Retrospective Observational Study of Outcomes in HER2-Positive Metastatic Breast Cancer (mBC) Patients Treated with Ado-Trastuzumab Emtansine (T-DM1) and Subsequent Treatments After T-DM1 in the United States

This was a retrospective, observational study of adult patients with HER2+ mBC from US Oncology Network practices utilizing the iKnowMed™ (iKM) electronic health record (EHR). Eligibility criteria included ≥ 18 years old at mBC diagnosis, two or more office visits, HER2+ status documented in iKM as either immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH)–positive, and T-DM1 initiation for mBC between 1 January 2013 and 30 September 2018. T-DM1 initiation was the index event. Patients were followed through 31 December 2018 until last patient record or end of the study period, whichever occurred first. Patients participating in clinical trials during the study period, patients who received T-DM1 in the neo/adjuvant setting (i.e., those with nonmetastatic disease), and those with other documented primary cancer diagnoses were excluded.

The US Oncology Network is a network of community oncology clinics affiliated with approximately 1400 physicians in over 500 sites of care across 25 states in the US and treats over 1.2 million patients annually [8]. iKM is an integrated web-based, oncology-specific EHR. iKM captures outpatient medical oncology practice encounter history for patients under community-based care, including patient demographics, clinical information (e.g., staging, biomarker testing, performance status), and treatment information (e.g., chemotherapy regimens, lines of therapy). iKM has been implemented across the majority of practices in The US Oncology Network.

Data were extracted via programmatic data queries from structured data fields in the iKM database, along with chart review abstraction to capture unstructured data. Structured data are entered into standardized fields in the EHR: examples include patient demographics, treatment dates and dosages, and laboratory results. Examples of unstructured data from charts include free text in progress notes, scanned documents (e.g., imaging), or other non-standardized fields.

Vital status was supplemented with death data from the US Social Security Administration Limited Access Death Master File. The study was approved by the US Oncology, Inc. Institutional Review Board. Supplementary Table 1 lists variables and data sources in further detail (see the Electronic Supplementary Material).

Descriptive analyses were performed to describe demographic and clinical characteristics among patients treated with T-DM1 and those treated with pertuzumab before T-DM1, and treatment regimens before and following T-DM1. Treatment regimens included chemotherapy and HER2-based treatments only, while endocrine therapies were excluded. Cycles of T-DM1 were defined as the total number of treatment administrations, with one treatment given every 21 days. The Kaplan-Meier method was used to estimate time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and OS from T-DM1 initiation and for post–T-DM1 treatments. TTD was defined as the interval between treatment initiation and discontinuation for any reason. OS was defined as the interval between T-DM1 initiation and death date. Dates of disease progression for rwPFS were obtained through provider assessments from progress notes. Patients without treatment discontinuation, progression, or death during the study observation period were censored on the earliest of the study end date or the last visit date. Follow-up time was defined as time from index treatment (initiation of T-DM1) to end of the study, last visit to a US Oncology Network clinic, or death, whichever occurred first. Adverse events of special interest consistent with T-DM1 product labeling were collected using Medical Dictionary for Regulatory Activities terms from progress notes during chart review and were also derived from laboratory test results performed throughout the T-DM1 treatment duration. Grading for laboratory values was categorized based on Common Terminology Criteria for Adverse Events laboratory criteria.

Over 600,000 patients with breast cancer were identified from iKM, including over 67,000 with documented HER2+ disease; 520 received T-DM1 during the study period, and 318 patients met all eligibility criteria and were included in the analysis (Fig. 1). Median duration of follow-up was 11.7 months (range 0.0–69.5).

Table 1 describes the overall study population. Median age was 58 years (range 25–90+), 68.9% were Caucasian, and all except four patients were female. The highest proportion of patients had three or more organs with metastasis at the time of T-DM1 treatment (40.3%); the most common were bone, liver, and lung (57.9%, 44%, and 39.9%, respectively). Visceral disease was present in 93.4%, and 22.3% had baseline brain metastasis. Performance status was good, with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 in 13.2% or ECOG PS 1 in 62.6% at the time of treatment. Most (63.8%) had hormone-receptor–positive disease.

There were 184 patients (57.9%) who received trastuzumab and pertuzumab before T-DM1; approximately one third had stage IV disease at initial diagnosis (Table 1). Their patient characteristics were similar to those of the overall study population.

