib increases the activity of trastuzumab-derived ADCs in HER2-positive breast cancer models. Here, we provide mechanistic insight that tucatinib potentiates the activity of T-DM1 by modulating HER2 protein dynamics and facilitating increased cytotoxic maytansinoid drug delivery. Methods: To assess changes to HER2 protein levels upon treatment with tucatinib, HER2-amplified breast cancer cell lines were analyzed by Western blot and quantitative FACS (qFACS). To probe the dynamics of HER2 at the cell surface upon binding to antibody therapeutics, SK-BR-3 cells were incubated with fluorescently labeled trastuzumab to mark HER2 at the cell surface. Cells were imaged over 72 hours to observe the internalization of surface-bound antibody. Concurrent experiments were conducted with trastuzumab labeled with QF01, a quenched fluor which fluoresces only upon lysosomal processing and can serve as a proxy for antibody catabolism. To directly measure the rates of ADC catabolism, lysates were generated from BT-474 cells treated with T-DM1 in the presence or absence of tucatinib over a 72 hour time course, and were analyzed by mass spectrometry for the T-DM1 adduct, Lys-MCC-DM1. Results: In HER2-amplified breast cancer cell lines, treatment with tucatinib increased overall and cell membrane-localized HER2 levels. As demonstrated by internalization assays, tucatinib had an initial effect that increased the dwell time of HER2 at the cell surface of SK-BR-3 cells. At later timepoints, HER2 bound to trastuzumab was internalized and directed towards lysosomes. These data were supported by parallel intracellular Lys-MCC-DM1 measurements, which demonstrated increased concentration of the adduct when TDM-1 was administered in combination with tucatinib. These data provide a mechanistic rationale as to why the co-administration of tucatinib with T-DM1 in vitro was synergistic by isobologram analysis, and why the combination of tucatinib with T-DM1 was more effective in vivo than either single agent alone in BT-474 xenografts and in PDX models tested, producing a higher proportion of partial or complete tumor regressions. Conclusions: The described preclinical in vitro and in vivo data of simultaneous dual HER2 inhibition with tucatinib and T-DM1, along with the results of the phase IB/2 clinical trial demonstrating preliminary safety and efficacy of the combination, warrant further clinical development of tucatinib in combination with T-DM1. These results also support the evaluation of tucatinib in combination with other HER2-targeted ADCs in patients with HER2-positive mBC. Citation Format: Anita Kulukian, Janelle Taylor, Nishi Jain, Devra Olson, Margo Zaval, Robert Thurman, Shawna Hengel, Lauren Farr, Thomas Pires, Scott R. Peterson. Tucatinib potentiates the activity of the antibody-drug conjugate T-DM1 in preclinical models of HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-08.

Abstract PS10-37: Real-world experience of patients treated for HER2-positive metastatic breast cancer at the centre hospitalier universitaire de Quebec: A retrospective cohort study

Abstract Introduction: Multiple HER2-targeted therapies are now available and have significantly altered the natural course of HER2-positive metastatic breast cancer (mBC), with overall survival (OS) now exceeding 4 years. However, patients with HER2-positive mBC represent a heterogeneous population with some patients presenting with a history of a localized cancer and some with de novo metastatic disease. Our aim was to study the outcomes of HER-positive mBC in a real-life setting and compare the evolution between patients with “recurrent” breast cancer compared to those with “de novo” disease. Methods: In this single-center, retrospective study, we included patients with HER2-positive mBC treated at the Centre hospitalier universitaire (CHU) de Quebec using the local cancer registry and patients’ medical charts. We included all female patients &amp;gt; 18 years of age who received one or more anti-HER2 therapy for mBC. Patients whose follow-up at our center was incomplete were excluded. We identified patients who developed mBC after the occurrence of a localised disease (“Recurrent” group) and patients diagnosed with metastatic disease upon first presentation (“De novo” group). Primary outcome was OS. Secondary outcomes were progression-free survival (PFS) for each line of treatment and for each type of treatment (trastuzumab [T], pertuzumab [P], lapatinib [L] and trastuzumab emtansine [T-DM1]). We performed survival analysis using the Kaplan-Meier method and the log rank test. Results: A total of 106 patients in the Recurrent group and 58 patients in the De novo group were identified between May 2002 and December 2018 and data were collected between March and June 2019, by which time 97 (59.1%) had died. There were differences in baseline characteristics between the Recurrent and the De novo groups regarding age at first metastasis (50.7 vs 57.4 years, p=0.001). A total of 44.3 % vs 32.8 % of patients developed brain metastasis respectively (p=0.15). There was no statistical difference between the two groups regarding OS (3.8 years for Recurrent vs 4.2 years for De novo, p=0.17). PFS were also similar between the 2 groups for every anti-HER2 treatment available during the study period (Table 1). Median PFS could not be established for P in the De novo group since 80 % of patients were censured at the time of data collection. In the Recurrent group, P, L and T-DM1 had median PFS at least as long as those reported in landmark clinical trials. PFS were also similar between groups when comparing treatment lines (Table 2). Conclusion: In this retrospective study of patients from a real-world setting, anti-HER2 therapies offered similar OS between HER2-positive mBC patients with recurrent disease and with de novo metastatic disease. Median PFS are also equivalent between groups, with durations in the range of the PFS reported in major RCTs. Table 1TreatmentRecurrent groupRecurrent groupDe novo groupDe novo groupP valuenMedian PFS (years)nMedian PFS (years)Trastuzumab741.7441.90.14Pertuzumab333.115-0.15Lapatinib290.7110.60.17T-DM1310.7120.70.52 Table 2LineRecurrent groupRecurrent groupDe novo groupDe novo groupP valuenMedian PFS (years)nMedian PFS (years)1sd1061.6582.00.142nd490.7200.60.273rd230.990.70.794th100.430.80.53 Citation Format: Vincent Douville, Christine Desbiens, Valérie Théberge, Caty Blanchette, Julie Lemieux. Real-world experience of patients treated for HER2-positive metastatic breast cancer at the centre hospitalier universitaire de Quebec: A retrospective cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-37.

