Lapatinib In Patients Research Articles

Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors

3541 Background: The current paradigm of histology-specific drug development may not be optimal in the era of targeted therapeutics. We sought to explore the activity of lapatinib, an oral tyrosine kinase inhibitor of HER2, with a trial design focused on the target rather than on tumor-type. Methods: Patients (pts) with HER2-amplified treatment-refractory metastatic gastro- esophageal (G/E), bladder (B), ovarian (O), or uterine (U) tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1500 mg PO daily (malignancies selected based on reported frequencies of HER2 amplification). The planned sample size was 250 HER2+ pts, with the goal of then randomizing 100 pts with SD at week (wk) 12 to either lapatinib or placebo until progressive disease (PD). Pts who responded at wk 12 (CR or PR) continued on lapatinib; those who progressed were discontinued from study. Primary objectives were response rate at 12 wks and percentage of pts who remain progression free at 24 wks. Secondary objectives were duration of response, progression free survival (PFS) after randomization, and determination of the incidence of HER2 amplification in multiple tumor types. Futility analyses were preplanned to ensure feasibility of screening and of randomization (i.e. a sufficient rate of non- progression at 12 wks). Results: A total of 145 pts were screened (G/E=47, B=35, O=58, U=5); 42 were HER2-amplified (G/E=16, B=13, O=13, U=0) and 32 (G/E=13, B=9, O=10) were enrolled. At wk 12, 1 (3%) patient had a CR, 10 (31%) had SD, 19 (59%) had PD, and 2 (6%) were unknown. Median time to progression during open-label lapatinib was 78 days, 95% CI (42, 92). Only 7 pts with SD underwent randomization. Two pts with esophageal cancer remain on study; one (CR at wk 12) remains a CR at wk 60 and the other (SD at wk 12) remains with SD at wk 36. Low response rate coupled with slow screening and enrollment led to early study closure. Conclusions: Basing trial eligibility on a target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy in refractory disease is associated with a low level of objective responses. [Table: see text]

Safety of a novel capecitabine dosing schedule when combined with lapatinib in patients with HER2-positive metastatic breast cancer refractory to trastuzumab

1131 Background: Capecitabine (C) is active in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal schedule for C to be 7d followed by a 7d rest (7 - 7) (Norton et al, Amer Assn Can Res. 2005). The MTD of C(7 - 7) is 2,000mg BID (Traina et al, J Clin Oncol. April 2008). Lapatinib (L) improves time to progression when added to C(14 - 7) in patients (pts) with HER-2-positive (+) metastatic breast cancer (MBC) that progressed after trastuzumab (T). To optimize this effective combination, we are testing C(7 - 7) + L in a phase II trial. Methods: Eligible pts have measurable, HER-2(+) MBC that has progressed after T. HER-2(+)=IHC 3+ or FISH>2. Pts have normal LVEF by MUGA, ECOG performance status (PS) <2 and normal organ function. <3 prior chemotherapy (CRx) regimens are permitted. Prior fluoropyrimidine is excluded. Therapy (tx) consists of C (2,000 mg BID, 7 - 7) and L (1,250 mg, daily). Cycle length = 4 wk. Pts are evaluated for toxicity q4 weeks (wk), for response q12wk; LVEF by MUGA q12wk. Primary endpoint: response rate (RR). Secondary endpoints: toxicity, stable disease >6 months, PFS. Using a Simon optimal 2-stage design, with alpha = 10%, power = 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the first stage. If >2 pts respond, 29 additional pts will be enrolled. If >7/ 40 pts respond, then C(7 - 7) + L will be considered worthy of further study. Results: As of January 5, 2008, 6 pts are enrolled and evaluable. Median (med) age 64 yrs (42–71), med ECOG PS 1 (0–1), ER/PR(+) 3, HER-2(+) 6, sites of MBC: bone (2), viscera (4), soft tissue (5). Med baseline LVEF 62% (51–68%). Prior tx: Adjuvant: CRx (5), hormone tx (3), T (3); MBC: CRx (2), hormone tx (1), T (3). After a med of 3 cycles (1–4), there were no grade 3, 4, or 5 events. Tx-related toxicity is: Gr 2 fatigue (1); Gr 1 AST (4), diarrhea (3), ALT (2), vomiting (1), hand-foot (1), fatigue (1). No withdrawls due to reduced LVEF. Two pts evaluable for response: PR = 1, SD<6 mo = 1. Conclusions: Capecitabine (7 - 7) + lapatinib appears well tolerated compared to C(14 - 7)+L (Geyer et al). Additional safety and efficacy data is anticipated prior to this meeting. [Table: see text]

