Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: Pooled analysis in advanced HER2-positive breast cancer

European Journal of Cancer 126 (2020) 65e73

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.ejcancer.com

Original Research

Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: Pooled analysis in advanced HER2positive breast cancer Noam Ponde´ a,b, Lieveke Amaye c, Matteo Lambertini d,e, Marianne Paesmans c, Martine Piccart f, Evandro de Azambuja a,* a

Academic Promoting Team, Research Department, Institut Jules Bordet, Brussels, Belgium AC Camargo Cancer Center, Sao Paulo, Brazil c Statistical Department, Institut Jules Bordet, Brussels, Belgium d Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy e Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy f Research Department, Institut Jules Bordet, Brussels, Belgium b

Received 18 September 2019; received in revised form 25 November 2019; accepted 29 November 2019

KEYWORDS Breast cancer; T-DM1; Cardiotoxicity

Abstract Introduction: T-DM1 has been approved for the treatment of HER2þ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. Methods: We have conducted a pooled analysis of T-DM1 trials in advanced HER2þ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. Results: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 þ pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%e4.3%). Multivariate analysis showed patient’s age 65 (OR 3.0; 95% CI, 1.77e5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29e5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation.

* Corresponding author: Institut Jules Bordet, BLvd de Waterloo, 121, 1000 Brussels, Belgium. E-mail address: [email protected] (E. de Azambuja). https://doi.org/10.1016/j.ejca.2019.11.023 0959-8049/ª 2019 Elsevier Ltd. All rights reserved.

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Conclusion: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment. ª 2019 Elsevier Ltd. All rights reserved.

1. Introduction

2. Methods

Trastuzumab emtansine (T-DM1) is an antibodyedrug conjugate comprising the anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab bound to the anti-microtubule agent emtansine [1]. T-DM1 is currently approved for use in both early and advanced HER2-positive breast cancer. In the advanced setting, T-DM1 proved to be both more effective and less toxic than capecitabine plus lapatinib (in second line) and physicians’ choice of therapy (in third line or more) [2e5]. In the early setting, recent data from the KATHERINE trial showed a substantial improvement in outcomes for patients with residual disease after neoadjuvant therapy with the use of post-neoadjuvant T-DM1 rather than the standard trastuzumab (3 years invasive disease free survival of 88.3% vs 77.0%, hazard ratio 0.50; 95% confidence interval (CI), 0.39e0.64; P < 0.001)6. T-DM1 is therefore currently considered as the standard of care for second-line advanced HER2-positive breast cancer. More recently, it has also become standard as postneoadjuvant treatment for patients who do not achieve a complete pathological response after neoadjuvant trastuzumab with or without pertuzumab. As survival times lengthen in the advanced setting and cure rates improve in the early setting, increasing attention should be payed to toxicities [7,8]. The pivotal trials that led to the approval of trastuzumab revealed that it could cause cardiotoxicity, likely due to the important role played by HER2 signalling in cardiomyocyte function [9]. Though trastuzumab-associated cardiotoxicity is a well-known entity, the cardiotoxicity of more recent anti-HER2 agents is less well understood due to the overall small number of reported patients who experienced cardiotoxicity in each of the individual trials and the unavailability of substantial real world evidence [3,5,10,11]. Following the results of the KATHERINE trial, cardiotoxicity, an adverse event (AE) with potential for short- and long-term morbidity, becomes a particularly relevant subject for research. We have conducted an individual patient-level data pooled analysis of trials testing T-DM1 in the advanced setting to investigate T-DM1-induced cardiotoxicity, with a focus on the incidence of CEs, clinical presentation of CEs, impact on treatment continuity, reversibility as well as in any potential risk factors that could aid in patient selection and follow-up.

