Lapatinib In Patients Research Articles

The efficacy of lapatinib in patients with metastatic HER2 positive breast cancer who received prior therapy with monoclonal antibodies and antibody-drug conjugate: a single institutional experience

The choice of the anti-HER2 agent depends on country-specific availability, the specific, previously administered anti-HER2 therapy and the relapse-free interval, although there is not much published data on the use of lapatinib after progression on pertuzumab and/or T-DM1. The aim of this research is to determine efficacy of lapatinib in this setting. This research included 111 patients with metastatic HER2 positive breast cancer who received lapatinib with capecitabine at The Oncology Institute of Vojvodina. Lapatinib was given to 83 patients after trastuzumab without prior exposure to pertuzumab or T-DM1 while 28 patients received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1. In order to determine efficacy of lapatinib in both groups, we measured progression free survival (PFS) and overall survival (OS), as well as by subsets: hormonal status (ER-positive and/or PR-positive tumours versus ER-negative and PR-negative tumours), the number of positive axillary lymph nodes (four or more positive axillary lymph nodes versus less than four positive axillary lymph nodes), marker of proliferation (Ki-67 ≥ 30 versus Ki-67 < 30), disease free interval (metastatic recurrence ≤ 1 year after initial diagnosis versus metastatic recurrence > 1 year after initial diagnosis or de novo metastatic disease. Median PFS was 5.6 months (95% CI 4.6–6.6) in the group of patients who received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM 1 and 7.4 months (95% CI 6.1–10.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.79; 95% CI 0.61–0.98; P = 0.09). The patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes, marker of proliferation Ki 67 ≥ 30 and metastatic recurrence ≤ 1 year after initial diagnosis, had a similar PFS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Median OS was 10.1 months (95% CI 8.6-NR) in the group that received lapatinib after exposure to trastuzumab, pertuzumab and/or T-DM1 and 16.3 months (95% CI 14.4–20.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.76; 95% CI, 0.59–0.94; P = 0.04). Patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes and marker of proliferation Ki 67 ≥ 30, had no distinctly worse OS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Lapatinib with capecitabine is an effective therapeutic option, especially in patients with negative prognostic factors, who have received prior chemotherapy, trastuzumab, pertuzumab, T-DM1 and remains an acceptable option for HER2 positive metastatic breast cancer until the novel drugs are approved in developing countries.

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

BackgroundPoly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC.MethodsA first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded.ResultsTwenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders.ConclusionsLapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.Trial registrationClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

Abstract PS10-30: An open label, pilot study of veliparib and lapatinib in patients with metastatic, triple negative breast cancer

Abstract Purpose: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2(gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple negative breast cancer (TNBC) with intact DNA repair, we previously showed an induced synthetic lethality with combined EGFR inhibition and PARPi. We report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Experimental Design: A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline and taxane therapy. Patients with gBRCA1/2 mutations were excluded. Results: Twenty patients were enrolled of which 17 were evaluable for response. Median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Gene expression analysis suggest baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions: Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Citation Format: Erica M Stringer-Reasor, Jori E May, Eva Olariu, Valeria Caterinicchia, Yufeng Li, Deborah Della Manna, Gabrielle B Rocque, Christos Vaklavas, Carla I Falkson, Lisle M Nabell, Edward P Acosta, Andres Forero-Torres, Eddy S Yang. An open label, pilot study of veliparib and lapatinib in patients with metastatic, triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-30.

NRG Oncology/RTOG 1119: PHASE II Randomized Study of Whole Brain Radiotherapy/Stereotactic Radiosurgery with Concurrent Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer — A Collaborative Study of NRG and KROG (NCT01622868)

NRG Oncology/RTOG 1119: PHASE II Randomized Study of Whole Brain Radiotherapy/Stereotactic Radiosurgery with Concurrent Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer — A Collaborative Study of NRG and KROG (NCT01622868)

Real-world data of lapatinib and treatment after lapatinib in patients with previously treated HER2-positive metastatic breast cancer: A multicenter, retrospective study.

