The combination of letrozole and trastuzumab as first ... - Springer Link

Breast Cancer Res Treat (2007) 102:43–49 DOI 10.1007/s10549-006-9307-8

CLINICAL TRIAL

The combination of letrozole and trastuzumab as first or secondline biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers P. Kelly Marcom Æ Claudine Isaacs Æ Lyndsay Harris Æ Zee Wang Wong Æ Aruna Kommarreddy Æ Nellie Novielli Æ Gretchen Mann Æ Yu Tao Æ Matthew J. Ellis

Received: 3 June 2006 / Accepted: 12 June 2006 / Published online: 8 August 2006 Springer Science+Business Media B.V. 2006

Abstract Background Estrogen receptor (ER) and/or progesterone receptor expression occurs in ~50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study. Methods Patients with ER+ and/or PgR+ and HER2+ (IHC 2+ or 3+ or FISH+) advanced breast cancer were treated with trastuzumab plus letrozole Note: Aspects of this work were presented at the ASCO Annual Meeting 2005. Disclosure: Washington University conflicts of interest committee requires the following disclosures. Novartis Pharma and Genentech provided financial support for this clinical trial. Dr M.J. Ellis is a paid consultant for Novartis and Genentech and has also received speaking honoraria. A. Kommarreddy Æ Y. Tao Æ M. J. Ellis (&) Siteman Comprehensive Cancer Center, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8056, St Louis, MO, USA e-mail: [email protected] C. Isaacs Æ N. Novielli Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA L. Harris Dana Farber Cancer Institute, Harvard University, Boston, MA, USA Z. W. Wong Singapore National Cancer Institute, Singapore, Singapore P. K. Marcom Æ G. Mann Duke Comprehensive Cancer Center, Duke University, Durham, NC, USA

until disease progression or unacceptable toxicity. Results Thirty-three patients were enrolled, of which thirty one were considered evaluable. The majority of patients (82%) had received tamoxifen and 82% had HER2 FISH+ and/or IHC 3+ tumors. Eight patients responded (1 CR and 7 PR) for an overall response rate (ORR) of 26% and a clinical benefit rate (CBR) of 52%. The median time to progression (TTP) was 5.8 months and the median duration of response (DOR) was 20.6+ months. Excluding IHC 2+, FISH– tumors, the OR was 24%, CBR 44%, TTP 5.5 months and DOR 17+ months. The combination was well tolerated with only two toxicity events requiring termination of study medication. Conclusions Combined trastuzumab and letrozole treatment for patients with HER2+ and ER+ advanced breast cancer produced durable responses consistently lasting at least 1 year in one quarter of the patients. While these data are promising for a subgroup, for half the patients, trastuzumab plus letrozole was inactive. This finding demonstrates ER+ HER2+ advanced disease is heterogeneous and additional agents will be required for optimal management based on targeted therapeutics alone. Keywords Breast cancer Æ Letrozole Æ Trastuzumab Æ Phase 2 clinical trial

Background HER2 gene amplification and consequent HER2 protein over-expression occurs in ~25% of breast cancers. These events are associated with a poor prognosis [1]. Trastuzumab is a humanized murine monoclonal anti-