2.1. Study design This is an individual patient-level data pooled analysis of seven phase II and III multicentric trials in which TDM1 was tested in advanced HER2þ breast cancer [2e5,10,12e15]. Appendix 1 describes the most important elements of the design of the included trials. Briefly, the included studies were single-arm studies testing TDM1 (three studies) or T-DM1 þ pertuzumab (one study), as well as three studies with two or more arms studying T-DM1 (with or without pertuzumab in comparison with other regimens). Four of these trials were phase II studies and three were phase III studies. Access to individual patient-level data was obtained through the clinical trial data request website (https://www. clinicalstudydatarequest.com). 2.2. Definition of cardiac events Cardiac events were defined as reported AEs in the database, as per the reporting rules used in each trial occurring during study participation (and therefore either during or after study treatment) and included the following categories: (1) congestive heart failure (CHF) of any grade as reported by each trial; (2) reported left ventricular ejection fraction decrease (LVEF drop) of any grade; (3) acute cardiac ischemia of any grade and (4) cardiac arrhythmia of any grade. All CEs reported were counted, regardless of investigator opinion on the relationship between CE and study treatment. Appendix 2 shows the specific terms for reported AEs which were included into each of the abovementioned categories. For patients experiencing multiple reported CEs within the same category, the CE with the highest grade was considered for the purposes of this analysis. For patients with multiple reported CEs in different categories, more than one CE could be counted. Grading was as per the NCI CTCAE grading system used in each individual trial. For the purposes of our analysis, CHF of any grade and grade 3 or 4 LVEF drop were grouped together as this makes more sense from a clinical perspective. Recovery from a CE was defined as the AE being reported as resolved in the clinical database. Duration of CE was defined as the time elapsed between AE start date and end date. Treatment interruptions were defined as any temporary halt in T-DM1 use due to any cause. Treatment discontinuation was defined as the

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permanent halt in T-DM1 treatment due to any cause. Appendix 3 includes the cardiac safety guidelines used in each of the trials, as well as the recommended guidelines on when treatment should be temporarily interrupted or permanently discontinued due to a CE. 2.3. Statistical analysis Patients were included in the analysis if they received at least one dose of T-DM1 (safety analysis), regardless of original treatment assignment (in the randomized trials). To assess the differences in patients with and without CEs in categorical variables, the likelihood ratio chisquare test or Fisher Exact test was used. Odds ratio with 95% confidence limits were calculated. Logistic regression was used to determine the independent risk factors associated with CEs. Stepwise forward variable selection was performed. A loess smoother (locally weighted scatterplot smoother) was applied to assess the evolution of LVEF during the first year from the first dose of T-DM1. We considered a P-value <0.05 as statistically significant. All statistical analyses were performed using the SAS provided by Clinical Trial Transparency (https://mseprod.ondemand.sas.com/ctdt). 3. Results 3.1. Patients characteristics A total of 1961 patients with advanced HER2þ breast cancer who received at least one dose of T-DM1 in seven trials were included in this analysis. Of these, 417 (21.2%) received T-DM1 in combination with pertuzumab and 1544 (78.8%) T-DM1 alone. Mean age was 52.8 (range 25e89) for the entire study population, with only 15% of patients being 65 or older. Median followup was 21 months. At baseline, hypertension was present in 513 (26.2%) patients, while previous heart disease and diabetes were less common, being present in 115 (5.9%) and 177 (9.0%) patients, respectively. In total, 1958 patients had identifiable baseline LVEF measurements, with a mean value of 63% (range 45%e90%). Table 1 summarizes the relevant patient characteristics for the entire study population. Appendix 4 further details patient characteristics. 3.2. Cardiac events in the study population Sixty-six patients experienced at least one CE after receiving T-DM1 (3.37% of the entire study sample). The most common type of CE reported were low-level (grade 1 or 2) LVEF drops which occurred in 40 patients (2.04%). CHF of any grade or grade 3/4 LVEF drops occurred in 14 patients (0.71%), as did cardiac arrhythmias. Cardiac ischemia was reported in two patients (0.1%) totalling 70 CEs. Most patients with CEs

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Table 1 Patient characteristics. Characteristics AGE < 65 65 ETHNICITY Non-Caucasian Caucasian BMI 25 <25 Missing info PREVIOUS HEART DISEASE No Yes HYPERTENSION No Yes DIABETES No Yes PREVIOUS ANTHRACYCLINE No Yes LEFT-SIDE RADIOTHERAPY No Yes BASELINE LVEF <55 55 < 64.9 65 Missing info PERTUZUMAB þ T-DM1 No Yes

Number of Patients (N Z 1961)

