Efficacy of trastuzumab-emtansine in breast cancer patients prior treated with pertuzumab

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Örebro University

School of Medical Sciences Degree project, 15 ECTS May 2019

Efficacy of trastuzumab-emtansine in breast cancer

patients prior treated with pertuzumab

Version 2

Author: Anu-Johanna Sundfors Supervisor: Antonios Valachis, MD, PhD

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ABSTRACT

Background: T-DM1 is preferred treatment option as 2nd line treatment in patients with

metastatic HER2-positive breast cancer after progression in trastuzumab-based 1st line

treatment. When T-DM1 became the preferred treatment strategy as 2nd line therapy, the 1st

line treatment did not include pertuzumab which is currently standard of care. Therefore, there is lack of knowledge about T-DM1 response in patients who received prior pertuzumab.

Aim: To study the efficacy of T-DM1 in patients prior treated with pertuzumab as a 1st line treatment compared to patients without prior pertuzumab use.

Patients and methods: We performed a retrospective cohort study including all patients with

HER2 positive metastatic breast cancer treated with T-DM1 at 3 Hospitals (Eskilstuna, Uppsala, Örebro) between 2014 and 2017. This study included 35 patients.

Results: Objective response rate (complete response or partial response), stable disease and

progressive disease was 50%, 33.3% and 16.7%, respectively in patients with prior

pertuzumab treatment whereas the rates in no prior pertuzumab patients were 41.2%, 29.4% and 29.4%, respectively. No significant difference in time to progression (TTP) was observed between prior pertuzumab and no prior pertuzumab groups (log-rank test with p-value=0.227).

TTP was comparable between patients who received T-DM1 as 2nd line and patients who

received T-DM1 as ≥ 3rd line treatment (log-rank test with p-value=0.601).

Conclusion: Prior pertuzumab use did not seem to jeopardize T-DM1 efficacy in breast

cancer patients with HER2-positive metastatic breast cancer. T-DM1 is an effective treatment strategy irrespective of the line of treatment.

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INTRODUCTION

Breast cancer is the most common cancer disease amongst women. During 2017, 7687 patients were diagnosed with breast cancer [1], and 1400 died of this disease in Sweden[2]. Breast cancer is the uncontrolled proliferation of breast cells that attains malignancy [3]. The most common sites for metastasis are bone, lymph nodes, lungs, brain and liver [4].

Of the 7687 women who were diagnosed with breast cancer, 1048 were HER2- positive, 13.6% of all breast cancer patients [1]. HER2, also known as erbB2, is a tyrosine kinase receptor (TRK) belonging to epidermal growth factor (EGF) family together with 3 other receptors; HER1(erbB1), HER3(erbB3) and HER4(erbB4) [5: 2]. Her2 is a more potent oncogene than the other receptors in EGF family because it does not have an identifiable ligand compared the other receptors. It is capable of undergoing ligand- independent dimerization with other EGF receptors, most likely with HER3. Amplification of HER2 leads to an altered equilibrium, with higher rate of

heterodimer formation rather than homodimer formation, leading to a prolonged and enhanced downstream signalling and consequently to a higher proliferation activity, growth and depressed adhesion and apoptosis [5–7].

HER2-positive breast cancer has traditionally been associated with poor prognosis, but with trastuzumab the prognosis has radically been improved [8]. Trastuzumab is a humanized

monoclonal antibody that targets an extracellular domain of HER2-receptor and is the cornerstone of treatment strategy in all settings in patients with HER2- positive breast cancer [8]. In recent years, a second monoclonal antibody against HER2 (Pertuzumab) has been approved. Pertuzumab binds to a different extracellular domain on HER2- receptor than trastuzumab and its addition to standard treatment with chemotherapy and trastuzumab in patients with HER2-positive metastatic breast cancer has shown a 16-month improvement in median overall survival [9]. As a result, the current first-line treatment for HER2-positive metastatic breast cancer is a combination of chemotherapy, trastuzumab and pertuzumab (Figure 1 and 2).

In case of progression to first-line treatment, trastuzumab-emtansine (T-DM1) is recommended as second line therapy [10]. T-DM1 is trastuzumab linked to DM1, which is a microtubule inhibitor. The linkage is caused by a nonreducible thioether linkage (SMCC). Trastuzumab functions as a conjugate by binding to HER2- receptor. Thereafter the DM1 is internalized in the cell via

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endocytosis. When internalized, cytotoxic metabolites are released after undergoing proteolytic degradation in the lysosome and thereafter causing cell apoptosis [11: 2].