Lapatinib is widely used in the later lines treatment of HER2 positive metastatic breast cancer (MBC). EGF104900 study suggested that among patients who experienced progression on prior trastuzumab‐containing regimens, lapatinib plus trastuzumab had better effects than trastuzumab alone. However, no evidence was discovered in terms of lapatinib plus capetabine compared with lapatinib plus trastuzumab plus chemotherapy, as well as a treatment after progression on lapatinib. We evaluated the medical records retrospectively of all MBC patients with HER2 positive disease who progressed on prior trastuzumab‐containing regimens (advanced setting) and a taxane (any setting) and received lapatinib‐based treatment from 2015 to 2018 in five institutions in China. A total of 242 patients were available for analysis. Among them, 164 (68%) patients received lapatinib plus capetabine (LX) and 78 (32%) patients received lapatinib plus trastuzumab and one chemotherapy (HLC). The median progression‐free survival (PFS) of the HLC group was significantly superior to the LX group (8.8 months vs 5.0 months, P < .0000001). No significant difference in grade 3 or worse adverse events was observed in two groups (P = .57). A total of 175 patients were available for the analysis of the postlapatinib treatment. Continuation of lapatinib showed superior mPFS results compared to the non‐anti‐HER2 treatment (4 months vs 2 months, P = .01) and similar results compared to switch to other anti‐HER2 treatments (4 months vs 4 months, P = .88). In patients who had progressed on prior trastuzumab‐base therapy, HLC provided a new dual‐targeting treatment option for the later lines therapy of patients with HER2 positive MBC. Moreover, evidence of cross‐line use of lapatinib was provided.

Abstract OT3-18-01: Detect III/IV study trial - The multicenter study program in patients with HER2-negative MBC and circulating tumor cells

Abstract Background: The collaborative DETECT study program represents a large program on metastatic breast cancer (MBC) worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trials translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT-III trial is a multicenter, randomized, phase III study comparing standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative MBC and HER2-positive CTCs. Patients with HER2-negative MBC and only HER2-negative CTCs can be included within the DETECT-IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative MBC. Within the DETECT-IV study setting postmenopausal patients with hormone-receptor positive MBC are treated with the CDK 4/6 inhibitor ribociclib and endocrine therapy, while women with triple negative MBC or a hormone-receptor positive tumor and indication for chemotherapy will receive eribulin. Specific aims: The DETECT study program offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in the controlled setting of a single large clinical trial program. The primary endpoint of the DETECT III trial is the comparison of efficacy as assessed using CTC clearance rate between patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups. The primary objectives of the DETECT- IV trial are to evaluate CTC clearance rate for the ribociclib cohort and progression-free survival (defined as time interval from date of recruitment until progressive disease) for the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” of CTCs may provide new information about their potential function in terms of a repeatedly performed liquid biopsy to assess the patients’ response to therapy. Citation Format: Sabrina Krause, Thomas WP Friedl, Peter A Fasching, Andreas Schneeweiss, Volkmar Müller, Sabine Riethdorf, Klaus Pantel, Florin-Andrei Taran, Arkadius Polasik, Marie Tzschaschel, Amelie de Gregorio, Franziska Meier-Stiegen, Jens Huober, Wolfgang Janni, Tanja Fehm. Detect III/IV study trial - The multicenter study program in patients with HER2-negative MBC and circulating tumor cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-18-01.

473P - Phase I study of lapatinib and trametinib in patients with KRAS mutant colorectal, non-small cell lung and pancreatic cancer