Target-specific randomized discontinuation trial design: a novel approach in molecular therapeutics

To describe a phase II study design to evaluate the activity of novel anti-cancer agents that focuses on molecular pathogenesis rather than tumor histology. We propose an enrichment design that enrolls patients across histologies expressing target X and incorporates randomized discontinuation of drug Y after an initial treatment period to evaluate for potential cystostatic activity. We are currently evaluating the activity of lapatinib in patients with HER-2 amplified solid tumors using the target-specific, histology-independent, randomized discontinuation design. Patients receive treatment with lapatinib for an initial 12-week period. After restaging, patients with disease progression are removed from study, patients achieving an objective response continue treatment, and patients with stable disease are randomized to continue lapatinib versus initiate treatment with placebo. The primary endpoints are to evaluate the objective response rate during the initial treatment period and to evaluate the proportion of patients progression-free 12 weeks post-randomization. The target-specific, histology-independent, randomized discontinuation design is an attractive alternative to the traditional phase II design for the development of "targeted" therapeutics.

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer

To evaluate the response to lapatinib, an inhibitor of epidermal growth factor receptors 1 and 2, in patients with advanced bilary tree cancer (BTC) and hepatocellular cancer (HCC). Lapatinib was dosed at 1,500 mg/day orally continuously. Fifty-seven patients were accrued (BTC 17, HCC 40). Therapy was well tolerated. The response in BTC was 0% and in HCC was 5%. The progression free survival (PFS) for BTC and HCC patients was 1.8 (95% CI: 1.7-5.2) months and 2.3 (95% CI: 1.7-5.6) months. The median survival for BTC and HCC patients was 5.2 (95% CI 3.3-infinity) months and 6.2 (95% CI: 5.1-infinity) months. EGFR genotyping indicated HCC patients with <20 repeats have the lowest PFS. The occurrence of any skin rash significantly prolonged PFS and survival. Lapatinib was well-tolerated. There was evidence of activity in HCC, but therapy with lapatinib did not meet the predefined efficacy rate.

Phase 2 study of dual VEGF/HER2 blockade with pazopanib + lapatinib in patients with first-line HER2 positive advanced or metastatic (adv/met) breast cancer.