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body developed to target HER2. Several studies have demonstrated that combination of trastuzumab and chemotherapy improves the survival of patients with metastatic breast cancer [2, 3]. However, despite the fact that approximately half of HER2+ breast cancers also express ER [4] there are currently no data in the addressing the clinical efficacy of trastuzumab in combination with endocrine treatment. Preclinical and clinical studies have suggested that patients with ER+ and HER2+ metastatic breast cancer exhibit resistance to endocrine treatment [5]. For example, advanced disease patients with elevated levels of HER2 extracellular domain (ECD) (almost all of whom exhibit tumor HER2 over-expression) respond poorly to second line endocrine therapy [6]. Even in the more favorable setting of first line endocrine therapy with letrozole, patients with elevated serum HER2 ECD have worse outcomes [7]. A recent meta-analysis of 12 trials examining the interaction between endocrine therapy outcomes and HER2 status in the advanced disease setting assigned a relative risk of 1.42 (P < 0.00001) for endocrine treatment failure for HER2+ versus HER2– disease [8]. In the adjuvant endocrine treatment of early stage breast cancer, studies have also shown that HER2 expression is a risk factor for tamoxifen failure [9]. Similar data has now been presented for aromatase inhibitor therapy [10]. In neoadjuvant endocrine treatment studies, HER2+ tumors showed impaired anti-proliferative responses regardless of whether they are treated with letrozole, other aromatase inhibitors or tamoxifen [11, 12]. On the other hand, letrozole is clinically active as preoperative treatment for ER+ HER2+ primary breast cancer and is more effective than tamoxifen [12, 13]. Letrozole is, therefore, a reasonable choice for Phase 2 and Phase 3 trials that assess the benefit of adding a HER2 targeting agent to an aromatase inhibitor in an attempt to modulate aromatase inhibitor resistance. The molecular basis of HER2 driven endocrine therapy resistance has been addressed in preclinical models. HER2 gene transfection induces tamoxifen resistant growth in an MCF-7 cell based xenograft model [14]. In contrast estrogen deprivation was initially effective in this model despite HER2 overexpression, however, tumor growth recommences under low estrogen conditions after a longer period of observation [15]. The pattern of HER2 driven tamoxifen failure in these MCF-7 based models can therefore, be termed primary resistance (no initial response), in contrast to a pattern of secondary or acquired resistance with estrogen deprivation (regression followed by tumor re-growth). Experiments using

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Breast Cancer Res Treat (2007) 102:43–49

trastuzumab have demonstrated restoration of tamoxifen sensitivity in HER2 positive resistant cell lines, suggesting that adding HER2 directed therapy could reverse endocrine therapy resistance [16]. These preclinical and clinical observations provided the rationale for conducting a clinical trial that combined aromatase inhibitor-based estrogen deprivation therapy and HER2 directed monoclonal antibody therapy in patients with HER2 and hormone receptor expressing metastatic breast cancer.

Methods and patient population Patient population Patients were eligible if they had treatment naı¨ve or tamoxifen resistant metastatic breast cancer. All patients were either post-menopausal or undergoing ovarian suppression with an LHRH agonist. Breast cancer was histologically confirmed as HER2 positive (IHC 2+ or 3+ or FISH+) and hormone receptor positive (ER and/or PgR+) in all cases. HER2 IHC was initially used as the basis for eligibility on the basis of the original recommendations for the use of trastuzumab, however, HER2 FISH status was subsequently determined where possible and was ascertained in all IHC 2+ cases in the study, except one. In the results section this case was grouped with the IHC 2+ FISH– group since the majority of IHC 2+ cases are not amplified. Biomarker status was determined using either primary or metastatic tissue, although the most recent sample was required to meet eligibility criteria. Patients could not have initiated treatment with an aromatase inhibitor more than 28 days prior to entry. The following additional criteria also had to be met: ECOG status 0–2, life expectancy >6 months,adequate laboratory parameters and a cardiac ejection fraction 50% or greater. Exclusion criteria included: prior treatment with anthacycline >360 mg/m2, prior trastuzumab, brain metastases, life threatening lymphangitic or large volume lung or liver disease, prior radiation to the qualifying lesion and previous malignancies except where treated with curative intent and relapse risk less than 30% and inability to understand the informed consent or with the protocol. Study design Patients received letrozole 2.5 mg daily by mouth. Patients may have initiated an aromatase inhibitor for advanced disease prior to study entry if the first dose of


trastuzumab was administered within 28 days of aromatase inhibitor exposure (patients were switched to letrozole as necessary). One patient was granted a protocol exception and received her first dose of trastuzumab 33 days after initiation of letrozole. Trastuzumab was initially given as a 4 mg/kg loading dose followed by 2 mg/kg weekly. In December, 2001 the protocol was amended to give an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks to improve patient compliance as 3 week treatment has been shown to produce pharmacokinetics equivalent to weekly dosing [17].