BackgroundKRAS oncogene mutations are causing sustained signaling through the mitogen-activated protein kinase (MAPK) pathway resulting in uncontrolled cell growth. Efforts to target KRAS directly or to inhibit downstream effectors have been unsuccessful. Preclinical research revealed that KRAS mutated (KRASm) cells are intrinsically resistant to MEK inhibitors due to upstream growth receptors that reactivate the MAPK and phosphoinositide 3-kinase (PI3K) pathway. Concurrent inhibition of MEK, EGFR and HER2 resulted in synergistic anti-tumor activity, with complete inhibition of tumor growth in vitro and in vivo. MethodsThis is a single-center, phase I dose-escalation study to assess the safety, tolerability and anti-tumor activity of the MEK inhibitor trametinib combined with the dual EGFR/HER2 inhibitor lapatinib in patients with advanced KRASm and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic cancer. Patients received escalating doses of continuous or intermittent, once daily (QD) orally administered lapatinib and trametinib, starting at 750mg and 1mg, respectively. The primary objective was to determine the recommended phase 2 dose (RP2D) and schedule. ResultsThirty-four patients with CRC (n=16), NSCLC (n=15) or pancreatic cancer (n=3) were enrolled across five dose-levels, 2 patients are still on treatment. Dose-limiting adverse events were reported in twelve patients; grade 3 diarrhea (n=3), rash (n=2), nausea (n=1), several grade 2 toxicities (n=1) and aspartate aminotransferase elevation (n=1) resulting in inability to receive 75% of the planned doses (n=2) or treatment delay (n=2). The established RP2D was 750mg lapatinib QD and trametinib 1.5mg QD 5 days on/2 days off. Out of 22 patients evaluable for response, regression of target lesions was seen in six, with one confirmed partial response in NSCLC. Reductions in pERK and pS6 levels were demonstrated in paired tumor biopsies. Pharmacokinetic results were as expected. ConclusionsLapatinib and trametinib could be combined in an intermittent dosing schedule with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed with sufficient target engagement. Clinical trial identificationNCT02230553. Legal entity responsible for the studyThe Netherlands Cancer Institute. FundingNovartis. DisclosureN. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Meyers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. K. Monkhorst: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Benecke; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: Abbvie; Advisory / Consultancy: Diaceutics. J.H.M. Schellens: Shareholder / Stockholder / Stock options, and patent holder on oral taxanes: Modra Pharmaceuticals. All other authors have declared no conflicts of interest.

A Systematic Review and Meta-analysis of the Combination of Vinorelbine and Lapatinib in Patients With Her2-positive Metastatic Breast Cancer.

The development of effective human epidermal growth factor receptor 2 (HER2)-targeted therapies has been heralded as a significant milestone in breast cancer treatment, resulting in improvement of the outcome for those with HER2-positive metastatic breast cancer. Despite these advantages, metastatic breast cancer is still regarded as an incurable disease. In heavily pretreated patients with increasingly limited options for palliative management, ensuring control of disease and maintenance of quality of life is an important goal. Vinorelbine and lapatinib is a combination used in later-line treatment of metastatic HER2-positive breast cancer. The current article presents a systematic review and meta-analysis of prospective series of the vinorelbine/lapatinib doublet for efficacy and toxicity in metastatic HER2-positive breast cancer. Altogether seven prospective trials involving 235 evaluable patients were retrieved for analysis. Pooled estimates of response rate and disease control rate were 24.4% and 63.3% respectively. Furthermore, overall survival was 20.1 months and progression-free survival was 5.44 months. The most common grade 3 and 4 toxicities were seen in fewer than 10% of cases. Vinorelbine/ lapatinib combination regimen may serve as an option for pre-treated patients with metastatic HER2-positive breast cancer.

Lapatinib with chemotherapy for gastro-oesophageal cancer.

Results from a phase 2 clinical trial of standard chemotherapy versus modified chemotherapy plus lapatinib in patients with gastro-oesophageal cancer have shown that addition of lapatinib was feasible, with an increase in toxic effects.

