Impact of obesity on safety outcomes and treatment modifications with ado-trastuzumab emtansine in breast cancer patients

Abstract

Introduction

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate indicated for the treatment of HER2-positive breast cancer. The 2012 American Society of Clinical Oncology guidelines on chemotherapy dosing in obesity recommend using full weight-based cytotoxic chemotherapy doses to treat obese patients with cancer. These guidelines were published prior to the advent of anticancer antibody-drug conjugates. There is a need to investigate the safety of T-DM1 in obese patients.

Methods

This retrospective chart review included adult patients with breast cancer receiving T-DM1. The primary endpoint was a composite of the incidence of T-DM1 treatment modifications secondary to an adverse event. Secondary outcomes included the incidence of dose reductions, dose delays, treatment discontinuations, and adverse events.

Results

A total of 119 patients with HER2-positive breast cancer who received T-DM1 therapy were included in this study: 44 obese patients and 75 non-obese patients. The composite outcome of treatment modifications due to toxicity was significantly higher in obese patients compared to non-obese patients (45% vs 25%, p = 0.024). Treatment delays were significantly higher in obese patients (36% vs 16%, p = 0.011). All-grade adverse events with a higher incidence in obese patients included left ventricular ejection fraction decrease (11% vs 5%), bilirubin increase (32% vs 12%), thrombocytopenia (61% vs 55%), and peripheral neuropathy (34% vs 27%).

Conclusions

This study suggests obese patients receiving T-DM1 may require more treatment modifications secondary to adverse events compared to non-obese patients. Larger studies are needed to determine if obese patients are at higher risk for specific T-DM1-induced adverse events.

Keywords

Trastuzumab emtansine obesity breast cancer adverse event

Introduction

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the anti-human epidermal growth factor 2 (HER2) antibody trastuzumab with the cytotoxic agent DM1.¹ T-DM1 was approved for the treatment of HER2-positive metastatic breast cancer in patients who have previously received trastuzumab and a taxane, separately or in combination, in February 2013.² In May of 2019, T-DM1 was approved as adjuvant treatment for HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based therapy.³ T-DM1 is initially dosed at 3.6 mg/kg given as an intravenous infusion with no recommended maximum dose. Common adverse events associated with T-DM1 include peripheral neuropathy, thrombocytopenia, cardiotoxicity, and hepatotoxicity.¹

The 2012 American Society of Clinical Oncology Appropriate Chemotherapy Dosing for Obese Adult Patients with Cancer Guidelines recommend using full weight-based cytotoxic chemotherapy doses to treat obese patients with cancer.⁴ Many of the recommendations in these guidelines were derived from observational studies and retrospective analyses of clinical trials. These guidelines were published before many antibody-drug conjugates, such as T-DM1, and other anticancer targeted therapies were approved. With the advent of antibody-drug conjugates in cancer therapy, there is a need to investigate tolerability and safety of these medications in obese patients. The 3.6 mg/kg dose for T-DM1 was studied and found to be safe for patients in phase I trials.⁵ Dose reductions and treatment discontinuation due to an adverse event have been reported in up to 14% and 18% of patients, respectively, receiving T-DM1 in randomized, controlled trials.^3,6 No dose cap has been used in studies with TDM-1 to the best of our knowledge. The purpose of our study was to determine if obese patients receiving T-DM1 are at an increased risk of dose reductions, delays of treatment, discontinuation of therapy, and adverse events as compared to non-obese patients.

Methods

This was a single-center, retrospective chart review conducted at a large, multistate health system with several different medical oncology practice sites. This study was reviewed and approved by the institutional review board. Eligible patients included those at least 18 years of age who received at least one dose of T-DM1 for the treatment of breast cancer between February 22, 2013 and October 31, 2019. Patients were identified through a computer-generated report via the electronic medical record. Patients were divided into two groups based on their body mass index (BMI): non-obese (BMI < 30) and obese (BMI ≥ 30). Patient demographics collected include age, sex, ethnicity, body mass index, breast cancer stage, and comorbidities.

