Clinical recommendations for the use of lapatinib ditosylate plus capecitabine for patients with advanced or metastatic HER2-positive breast cancer

Primary and acquired resistance to trastuzumab pose a therapeutic challenge when treating patients with HER2 (erbB-2)-positive locally advanced or metastatic breast cancer (MBC). The recent introduction of lapatinib (Tykerb/Tyverb, GlaxoSmithKline, Brentford, UK) provides a new management option for such patients. A prospective, randomized phase III clinical trial has confirmed that lapatinib in combination with capecitabine extends time to progressive disease in HER2-positive MBC, compared with capecitabine alone in patients with disease progression despite prior anthracycline, taxane and trastuzumab therapy. Preliminary data also indicate that lapatinib may exert a beneficial effect on brain metastases, a common sanctuary site for HER2-positive breast cancer following trastuzumab treatment. The tolerability of lapatinib is commensurate with that of other erbB family tyrosine kinase inhibitors and no significant new adverse events have emerged following its introduction into clinical practice. In particular, no additive cardiotoxicity has been observed when lapatinib is prescribed after trastuzumab therapy. Based on the published literature and supplemented by clinical experience, this article provides practical management recommendations for the use of lapatinib plus capecitabine in patients with MBC. Issues addressed include patient selection, baseline evaluation and monitoring for clinical benefit. The minimization and management of adverse events is also discussed in detail, particularly the dermatological and gastrointestinal effects, which are the most clinically significant side-effects of lapatinib therapy. Further recommendations cover the minimization of drug interactions, anticipated dosing alterations and the optimal employment of oral anticancer regimens.     

A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer

BackgroundThe 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 methodsIn 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.ResultsMost (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.ConclusionsLapatinib 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.     

An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer

BackgroundThe Lapatinib Expanded Access Program (LEAP) was designed to provide access to lapatinib plus capecitabine for HER2-positive metastatic breast cancer patients who previously received an anthracycline, a taxane, and a trastuzumab and had no other treatment options.Patients and methodsLEAP opened globally and enrollment continued until lapatinib received regulatory approval in each participating country. Patients were assessed for progression-free survival (PFS) and overall survival (OS) and monitored for serious adverse events (SAEs).ResultsAs of 30 September 2008, 4283 patients from 45 countries enrolled in LEAP. The median treatment duration was 24.7 weeks. The most common drug-related SAEs were diarrhea (9.7%), vomiting (4.3%), and nausea (2.4%) and were mainly grade 3 or higher. The incidences of special interest SAEs were decreased left ventricle ejection fraction (0.5%), interstitial lung disease/pneumonitis (0.2%), and serious hepatobiliary events (0.4%). This safety profile is consistent with the overall lapatinib program. The median PFS and OS were 21.1 [95% confidence interval (CI) = 20.1–22.3] and 39.6 (95% CI = 37.7–40.7) weeks, respectively (n = 4006). Subgroup analysis showed longer PFS and OS in patients who had not received prior capecitabine.ConclusionsThese results demonstrate the safety and efficacy of lapatinib in a broader patient population compared with a clinical trial.     

Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients

Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.     

Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases

Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9–68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.     

HER2-positive advanced breast cancer

It is important when treating a patient who has advanced breast cancer to establish the biologic characteristics of the tumor. In addition to knowing the hormone receptor status (estrogen and progesterone), human epidermal receptor 2 (HER2) should be evaluated. The measurement of this parameter is essential to optimizing the systemic management. This article reviews the biology of HER2, testing for HER2, clinical studies evaluating HER2-based therapies, side effects (specifically cardiotoxicity), and strategies for HER2-based therapies.     

Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine

BackgroundIn the present study, we investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC).MethodsOf 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine.ResultsMedian age was 45 years (range 24–75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4–6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01).ConclusionsLC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression.     

RON confers lapatinib resistance in HER2-positive breast cancer cells

Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d’Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer.     

A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy

A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer.     

Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer

BackgroundPreclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells.Patients and methodsBetween January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression.ResultsVisceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5–10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2–5.6) and overall survival (OS) 19.4 months (95% CI 14.0–25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021).ConclusionRetreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.     

Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens

Background: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy.Patients and methods: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH.Results: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for ≥24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%).Conclusions: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.     

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BackgroundLapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.Patients and methodsDNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher’s exact test, Kaplan–Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.ResultsThere were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).ConclusionOur findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.     

A case of breast cancer liver metastases responding to lapatinib and capecitabine therapy

We report a 55-year-old female with liver metastases from breast cancer who responded to lapatinib and capecitabine combination therapy as third-line. She was diagnosed as invasive ductal carcinoma (T1cN1M0, stage IIA). Biomarker of breast cancer was negative hormone receptor (ER-, PgR-) and overexpression of HER2(HercepTest 3+). We started preoperative chemotherapy with weekly paclitaxel followed by FEC100. Then mastectomy with axillary dissection was performed. Histopathology of the breast and lymph nodes showed complete disappear of invasive cancer cells( pCR, grade 3). We performed her adjuvant therapy with trastuzumab after surgery. The liver metastases developed 5 months after surgery. We treated her in trasutumab combined with vinorelbine, and followed by docetaxel during one year and four months. Because liver metastases re-grew during the combination therapy with trastuzumab, we switched to lapatinib and capecitabine combination therapy. After four months of administration, abdominal CT revealed liver metastases were remarkably reduced in size. The efficacy of chemotherapy lasted for eight months.     

Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2

Background:

To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab.

Methods:

In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m⁻²) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated.

Results:

Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3′ (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3–4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3–4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30–40% compared with DL1.

Conclusion:

The MTD LPT 1000 mg/VNR 22.5 mg m⁻² (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.     

Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea

ABSTRACT: Purpose: To evaluate efficacy in patients with brain metastasis (BM) on entry into the lapatinib expanded access program (LEAP). METHODS: LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m2 daily in two divided doses, days 1-14, every 21 days and lapatinib 1250 mg once daily. RESULTS: Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression-free survival (PFS) was 18.7 weeks in patients with BM and 19.4 weeks without BM (P=0.88). In patients with BM, brain response was synchronized with systemic responses (P=0.0001). Overall survival (OS) was 48.9 weeks in patients with BM and 64.6 weeks without BM (P=0.23). Multivariable analysis found hormone receptor positivity (P=0.003) and clinical benefit rate (CBR) of combined systemic and brain disease (P<0.0001) significantly associated with prolonged brain PFS, and CBR of combined systemic and brain disease (P=0.03) and longer trastuzumab use (P=0.047) associated with prolonged OS in patients with BM; prior capecitabine did not affect PFS or OS in patients with BM. CONCLUSION: Lapatinib plus capecitabine is equally effective in patients with or without BM.     

HER2-positive advanced breast cancer treatment in 2020

HER2-positive breast cancer is an aggressive subtype identified in the 1980s. The development of therapies targeting the HER2 has improved outcomes. The current standard of care, established in 2012 is dual blockade with trastuzumab + pertuzumab as first-line followed by TDM-1 as second-line. Several suboptimal choices are available in third-line or more. In 2019 the presentation of several trials evaluating new drugs and regimens in third-line has re-opened questions about sequencing, treatment of triple positive disease and treatment choice after exposure to TDM-1. These include tucatinib, neratinib and trastuzumab-deruxtecan. Other agents – including other antibody drug conjugates and bispecific antibodies as well as combinations - will lead to further changes in coming years. Additionally, should the numerous putative biomarkers thus identified ever come into use at the clinic, choice of treatment and response evaluation may be substantially changed.