Figure 1. Illustration of treatment pattern in patients with metastatic HER2- positive breast cancer

before T-DM1 treatment was approved as a treatment option.

Figure 2. Illustration of treatment pattern in patients in metastatic HER2-positive breast cancer

after T-DM1 was approved as a treatment option in 2014.

The pivotal randomised phase 3 EMILIA study is a study done to investigate the efficacy of T-DM1 as a second-line treatment compared to the former second-line treatment consisting of lapatinib and capecitabin in HER2-positive locally advanced or metastatic breast cancer. This study included a total of 991 patients from 213 centres in 26 countries and showed an overall survival benefit of nearly 6 months in favour of T-DM1. However, no patient in EMILIA study

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received pertuzumab as a part of 1st line treatment because the drug was available only as

investigational therapy at the time being. As a result, the efficacy of T-DM1 in patients previously treated with pertuzumab has not been investigated in prospective studies [12].

The first report to demonstrate T-DM1 efficacy in patients with prior treatment of pertuzumab was done by Dzimitrowicz et al. This retrospective study included 78 patients from three institutions in the USA between years 2013 and 2015. This study provides support for meaningful activity of T-DM1 as a second-line treatment in patients with HER2 positive MBC irrespective of prior pertuzumab use [13: 1]. Additional evidence of T-DM1 efficacy in patients previously treated with pertuzumab was also observed in an exploratory sub-analysis of two randomized trials including 76 patients [14]. However, two additional studies showed a potential detrimental effect of prior pertuzumab use on T-DM1 efficacy [15,16]. The biological rationale of a potential detrimental effect of prior pertuzumab use on T-DM1 is the risk that both trastuzumab and

pertuzumab may cause a downregulation of HER2, therefore limiting the efficacy of T-DM1 [16]. The purpose of this study was to explore the efficacy of T-DM1in pertuzumab-naïve patients

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PATIENTS AND METHODS

Patient population

We performed a retrospective cohort study including all patients with HER2 positive metastatic breast cancer treated with T-DM1 at 3 Hospitals (Eskilstuna, Uppsala, Örebro) between 2014 and 2017. This study included 35 patients. We included all patients that received T-DM1 regardless line of treatment. We excluded patients that had received T-DM1 as a part of curable treatment. Patients were identified via electronic databases for chemotherapy treatment delivery in Eskilstuna

(MOSAIQ) and Örebro (Cytodos) and via the real-time database for breast cancer patients in Uppsala (Real-Q).

Data collection

The following data items were collected: Age at diagnosis; comorbidities according to Charlson comorbidity index; diabetes; hypertension; cardiac disease; date of diagnosis of primary breast cancer; metastasis at diagnosis; histological type of breast cancer; type of surgical resection of breast and lymph nodes; TNM at primary diagnosis; grading according to Elston-Ellis method; stage at diagnosis; ER-status; PgR-status; HER2 IHC; HER2 FISH(gene copy number and ratio); Ki-67; PAD number; type of adjuvant treatment; end date of adjuvant trastuzumab; recurrence within 1 year from trastuzumab; date of metastatic recurrence; age at metastatic recurrence; sites of metastasis at recurrence; biopsy when metastatic recurrence; performance status at recurrence; date initiation trastuzumab; combination with pertuzumab; combination with chemotherapy or endocrine therapy; tumour response; start date for maintenance treatment with trastuzumab,

maintenance with pertuzumab and/or endocrine therapy; treatment strategy at 2nd, 3rd, etc line; best

response at 2nd, 3rd, etc line; reason for termination of 2nd, 3rd, etc line; cause of death; date of death.

This study is a part of a multicentre cohort study aimed to investigate the treatment pattern in breast cancer patients with metastatic HER2-positive breast cancer and this is the reason why we collected a wide range of data. To answer our aim in this study, we only needed to use a part of our collected data. The ethical approval (see ethical considerations) is applied to all the data collected.

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The primary outcome of interest was the rate of objective response (complete remission or partial response) during T-DM1 treatment in naïve patients compared to prior pertuzumab-treated patients. Secondary outcomes were the time to progression (TTP) during T-DM1 between pertuzumab-naïve and prior pertuzumab-treated patients and the efficacy of T-DM1 (measured by

objective response rate and TTP) as 2nd line treatment compared to ≥ 3rd line treatment.