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mal evaluable sample size of 30 patients. In this case, if the true response rate to combined therapy was 42.6% or more, then the statistical power would be over 80% of observing a response rate that is significantly higher than 20% at a statistical significance level of 5% (exactly 2.6%). If the observed response rate were 35%, serious consideration would be given to performing a randomized study.

Results Patient characteristics

Efficacy and toxicity assessments Response criteria used WHO methodology, allowed bone only disease and all patients were required to have at least one bi-dimensionally measurable lesion. Bone lesions were considered not evaluable if bisphosphonate treatment was initiated after enrollment. Patients were evaluated for response every 12 weeks. All reported responses were therefore, of at least 3 months duration. The stable disease (SD) category required the absence of progression at the 24 week assessment and target lesions that did not meet WHO criteria for response or progression. Time to progression (TTP) was defined as the time from treatment initiation to the first evidence of disease progression. Time to treatment failure (TTF) included all patients from the time of treatment initiation to the time of treatment termination. Duration of response (DOR) was defined as the time from treatment initiation to the time of disease progression for those patients who experienced a PR or CR. The evaluable population included all patients except those who withdrew before the first response evaluation for non-protocol defined reasons (see toxicity section). Cardiac function was assessed by either MUGA scan or echocardiogram at baseline and every 6 months on treatment. Trastuzumab was discontinued if signs or symptoms of congestive heart failure developed or if the ejection fraction dropped either below the normal range for the institution or more than 20%. Statistical methods The primary objective was determination of the response rate to the combination of letrozole with trastuzumab in patients with HER2+ and ER and/or PgR positive advanced breast cancer. Secondary objectives included assessment of time to progression, time to treatment failure, duration of response and safety profile. The study was designed to have a mini-

A total of 33 patients were enrolled in the study at three sites between February, 2000 and October, 2004. The baseline patient characteristics are given in Table 1. Twenty-five cases had tumors that were FISH amplified and/or HER2 IHC 3+. Most patients (55%) had received prior adjuvant chemotherapy and tamoxifen. Sixteen patients (48%) had developed a recurrence while taking tamoxifen. Six patients were stage 4 at initial presentation, and three of these patients had received palliative tamoxifen before study entry. Only six patients were tamoxifen naı¨ve: three who presented with metastatic disease, two who had received adjuvant chemotherapy only, and one had received no adjuvant chemotherapy or endocrine therapy. The range for time to recurrence from initial diagnosis was wide (0–321 months) and the median was 35 months. Metastatic sites included visceral disease in the majority (73%) of patients. Table 1 Characteristics of the patients entered into the clinical trial Median age at study entry, years (range) Median time to disease recurrence after initial diagnosis, months (range) Site of disease, N (%) Soft tissue only Bone only Soft tissue and bone Visceral only Visceral and other sites Hormone receptor status, N (%) ER-positive and PgR-positive ER-positive and PgR-negative ER-negative and PgR-positive Prior therapy, N (%) Adjuvant tamoxifen and chemotherapy Adjuvant tamoxifen, no chemotherapy Adjuvant chemotherapy only No adjuvant therapy for early stage disease Metastatic at presentation Tamoxifen naı¨ve Disease recurrence on tamoxifen

57 (36–72) 35 (0–321)

5 (15) 3 (9) 1 (3) 3 (9) 21 (64) 20 (61) 11 (33) 2 (6) 18 (55%) 3 (9%) 2 (6%) 4 (12%) 6 (18%) 6 (18%) 16 (48%)