SUN-442 EGFR/ErbB2 Targeted Therapy for Aggressive Prolactinomas

Introduction: Prolactinomas are usually benign and respond well to dopamine agonist therapy. However, approximately 20% are resistant, and 10% behave aggressively and persist or recur. Treatment resistance has been associated with ErbB receptor expression, prompting us to conduct a trial of ErbB targeted therapy in patients with aggressive prolactinomas. Objective: To evaluate efficacy of the EGFR/ErbB2 tyrosine kinase inhibitor lapatinib in patients with aggressive prolactinomas. Study design: We conducted a prospective 6-month phase IIa multicenter trial of oral lapatinib 1250 mg/d in adult patients with continued tumor growth on maximally tolerated dopamine agonist therapy. Pregnant women and patients with unstable visual fields were excluded. MRI was performed every 3 months. Primary endpoint was 40% reduction in tumor size; secondary endpoints were 50% PRL reduction, PRL normalization, % PRL reduction, % tumor size reduction, and immunohistochemical correlation of clinical response with ErbB receptor expression. A target sample size of 24 subjects was estimated to achieve power >80%, using one tailed hypothesis, an alpha of 0.10, and an effect size of 0.20. Numerical variables were summarized as median (range). Results: Due to rigorous inclusion criteria, 6 subjects were enrolled. Four were female; median age was 29 years (19-70) and median disease duration 8 years (1-30). Median tumor size was 40 mm (16-60) at diagnosis. Three subjects underwent 1 surgery and 3 had 2 surgeries; 1 had radiation therapy. At study start, median maximal tumor diameter was 25 mm (13-48) and baseline PRL was 379 ng/mL (114-11748). After 6 months on lapatinib, tumor size was stable in 3 subjects, decreased in 1 with 22% tumor volume reduction, and increased in 2. PRL decreased in 3 subjects, with a median decrease of 42% (-78% to -42%) and increased in 3 by 59% (28% to 103%). Median nadir PRL was 200 ng/mL (40-11753), for an overall 25% reduction (-87% to 25%). Final median PRL was 181 ng/mL (67-1726), with a median decrease of 7% (-79% to 103%). One subject with widely metastatic pituitary carcinoma initially experienced a 25% decrease in PRL but was withdrawn at 3 months when PRL increased and metastases progressed. Excluding this subject, overall median PRL decrease was 42% (-79% to 59%). EGFR and ErbB2 expression was not detectable in tumors derived from 3 subjects and did not correlate with treatment response. Lapatinib was well tolerated with reversible grade 1 transaminitis observed in 2 subjects, grade 2 rash in 4 subjects, and grade 1 asymptomatic bradycardia in 1 subject. Conclusions: Preliminary results suggest that lapatinib may be effective in controlling tumor growth in select patients with aggressive prolactinomas. Confirming the benefit of lapatinib in aggressive prolactinomas requires a larger cohort size.

Abstract OT1-10-01: DETECT III/IV study trial – The multicenter study program in patients with HER2-negative metastatic breast cancer and circulating tumor cells

Abstract Background: The collaborative DETECT study program represents one of the largest study program on metastatic breast cancer worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trial translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT III trial is a multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. Patients with persisting HER2-negative circulating tumor cells (CTCs) can be included within the DETECT IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative metastatic breast cancer. Within the DETECT IV study setting postmenopausal patients with hormone-receptor positive metastatic breast cancer are treated with everolimus or ribociclib and endocrine therapy, while women with triple negative metastatic breast cancer or a hormone-receptor positive tumor and indication for chemotherapy receive eribulin. Specific aims: The DETECT study program comprises all breast cancer subtypes and therefore offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in a controlled setting of a single large clinical trial. The primary endpoint of the DETECT III trial is the comparison of patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone, with regard to the CTC clearance rate. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups (Progression free survival, overall response rate and dynamic of CTCs). Primary objective of the DETECT IV trial is to evaluate CTC clearance rate within the everolimus/ribociclib cohort and additionally assess progression-free survival defined as time interval from date of recruitment until progressive disease within the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” may give new information about CTCs potential function as liquid biopsy in order to determine their relevance for therapy prediction. Citation Format: Krause S, Friedl T, Romashova T, Fasching PA, Schneeweiss A, Müller V, Taran F-A, Arkadius P, Marie T, De Gregorio A, Meier-Stiegen F, Huober J, Janni W, Fehm T. DETECT III/IV study trial – The multicenter study program in patients with HER2-negative metastatic breast cancer and circulating tumor cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-10-01.

Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status.

Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.

A sensitive LC-MS-MS assay for the determination of lapatinib in human plasma in subjects with end-stage renal disease receiving hemodialysis

Most bioanalytical methods reported in literature for the quantitation of lapatinib in human plasma are either for lapatinib alone or lapatinib administered along with other tyrosine kinase inhibitors (TKIs) for therapeutic drug monitoring (TDM) in cancer patients. Recently there was a need for the quantitation of lapatinib in patients with end-stage renal disease (ESRD) receiving hemodialysis (HD). This special patient population normally receives many concomitant medications which have the potential to interfere with the quantitation of lapatinib. Here we describe an LC-MS-MS bioanalytical assay for the quantitation of lapatinib in human plasma containing potential concomitant medications which are commonly given to patients with ESRD receiving HD. The lapatinib calibration curve range was 2.50–1000 ng/mL. Lapatinib was fortified with its isotopically labeled internal standard in a 50 μL plasma aliquot and extracted with protein precipitation. The chromatographic separation was achieved on a Zorbax SB-C18 (5 μm, 2.1 × 50 mm) column with isocratic elution. Assay precision, accuracy, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. No interferences were observed for the quantitation of lapatinib in the presence of concomitant medications. The validated LC-MS-MS method has been successfully applied to a clinical study for the determination of lapatinib concentrations in human plasma for patients with ESRD receiving HD.

