A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer that is defined by a rapid onset of distinct features such as diffuse skin erythema, edema involving more than two-thirds of the breast resulting in a pitted appearance (peau d’orange), as well as tenderness, induration, and warmth of the involved breast [1, 2]. IBC tumors are primarily estrogen-receptor-negative, have a high mitotic index (MIB1 > 20), and are characterized by overexpression of e-cadherin, cytoplasmic mucin 1, and human epidermal growth factor receptor 2 (HER2) [3‐5]. Standard treatment approaches integrate systemic chemotherapy, surgery, and radiotherapy [1]. In the first-line setting, trastuzumab-containing multi-chemotherapy regimens have shown efficacy in patients with IBC [6, 7]. Although the use of combined treatment modalities has led to improvement in survival in patients with IBC, the prognosis remains poor for patients who experience less than a pathological complete response to induction chemotherapy or who subsequently relapse [8, 9]. Limited data are available regarding second-line treatments for patients with advanced IBC.

Lapatinib is an oral tyrosine kinase inhibitor that targets both epidermal growth factor receptor (EGFR; ErbB1) and HER2 (ErbB2) receptors [10]. Administration of single-agent lapatinib (1,500 mg per day) in patients (n = 126) with HER2-positive (HER2+) IBC with disease progression after prior treatment resulted in an overall response rate (ORR) of 39 % [all partial responses by combined clinically evaluable skin disease criteria and Response Evaluation Criteria in Solid Tumors (RECIST)] and median duration of response of 20.9 weeks [11]. Lapatinib’s activity in IBC has also been demonstrated in the neoadjuvant setting in which lapatinib monotherapy for 14 days followed by lapatinib + paclitaxel for 12 weeks was associated with a combined clinical response rate of 78.6 % (33 of 42), based on RECIST and clinically evaluable skin disease criteria in treatment-naïve IBC patients [12].

Angiogenesis is thought to play a role in IBC tumorigenesis [13]. Preclinical and early clinical evidence suggests that the combination of anti-angiogenic and anti-HER2 therapies may have a role in the treatment of HER2+ breast cancer [14, 15]; and vascular endothelial growth factor (VEGF)-targeted therapy with bevacizumab in combination with chemotherapy demonstrated anti-tumor activity in previously untreated IBC patients [16]. Pazopanib is an oral angiogenesis inhibitor targeting VEGF receptors-1/-2/-3, platelet-derived growth factor receptors-α/-β, and mast/stem-cell growth factor receptor [17, 18]. Results of a small, single-arm Phase II study provided early evidence that pazopanib alone may have cytostatic activity in patients with advanced, non-inflammatory breast cancer [19]. In a Phase II first-line study (VEG20007) in patients with locally advanced or metastatic HER2+ breast cancer [20, 21], there was a numerical increase in the objective response rate with the combination of pazopanib and lapatinib compared to lapatinib alone; however, the rates of disease progression at Week 12, the primary study endpoint, were statistically similar [Johnston, manuscript submitted].

These considerations provided the rationale for a randomized study evaluating the efficacy and safety of the combination of pazopanib and lapatinib in patients with relapsed HER2 overexpressing or amplified IBC.

IBC is a rare disease accounting for 1–2 % of all breast cancers in the US [23, 24], with higher incidence (5–7 %) reported in North Africa [25]. Due to this low incidence, few prospective studies have been conducted in this patient population. Multi-modal approaches have become standard for the primary treatment of IBC; however, there is currently no standard of care in relapsed or refractory disease. Current literature suggests that targeted therapies based on known biological characteristics offer the most promise to improve the outcome of patients affected by IBC [2]. The current study evaluating the combination of two targeted agents represents the first prospective randomized trial to be conducted in metastatic IBC.

The current study was designed to evaluate the combination of lapatinib and pazopanib at doses that previously proved effective in single-agent studies. Following the initiation of the trial, results of an ongoing study in HER2+ locally advanced or metastatic breast cancer (VEG20007) indicated that this dose combination was associated with 40 % incidence of grade 3/4 diarrhea as compared to 9 % observed with a lower dose combination of 1,000 mg lapatinib + 400 mg pazopanib [Johnston, manuscript submitted]. Therefore, the current study design was modified to specify the lower dose combination. Additionally, a third treatment arm of single-agent pazopanib was added to better isolate the additive anti-tumor activity of each targeted agent. The Inflammatory Breast Cancer Skin Assessment Tool (IBSAT) was used to assess skin disease in Cohort 2. As IBC is designated as non-measurable according to RECIST and there are no standardized skin assessment tools, the IBSAT was developed as a tool for the objective assessment of skin disease in IBC. Prior to use in this study, the IBSAT was retrospectively applied to a previous study in IBC (EGF103009) by three investigators who independently assessed patient photographs over time. There was a high degree of concordance among all three investigators, and between each of the investigators and the independent reviewer who initially assessed skin disease in EGF103009 [22].