The 318 patients treated with T-DM1 received a median of seven T-DM1 cycles (range 1–85), and 62.3% received two or more prior treatments for mBC (range 0–9). During the study observation period, 43.4% received a subsequent treatment; the most common were trastuzumab + vinorelbine (22.5%), HER2-targeted–only monotherapy or combination therapy (22.5%), trastuzumab + other chemotherapy (19.6%), or capecitabine + lapatinib (14.5%) (Table 2). The most common reasons for T-DM1 discontinuation were progression (50.3%), patients whose treatment may still be ongoing or who did not return for treatment (17.0%), hospice (9.1%), death (7.9%), and toxicity (5.0%).

Of the 318 patients receiving T-DM1, 252 patients (79.2%) had discontinued treatment and 66 patients (20.8%) had not discontinued T-DM1 at last follow-up and were censored. Among all 318 patients, median TTD was 5.9 months (95% confidence interval [CI] 4.6–6.9), median rwPFS was 5.9 months (95% CI 4.6–7.6), and median OS from T-DM1 initiation was 19.2 months (95% CI 16.8–24.5) (Fig. 2).

Treatment outcomes appeared similar in the 184 patients with pertuzumab exposure before T-DM1. Median TTD was 4.6 months (95% CI 3.5–6.0), median rwPFS was 5.1 months (95% CI 4.0–6.3), and median OS from T-DM1 initiation was 19.9 months (95% CI 14.3–28.2). Among all patients treated with T-DM1, outcome endpoints were observed to be shorter with subsequent therapy. In the 138 patients who received subsequent therapy post T-DM1, median TTD from the start of the subsequent therapy was 3.6 months (95% CI 3.1–4.2), median rwPFS from the start of subsequent therapy was 3.6 months (95% CI 3.2–4.9), and median OS from the start of T-DM1 initiation was 24.5 months (95% CI 19.2–31.4).

Among all 318 patients receiving T-DM1, adverse events were consistent with product labeling: infusion-related reactions in 1.9%, pulmonary toxicity (i.e., interstitial lung disease [ILD] or pneumonitis) in 0.6%, and peripheral neuropathy in 1.6%. Aspartate aminotransferase or alanine aminotransferase ≥ 5 × upper limit of normal (ULN) occurred in up to 1.9% and bilirubin ≥ 3 ULN in 0.3%; 5.3% experienced anemia (hemoglobin < 8 mg/dL), and 7.2% experienced thrombocytopenia (platelets < 50 mm³). In all patients treated with T-DM1, 4.1% experienced a reduction in left ventricular ejection fraction (LVEF) < 50%, as did 4.3% of those receiving pertuzumab prior to T-DM1 (n = 184).

This retrospective observational study included a relatively large population of patients receiving T-DM1 and subsequent treatments outside of clinical trials, thus providing insights into treatment utilization and outcomes in US community clinical practices.

Limitations include known methodologic considerations with retrospective analyses, including data completeness. Missing data can result from care or services provided outside of the practice that were not reported to or documented by the treating provider, or from differences in documentation patterns outside of clinical trials. Missing data cannot confirm the absence of a condition or value in a patient’s medical history, but only that it was not documented. The frequencies of follow-up assessments in routine care are not standardized outside of clinical trials, and thus progression endpoints cannot be interpreted the same as in clinical trials. Additionally, toxicity assessments for adverse events of special interest were performed with chart review, and attribution and severity were not assessed in the same manner as clinical trials. For the OS outcomes among the patients who received subsequent treatment after T-DM1, immortal time bias could be introduced since the index date was the treatment initiation date of T-DM1, and patients would have to survive from T-DM1 initiation to be able to receive subsequent treatment after T-DM1. Direct comparisons across trials may not be applicable due to trial design and differences in patient characteristics. Further, differences in healthcare systems could preclude generalizability of our results outside of the US.

Patients with HER2+ mBC who received T-DM1 in this study appeared to have more advanced disease than those treated in the T-DM1 clinical trials and received T-DM1 in later lines of therapy. Overall treatment durations and survival outcomes were shorter compared to clinical trials. Data are lacking on T-DM1 therapy effectiveness among patients with prior pertuzumab exposure, and our results suggest that many patients receive pertuzumab prior to T-DM1 and our survival outcomes appear similar to other studies.

This real-world evidence together with recent clinical trial data help provide context for treatment options and outcomes in patients with HER2+ mBC who receive treatment post–T-DM1. Short treatment durations and survival were observed in this study of T-DM1 therapy, along with treatment variability and limited benefits with subsequent therapy. As newly approved anti-HER2 therapies are utilized, future research is needed to determine the real-world clinical benefits and how best to optimize utilization and sequencing of these agents to improve outcomes for patients with HER2+ mBC.