Abstract PS18-23: Population pharmacokinetics (Pop PK) of MYL-1401O (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer (mBC)

Abstract Background: Mylan trastuzumab (MYL-1401O) is a biosimilar to trastuzumab (Herceptin®). A multicenter, double blind, randomized, phase III study (HERITAGE) compared the efficacy, safety, Pop PK and immunogenicity of MYL-1401O and trastuzumab in patients with HER2-positive mBC. Patients were randomized 1:1 to receive either MYL-1401O or Herceptin®, in combination with taxane Q3W for 24 weeks followed by monotherapy until unacceptable toxicity, disease progression or early discontinuation.Objectives: The objectives of the Pop PK analysis were to compare the Pop PK derived AUC, Cmax, clearance, Vd, and T1/2 profiles of MYL1401O and Herceptin® and to perform an exploratory assessment of the impact of shed extracellular domain (ECD) fragments of the HER2 receptor (HER2/ ECD) on PK parameters.Methods: One end of infusion PK sample was collected at Cycle 1 and Cycle 6, and 1 trough sample per cycle from all patients; additional samples were taken in a Pop PK subset (MYL-1401O: 45; Herceptin®: 37) in the first dosing interval and at subsequent times. Pop PK modeling was performed using NONMEM. Individual patient empiric Bayesian parameter estimates were used to estimate PK measures. The impact of HER2/ECD presence on PK levels was evaluated in the primary covariate analysis. Results: Two hundred forty-five (245) patients in the PK population received MYL-1401O, while 240 received Herceptin® of which 482 were included in the base model Pop PK analysis. 3170 concentration records with sufficient information were included in the Pop PK analysis. There were no notable demographic differences between the treatment groups. Bayesian parameter based exposure estimates at or near steady-state dosing were comparable between treatments, confirming similar PK (Table 1). Treatment was not a significant covariate of clearance (p=0.177) or volume of the central compartment (p=0.584) using the likelihood ratio Chi-square test.The test-to reference mean ratios of Cmin for Cycle 1 and Cycle 6 (end of cycle) were 103.11(90% CI = 90.61, 117.33) and 104.16 (90% CI = 94.00, 115.42), respectively.The HER2/ECD concentrations were a significant covariate of trastuzumab clearance. Conclusion: Pop PK profiles of MYL-1401O vs. Herceptin® were similar in patients with HER2positive mBC. Model-based exposure measures were similar between treatments. HER2/ECD concentrations were a strong determinant of trastuzumab clearance, and clearance was similar between treatments. The observed trough concentrations were similar between treatments at the end of Cycle 1 and at Cycle 6.Clinical trial identification: EudraCT Number: 2011-001965-42Legal entity responsible for the study: Mylan GmbHFunding: Mylan GmbH Table 1:Bayesian Parameter Based Exposure Estimates at Cycle 6MYL-1401O (N=245)Herceptin®(N=240)Total(N=485)Parametern*213202415Dose (mg)Mean (SD)420.70 (90.46)421.25 (97.67)420.97 (93.92)Clearance (L/day)0.27 (0.10)0.28 (0.08)0.27 (0.09)Volume of Central Compartment (L)3.16 (0.60)3.20 (0.60)3.18 (0.60)Volume at Steady State (L)6.36 (1.19)6.32 (1.14)6.34 (1.16)AUC (ug*day/mL)40501.40 (13037.04)38816.90 (11966.26)39681.40 (12540.58)Dose-normalized AUC (ug*day/mL/mg)98.50 (30.56)94.41 (28.90)96.51 (29.80)Cmax,ss (ug/mL)177.00 (37.76)171.52 (34.61)174.33 (36.32)Dose-normalized Cmax,ss (ug/mL/mg)0.43 (0.10)0.42 (0.09)0.43 (0.10)Half-life (day)Median (SD)25.12 (7.50)24.34 (6.89)24.74 (7.21)*concentrations below lower limit of quantification and samples before first dose with values &amp;gt;zero were excluded from Pop PK analysis, as were some patients with incomplete information for covariates significant in the final model. Citation Format: Joel Owen, Russell Rackley, Mark Liu, Adolfo Fuentes-Alburo, Tazeen Idris, Subramanian Loganathan, Abhijit Barve, Cornelius F. Waller, Hope S. Rugo. Population pharmacokinetics (Pop PK) of MYL-1401O (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-23.