The primary outcome was a composite of the incidence T-DM1 treatment modifications secondary to an adverse event. Treatment modifications were defined as a dose reduction from the initial starting dose, delay in treatment, or discontinuation of therapy. Secondary outcomes included the incidence of dose reductions, dose delays, treatment discontinuations, and T-DM1-induced adverse events. Adverse events of interest included hepatotoxicity, cardiotoxicity, thrombocytopenia, and new or worsening peripheral neuropathy. Hepatotoxicity was defined as elevations in alanine transaminase (ALT), aspartate transaminase (AST), and/or total bilirubin. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction. The severity of thrombocytopenia, hepatic, and cardiac adverse events was graded by the investigators according to the Common Terminology Criteria for Adverse Events version 5.0.⁷ Due to the present study being retrospective in nature, peripheral neuropathy was not graded in severity and was determined to be either new-onset or worsening peripheral neuropathy based on physician clinic visit notes. Indications for T-DM1 treatment modifications were determined via physician clinic visit notes.

A total of 114 patients are needed to detect a 25% difference in the proportion of T-DM1 treatment alterations between obese and non-obese patients with a 1:2 allocation ratio with an α of 0.05 and power of 80%. Nominal data were analyzed using Fisher’s exact tests. The distribution of continuous data was tested for normality with a Shapiro-Wilk normality test; a p < 0.05 represented a nonparametric distribution of the data. Continuous data were compared using Student’s t-test for normally distributed data and Mann-Whitney U test for nonparametric data. R version 3.6.2 was used for all data analysis.

Results

A total of 119 patients with breast cancer received a dose of T-DM1 between February 22, 2013 and October 31, 2019. Baseline patient demographics are described in Table 1. Forty-four patients were obese, and seventy-five patients were non-obese. Of the obese patients, 25 (57%), 12 (27%), and 7 (16%) patients met the criteria for Class I, Class II, and Class III obesity, respectively. The median age was 56 years old (range 29-88). Most patients had stage IV breast cancer (n = 87; 73%). Baseline laboratory values including LVEF, ALT, AST, and total bilirubin were similar between both groups.

Table 1.

Baseline patient demographics.

	Obese(n = 44)	Non-Obese(n = 75)	p value
Age (years), median (range)	56 (29–79)	57 (29–88)	0.184
No. of females (%)	43 (98%)	75 (100%)	0.370
Race
White	23 (52%)	55 (73%)	0.028
Black	21 (48%)	19 (25%)	0.016
Other	0	1 (2%)	1.0
Weight (kg), median (range)	94.4 (66.8–149.5)	64.8 (44.0–88.0)	<0.001
BMI (kg/m²), median (range)	34.0 (30.3-51.6)	25.1 (17.8–29.6)	<0.001
Obesity class
Class I (BMI 30–34.9)	25 (57%)	N/A	N/A
Class II (BMI 35–39.9)	12 (27%)
Class III (BMI >40)	7 (16%)
Hormone receptor status
ER positive	29 (66%)	49 (65%)	0.703
PR positive	19 (43%)	36 (48%)	0.704
Tumor stage, no. of patients (%)
I	1 (2%)	0	0.370
II	9 (21%)	16 (21%)	1.0
III	3 (7%)	3 (4%)	0.669
IV	31 (70%)	56 (75%)	0.671
Prior therapy, no. of patients (%)
Anthracycline	5 (11%)	13 (17%)	0.438
Capecitabine	7 (16%)	9 (12%)	0.585
Carboplatin	23 (52%)	32 (43%)	0.345
Cyclophosphamide	7 (16%)	18 (24%)	0.356
Endocrine therapy	18 (41%)	38 (51%)	0.345
Eribulin	1 (2%)	1 (1%)	1.0
Pertuzumab	36 (82%)	58 (77%)	0.645
Taxane	41 (93%)	64 (85%)	0.249
Trastuzumab	44 (100%)	71 (95%)	0.295
Vinorelbine	3 (7%)	4 (5%)	0.709
Past medical history
Diabetes	10 (23%)	7 (9%)	0.058
Hepatic disease	3 (7%)	2 (3%)	0.357
Peripheral neuropathy	13 (30%)	18 (24%)	0.523
Baseline LVEF (%), median (range)	60 (50–70)	60 (45–75)	0.149
Baseline ALT (IU/L), median (range)	22 (7–198)	20 (6–106)	0.273
Baseline AST (IU/L), median (range)	25 (9–177)	26 (11–351)	0.778
Baseline Total bilirubin (mg/dL), median (range)	0.45 (0.1–2.1)	0.5 (0.2–11.2)	0.995

ALT: alanine transaminase; AST: aspartate transaminase; BMI: body mass index; LVEF: left ventricular ejection fraction.