An open label, pilot study of veliparib (ABT-888) and lapatinib in patients with metastatic, triple negative (ER, PR, and HER-2 negative) breast cancer.

1095Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC), often resistant to standard of care therapies. We previously showed an induced synthetic lethal ...

Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis.

Lapatinib is a tyrosine kinase inhibitor that targets the human epidermal growth factor receptor 2 (HER2) and the epidermal growth factor receptor (EGFR/HER1), and there are concerns about its cardiac toxicity. Recent studies of lapatinib have reported cardiac adverse events; however, the results have been inconsistent among the studies. The aim of our study was to estimate the cardiac toxicity of lapatinib in patients with breast cancer and other HER2-positive cancers. To evaluate the cardiotoxicity of lapatinib, the results of previous studies were quantitatively integrated using meta-analysis. Forty-five articles regarding cardiac adverse events, including left ventricular dysfunction, left ventricular ejection fraction (LVEF) decrease, arrhythmia, and other cardiac adverse events, were assessed. As a subgroup analysis in patients with breast cancer, 26 studies of lapatinib-induced cardiac adverse events were assessed. The overall incidence of cardiac adverse events was 2.70% (95% confidence interval [CI] 1.60-4.50%). The incidences of left ventricular dysfunction and LVEF decrease were 1.60% (95% CI 1.30-2.00%) and 2.20% (95% CI 1.30-3.60%), respectively. The overall incidence of cardiac adverse events was 3.00% (95% CI 1.50-6.10%) in patients with breast cancer, which was marginally higher than the rate in patients with all type of cancers. The overall incidence of lapatinib-induced cardiac toxicity was relatively low based on an indirect comparison with trastuzumab. However, careful monitoring of cardiac toxicity is still needed when patients are treated with lapatinib because the related risk factors have not been clearly identified.

Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial

The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m2 self-administered orally twice daily on days 1-14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1-21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3-34·1] vs 25·9 months [95% CI 22·7-28·3]; hazard ratio 0·75 [95% CI 0·64-0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5-26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar-plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]). This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population. F Hoffmann-La Roche/Genentech.

Abstract OT1-04-02: NRG oncology/RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain met from HER2-positive breast cancer — A collaborative study of RTOG &amp; KROG (NCT01622868)

Abstract Background: The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients (pts) with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastases (mets) in these pts. Half of these pts die of intracranial disease progression rather than extracranial systemic disease. Therefore, strategies to improve survival must include increased CNS disease control. Lapatinib crosses the BBB &amp; demonstrates modest activity against intracranial mets. Based upon preclinical data &amp; phase I study results, it's hypothesized that lapatinib plus whole brain radiotherapy (WBRT) can improve the intracranial disease control compared to WBRT alone. Trial design: A randomized phase II trial that will evaluate if there is a sufficient enough signal in improved 12-week complete response (CR) rate following WBRT with the addition of lapatinib vs. WBRT alone in pts with mets from HER2+ breast cancer to warrant a future phase III trial. An amendment to allow protocol RT to be delivered as WBRT or stereotactic radiosurgery (SRS) is in process. Eligibility Criteria: Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain met (≥10 mm if solitary, &amp; &amp;gt; 5 mm if multiple on enhanced MRI). The two populations targeted for accrual include pts with 1) newly diagnosed, multiple brain mets or 2) progressive brain mets after SRS or surgical resection of 1-3 mets. Pts are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; &amp; prior SRS or surgical resection. Non-CNS penetrating HER2 targeted therapy is permitted throughout the study, but ptsnot on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after its completion. Prior lapatinib is allowed, last dose &amp;gt; 21 days prior to study entry. Specific aims: Primary objective is to determine if there is an increase in CR rate in the brain at 12weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT vs. WBRT alone. Secondary objectives includes: CR rate at 4 weeks on MRI post WBRT, objective response rate on MRI at 4 &amp; 12 weeks, evaluation of lesion specific MRI response rates; CNS progression-free survival rate, overall survival rate, &amp; adverse event rates. Statistical methods: The randomization of experimental &amp; control arms is set as 1:1. With 114 eligible pts there will be 86% power to detect a 15% absolute increase in CR rate at a significance level of 0.10, using a 1-sided Z-test for 2 proportions. Targeted accrual is 143 accounting for up to a 5% ineligibility rate, 15% pts not evaluable for the primary endpoint due to death, pt withdrawal, or other reasons. Activated:7/26/2012. Present accrual (5-1-2016): 85. Targeted accrual: 143. Contact Information: Protocol: CTSU member web site https://www.ctsu.org. Enrollment: OPEN at https://open.ctsu.org. Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422 &amp; UG1CA189867. Citation Format: White JR, Moughan J, Kim IA, Peereboom DM, De Los Santos JF, Sperduto PW, Mehta MP. NRG oncology/RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain met from HER2-positive breast cancer — A collaborative study of RTOG &amp; KROG (NCT01622868) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-02.