The response rates in the current study (29 % in Cohort 1 and 47 % in Cohort 2) support the reported activity of single-agent lapatinib in a previous study in which 49 of 126 (39 %) patients with HER2+ relapsed or refractory IBC had a partial response [11], although comparisons between studies are confounded by differences in patient populations and study methodologies. The favorable response to lapatinib in IBC has been postulated to result from the presence of phosphorylated (p) HER2 and pHER3 coexpression in tumors [26]. As previously observed [11, 26], the response to lapatinib did not appear to be markedly affected by prior trastuzumab therapy.

Compelling rationale had existed to evaluate the combination of an anti-angiogenic agent with an inhibitor of HER2 signaling in patients with HER2+ IBC. Upregulation of signalling pathways associated with angiogenesis and lymphangiogenesis is thought to contribute to IBC’s aggressive phenotype [13, 27, 28], and preclinical and preliminary clinical data suggested that there may be an enhanced effect when these targeted therapies are combined. Administration of the anti-VEGF monoclonal antibody bevacizumab for one cycle in patients with previously untreated IBC (n = 20) or locally advanced breast cancer (n = 1) with the addition of cytotoxic chemotherapy in subsequent cycles had yielded an objective response rate of 67 % [16]. The combination of bevacizumab and trastuzumab demonstrated activity in a Phase II trial in metastatic breast cancer, with partial clinical response documented in 13 of 28 (46 %) evaluable patients [15]. In the current study, however, the combination of pazopanib with lapatinib did not produce a clinically significant improvement in ORR compared to lapatinib alone. Likewise, there was no difference in PFS for the combination arm versus the lapatinib monotherapy arm in either cohort. Recently reported results in non-inflammatory breast cancer also indicate equivocal results for regimens containing a combination of VEGF and EGFR/HER2 inhibitors. In a randomized, double-blind trial (n = 96), the addition of bevacizumab to chemotherapy (paclitaxel ± carboplatin) plus trastuzumab as first-line treatment of HER2+ metastatic breast cancer did not result in an improvement in best overall response or PFS [29]. Similarly, in a randomized Phase III trial (AVEREL) evaluating bevacizumab in combination with trastuzumab + docetaxel (n = 216) compared to trastuzumab + docetaxel (n = 208) as first-line therapy for HER2+ locally recurrent/metastatic breast cancer, there was no statistically significant difference between the treatment arms for the predefined primary endpoint of PFS by the investigator assessment, although ad-hoc results by independent assessment were significant [30]. Thus, it is unclear if the combination of HER2 and VEGF inhibition has improved efficacy in the treatment of HER2+ breast cancer.

The types of AEs reported in the current study generally reflect the safety profiles of lapatinib and pazopanib established in other studies. The higher dose combination of the two agents administered in Cohort 1 was associated with a higher incidence of gastrointestinal toxicity, as well as LFT abnormalities, hypertension, and rash compared with lapatinib monotherapy. With the lower dose combination administered in Cohort 2, the incidence of gastrointestinal events was substantially lower and showed feasibility of the treatment, but still with significantly higher toxicity and related dose reductions, interruptions, and treatment discontinuation for the combination. The impact of these deviations from the planned treatment schedule upon efficacy results is uncertain.

Hepatotoxicity has been associated with both single-agent lapatinib and pazopanib, and this was the most common toxicity leading to permanent discontinuation of study drug in the combination arm in both cohorts. Furthermore, elevations in liver enzymes were more frequent in the combination arms than in the single-agent arms even with the lower dose combination in Cohort 2.

Both lapatinib and pazopanib have been associated with cardiac dysfunction, particularly in patients previously exposed to prior anthracycline chemotherapy. In the present study, 137 (84 %) patients had received prior anthracycline therapy. Inhibition of HER2 signaling with agents such as lapatinib and trastuzumab and, in the case of pazopanib, an increase in blood pressure and cardiac afterload are mechanisms thought to be responsible for the precipitation of cardiac dysfunction. Nine patients experienced cardiac dysfunction, 6 of these cases in the combination arm, although the majority of these cases were grade 1. There were 2 fatal AEs associated with cardiac dysfunction: respiratory failure/acute cardiovascular insufficiency in the combination arm of Cohort 1, and cardiopulmonary failure in the pazopanib arm of Cohort 2. The nature of fatal AEs was varied in the treatment arms of both cohorts and, in some cases, was confounded by the underlying disease and pneumonia.

Despite preclinical and early clinical evidence of enhanced activity when an anti-angiogenic agent was added to an anti-HER2 agent, the combination of lapatinib and pazopanib in the present study was associated with a numerically higher response rate but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Results of the current study are consistent with other studies showing that inhibitors of VEGF signaling added to inhibitors of HER2 fail to provide a clinically meaningful improvement in efficacy in patients with HER2+ breast cancer, particularly when considering the added toxicity of combination therapy. Future studies should consider inhibition of other critical pathways in IBC to improve efficacy of lapatinib and other inhibitors of HER2 in this aggressive disease.