Annals of Oncology Advance Access originally published online on February 17, 2008
Annals of Oncology 2008 19(6):1068-1074; doi:10.1093/annonc/mdm601
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breast cancer |
A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer
1 Medical Oncology, Dana Farber Cancer Institute, Boston, MA
2 Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN
3 Oncology, Memorial Cancer Institute, Hollywood, FL
4 Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA
5 Oncology, Duke University Medical Center, Durham, NC, USA
* Correspondence to: Dr H. J. Burstein, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel: +1-617-632-2624; Fax: +1-617-632-1930; E-mail: hburstein{at}partners.org
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Abstract |
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Background: The efficacy and tolerability of the epidermal growth factor receptor/human epidermal growth factor receptor type 2 (HER2) tyrosine kinase inhibitor lapatinib in refractory metastatic breast cancer were assessed.
Patients and methods: In a phase II, open-label study, patients with previously treated HER2-positive (n = 140) or HER2-negative (n = 89) metastatic breast cancer received once-daily oral lapatinib 1500 mg/day.
Results: Most (76%) patients had received four or more lines of prior therapy. The response rate in the HER2-positive cohort was 4.3% by investigator assessment and 1.4% by independent assessment. Both assessments established that 
6% of HER2-positive patients derived clinical benefit from lapatinib, being progression free for 
6 months. No objective tumor responses occurred in the HER2-negative cohort. Independent review assessments of median time to progression and median progression-free survival were similar in the HER2-positive and HER2-negative cohorts (9.1 and 7.6 weeks, respectively). All responders exhibited HER2 overexpression (3+ by immunohistochemistry), and five of six responders were HER2 amplified by FISH. Lapatinib-related adverse events, including diarrhea (54%), rash (30%), and nausea (24%), were primarily mild to moderate in severity.
Conclusions: Lapatinib monotherapy had modest clinical activity in HER2-positive metastatic breast cancer that progressed on prior trastuzumab regimens. No apparent clinical activity was observed in chemotherapy-refractory, HER2-negative disease.
Key words: breast cancer, EGFR, ErbB2, targeted therapy, tyrosine kinase inhibitor, trastuzumab
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Human epidermal growth factor receptor type 2 (HER2 or ErbB2) is a member of the ErbB family of tyrosine kinase transmembrane receptors. Homodimerization or heterodimerization of HER2 with other ErbB receptors [e.g. epidermal growth factor receptor (EGFR) (ErbB1) or ErbB3] triggers a cascade of signal transduction events that mediate cell growth and survival [1, 2]. Dysregulated HER2 activity is associated with cancer development and progression; overexpression of the HER2 receptor increases activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, resulting in uncontrolled cell proliferation, increased metastasis and angiogenesis, decreased sensitivity to apoptotic signals, and genetic instability [3]. Between 20% and 25% of human breast cancers overexpress HER2 [4, 5]; HER2-positive breast cancer tends to be more aggressive and associated with a greater risk for disease recurrence and death [5, 6].
Trastuzumab (Herceptin®; Genentech, San Francisco, CA) is a recombinant, humanized, mAb that binds to the extracellular domain of HER2; trastuzumab plus taxane-based chemotherapy is the current standard of care for HER2-positive metastatic breast cancer [7]. Most patients with metastatic breast cancer eventually, however, develop resistance to current standard therapy, resulting in disease progression [8, 9]. Because increased EGFR expression is one potential mechanism of resistance to HER2 inhibitors, clinical benefit may be derived from the simultaneous inhibition of EGFR and HER2. Indeed, the combination of gefitinib (an EGFR inhibitor) and trastuzumab had a greater apoptotic effect on breast cancer cell lines compared with either agent alone [10].
Lapatinib (Tykerb®/Tyverb®; GlaxoSmithKline, Philadelphia, PA) is an orally active, small molecule dual tyrosine kinase inhibitor of EGFR and HER2 [11, 12]. Lapatinib is approved in the United States and other countries for the treatment of HER2-positive advanced or metastatic breast cancer that progressed on treatment regimens containing an anthracycline, a taxane, and trastuzumab. In this setting, lapatinib plus capecitabine resulted in a statistically significant improvement in time to disease progression (TTP) compared with capecitabine monotherapy (median, 8.4 versus 4.4 months; hazard ratio = 0.49; P < 0.001) [13]. In a subsequent exploratory analysis, lapatinib plus capecitabine achieved a significant reduction in the occurrence of brain metastases as the site of first progression (2% versus 6%; P = 0.045) [14].