Percentage

1667 294

85.0% 15.0%

520 1441

26.5% 73.5%

1031 885 45

54% 46%

1846 115

94.1% 5.9%

1448 513

73.8% 26.2%

1784 177

91.0% 9.0%

718 1243

36.6% 63.4%

1473 488

75.1% 24.9%

146 1016 796 3

7.5% 51.9% 40.7%

1544 417

78.7% 21.3%

BMI: body mass index; LVEF: left ventricular ejection fraction.

had NCI-CTCAE grade 1 (14 patients) or 2 (39 patients) events. Thirteen patients had grade 3 events and no grade 4 events were reported nor were any cases of cardiac death reported either. Table 2 summarizes CEs recorded and their grades. Half of the CEs occurred early with 48% reported within the first 100 days of treatment (approximately five 21-day long cycles of T-DM1 in the usual schedule), with month 2 of treatment being the one with the highest number of events. Few CEs (12%) were reported later than 1 year after the start of study treatment. Fig. 1 represents the timing of CEs in the entire population. The majority of patients experiencing a CE (79%) achieved a cardiac recovery. The median duration of CEs was of 26 days (range 1 daye2 years). Patients without reported CEs had a stable LVEF without any sign of reduction to below normal levels (Fig. 2A). In patients with reported CEs, LVEF dropped rapidly within the first two months of treatment but went on to near recovery within 1 year; nevertheless, levels never fully returned to normal (Fig. 2B).

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Table 2 Cardiac events summary. Incidence Rate (95% CI)

Patients with CHF (any grade) or grade 3/4 LVEF drop Patients with cardiac ischemia Patients with cardiac arrhythmia Patients with grade 1/2 LVEF drop Total number of patients with CEsa

NCI CTCAE Grade I

II

III

IV

14/1961

0.71% (0.39e1.19) 2

1

11

0

2/1961

0.10% (0.01e0.37) 1

1

0

0

also increased the risk of CE on multivariate analysis (odds 5% increase per one-year increase, P-value <0.001). Existence of hypertension at baseline did not add statistically significant information to the above multivariate model (P-value Z 0.27). Duration of previous trastuzumab use, time between last trastuzumab dose and first T-DM1 dose as well as previous anthracycline use were not identified as risk factors for CEs. 3.4. Treatment interruptions and discontinuations

14/1961

0.71% (0.39e1.19) 5

7

2

0

40/1961

2.04% (1.46e2.77) 6

34

0

0

66/1961

3.37% (2.61e4.26) 14

39

13

0

Note: CHF: congestive heart failure; CI: confidence interval; NCICTCAE: National Cancer Institute e Common Terminology Criteria for adverse events; LVEF: left ventricular ejection fraction; CE: cardiac event. a A patient can have more than one cardiac event. In total, 70 cardiac events were seen in 66 patients.

3.3. Risk factors for cardiac events Table 3 shows the univariate and multivariate analyses to identify baseline characteristics that could predict the occurrence of a CE during T-DM1 treatment. On univariate analysis; patients with CEs tended to be older, of Caucasian ethnicity, more often had hypertension at study entry and had a LVEF <55% at baseline. They were, likewise, more often treated with a TDM1 þ pertuzumab combination. In stepwise variable selection in a multivariate analysis, the following independent risk factors remained significant: age 65 (OR 3.0; 95% CI, 1.77e5.14; P-value <0.001); baseline LVEF<55% (OR 2.62; 95% CI, 1.29e5.32; Pvalue Z 0.008); and concomitant pertuzumab use (OR 2.08; 95% CI 1.23e3.51; P-value Z 0.006). Patient’s age

The rate of patients with a least one temporary treatment interruption due to an AE was 56.1% (37/66) in patients with CEs versus 27.8% (527/1895) in patients with only non-cardiac AEs, P-value <0.001 (Table 4). Furthermore, in 21 of the 37 patients (57%) with a cardiac AE who interrupted treatment due to AE, the cardiac AE was reported as the cause of interruption. Median time to temporary treatment interruption was 4 months. The rate of patients who discontinued treatment due to AE was 28.8% (19/66) in patients with CEs versus 10.3% (195/1895) in patients with only non-cardiac AEs, P-value <0.001. In 11 of the 19 patients (58%) with a CE who discontinued treatment due to AE, the CE was reported as having caused the treatment discontinuation. Median time to treatment discontinuation was 3 months. 4. Discussion This is to our knowledge the largest study conducted in order to evaluate T-DM1-associated cardiotoxicity, including data from seven multicentric phase II and III trials. Our results are reassuring, showing that CEs during T-DM1 use are uncommon, at least in a clinical trial setting, in which patients tend to be highly selected [16]. On the other hand, our data on treatment interruptions and discontinuations suggest a meaningful impact of cardiotoxicity, however rare they may be, on the ability to continue treatment, though this is likely

Fig. 1. Timing of occurrence of cardiac events. Legend: no legend necessary.