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Toxicity The combination of trastuzumab and letrozole was well tolerated. Most side effects were grade one and two, and were consistent with those known to be associated with letrozole or trastuzumab monotherapy. One patient reported no side effects and 76% had grade one or two toxicities. Table 2 gives the frequency of combined grade one and two toxicities that occurred in more the 15% of patients, regardless of treatment relationship. Fatigue, hot flashes, pain, and arthralgias were among the more commonly experienced side effects Grade three toxicities were seen in 8 (24%) of patients. No grade four toxicities were observed. Two patients developed grade 3 arthralgias, one of whom also had preexisting peripheral neuropathy and weakness that led to study withdrawal after 8 months. Five other patients had grade 3 toxicities that did not lead to withdrawal: hypokalemia with hyperglycemia, pneumonia, cellulitis, dyspnea, groin pain, headaches, and back pain. Significant cardiac toxicity was observed in one patient who developed clinically significant congestive heart failure and withdrew from the study. Her baseline ejection fraction was 52%, but dropped to 23% after 2 months of therapy and prior to her first evaluation for response. After treatment for heart failure and withdrawal of trastuzumab her cardiac function partially recovered and her symptoms resolved. Altogether, six patients withdrew from the Table 2 Grade 1 and 2 toxicities experienced by patients entered into the study, uncommon instances of Grade 3 toxicities are discussed in the text

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study for reasons other than disease progression: two withdrew due for toxicity, one developed ovarian cancer, one withdrew consent after 13 months to pursue other therapy and two were not evaluable. One of the inevaluable patients underwent an ablation of her solitary liver lesion before the first tumor evaluation and one withdrew consent 1 month after study initiation. Efficacy evaluation After excluding two non-evaluable patients the analysis of response was based on thirty-one patients, including the patient with an early grade 4 cardiac toxicity who was withdrawn from the study. Time to progression was based on 27 patients, because four patients came off study for reasons other than disease progression. A secondary analysis was performed on 25 evaluable patients who had either FISH positive and/or IHC 3+ (not evaluated by FISH) tumors. Response rates and time dependent variables for both groups are provided in Table 3. For evaluable patients the objective response rate was 26% (1 CR and 7 PR). Eight additional patients had stable disease at 24 weeks, for a clinical benefit rate of 52%. The results were similar for the 25 FISH+ and/or IHC 3+ patients, with an objective response rate of 24% (1 CR and 5 PR) and a clinical benefit rate of 44%. The median TTP for the 31 evaluable patients was 5.8 months, with 44% of

Toxicity

Grade one [%]

Grade two [%]

Sum [%]

Fatigue Hot Flashes Dyspnea without CHF Pain Arthalgias Nausea Diarrhea Myalgia Rhinitis/Allergies Insomnia Rash Headache Cough Lymphedema Lower extremity edema Back pain Anorexia Back pain Peripheral neuropathy Constipation Weight increase Fever Abdominal pain Pruritis Palpitations

61 36 33 21 36 33 33 24 21 24 27 21 21 15 18 9 18 9 15 9 15 18 15 15 15

15 27 18 24 6 9 9 9 12 6 3 3 3 6 3 12 3 12 3 9 3 0 3 3 3

76 64 52 45 42 42 42 33 33 30 30 24 24 21 21 21 21 21 18 18 18 18 18 18 18


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Table 3 Response and time dependent variables for patients entered into the study

Objective RR CR PR SD CBR Median TTP Median TTF Median DOR

All evaluable patients (N = 31)

HER2 FISH+ or IHC 3+ (N = 25)§

8 (26%) 1 7 8 16 (52%) 5.8 months 8.3 months 20.6+ months with three remaining on treatment

6 (24%) 1 5 5 11 (44%) 5.5 months 5.6 months 17+ months with two still on treatment

PR, partial response; CR, complete response; ORR, overall response rate; CBR clinical benefit rate; TTP, time to progression; TTF time to treatment failure; DOR; duration of response. § Tumors that were either HER2 FISH+ or HER2 immunohistochemistry (IHC) 3+ and FISH data not available. IHC 2+ FISH– cases were excluded from the data in this column

patients free of progression at one year (Fig. 1). The median TTF for the evaluable patients was 8.3 months, also with 44% of patients free of progression at 1 year. For the subset of 25 evaluable patients with HER2 FISH+ and/or HER2 3+ tumors the TTP was 5.5 months with a 33% probability of freedom from progression at 1 year (Fig. 2). The TTF was 5.6 months and 35% were progression-free at 1 year. The responses were durable and all persisted for longer than 1 year. The median DOR was at least 20.6 months for all evaluable patients and for the five responding patients with ER+ HER2 FISH+ and or HER2 3+ tumors, the DOR was at least 17 months.