The objective of this study was to evaluate the efficacy and safety of lapatinib monotherapy in patients with advanced or metastatic breast cancer refractory to standard agents including trastuzumab and chemotherapy.
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patients and methods |
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patient eligibility
Women
18 years with a life expectancy 12 weeks and measurable [defined by Response Evaluation Criteria in Solid Tumors (RECIST)] refractory advanced (stage IIIb) or metastatic (stage IV) breast cancer were eligible. Refractory breast cancer was defined as progression after previous therapy including (i) four or more cycles of anthracycline- and taxane-containing regimens or (ii) two or more cycles, provided disease progression occurred while on anthracycline- or taxane-containing regimens. Patients who relapsed >6 months after completion of anthracycline-containing adjuvant chemotherapy and for whom further anthracycline therapy was not indicated were eligible, provided the following criteria were satisfied: progression after 6 weeks of a capecitabine-containing regimen and, for HER2-positive patients, 6 weeks of prior trastuzumab alone or in combination with other chemotherapy. Trastuzumab treatment had to be discontinued 2 weeks before starting lapatinib. Two cohorts of patients were enrolled. Patients eligible for cohort A had tumors that overexpressed HER2, defined as either 3+ by immunohistochemistry (IHC) or 2+ by IHC and HER2 amplified by FISH. Patients eligible for cohort B had tumors that did not overexpress HER2 (0 or +1 by IHC or FISH negative). All patients had to have archived tumor tissue available to reevaluate intratumoral HER2 expression levels by IHC and FISH. Patients with stable central nervous system metastases were eligible for study enrollment. In addition, eligible patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and a cardiac ejection fraction within the institutional range of normal.
Patients were excluded from study participation if they were receiving concurrent cancer therapy; had received prior therapy with an EGFR and/or HER2 inhibitor other than trastuzumab; had a history of another malignancy, except nonmelanoma skin cancer or successfully treated in situ carcinoma; or had a known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.
Ethics approval was obtained from the relevant local ethics committees, and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before enrollment.
study design and treatment
This was a phase II, open-label, single-arm, two-cohort, multicenter study. Patients received lapatinib 1500 mg once daily (q.d.) 1 h before or after the morning meal. Patients received lapatinib until disease progression, development of unacceptable toxicity, or withdrawal of consent. Reduction of lapatinib doses to 1250 mg/day was considered in the event of grade 3/4 toxicity. Lapatinib treatment could be delayed for 
2 weeks to allow for resolution of toxicity.
efficacy assessments
Objective tumor response rate (RR), defined as the percentage of patients who achieved a complete response (CR) or partial response (PR) by RECIST, was the primary efficacy end point. Radiological assessments were carried out via computerized tomography or magnetic resonance imaging at baseline and at 8-week intervals. Assessments were also reviewed by a blinded independent review committee. Secondary end points included clinical benefit [CR, PR, or stable disease (SD) for 24 weeks or 16 weeks], TPP, 4-month progression-free survival (PFS), 6-month PFS, and overall survival (OS).
safety assessments
Safety assessments included adverse events (AEs), cardiac function assessments, clinical laboratory tests, ECOG PS, and physical examinations and vital signs. AEs were graded according to the National Cancer Institute Common Toxicity Criteria (CTC), version 3.0. To assess cardiac function, left ventricular ejection fraction (LVEF) was assessed via echocardiograms or multigated acquisition scans at baseline and every 8 weeks.
biomarker assessments
Paraffin-embedded tissue blocks from archived tumor samples were tested via IHC to determine intratumoral expression of EGFR and HER2. Depending on the availability of tumor samples, expression of additional biomarkers including ErbB3, ErbB4, insulin-like growth factor 1 receptor (IGF1R), and phosphorylated extracellular regulated kinase was also examined. Serum concentrations of EGFR and HER2 were determined from samples collected at baseline and every 4 weeks using enzyme-linked immunosorbent assays. Patients were tested for her2 gene amplification by FISH.