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Fig. 2. A: LVEF measurements during T-DM1 treatment for patients with cardiac events (CEs). Legend: left ventricular ejection fraction within 1 year of baseline measurements for patients: Patients without CEs; the red curve is the estimated loess smoother, grey curves show the 95% confidence limits. B; LVEF measurements during T-DM1 treatment for patients without CEs. Legend: B: patients with CEs. Red curve is the estimated loess smoother, grey curves show the 95% confidence limits. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

due to the strict discontinuation rules used in clinical trials. It is also notable that patients who develop CEs do seem to experience a long-term (longer than 1 year) small decline in LVEF levels as compared to baseline (Fig. 2A). Most patients (78%) in our sample recovered from CEs. Unlike in the clinical trial setting, patients receiving T-DM1 and experiencing a CE should not be considered for interruption/discontinuation as first measure, unless the event is severe and symptomatic, given the important benefit derived from this drug. The results of KATHERINE have radically changed the predicted number of patients who will

be exposed to T-DM1. Considering the much larger number of patients who are diagnosed with early disease, as well as the strong trend towards neoadjuvant treatment in early HER2þ breast cancer, TDM1 toxicities with a potential for long-term consequences are an important topic for deeper research. In the KATHERINE trial, only 1.4% of patients (10 patients) discontinued treatment due to an LVEF drop in the trastuzumab arm, and 1.2% (9 patients) in the T-DM1 arm [6]. The short follow-up period for the presented data, however, precludes a better understanding of the potential for long-term cardiac

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Table 3 Risk factors for cardiac events (univariate and multivariate). Characteristic

Cardiac Event No (N Z 1895)

Univariate Analysis Yes (N Z 66)

Multivariate Analysis

Odds Ratio

AGE (in years) <65 1623 (85.7%) 44 (66.7%) 2.98 (65 vs. < 65) 65 272 (14.4%) 22 (33.3%) ETHNICITY Non-Caucasian 509 (26.8%) 11 (16.7%) 1.84 (Caucasian vs. Caucasian 1386 (73.1%) 55 (83.3%) non-Caucasian) BODY MASS INDEX ((kg/m2) 25 990 (53.5%) 41 (62.1%) 1.42 (25 vs. < 25) <25 860 (46.5%) 25 (37.9%) PREVIOUS HEART DISEASE No 1786 (94.3%) 60 (90.9%) 1.64 (yes vs. no) Yes 109 (5.8%) 6 (9.1%) HYPERTENSION No 1407 (74.3%) 41 (62.1%) 1.76 (yes vs. no) Yes 488 (25.8%) 25 (37.9%) DIABETES No 1727 (91.1%) 57 (86.4%) 1.62 (yes vs. no) Yes 168 (8.9%) 9 (13.6%) LEFT SIDE RADIOTHERAPY No 1429 (75%) 44 (67%) 1.53 (yes vs. no) Yes 466 (25%) 22 (33%) PREVIOUS ANTHRACYCLINE USE No 690 (36.4%) 28 (42.4%) 0.78 (yes vs. no) Yes 1205 (63.6%) 38 (57.6%) PREVIOUS TRASTUZUMAB USE No 529 (27.9%) 20 (30.3%) 0.89 (yes vs. no) Yes 1366 (72.1%) 46 (69.7%) TRASTUZUMAB DURATIONa <1 year 540 (41.7%) 14 (35.0%) 1.33 (1 year vs. < 1) 1e2 years 383 (29.6%) 12 (30.0%) >2 years 371 (28.7%) 14 (35.0%) TIME FROM LAST TRASTUZUMAB DOSE TO RANDOMIZATION <1 year 976 (74.4%) 26 (63.4%) 1.68 (1 year vs. < 1) 1e2 years 188 (14.3%) 10 (24.4%) >2 years 147 (11.2%) 5 (12.2%) BASELINE LVEF <55 136 (7.2%) 10 (15.2%) 2.31 (<55 vs.  55) 55e64.9 985 (52.1%) 31 (47.0%) 65 771 (40.8%) 25 (37.9%) T-DM1 CONCOMITANT WITH PERTUZUMABb No 1501 (79.2%) 43 (65.2%) 2.04 (yes vs. no) Yes 394 (20.8%) 23 (34.9%)