The primary end point of treatment modifications due to TDM-1-induced adverse events was significantly higher in obese patients compared to non-obese patients (45% vs 25%, p = 0.028) (Table 2). Treatment delays due to toxicity were significantly higher in obese patients compared to non-obese patients (36% vs 16%, p = 0.015). The most common adverse event to contribute to T-DM1 treatment delays in the obese group was thrombocytopenia (14%). No significant difference was found between obese and non-obese patients regarding T-DM1 dose reductions (23% vs 15%, p = 0.322) and treatment discontinuations (16% vs 9%, p = 0.378). The most common adverse event to contribute to T-DM1 dose reductions was thrombocytopenia (9%) in the obese group and peripheral neuropathy (7%) in the non-obese group. The most common adverse event to contribute to treatment discontinuation in the obese group was peripheral neuropathy (9%).

Table 2.

Treatment delays, T-DM1 dose reductions, and treatment discontinuation.

	Obese(n = 44)	Non-Obese(n = 75)	p value
Composite of treatment delay, dose reduction, or treatment discontinuation due to toxicity	20 (45%)	19 (25%)	0.028
Treatment delay for toxicity	16 (36%)	12 (16%)	0.015
ADRs contributing to treatment delay
Decreased LVEF	2 (5%)	1 (1%)	0.554
Fatigue	1 (2%)	2 (3%)	1.0
Hepatotoxicity	3 (7%)	2 (3%)	0.357
Musculoskeletal pain	1 (2%)	0	0.370
Nausea/vomiting	1 (2%)	0	0.370
Peripheral neuropathy	2 (5%)	2 (3%)	0626
Rash	1 (2%)	0	0.370
Thrombocytopenia	6 (14%)	3 (4%)	0.302
Dose reduction for toxicity	10 (23%)	11 (15%)	0.322
ADRs contributing to T-DM1 dose reduction
Hepatotoxicity	2 (5%)	3 (4%)	1.0
Fatigue	0	3 (4%)	0.214
Musculoskeletal pain	1 (2%)	1 (1%)	1.0
Peripheral neuropathy	2 (5%)	5 (7%)	0.362
Thrombocytopenia	4 (9%)	1 (1%)	0.149
Treatment discontinuation for toxicity	7 (16%)	7 (9%)	0.378
ADRs contributing to T-DM1 discontinuation
Decreased LVEF	1 (2%)	1 (1%)	1.0
Hepatotoxicity^a	2 (5%)	2 (3%)	0.626
Keratopathy	1 (2%)	0	0.370
Peripheral neuropathy	4 (9%)	2 (3%)	0.192
Pneumonitis	0	1 (1%)	1.0

LVEF: left ventricular ejection fraction; T-DM1: trastuzumab emtansine.

^aHepatotoxicity defined as increases in AST, ALT, and/or total bilirubin.

Within the obese cohort, the primary endpoint of treatment modifications due to T-DM1-induced adverse events was met in 11 (44%), 7 (58%), and 2 (29%) patients with Class I, Class II, and Class III obesity, respectively. In patients with Class I, II, and III obesity. T-DM1 treatment delays occurred in 8 (32%), 6 (50%), and 2 (29%) patients with Class I, II, and III obesity, respectively. T-DM1 was dose reduced in 5 (20%), 4 (33%), and 1 (14%) patient with Class I, II, and III obesity, respectively.

The most common adverse events were aspartate transaminase elevations (74%), and thrombocytopenia (57%), with similar rates between both groups (Table 3). An increase in total bilirubin occurred in 32% of patients in the obese group compared to 12% of patients in the non-obese group. A decrease in left ventricular ejection fraction occurred in 11% of obese patients compared to 5% of non-obese patients. New or worsening of peripheral neuropathy occurred in 34% of obese patients compared 27% of non-obese patients. More cases of new-onset peripheral neuropathy were reported in the obese group (32%) compared to the non-obese group (23%). One patient in each group experienced an infusion-related reaction due to T-DM1.

Table 3.

Select adverse events with T-DM1.

	Obese (n = 44)		Non-Obese(n = 75)
	Any grade	Grade 3/4	Any grade	Grade 3/4
ALT increase	12 (27%)	0	25 (33%)	0
AST increase	34 (77%)	0	54 (72%)	3 (4%)
Bilirubin increase	14 (32%)	0	9 (12%)	1 (1%)
LVEF decrease	5 (11%)	0	4 (5%)	0
Thrombocytopenia	27 (61%)	2 (5%)	41 (55%)	4 (5%)

ALT: alanine transaminase; AST: aspartate transaminase; LVEF: left ventricular ejection fraction.