We defined a response to treatment as complete remission (CR) when all lesions disappear, partial response (PR) when at least a 30% decrease in all lesions was observed, progressive disease (PD) when at least a 20% increase in at least one lesion or a new lesion was observed and stable disease (SD) when neither PR nor PD was observed [17]. TTP was defined as time from T-DM1 start until objective tumour progression [18].

Statistical analysis

Categorical variables were summarized by numbers and percentage of patients in each category whereas continuous variables by median, minimum and maximum.

Bivariate analyses of objective response rate in variables of interest (pertuzumab-naïve vs. prior

pertuzumab-treated and 2nd line T-DM1 vs. ≥ 3rd line T-DM1) were compared by chi-square test.

Kaplan-Meier curves for TTP were constructed and log-rank test was used to compare variables of interest (pertuzumab-naïve vs. prior pertuzumab-treated and 2nd line DM1 vs. ≥ 3rd line T-DM1).

Cox proportional hazards regression model was used to investigate the potential association of variables of interest (prior pertuzumab use and line of T-DM1) after adjustment for confounding factors (de novo metastatic disease, ER-status, bone-only disease, visceral metastasis, performance status).

Ethical considerations

Patients’ integrity and anonymity was protected by changing patients’ social security number to trial-specific ID-number that has been used during the whole trial process. The study has been approved by the Swedish Ethical Review Authority (Reference number Dnr: 2018/191-31/2 and 2019-01591)

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RESULTS

Patient cohort

We retrospectively identified 35 HER2-positive MBC patients treated with T-DM1 at Uppsala, Eskilstuna and Örebro. Table 1 shows the baseline patient and tumour characteristics. Median age at breast cancer diagnosis was 52 years (range: 21-78). Of the 35 patients, 11 (31%) had a de novo metastatic disease. Histologically, 30 patients (94%) had ductal carcinoma, one patient had lobular carcinoma and one had other type of carcinoma. Median age at diagnosis of metastatic disease was 59 years (range 24-80). These categorical variables have been summarized using descriptive statistics to describe the patient cohort.

The most common site of metastasis was bone (49%), followed by liver (43%).

Table 1: Baseline characteristics of the study population (n=35).

Variables N (%) County Uppsala Eskilstuna Örebro Total 14 (40) 13 (37) 8 (23) 35 (100)

Age at diagnosis, median (range) 52 (21-78)

Charlson Comorbidity Index, median (range) 1 (0-5)

Diabetes Mellitus No

Yes, without complications Missing 30 (86) 1 (3) 4 (11) Hypertension No

Yes, without complications Missing 24 (69) 7 (20) 4 (11) Heart diseases None Angina pectoris Arrhythmia

Prior myocardial infarction Missing 22 (63) 1 (3) 1 (3) 1 (3) 10 (28) De novo No Yes Total 24 (69) 11 (31) 35 (100)

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8 Histology Ductal Lobular Other Missing 30 (86) 1 (3) 1 (3) 3 (8) Type of surgery Mastectomy BCS No surgery Missing 20 (57) 9 (26) 5 (14) 1 (3) Type of axillary surgery

ALND SLNB None Missing 24 (69) 6 (17) 4 (11) 1 (3) Tumour grading 1 2 3 Missing 9 (26) 12 (34) 5 (14) 9 (26) Lymph node grading

1 2 3 Missing 10 (28) 1 (3) 9 (26) 15 (43) Elston grading 2 3 Missing 8 (23) 21 (60) 6 (17) Stage at diagnosis 1 2 3 4 Missing 5 (14) 1 (3) 16 (46) 11 (31) 2 (6) ER-status Positive Negative Missing 18 (51) 15 (43) 2 (6) PgR-status Negative Positive Missing 22 (63) 11 (31) 2 (6)

Ki-67-status, median (range) 44 (5-90)

Age at metastasis, median (range) 59 (24-80)

Performance status at metastasis 0-1 2-4 Missing 18 (51) 16 (46) 1 (3)

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9 Site of metastasis Visceral Bone Liver Multiorgan LN Lung CNS Bone only Skin

Other metastatic site

22 (63) 17 (49) 15 (43) 14 (40) 10 (29) 9 (26) 5 (14) 5 (14) 3 (9) 2 (6)

Abbreviations: BCR, breast conserving surgery; ALND, axillary lymph node dissection; SLND, sentinel lymph node dissection; ER, oestrogen; PgR, progesterone.