statistical analysis
The efficacy analysis was on the basis of the intent-to-treat population, defined as all patients who received one or more dose of lapatinib. The null and alternative hypothesis RRs were 5% and 15%, respectively. This study employed a two-stage design, with a stopping rule to allow early termination at the end of stage 1 if there was sufficient evidence of lack of efficacy on the basis of the independently assessed RR observed in the first 40 patients in each cohort followed for 16 weeks. Because enrollment, however, was completed before the results of stage 1 were analyzed, the interim analysis could not influence the progress of the study. At the end of stage 2, an exact test (binomial distribution) at the one-sided 5% level was carried out. For both cohorts, there was >90% power to correctly conclude the treatment was effective if the true RR was 15%. Time to progression, PFS, and OS were estimated using Kaplan–Meier curves.
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patient population
A total of 229 women with refractory advanced or metastatic breast cancer were enrolled at 78 centers worldwide from November 2003 to August 2004. Nearly 60% of patients were enrolled at centers in the United States. Data through February 2005 are reported. Patients were enrolled into two cohorts on the basis of HER2 status. Cohort A (HER2 positive) enrolled 140 patients and cohort B (HER2 negative) enrolled 89 patients.
patient demographics and baseline characteristics
Most patients in both cohorts had stage I or II disease at initial diagnosis (Table 1). At study entry, 95% of patients had stage IV disease, 65% had three or more metastatic sites, and 72% had both visceral and nonvisceral involvement. The most common metastatic sites in >40% of patients were bone, liver, lymph nodes, and lung. Almost all patients had received three or more lines of prior anticancer therapy (Table 2). Seventy-six percent of patients had received four or more lines, and 45% of patients had received more than five lines of prior therapy. Most patients had received prior treatment with anthracyclines, taxanes, and capecitabine; two patients had not received prior treatment with capecitabine, one patient had not received prior treatment with taxanes, and one patient had not received prior treatment with anthracyclines. Among HER2-positive patients, 97% had received >12 weeks of prior trastuzumab. Only two HER2-negative patients had received prior trastuzumab.
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previous and current treatment
The mean daily dose of lapatinib was 1484 mg (range 1000–1500 mg), and the median duration of lapatinib therapy was 8 weeks (range, 1–33 weeks). Almost all (96%) patients discontinued lapatinib; 10 (4%) patients were ongoing at the time of data cut-off. Most (65%) patients discontinued lapatinib because of radiologically confirmed disease progression. The remaining reasons for discontinuation of lapatinib included symptomatic progression of cancer (24%), AEs (7%), death (1%), withdrawal of consent (1%), and other reasons (1%).
response
Among HER2-positive patients, the RR as assessed by the investigator was 4.3% (three CR and three PR) and was 1.4% (two PR) by independent review (Table 3). Two patients had SD for 24 weeks in the investigator review, and six patients had SD for 24 weeks in the independent review. Consequently, 5.7% of HER2-positive patients received a clinical benefit (CR, PR, or SD 24 weeks) according to both investigator and independent review. An additional 9 patients by investigator review and 20 patients by independent review had SD 16 weeks. According to investigator and independent review, respectively, 10.7% and 15.7% of HER2-positive patients experienced a clinical benefit 16 weeks.
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In contrast, no objective tumor responses were reported in the HER2-negative cohort, no patients had SD
24 weeks, and only one patient, by both investigator and independent review, had SD 16 weeks.
disease progression and survival
Median TTP and PFS, as assessed by independent review, were both 9.1 weeks in the HER2-positive cohort and 7.6 weeks in the HER2-negative cohort (all deaths were a result of progression of breast cancer; Figure 1). After 4 and 6 months, the estimated probability of being progression free in the HER2-positive cohort was 34% and 18%, respectively. Corresponding values in the HER2-negative cohort were 7% and 0%, respectively. Median survival was 29.4 weeks in the HER2-positive cohort and 18.6 weeks in the HER2-negative cohort.