Systematic Review: Economic Evaluation of Treatment for Human Epithelial Growth Factor Receptor 2-positive Metastatic Breast Cancer from a National Health Insurance Perspective

Background: Economic evaluation is often held from the societal perspective. Even it is important, as the therapy affects greatly to the patients’ life in society, economic evaluation from the payer perspective, is as important as it may help National Health Insurance (NHI) as the payer avert budget deficit as was observed in Indonesia. Unfortunately economic evaluation from the payer’s perspective is very rare to be done. This article compiles and reviews research articles of economic evaluation of therapy for human epithelial growth factor receptor 2-positive metastatic Breast Cancer (mBC) as an alternative to trastuzumab therapy, which has recently been removed from Indonesia’s National Health Insurance coverage. Methods: The literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and PICO methodology (Population, Intervention, Comparison, and Outcome). Relevant articles were retrieved from online biomedical databases Scopus, PubMed, ScienceDirect, and SAGE Journals. Quality appraisal was performed using a standardized checklist which consisted of items in the CHEC checklist. Results: A total of six articles pertaining to economic evaluation of therapy for HER2-positive mBC from the NHI perspective (period: 2008–2018) were reviewed. Trastuzumab+chemotherapy showed the longest overall survival (OS, 37.8 months) with Progression-free Survival (PFS) of 12.7 months. Trastuzumab+docetaxel as 1st line therapy were associated with the longest PFS (19 months) with a total cost of US$ 12,732. With respect to therapy sequence, 1st line, trastuzumab+pertuzumab+docetaxel; 2nd line, trastuzumab+emtansine ; and 3rd line, lapatinib+capecitabine was associated with the highest quality-adjusted life year (QALY; 1.81) but also the highest total cost and incremental cost (US$360,880 and US$197,250, respectively). The sequence of 1st line, trastuzumab/docetaxel; 2nd line, T-DM1; and 3rd line, trastuzumab/lapatinib was associated the lowest QALY (1.27) but was the most cost-effective (total cost: $158,293). Lapatinib+capecitabine as 2nd line therapy and exemestane monotherapy were associated with the lowest total cost (US$3,190). Conclusion: Lapatinib+capecitabine as 2nd line therapy and exemestane monotherapy show potential as alternatives to trastuzumab therapy for HER-2 positive mBC.

PCN104 Cost-Utility MODEL of Trastuzumab Emtansine (T-DM1) in HER2-Positive, Unresectable, Locally Advanced or Metastatic Breast Cancer Previously Treated with Trastuzumab and a Taxane, Compared with Capecitabine PLUS Lapatinib, Trastuzumab PLUS Capecitabine and Capecitabine ALONE in Turkey

In Turkey, 5,930 people are affected by HER2-positive breast cancer in 2019. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate being studied in HER2-positive cancers and it is designed to target and inhibit HER2 signaling. The aim of the cost effectiveness (CE) model is to assess the CE of T-DM1 versus: Capecitabine plus lapatinib (LapCap), trastuzumab plus capecitabine (TrastCap), capecitabine alone (Cap) and vinorelbine alone (Vin) for patients previously treated with taxane and trastuzumab in HER2-positive mBC from the perspective of Social Security Institution (national payer) in Turkey. T-DM1 is compared with all relevant mBC treatments using a partitioned survival cost effectiveness model. The model considers three health states: progression-free survival (PFS), progression (PD), and death. Transition probabilities determine the movement of patients between these health states. The model cycle length is one week. Time horizon is 7 years in the base scenario due to the progressive state of metastatic breast cancer. Discount rate of 3.5% applied for utilities & costs. The model findings validated with Probabilistic Sensitivity Analysis (PSA). The main model outcome is determined according to the incremental cost-effectiveness ratio (ICER) based on the life years gained. Base case model analysis shows an ICER of T-DM1 vs. LapCap as 165,301TRY. The results of economic comparison based on the systematic review and indirect treatment comparison show a life years gained ICER of T-DM1 vs. TrastCap as 91,412TRY, T-DM1 vs. Cap as 119,146TRY and T-DM1 vs Vin as 116,239TRY. In conclusion, trastuzumab emtansine is a cost effective option compare to a lapatinib plus capecitabine regimen. Regardless of treatment line, trastuzumab emtansine regime is cost effective compared to LapCap regimen in Turkey. Probabilistic sensitivity analysis concludes that ICER compared to LapCap is 166,057TRY which is similar to base-case.