Pertuzumab and T-DM1 efficacy

Figure 3 shows tumour response in pertuzumab-naïve patients and in patients with prior

pertuzumab treatment. Seventeen patients in this study population were pertuzumab-naïve and 18 had previously received pertuzumab as a part of a treatment. CR/PR, SD and PD in pertuzumab-naïve patients was 41%, 29% and 29%, whereas in patients with prior pertuzumab treatment the same variables show 50%, 33% and 16%, respectively. The potential association between prior pertuzumab use and T-DM1 efficacy was analysed by chi-square test. No statistically significant difference between the two treatment groups was observed (p-value=0.653).

Figure 3. T-DM1 efficacy on pertuzumab-naïve patients compared to patients with prior

pertuzumab treatment.

CR/PR stands for a complete or partial remission, SD for stable disease and PD for progressive disease. 0,0 % 10,0 % 20,0 % 30,0 % 40,0 % 50,0 % 60,0 % CR/PR SD PD

Trastuzumab-emtansine response according to

prior pertuzumab treatment status

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Time to progression in pertuzumab-naïve versus prior pertuzumab treated patients

Kaplan-Meier curve (Figure 4) shows time to progress (TTP) probability in patients with prior pertuzumab treatment compared to pertuzumab-naïve patients. Median TTP for pertuzumab-naïve patients was 10 months (95% CI: 8.7 - 23.5) and for prior pertuzumab treated patients 5 months (95% CI: 4.7 - 11.4). No statistically significant difference was observed with log-rank test (p=0.227).

Figure 4: Time to progress (TTP) probability in patients with prior pertuzumab treatment

compared to pertuzumab-naïve patients.

TTP is defined as time from T-DM1 start until objective tumour progression. Red line represents TTP in pertuzumab-naïve patients and green line represents TTP in patients with prior pertuzumab treatment. Every notch refers to progression in one patient. The perpendicular lines on the main lines show censored patient during follow-up.

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Line of treatment and T-DM1 efficacy

Kaplan-Meier curve (Figure 5) describes TTP probability in patients who received T-DM1 as 2nd

line treatment compared to patients who received T-DM1 in later treatment lines. The median TTP

when T-DM1 was administered as 2nd line treatment was 6 months (95% CI: 7.6 – 24.1) whereas

in later treatment lines the TTP was 10 months (95% CI: 2.7 – 16.7) (log-rank test with p-value=0.601).

Figure 5: Time to progression probability in patients that received T-DM1 as a 2nd line treatment

versus T-DM1 treatment in 3rd or later lines of treatment.

Predictors of TTP in T-DM1 treated patients

Multivariate analysis with Cox proportional hazards regression model was performed to identify potential variables of interest (prior pertuzumab use, line of T-DM1) or other variables (de novo metastatic disease, ER-status, bone-only metastatic disease, visceral metastases, performance status) that could independently affect the TTP, positively or negatively. The analysis included 31 cases, using complete-case approach, and 23 events (66%) as well as 8 censored cases (23%). Neither prior pertuzumab use (HR: 1.793 95%; CI: 0.555 - 5.794; p-value=0.330) nor line of

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DM1 treatment (HR: 1.054; 95% CI:0.315 - 3.528; p-value=0.932) were associated with TTP in the model.

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DISCUSSION

We analysed data from 35 patients that had received T-DM1 at some point of their palliative treatment with a retrospective cohort study with aim to investigate whether prior pertuzumab treatment affected DM1 efficacy. We could not find any statistically significant difference in T-DM1 efficacy between pertuzumab-naïve and prior pertuzumab treated patients in terms of objective response and TTP. In addition, T-DM1 was effective irrespective of the treatment line that it was administered.

Our study results are in accordance with two prior studies showing that T-DM1 is an effective treatment strategy even in prior pertuzumab treated patients. In fact, Dzimitrowicz et al. analysed 78 patients who received T-DM1 after trastuzumab and pertuzumab and found that 30.8% of patients had at least 6 months T-DM1 treatment duration [13]. Furthermore, Urruticoechea et al. analysed 75 patients who received T-DM1 after progression to pertuzumab and trastuzumab and found an adequate clinical efficacy in terms of TTP and overall survival [14]. On the contrary, two other studies indicate a detrimental effect of prior pertuzumab use on T-DM1 efficacy. Fabi et al. included 117 patients and found significant difference of 23.8% in objective response rate in favour of pertuzumab-naïve patients and a 6-month difference in progression-free survival in favour of pertuzumab-naïve patients [16]. In addition, Vici et al. analysed 250 patients and found no difference in T-DM1 objective response rate or in progression-free survival between

pertuzumab-naïve and prior pertuzumab treated patients but there was a significant worse survival

for patients who received T-DM1 as 2nd line treatment after pertuzumab-containing therapy

compared to T-DM1 as 2nd line treatment without prior pertuzumab exposure [15].