95% IC

P-value

Odds Ratio

95% IC

P-value

1.76e5.06

<0.001

3.0 (65 vs. < 65)

1.77e5.14

<0.001

0.95e3.54

0.05

0.86e2.36

0.17

0.69e3.88

0.28

1.06e2.92

0.03

0.79e3.34

0.19

0.91e2.59

0.12

0.44e1.28

0.32

0.52e1.52

0.67

0.69e2.57

0.39

0.88e3.21

0.13

1.15e4.62

0.03

2.62 (<55 vs.  55)

1.29e5.32

0.008

1.21e3.42

0.009

2.08

1.23e3.51

0.006

Note: LVEF Z left ventricular ejection fraction; y Z year. a All instances of use are added together for patients who received trastuzumab as part of more than one treatment regimen. b At least one dose.

sequelae. In the KRISTINE trial, which compared chemotherapy plus dual blockade with trastuzumab and pertuzumab versus T-DM1 plus pertuzumab

only one case of LVEF drop was reported in the TDM1 arm, and no cases of CHF [11]. Although again, this is reassuring, longer follow-up and real-

Table 4 Interruptions and discontinuations due to AEs. Category

Discontinuation Due to any AE

Due to CE

Due to any AE

Due to CE

All patients (N Z 1961) Patients with CE (N Z 66) Patients without CEs (N Z 1895)

214 (10.9%) 19 (28.8%) 195 (10.3%)

NA 11 (16.7%) NA

564 (28.8%) 37 (56.1%) 527 (27.8%)

NA 21 (31.8%) NA

Note: AE: adverse events, CE: cardiac event.

At Least one Treatment Interruption

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life data are necessary to better evaluate the longterm consequences of T-DM1 cardiotoxicity. Our study also suggests that a few specific risk factors can increase the risk of CEs. Age (65) was the most clinically important among them, while increasing age augmented the risk of CE by 5%. Age as a risk factor is in line with findings from the studies conducted on trastuzumab-associated cardiotoxicity. However, it is important to note that the trastuzumab registration trials (HERA, NSABP B-31 and N9831) have generally shown that patients 60 are at a higher risk of CE. The discrepancy (65 vs. 60 years) is likely explained by a difference in the number of older patients taking part in the studies, which was very small in the trastuzumab registration trials [17,18]. Clearly, specific studies targeted at better understanding the toxicity of T-DM1 in the older population are necessary, particularly trials that integrate older specific evaluation of toxicity and functionality [19]. The sole data point currently available on the toxicity of T-DM1 in older patients (including 373 patients 65 or older) suggests that older patents have a globally higher risk of T-DM1 toxicity (not cardiac-specific) [20]. A baseline LVEF below 55% was also identified in multivariate analysis as an important risk factor. Considering that in previous adjuvant trastuzumab studies, including the recently presented combined analysis of HERA, NSABP-B31 and NCCTCG 9831, LVEF values at the lower end of the normal spectrum were also associated with CEs, closer follow-up when introducing T-DM1 in patients with LVEF values below 55% [17,21e23]. This could include previous evaluation with a cardiologist, introduction of cardio-protective strategies and/or shorter periods between echocardiograms. The increased risk of CEs in patients receiving combined T-DM1 þ pertuzumab treatment was surprising, considering the fact that so far studies conducted in the early and advanced disease setting with trastuzumab þ pertuzumab have not identified pertuzumab use as increasing the risk of trastuzumabassociated cardiotoxicity [24e27]. Nevertheless, it is important to stress that the overall percentage of patients who received T-DM1þ pertuzumab and developed CEs was relatively low (23/417 Z 5.5%) and that only 7 (1.7%) were of grade 3. Moreover, these results cannot be extrapolated to trastuzumab plus pertuzumab combinations as the possibility that emtansine can cause cardiotoxicity remains, based on pre-clinical evidence [28]. Additionally, the lack of increased risk for patients with previous anthracycline use likely reflects the time elapsed between T-DM1 use and anthracycline use. For trastuzumab, concomitant or sequential use with anthracyclines is one of the most important risk factors for cardiotoxicity [9]. Our study has some limitations: (i) definitions of CEs were as per AEs reported in the individual trials, and are