Abstract P1-12-10: Safety and efficacy of trastuzumab emtansine (T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study

Abstract Introduction T-DM1 treatment significantly improved overall survival and had a lower incidence of grade ≥3 adverse events (AEs) vs capecitabine plus lapatinib in patients (pts) with HER2-positive advanced breast cancer (BC) in the EMILIA study, including pts with treated, asymptomatic CNS metastases (mets). KAMILLA is an ongoing, single-arm, open-label, phase 3b global safety study of T-DM1 in pts with HER2-positive locally-advanced or metastatic BC (target n=2220). In this interim analysis we describe clinical characteristics, safety, and efficacy in pts with stable CNS mets at baseline (BL). Methods Eligible pts received prior HER2-directed therapy and chemotherapy and progressed on or after most recent treatment for advanced BC, or within 6 months of completing adjuvant therapy. Pts with asymptomatic CNS mets were eligible, including pts with stable CNS disease with prior radiation therapy. Pts received T-DM1 3.6 mg/kg every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. This exploratory analysis describes pts with BL CNS mets. Median progression-free survival (PFS) was estimated using the Kaplan-Meier method. Results As of April 4, 2016, data were available for 2017 treated pts, of whom 399 (20%) had BL CNS mets, with a median follow-up of 33 months. Table 1 presents demographic and BL characteristics. The incidence of AEs was similar between pts with and without BL CNS mets. Serious AEs (SAEs) occurred in 112 pts with BL CNS mets (28%) vs 311 of 1618 pts without BL CNS mets (19%), and the frequency of SAEs was comparable to that observed in EMILIA. However, nervous system disorder SAEs, such as seizure, epilepsy, and brain edema, occurred more frequently in pts with BL CNS mets (30 pts [8%]) vs 18 pts [1%] with no BL CNS mets. Mean T-DM1 treatment duration was 8.0 months (median 8 cycles; range 1–55) in pts with BL CNS mets and 9.4 months (median 9 cycles; range 1–57) in pts with no BL CNS mets. Median PFS was 5.5 months in pts with BL CNS mets vs 7.9 months in pts with no BL CNS mets. A decrease in the size of brain target lesions was observed during T-DM1 treatment in 84 of 126 pts with measurable CNS lesions. Table 1. BL characteristics CNS mets at BL (n=399)No BL CNS mets (n=1618)Median age, yrs (range)52 (28–83)55 (26–88)ECOG performance status, n (%) 0193 (48)929 (57)1174 (44)605 (37)232 (8)83 (5)Hormone receptor status, n (%) ER and/or PR positive246 (62)992 (61)ER and PR negative149 (37)593 (37)Median time since initial BC diagnosis, yrs (range)4.8 (0–28)5.0 (0–53)Median time since first metastasis, yrs (range)2.4 (0–25)2.6 (0–35)Median number of prior therapies for metastatic BC (range)3 (0–&amp;gt;10)2 (0–&amp;gt;10) Conclusions This subgroup analysis of KAMILLA is the largest reported cohort of pts with CNS mets treated with T-DM1. The overall safety profile of T-DM1 in pts with BL CNS mets was comparable to that of pts without CNS mets. As might be expected in pts with CNS disease, serious neurological AEs occurred more frequently in pts with BL CNS mets vs those without. Response to T-DM1 was seen in the CNS in pts with BL CNS mets, however, median PFS was lower in pts with BL CNS mets vs those without BL CNS mets. Citation Format: Montemurro F, Ellis P, Delaloge S, Wuerstlein R, Anton A, Button P, Lindegger N, Barrios C. Safety and efficacy of trastuzumab emtansine (T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-10.