Abstract Abstract #4114 Background: Evidence indicates a direct molecular link between HER2 amplification and up-regulation of VEGF in HER2+ breast cancer. Concurrent over-expression of HER2 and VEGF is associated with a poorer clinical outcome than over-expression of either alone. These data provide the rationale for simultaneous blockade of both pathways. Pazopanib (P) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit. Lapatinib (Tykerb®) (L) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2). This study (VEG20007) evaluated the efficacy and safety of dual pathway inhibition in patients (pts) with HER2+ adv/met breast cancer.&amp;#x2028; Methods: Eligible pts received no prior chemotherapy or HER2-directed therapy for met disease and had measurable disease per RECIST. Pts were enrolled in one of 2 cohorts. In cohort 1 (C1), pts were randomized to P 400 mg/d + L 1000 mg/d or L alone (1500 mg/d). Enrollment to cohort 2 (C2) began after completion of enrollment to C1. In C2 pts received the combination at doses of P 800 mg/d and L 1500 mg/d. Following disease assessment at week (wk) 12, pts with an objective response could continue on study treatment following re-consent; those with stable disease could continue only where trastuzumab was unavailable. The primary endpoint of C1 was progressive disease rate (PDR) at wk 12 in HER2 FISH+ pts. The primary endpoint of C2 is week 12 response rate in HER2 FISH+ pts.&amp;#x2028; Results: 140 pts were included in the randomized cohort analysis which was previously reported [J Clin Onc 26:2008 (May 20 suppl; abstr 1016)]. Enrollment in C2 has been completed; 40 pts (36 confirmed FISH+) have been enrolled. A preliminary safety analysis has been performed. The most common adverse events of any grade were diarrhea, nausea, fatigue, hypertension, and rash. The most common laboratory abnormalities were ALT and AST increase. Efficacy data will be analyzed when the last pt has completed the week 12 assessment.&amp;#x2028; Conclusion: This is the first Phase II trial to evaluate the combination of 2 oral targeted agents in first-line Her2+ adv/met breast cancer. The lower dose combination demonstrated improved response rate compared to L monotherapy. Previously unreported efficacy and safety data from the higher dose cohort will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4114.

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

A Multi-Institutional Phase II Study of the Efficacy and Tolerability of Lapatinib in Patients with Advanced Hepatocellular Carcinomas

A Multi-Institutional Phase II Study of the Efficacy and Tolerability of Lapatinib in Patients with Advanced Hepatocellular Carcinomas

Lapatinib in the Treatment of Breast Cancer

Lapatinib is an oral dual tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR) and HER-2/ neu (HER2). The success of trastuzumab in breast cancer prompted investigations of lapatinib in breast cancer, which revealed that lapatinib has effectiveness similar to that of trastuzumab. Clinical trials showed that lapatinib is effective for patients with HER2-positive breast cancer. Furthermore, lapatinib may be effective in patients with central nervous system metastasis that developed after trastuzumab therapy. Lapatinib may have synergistic effects with trastuzumab or hormonal therapy. There are encouraging preliminary data on the efficacy of lapatinib in patients with inflammatory breast cancer. Ongoing trials may give us exciting data on lapatinib as adjuvant therapy. HER2 positivity is a strong predictor of response to lapatinib, but the predictive value of EGFR positivity is less clear. While cardiac toxic effects have been observed with lapatinib, their incidence and severity are less significant than with trastuzumab. Current data indicate that lapatinib is a promising agent with unique potential benefits in the treatment of metastatic breast cancer.

Lapatinib: A small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor—2 tyrosine kinases used in the treatment of breast cancer

Background: Lapatinib is an oral, small-molecule, reversible inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases. In March 2007, the US Food and Drug Administration approved lapatinib for use in combination with capecitabine in the treatment of advanced breast cancer overexpressing HER2 (HER2+). Objectives: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of lapatinib, and to review studies of the approved and investigational uses of lapatinib. Methods: English-language reports of clinical trials of lapatinib in patients with cancer were identified through searches of PubMed/MEDLINE (1990–October 2009) and the American Society of Clinical Oncology abstracts database (2003–2008). Search terms included lapatinib, Tykerb, HER2, EGFR, breast cancer, dual tyrosine kinase inhibitor, and GW572016. Results: Lapatinib was well tolerated in a Phase II monotherapy trial in patients with advanced breast cancer; however, the response was minimal in HER2+ patients, and no HER2− patients achieved an objective tumor response. A Phase II trial of lapatinib monotherapy in 39 HER2+ patients with breast cancer and brain metastases yielded 1 partial response, although 15.4% of patients had stable disease for ≥16 weeks. In a Phase III trial comparing lapatinib plus capecitabine with capecitabine alone in HER2+ patients with advanced breast cancer that had progressed after trastuzumab therapy, the median time to progression was 8.4 months with combination therapy, compared with 4.4 months with capecitabine alone ( P < 0.001). There were no significant differences between combination therapy and capecitabine alone in terms of the overall response rate (22% and 14%, respectively) or overall survival. Conclusions: Lapatinib monotherapy was well tolerated, although the response rate was low in patients with advanced breast cancer. Lapatinib combined with capecitabine was associated with significant improvements in the time to progression and response rate compared with capecitabine alone. The available evidence suggests that clinical efficacy in breast cancer is limited to HER2+ disease.