Discussion

While previous studies have reported the efficacy and safety of T-DM1, this study is among the first to look at incidence of safety outcomes in obese patients compared to non-obese patients. Studies have investigated the impact of obesity on survival outcomes in HER2-positive metastatic breast cancer.^8,9 Krasniqi et al reported a cohort study that found a BMI ≥ 30 correlated with worse overall survival in patients with HER2-positive metastatic breast cancer who received pertuzumab and/or T-DM1.⁸ In contrast, Martel et al found that BMI was not associated with decreased overall survival in HER2-positive breast cancer patients treated with trastuzumab in a retrospective study.⁹ Further studies are needed to determine if obesity has an impact on survival outcomes in breast cancer patients.

Observational studies have demonstrated an increased risk of cardiotoxicity in obese patients with breast cancer receiving trastuzumab.^10,11 The effect of other comorbidities including dyslipidemia and diabetes have also been found to contribute to the incidence of trastuzumab-related cardiotoxicity.¹¹ Since trastuzumab is the antibody portion of T-DM1, we looked at the incidence of left ventricular ejection fraction decreases in obese patients to assess for T-DM1-induced cardiotoxicity. In our study, more patients in the obese group experienced a decrease in left ventricular ejection fraction in the obese group (11%) compared to the non-obese group (5%). In our total population, a decrease in left ventricular ejection fraction occurred in approximately 8% of our patients, which differs from the reported frequency of about 3%.¹ However, all the instances were low grade and there were no cases of serious grade 3/4 heart failure.

T-DM1 has been associated with the development of hepatotoxicity and the drug currently carries a boxed warning for this adverse event.¹ A recent meta-analysis found an increased risk of both all-grade and high-grade transaminitis with T-DM1 compared to control treatment, including cytotoxic chemotherapy.¹² In our study, the incidence of serious grade 3/4 elevations in liver function tests was relatively low. Most liver function test elevations in our patient population were grade 1/2. Grade 2 elevations in aspartate aminotransferase and alanine aminotransferase can be managed with a delay in T-DM1 administration until resolved to grade 1 or less.

In our present study, obese patients with a BMI ≥ 30 required more treatment modifications due to toxicity compared to non-obese patients. This composite outcome was mainly driven by a statistically significant difference in the incidence of treatment delays due to toxicity. Thrombocytopenia was the most common cause of treatment delays in our patient population. T-DM1-induced thrombocytopenia is typically managed with a dose delay until platelet recovery, with recommendations for a dose decrease in the event of a patient developing grade 4 thrombocytopenia. Despite the higher incidence of treatment delays in the obese group, there were no differences in the incidence of dose reductions or treatment discontinuation secondary to an adverse event between the two groups.

Limitations to our present study include retrospective study design. Due to the retrospective nature of this investigation, peripheral neuropathy was not able to be prospectively evaluated and graded due to the variable and subjective descriptions of this adverse event. There were more patients in the obese group with confounding factors for peripheral neuropathy including a history of diabetes, pre-existing peripheral neuropathy at baseline, and prior use of vinorelbine. Future studies with a larger patient population and prospective study design are needed as obesity has been shown to be a risk factor in the development of peripheral neuropathy with a variety of other anticancer agents.^13–16 Another limitation with the present study is that it did not evaluate the impact of obesity and treatment alterations on efficacy with T-DM1. In a pooled analysis of two trials evaluating T-DM1 in the metastatic breast cancer setting, early adverse events resulting in T-DM1 dose reductions and treatment interruptions was not associated with worse overall survival or progression-free survival.¹⁷ While the present study found a difference in safety outcomes between obese and non-obese patients receiving T-DM1, the sample size and design of our study limits our ability to make recommendations for alternative dosing methods of T-DM1.

Conclusion

In summary, this study showed that obesity may be associated with more treatment modifications secondary to T-DM1-induced adverse events. Compared to non-obese patients, patients with a BMI ≥ 30 required more treatment delays but did not require more dose reductions or treatment discontinuations due to an adverse event. Obese patients should be monitored closely for adverse events and be managed appropriately.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Moore reports participating on an advisory board for Oncopeptides.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Donald C Moore

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