Abstract P2-05-21: Predictive value of quantitative HER2 and HER3 levels combined with downstream signaling markers in HER2-positive advanced breast cancer patients treated with lapatinib

Abstract Background: Clinical correlates of lapatinib resistance have not been well defined. Previous studies implicated genes regulated by the estrogen receptor (ER) and activation or mutation of proteins downstream from HER family receptors. In the current study, HER2 and HER3 expression levels were quantitatively measured using a VeraTag® fluorescence-based assay, in addition to seven downstream signaling proteins determined by IHC. All biomarkers were correlated with overall survival (OS) in patients treated with lapatinib. Methods: Formalin-fixed, paraffin-embedded samples were obtained from the primary tumor of 191 patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark® Breast Cancer Assay (Monogram Biosciences, South San Francisco) was used to quantify HER2 protein expression levels. HER3 protein expression was quantified using the VeraTag® technology (Monogram Biosciences). Expression of ER, PTEN, Cyclin E, HIF-2alpha, p-p70S6K, p-AMPK and p-MAPK were determined by IHC (Duchnowska et al., Oncotarget 2016; 7:550). OS analyses of HER2 and HER3 were stratified by key clinical variables, including stage and presence of a brain metastasis prior to lapatinib-based therapy. Results: Among the downstream signaling molecules, HIF-2alpha (r = -0.23; p = 0.047) and ER (r = -0.27; p = 0.005) were negatively correlated with HER2 expression after adjustment for multiple testing. PTEN appeared to correlate with HER3, but was not significant after adjustment for multiple testing. OS was significantly shorter for both those below the cut-off level of positivity by the HERmark assay (HR = 1.8; p = 0.029), and those with above median HER2 levels (HR = 1.7; p = 0.009), as compared to cases with in between levels. The relationship between HER2 and OS is also captured by a U-shaped, parabolic function in HER2 (p = 0.005). Elevated HER3 showed a trend toward a correlation with longer OS (HR = 0.66/log; p = 0.16), somewhat stronger in the ER-negative subset (HR = 0.55/log; p = 0.085) and in the subset with above-median HER2 (0.48/log; p = 0.10), where inhibiting HER2 activation of HER3 may be more important. In multivariate Cox models, HER2 (parabola, intermediate HER2 best, p = 0.001), presence of brain metastases (HR = 2; p &amp;lt; 0.001), ER (HR = 0.60; p = 0.009) and either p-p70S6K (HR = 0.66; p = 0.018) or p-AMPK (HR = 0.67; p = 0.022) were significantly associated with OS (p-p70S6K and p-AMPK were mutually correlated). Conclusions: Patients with moderately increased HER2 levels may have best outcomes while receiving lapatinib following progression on trastuzumab. This supports recent findings of a less benefit from lapatinib in patients with high HER2 expression (Nunciforo et al., SABCS 2015, P3-07-08). HER3 levels do not seem to substantially impact the prognosis. Further studies are warranted to explore the predictive utility of quantitative HER2 and HER3 in guiding HER2-directed therapies. Citation Format: Duchnowska R, Sperinde J, Czartoryska-Arlukowicz B, Mysliwiec P, Winslow J, Radecka B, Petropoulos C, Demlova R, Orlikowska M, Kowalczyk A, Lang I, Ziólkowska B, Debska-Szmich S, Merdalska M, Grela-Wojewoda A, Zawrocki A, Biernat W, Huang W, Jassem J. Predictive value of quantitative HER2 and HER3 levels combined with downstream signaling markers in HER2-positive advanced breast cancer patients treated with lapatinib [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-21.

Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial

We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51-127), eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.