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safety
Oral lapatinib (1500 mg q.d.) was generally well tolerated. Consistent with previous lapatinib studies, the most common AEs, which occurred at a similar incidence in both cohorts, were diarrhea (59%), nausea (37%), and rash (32%). Grade 4 AEs occurred in 6% of patients (e.g. gastrointestinal disorder, increased bilirubin, hypercalcemia, and renal failure). Twenty-four percent of patients required dose adjustment and/or treatment interruption because of AEs, most commonly diarrhea (10%), nausea (6%), and rash (5%). Seven percent of patients discontinued lapatinib because of AEs including nausea, abdominal pain, diarrhea, and increased bilirubin (
1% of patients). Seventy-nine percent of patients experienced AEs that were considered related to lapatinib, most of which were grade 1 or 2 in severity. Diarrhea (54%), rash (30%), and nausea (24%) were the most common lapatinib-related events with a maximum severity of grade 3 (Table 4). The incidence of most lapatinib-related AEs was comparable between the two cohorts. Fifteen (13 HER2-positive and 2 HER2-negative) patients discontinued treatment because of lapatinib-related AEs.
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Serious adverse events (SAEs) were reported by 27% of patients. The most common SAEs were diarrhea, dehydration, nausea, and vomiting (3% each). Nine percent of patients experienced SAEs that were considered lapatinib related. Four patients experienced fatal SAEs. In one patient with renal failure, respiratory failure, and cardiac failure, a relationship to lapatinib could not be determined because of the rapid progression of symptoms resulting in death. The other three fatal SAEs (dyspnea, respiratory arrest, and respiratory failure) were judged not related to lapatinib.
Because of potential cardiotoxicity with anti-HER2 therapies, cardiac function was closely monitored. Nine (4%) patients, all HER2 positive, had 1 LVEF decrease <50% during treatment. One (<1%) patient experienced a symptomatic grade 3 decrease in LVEF, and the remaining eight (3%) patients were asymptomatic (grade 1 or 2). Three of the nine cases of decreased LVEF resolved at the time of study reporting.
biomarker assessments
Tumor tissue was available for central laboratory analysis from 128 HER2-positive patients and 78 HER2-negative patients. Among the 128 HER2-positive tumor samples, 60% were IHC 3+, and 16% were IHC 2+ and FISH positive. Among the remaining 22 (24%) tumor tissue samples, 13 classified as HER2 negative by IHC (0 or 1+) were FISH amplified. The remaining nine samples had insufficient tumor tissue for FISH analysis. Seventy-three percent of HER2-negative tumors were IHC 0 or 1+. Tissue samples were available from all six HER2-positive patients who had an objective response to lapatinib. All six patients had a HER2 expression level of 3+ by IHC, and all but one were also FISH amplified (the sixth patient did not have sufficient tumor tissue available for testing). No correlation was observed between EGFR expression level and response to lapatinib.
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discussion |
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The use of novel therapeutic agents in the treatment of heavily refractory advanced breast cancer is supported by limited clinical data. To explore the role of lapatinib in such a patient population, an international, multicenter, open-label, phase II study was conducted in patients with trastuzumab- and chemotherapy-treated HER2-positive breast cancer and in patients with chemotherapy-treated HER2-negative breast cancer. Lapatinib monotherapy demonstrated modest clinical activity in patients with refractory HER2-positive disease. In contrast, lapatinib had no apparent clinical activity among HER2-negative patients with tumors resistant to multiple lines of chemotherapy. Time to progression and PFS were also longer in HER2-positive than in HER2-negative patients. This indicates that lapatinib may provide meaningful clinical benefit even in HER2-positive patients where all other standard therapies have failed and argues that the kinetics of tumor growth are different between HER2-positive patients who receive anti-HER2 therapy and HER2-negative patients, even in the later stages of tumor development.
In the HER2-positive cohort, the RR determined by the independent reviewer (1.4%) was lower than the investigator assessment (4.3%). This difference appears to have occurred because of differences in lesion selection, the modality used to determine tumor burden, and subjective differences in the interpretation of scans. Four of five patients judged to have responded by the investigator had cutaneous/chest wall disease that was evaluated by clinical examination and photography. The remaining patient had lymph node involvement that was evaluated clinically and radiologically by the investigator whereas the independent reviewer was only able to perform a radiological assessment.