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therefore not homogeneous; (ii) the shorter cardiac follow-up period in these trials precludes a deeper understanding of what can be the medium- and long-term consequences from a cardiac stand point for these patients, an important point given the substantial increases in overall survival seen in the years after CLEOPATRA and EMILIA; (iii) we were not able to perform any comparison between T-DM1-containing and nonTDM1 containing arms which would add additional clinical significance to our study; (iv) we cannot identify whether reported CEs are exclusively due to the trastuzumab component or whether emtansine contributes to it to some level. The similarity in terms of presentation, clinical course and risk factors between trastuzumabassociated cardiotoxicity and T-DM1-associated cardiotoxicity suggest that it is the trastuzumab component, and not the emtansine component, which is the main driver of cardiotoxicity. Available in vitro data suggest that T-DM1, however, causes morphologic and functional damage to cardiomyocytes that is more akin to that of anthracyclines than the strictly functional nature of trastuzumab or pertuzumab toxicity [28]. Finally and most importantly, patients who enter clinical trials are often substantially healthier as compared to the average patient seen in clinical practice. It is therefore possible that in ‘real life’ T-DM1-associated cardiotoxicity is more common than in our sample, and this needs to be therefore further studied in large real world datasets. Despite these limitations, this study remains the largest data-set focusing exclusively on CEs occurring during T-DM1 use in the advanced setting and provides both re-assurance to most patients and specific risk factors which can help guide treatment choices. To conclude, our individual-patient level pooled analysis suggests that T-DM1 associated cardiotoxicity is a rare event, usually of low grade and reversible, but with the potential of negatively impacting the continuity of treatment. Further study of T-DM1-associated cardiotoxicity in the early setting and, particularly, in older patients (70 or more) is warranted. Funding sources This study received a grant from ‘Les Amis de L’institut Bordet in 2018 (grant number 2018-02). Conflict of interest Noam Ponde´ has received fees from Mundipharma and AstraZeneca, and travel grants from Novartis, Roche/Genentech and Mundipharma. Lieveke Amaye has no conflicts to report. Matteo Lambertini has received honoraria from Theramex, Takeda and Roche and served as consultant for Roche Diagnostic.

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Marianne Paesmans has no conflicts to report. Martine Piccart is a board member for Oncolytics and Radius. She has received honoraria from AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche PharmaMar, and Seattle Genetics. Her institute has received research grants from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier and Synthon. Evandro de Azambuja has received honoraria and is a member of advisory boards for Roche/Genetench; she received travel grants from Novartis, GSK and Roche/ Genentech. The institution she works for has received research grants for Roche/Genentech, AstraZeneca, GSK, Novartis and Servier.

Acknowledgements No acknowledgements. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejca.2019.11.023.

References [1] LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2positive cancer. Clin Cancer Res Off J Am Assoc Cancer Res 2011;17(20):6437e47. https://doi.org/10.1158/1078-0432.CCR-110762. [2] Krop IE, Lin NU, Blackwell K, Guardino E, Huober J, Lu M, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol 2015;26(1):113e9. https://doi.org/10.1093/annonc/mdu486. [3] Verma S, Miles D, Gianni L, Krop IE, Welslau M, Bines J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367(19):1783e91. https: //doi.org/10.1056/NEJMoa1209124. [4] Krop IE, Kim S-B, Martin AG, LoRusso PM, Ferrero J-M, Badovinac-Crnjevic T, et al. Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 2017;18(6):743e54. https://doi.org/10.1016/S14702045(17)30313-3. [5] Krop IE, Kim S-B, Gonza´lez-Martı´n A, LoRusso PM, Ferrero JM, Smitt M, et al. 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):689e99. https: //doi.org/10.1016/S1470-2045(14)70178-0. [6] von Minckwitz G, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab e mtansine for residual invasive HER2-positive breast cancer. N Engl J Med December 2018. https: //doi.org/10.1056/NEJMoa1814017.