The current evidence on T-DM1 efficacy after prior pertuzumab exposure is difficult to interpret due to the conflicting results and the high risk for bias in existing studies including the limited number of patients and their retrospective nature. There is a biological rationale for a potential detrimental T-DM1 efficacy after pertuzumab related to the reduced number of HER2-receptors on surface of cancer cells after pertuzumab treatment [19]. However, results from three studies, including the present one, do not support this hypothesis. An interesting hypothesis that is supported by Vici et al. [15] is the risk that the potential detrimental effect of pertuzumab to T-DM1 efficacy is present only when T-T-DM1 is administered directly after pertuzumab progression whereas the use of T-DM1 in a later treatment line might have an adequate efficacy due to the ability of cancer cells to increase the HER2-expression by time after pertuzumab progression.

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Further studies with a large number of patients and prospective evaluation of T-DM1 efficacy after pertuzumab are necessary to test this hypothesis.

An interesting observation in our study was that T-DM1 efficacy did not differ in 2nd line

treatment compared to later treatment lines. Thus, our data suggest that T-DM1 is an effective treatment strategy irrespectively the line of treatment. Our results are in accordance with phase 3, randomised, multicentre clinical trial called TH3RESA that included 602 patients from 146 centres in 22 countries. The patients had previously had progression on two or more HER2 directed regimens in palliative setting and received either T-DM1 or treatment of physician’s choice. The overall survival was significantly improved with T-DM1 (median 22.7 months) compared to physician’s choice (15.8 months) [20].

The strength of our study is the use of consecutive patients from 3 different hospitals; as a result, our study cohort represents a real-world clinical setting rather than a selected cohort or a single-centre clinical practice. However, there are several limitations in our study that need to be discussed. First, the number of patients is limited and, therefore, this study is too small to derive firm conclusion with statistical validity. Second, the retrospective nature of the study is associated with well-described biases as recall bias. In addition, some variables could not be retrieved from electronic medical records and potential relevant data are missing from the analyses.

CONCLUSION

In conclusion, our study found no association between prior pertuzumab use and T-DM1 efficacy in terms of objective response rate and TTP. In addition, T-DM1 seems to be effective irrespective of the treatment line. Considering our results, the conflicting results of current literature, and before further studies are available, there is no convincing evidence to withhold T-DM1 in patients prior treated with pertuzumab. In addition, T-DM1 should be offered as a treatment option after

progression to 1st line treatment irrespective of treatment line. Further studies with a larger number

of patients and prospective design are required to investigate the potential interaction between prior pertuzumab use and T-DM1 efficacy.

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KEYWORDS

HER2 metastatic breast cancer, Trastuzumab, Pertuzumab, T-DM1, first-line treatment, second-line treatment, efficacy, time to progression.

ABBREVIATIONS

ALND: axillary lymph node dissection BCS: breast conserving surgery

CNS: central nervous system CR: Complete response EGF: epidermal growth factor ER: oestrogen

ErbB:erythroblastosis oncogene B

FISH: fluorescence in situ hybridization HER1: human epidermal growth factor 1

HER2: human epidermal growth factor receptor 2 HER3: human epidermal growth factor 3

HER4: human epidermal growth factor 4 IHC: immunohistochemistry

LN: lymph node

MBC: metastatic breast cancer PD: progressive disease PgR: Progesteron

pN: number of lymph nodes that are engaged PR: partial response

PS: performance status pT: tumour size

SD: stable disease

SLNB: sentinel lymph node dissection SMCC: nonreducible thioether linkage T-DM1: trastuzumab-emtansine TRK: tyrosine receptor kinase

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TTP: time to progression.

ACKNOWLEDGEMENT

I want to give a special thank you to my excellent supervisor Antonios Valachis, for supporting me and showing great interest in this study. He has thoroughly answered my questions when needed and helped me understand the statistical analysis.

I would also like to thank the oncology department at Örebro University Hospital, for lending me working space and giving me access to patient journals. Thank you for your willingness to answer questions and for creating and pleasant working atmosphere.

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Efficacy of trastuzumab-emtansine in breast cancer patients prior treated with pertuzumab