The clinical activity of lapatinib monotherapy in HER2-positive metastatic breast cancer has previously been demonstrated in the first-line and refractory treatment settings. Administration of lapatinib (1500 mg q.d. or 500 mg b.i.d.) as first-line monotherapy to patients with HER2-amplified locally advanced or metastatic breast cancer resulted in a RR of 24% and a 6-month PFS of 43% [15]. In another study, similar to the current study in patients with refractory HER2-positive metastatic breast cancer (44% had 3 metastatic sites, 21% had received 3 lines of prior therapy, and 88% had received >12 weeks of trastuzumab), lapatinib monotherapy (1250–1500 mg q.d.) resulted in a tumor RR of 5.1% and a clinical benefit rate of 9.0% (Blackwell KL, Pegram MD, Tan-Chiu E, et al., unpublished data).
The results of this study indicate that HER2-positive breast cancer cells that develop resistance to trastuzumab may still be sensitive to lapatinib. Preclinical studies also demonstrated that lapatinib has activity against breast cancer cell lines selected for long-term outgrowth in trastuzumab-containing medium [16]. The potential lack of cross-resistance between lapatinib and trastuzumab may be because of the different effects of these agents on HER2 and the MAPK–ERK1/2 and PI3K–Akt signaling pathways. Several mechanisms can potentially contribute to the development of trastuzumab resistance, including the shedding of the HER2 extracellular domain resulting in p95HER2, mutations in PTEN (a dominant negative regulator of PI3K activity), and overexpression of IGF1R [17–24].
Lapatinib was well tolerated in the current study. Similar to other lapatinib studies, diarrhea and rash were the most common treatment-related AEs [25, 26]. Most AEs were mild to moderate in severity (CTC grade 1 or 2) and grade 4 AEs occurred in <1% of patients. To prevent the possible development of more severe complications, patients should be educated regarding the management of diarrhea with fluids and antidiarrheal medications. Cardiotoxicity, including decreases in LVEF, may occur in patients treated with HER2 inhibitors and is believed to stem from the protective effects of HER2 signaling against apoptosis in cardiac myocytes exposed to cardiotoxic agents [27, 28]. Trastuzumab is associated with 7% cardiac dysfunction (5% New York Heart Association class III and IV) when administered as monotherapy in patients previously exposed to cardiotoxic chemotherapy and 28% cardiac dysfunction when administered in combination with an anthracycline and cyclophosphamide [7]. In the current study, nine (4%) patients experienced one or more decrease in LVEF <50%. Only one patient, however, experienced a symptomatic decrease in LVEF. This is consistent with a meta-analysis of lapatinib studies that demonstrated a low incidence of asymptomatic (1.6%) and symptomatic (0.2%) LVEF decreases in lapatinib-treated patients regardless of prior anthracycline or trastuzumab exposure [29].
To predict which patients will derive the greatest benefit from targeted therapy, clinical studies are increasingly examining the relationship between the expression of various biomarkers and clinical response to treatment. In a recent study, elevated HER2 expression levels were associated with increased RR, clinical benefit, and TTP in patients with advanced or metastatic breast cancer treated with lapatinib as first-line therapy [30]. This is consistent with studies showing that response to trastuzumab also correlates with increased HER2 expression [31]. Consistent with these findings, all six responders in the current study had a HER2 expression level of 3+ by IHC, and five responders were HER2 amplified by FISH. Because of the small number of responders, conclusions regarding the relationship between HER2 expression and clinical response, however, are tentative.
In conclusion, lapatinib monotherapy has modest clinical activity in trastuzumab- and chemotherapy-resistant HER2-positive breast cancer, generating occasional tumor responses and delays in tumor progression. Lapatinib monotherapy does not appear to have clinical activity among HER2-negative patients who were heavily pretreated with chemotherapy.
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GlaxoSmithKline.
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We would like to thank Toni Dotter and Sophie Golding for their contributions to this study. We would also like to thank Jeff Riegel and Ann Marie Fitzmaurice, ProEd Communications, Inc.® for their medical editorial assistance.
Received for publication December 13, 2007. Accepted for publication December 17, 2007.
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