[7] Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin adjuvant (HERA) trial. The Lancet February 2017. https://doi.org/10.1016/S01406736(16)32616-2. [8] Roth Joshua A. Survival gains from advances in first-line systemic therapy for HER2 overexpressing metastatic breast cancer in the U.S., 1995-2015. In: Presented at the: ESMO; 2017 [Madrid]. [9] Ponde´ NF, Lambertini M, de Azambuja E. Twenty years of antiHER2 therapy-associated cardiotoxicity. ESMO Open 2016;1(4). https://doi.org/10.1136/esmoopen-2016-000073. e000073. [10] Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2epositive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol 2017;35(2):141e8. https://doi.org/10.1200/JCO.2016.67.4887. [11] Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol November 2017. https://doi.org/10.1016/S1470-2045(17)30716-7. [12] Burris HA, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limetani S, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;29(4):398e405. https: //doi.org/10.1200/JCO.2010.29.5865. [13] Krop IE, Beeram M, Modi S, Jones SF, Scott NH, Yu W, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010;28(16):2698e704. https://doi.org/10.1200/JCO.2009.26.2071. [14] Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, et al. A phase II study of trastuzumab emtans ine in patients with human epidermal growth factor receptor 2positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012;30(26):3234e41. https: //doi.org/10.1200/JCO.2011.40.5902. [15] Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 2013;31(9):1157e63. https://doi.org/10.1200/JCO.2012. 44.9694. [16] Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials 2015;16(1). https://doi.org/10.1186/s13063015-1023-4. [17] de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, et al. Trastuzumab-associated cardiac events at 8 years of median follow-up in the herceptin adjuvant trial (BIG 1-01). J Clin Oncol 2014;32(20):2159e65. https://doi.org/10.1200/JCO.2013.53.9288. [18] Brollo J, Curigliano G, Disalvatore D, Marrone MF, Criscitiello C, Bagnardi V, et al. Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: a systematic review of randomized controlled trials. Cancer Treat Rev 2013;39(1):44e50. https://doi.org/10.1016/j.ctrv.2012.03.009. [19] Hurria A, Mohile SG, Dale W. Research priorities in geriatric oncology: addressing the needs of an aging population. J Natl Compr Cancer Netw JNCCN 2012;10(2):286e8. [20] Barrios C, Anton A, Delaloge S, Montemurro F, Wuerstlein R, Robb S, et al. Safety of trastuzumab emtansine (T-DM1) in 373

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[21]

[22]

[23]

[24]

patients 65 years or older with HER2-positive advanced breast cancer: a subgroup analysis of the Kamilla study. ASCO 2015; 33(15_suppl):603. https://doi.org/10.1200/jco.2015.33.15_suppl.603. Advani PP, Ballman KV, Dockter TJ, Colon-Otero G, Perez EA. Long-term cardiac safety analysis of NCCTG N9831 (alliance) adjuvant trastuzumab trial. J Clin Oncol 2016;34(6):581e7. https: //doi.org/10.1200/JCO.2015.61.8413. Romond EH, Jeong J-H, Rastogi P, Swain SM, Geyer EG, Ewer MS, et al. Seven-yearfollow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012;30(31): 3792e9. https://doi.org/10.1200/JCO.2011.40.0010. De Azambuja E, Ponde N, Procter M, Rastogi P, Cecchini RS, Lambertini M. A pooled analysis of the cardiac events in the trastuzumab adjuvant trials. Breast Cancer Re Treat 2019. https: //doi.org/10.1007/s10549-019-05453-z. Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early

[25]

[26]

[27]

[28]

73

HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(1):25e32. https://doi.org/10.1016/S1470-2045(11)70336-9. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017; 377(2):122e31. https://doi.org/10.1056/NEJMoa1703643. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24(9):2278e84. https: //doi.org/10.1093/annonc/mdt182. Swain SM, Baselga J, Kim S-B, Ro J, Semiglasov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372(8):724e34. https://doi.org/10.1056/NEJMoa1413513. Iaffaioli RV, Coppola C, Piscopo G, Riccio A, Rienzo C, Maurea C, et al. Cardiotoxic effects of the novel anti-ErbB2 agent ado trastuzumab emtansine. Ann Oncol 2016;27(suppl_6). https: //doi.org/10.1093/annonc/mdw362.24.