QOLP-02. PATIENT-REPORTED OUTCOMES FOLLOWING PERTUZUMAB PLUS HIGH-DOSE TRASTUZUMAB IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER (MBC) AND CENTRAL NERVOUS SYSTEM (CNS) PROGRESSION POST-RADIOTHERAPY

Abstract Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.

Depth of Response and Early Tumor Shrinkage for Predicting Clinical Outcomes in HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab.

BackgroundTo evaluate whether the depth of response (DepRe) and early tumor shrinkage (ETS) are predictive factors of clinical outcomes in HER2-positive metastatic breast cancer (mBC) patients treated with trastuzumab.MethodsWe performed a retrospective study of 100 HER2-positive mBC patients who received trastuzumab combined with chemotherapy as first-line treatment. ETS and DepRe were calculated. We employed Youden’s index to determine the optimal cutoff value of ETS and DepRe for predicting progression-free survival (PFS) and overall survival (OS). We used Kaplan–Meier analysis, Log-rank tests, and Cox proportional hazards regression models to evaluate the impacts of ETS and DepRe on clinical outcomes.ResultsThe optimal cutoff values were 30% for ETS and 40% for DepRe; ETS and DepRe were observed in 51.0% (51/100) and in 56.0% (56/100) of patients, respectively. Both ETS≥30% and DepRe≥40% were significant tumor-size metrics for predicting PFS (ETS: median 1.43 vs 0.69 years, hazard ratio [HR] = 0.384; 95% confidence interval [CI]: 0.245 to 0.601; P=0.000030; DepRe: median 1.43 vs 0.59 years, HR = 0.390; 95% CI: 0.250 to 0.609; P=0.0000034), but only DepRe≥40% was a significant predictor for OS (median 4.02 vs 3.07 years, HR = 0.484; 95% CI: 0.255 to 0.919; P = 0.027). Multivariate analyses also identified DepRe as an independent prognostic factor for PFS (HR = 0.52; 95% CI: 0.29 to 0.93; P = 0.028) and OS (HR=0.37; 95% CI:0.15 to 0.90; P = 0.029).ConclusionETS≥30% and DepRe≥40% were significant predictors of better clinical outcomes in mBC patients treated with first-line trastuzumab-based chemotherapy. Further validation in prospective trials with larger patient populations is needed.

ZW25, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

TPS3145 Background: ZW25 is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action, including activation of ADCC and inhibition of ligand-dependent and -independent cellular growth. ZW25 is well tolerated and showed single-agent antitumor activity in patients (pts) with advanced HER2-positive cancers. Previous reports suggested that tislelizumab, an investigational anti-PD-1 antibody engineered to minimize binding of FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, was generally well tolerated and had antitumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. Combining HER2-targeted agents with chemotherapy has resulted in improved survival; the highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort phase 1B/2 study is designed to evaluate ZW25 plus chemotherapy ± tislelizumab as first-line therapy in pts (n≈50) with HER2-positive metastatic breast cancer (mBC; cohort 1) or advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). In cohort 1, pts with HER2-positive (IHC3+ or ISH amplified) mBC must be treatment-naïve for metastatic disease and will receive intravenous (IV) ZW25 30 mg/kg plus docetaxel 75 mg/m2 IV once every 3 weeks (Q3W). In cohort 2, treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive ZW25 30 mg/kg plus tislelizumab 200 mg IV and chemotherapy (CAPOX regimen: capecitabine 1000 mg/m2 twice daily and oxaliplatin 130 mg/m2 IV) Q3W. A safety lead-in phase is designed for the first six pts in cohort 2, followed by dose expansion after a safety monitoring committee review. Primary endpoints are the safety/tolerability profile and objective response rate; secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: Registered, NCT number pending will provide as soon as available .

Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis.

1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .

HER2-positive MBC has high short- and medium-term costs

HER2-positive MBC has high short- and medium-term costs