Discussion This trial provides the first published safety and efficacy data for the combination of an aromatase inhibitor with trastuzumab for the treatment of ER and/or PgR+ and HER2+ advanced breast cancer. The majority of patients had ER+ HER2+ disease whose tumors were either HER2 FISH+ or HER2 IHC 3+, FISH unknown. When we excluded six patients with HER2 IHC 2+ FISH– tumors conclusions regarding the primary endpoints were not altered. One quarter of the patients had a durable response that lasted at least a year and several patients are in their third or fourth year of treatment without disease progression. Overall about one-third of the patients experienced a clinical benefit lasting at least 1 year. The main aim of this Phase 2 trial was to determine if a randomized study of letrozole versus letrozole with trastuzumab should be initiated. Assuming a letrozole response rate of 20%, a response rate of at least 35% was prospectively set as evidence of additive benefit from the addition of trastuzumab and was the threshold to be used for the activation of a Phase 3 trial. On this basis the observed response rate of 24–26% in this Phase 2 study does not justify initiating a definitive Phase 3 investigation. However, after the initiation of our investigation, two papers were published that provided new information on the interaction between tumor HER2 status and the efficacy of endocrine therapy. In these studies, the HER2 ECD assay was used to assign HER2 status. Patients with elevated serum HER2 ECD receiving second line endocrine therapy with either letrozole, fadrozole, or megestrol

Fig. 1 Time to progression for all patients enrolled who could be evaluated for this endpoint

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Fig. 2 Time to progression for patients with FISH+ or IHC 3+ FISH unknown breast cancer

acetate) experienced a 7% response rate [6]. In the first line setting the response rate to letrozole in patients with elevated HER2 ECD was 17% [7]. These data suggest that the original power calculation probably over estimated the expected response rate to letrozole in ER+ HER2+ advanced disease. A more realistic range in a mixed population of second line patients with a few first line patients should probably be closer to 10%. If we accept this new estimate, then the 24– 26% response rate we observed with the trastuzumab and letrozole combination could be taken as evidence that a Phase 3 trial should be conducted. The response rate for single agent trastuzumab in a Phase 2 study in advanced HER2+ disease published by Vogel was 27% [18]. A response rate of 24–26% in the present study provokes the question of whether letrozole improves response over monotherapy with trastuzumab. While the response rate to the combination was not apparently enhanced over trastuzumab monotherapy, we have observed that the quality of the responses may be more durable. Trastuzumab monotherapy produces a median TTP of 3.5 months. The TTP for this trastuzumab and letrozole combination was 5.5– 5.8 months. The longer DOR could also be taken as evidence that letrozole might attenuate the development of secondary resistance in ER positive patients treated with trastuzumab. However, in the absence of a trastuzumab monotherapy control group a prolonged TTP could reflect a selection bias for patients with more indolent disease. Further Phase 3 studies that compare letrozole alone versus trastuzumab alone versus the combination will be necessary to address these considerations. In addition, results from an ongoing Phase 3

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trial comparing anastrozole with anastrozole and trastuzumab in combination will help to clarify the benefit of adding trastuzumab to an aromatase inhibitor. Despite dual targeting nearly half the patients in this ER+ HER2+ population experienced no clinical benefit from combined trastuzumab and letrozole therapy. This suggests that there may be common resistance mechanisms that impact on the efficacy of agents that target ER or HER2. Our sample size was too small for a thorough evaluation of this question at the molecular level. However, we hypothesize ‘‘downstream mutations’’ that create constitutively active signal transduction components common to ER and HER2 signal transduction are likely candidates [5]. In summary, the combination of trastuzumab and letrozole is an acceptable, effective, and well-tolerated treatment for patients with metastatic ER+ HER2+ breast cancer and should be investigated further, particularly in clinical settings that would allow studies on the molecular basis of response or resistance.

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