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Abstract LB-306: A Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas.

Abstract Background: Hepatocellular carcinoma (HCC) is on the rise in the US and the rest of the world. HCC responds poorly to systemic chemotherapy. EGFR 1 and 2 are both overexpressed in HCC. We reported that HER2/NEU (EGFR2) somatic mutations in HCC may predict response to EGFR-targeted agents. Lapatinib is an oral inhibitor of EGFR and HER2/NEU with evidence of activity in a number of tumor types. This trial was designed to determine the efficacy of lapatinib in HCC patients. Methods: A Fleming phase II design resulting in a single stage of 25 patients was utilized with a 90% power to detect a true response rate &amp;gt;20%. Adequate hematologic, renal and hepatic function were required. Eligible pts included Child’s A or favorable B group and ECOG PS of 0-1. One prior treatment regimen was allowed. Lapatinib dose was 1,500 mg/d orally without interruption. One cycle was 28 days and radiological assessment was done every 8 weeks. Tumor and blood specimens were analyzed for expression of EGFR/EGFRP, HER2/NEU/CEP17, status of downstream signal pathway molecules (including PTEN, P-Akt, cyclin D, p27 and p70S6K, p53 and others) and correlated to response. Results: 26 pts with HCC were accrued with the following characteristics: Males (17 pts), ECOG PS 0/1 (12/14 pts), median age of 58 yrs (range 29-83). A median of 2 cycles were administered (range 1-12). The most common toxicities were: diarrhea (69%) and nausea ( 54% ). Grade 3/4 toxicities were noted in 3 patients including diarrhea, rash and acute renal failure. There was no evidence of cardiac dysfunction. In 25 patients with HCC, no objective responses were observed. However, 8 (31%) patients had stable disease (SD) including 2 (7.6%) with SD lasting &amp;gt; 6 months. Survival data is being analyzed. The overall goal of correlative studies underway is to attempt to understand the molecular biology of this tumor and guide directed therapy for subsets of patients with hepatocellular carcinoma that may benefit from EGFR inhibition. Tissue and blood specimens were available on &amp;gt;95% of patients. No mutations in EGFR (exons 18-21) were found, consistent with our previous findings, although three single nucleotide polymorphisms (SNP) were found that correlate with SNPs in the NCBI SNP database. We did not find evidence of HER2/NEU somatic mutations. HER2/NEU copy number may be elevated in one patient with stable disease using FISH and is currently being confirmed by IHC staining. Studies are currently underway to assess the expression of EGFR/EGFR-P protein expression and the genes that regulate the cell cycle and apoptosis, which are either downstream of or cross-talk with the EGFR signaling pathway. KRAS mutational status is also underway as it is hypothesized that KRAS mutations will correlate with resistance to EGFR directed-treatment. Conclusions: Lapatinib is well-tolerated and may have some activity, mainly stabilization of disease, in HCC. Source of support: NCI-NO1-CM-62207.

Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC)

4502 Background: Lapatinib is an orally-active, reversible inhibitor of EGFR/ErbB2 tyrosine kinases. In Phase I/II trials, lapatinib has demonstrated activity in patients (pts) with advanced breast cancer. We report the first results of a randomized open-label Phase III trial ( EGF20001 ) of lapatinib vs. hormone therapy (HT) in pts with advanced RCC that express EGFR and/or ErbB2 by immunohistochemistry (IHC). The main endpoints were time to progression (TTP) and overall survival (OS). Methods: Pts with advanced RCC of any histology who had failed first-line cytokine therapy were stratified by Karnofsky performance score (KPS) and number of metastatic sites. Pts were randomized to receive oral lapatinib 1250 mg OD or HT. The primary efficacy endpoint was TTP, with 90% power to detect a 50% increase (i.e. 4 vs. 6 months) at a two-sided 5% significance level. All pt scans were interpreted by independent radiologic review. Results: At the time of the TTP analysis, 417 pts were randomized and 298 TTP events were reported. Demographic and baseline characteristics were similar between both arms; pooled results were: median age: 61 yrs; Stage IV disease: 97%, KPS 90–100: 59%, metastatic sites &gt;2: 49%, prior nephrectomy: 94%, prior interferon therapy: 64%. No unexpected toxicities were observed, and drug-related AE (all grades) for lapatinib vs. HT included rash (44%:3%), diarrhoea (40%:3%). When results from all pts were analysed, median TTP was 15.3 weeks for lapatinib vs. 15.4 weeks for HT (hazard ratio (HR) = 0.94; p = 0.60), and median OS was 46.9 weeks for lapatinib vs. 43.1 weeks for HT (HR=0.88; p=0.29). In the major subgroup of 241 pts with EGFR overexpressed disease (3+ by IHC), median TTP was 15.1 weeks for lapatinib vs. 10.9 weeks for HT (HR = 0.76; p = 0.06), and median OS was 46.0 weeks for lapatinib vs. 37.9 weeks for HT (HR = 0.69; p = 0.02). These results were confirmed by Cox Regression analysis, and additional biomarker evaluation, including FISH, is underway. Conclusions: The EGFR/ErbB2 dual targeted inhibitor, lapatinib, appears to prolong overall survival compared to hormone therapy in advanced RCC pts with overexpressed EGFR who failed prior therapy. [Table: see text]

An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer

3583 Background: Lapatinib is an orally active, reversible inhibitor of the tyrosine kinase activity of ErbB1 (EGFR) and ErbB2 (HER-2/neu). This multicenter, open-label, phase II study was designed to evaluate the safety and efficacy of single-agent lapatinib in patients with metastatic colorectal carcinoma, whose tumors progressed on first-line therapy with 5-fluorouracil in combination with irinotecan or oxaliplatin. Methods: Eighty-six (86) patients received 1250mg of oral lapatinib daily until disease progression or unacceptable toxicity. Safety and efficacy assessments were performed at 4-week and 8-week intervals respectively. Tumor response was determined by an independent review committee using RECIST guidelines. Results: The median age was 60 years (22–83) and median KPS was 90 (70–100). Patients were not selected based on ErbB expression; however, 54.2% and 44.1% of the patients had positive expression (+1, +2, +3) for ErbB1 and ErbB2, respectively. The most commonly encountered adverse events were: diarrhea (45% grade 1, 2, 5% grade 3), rash (33% grade 1, 2, 2% grade 3), fatigue (27% grade 1, 2, 2% grade 3), nausea (20% grade 1, 2, 1% grade 3), anorexia (16% grade 1, 2, 2% grade 3), and vomiting (14% grade 1, 2). In addition, 3 (3%) patients experienced a drug-related Grade 2 (≥20%) decrease in LVEF. All decreases in LVEF were asymptomatic and resolved within three weeks after discontinuation of lapatinib. One (1%) patient experienced a confirmed partial response; however, five patients experienced a minor response with cytoreduction of 20%, 22.4%, 22.8%, 26.8%, and 34% at week 8. Overall, five patients experienced clinical benefit with stable disease for ≥20 weeks. The median TTP and overall survival were 8 and 42.9 weeks respectively. Conclusions: Lapatinib was well tolerated, but demonstrated limited activity as second-line monotherapy in patients with recurrent metastatic colorectal cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline

Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib.

Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for > or =4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.