Lapatinib Exposure Research Articles

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study.

Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. First, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC-MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. The LC-MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies.

Characterization and comparison of human glioblastoma models

Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research.

Real-World Analysis of the Efficacy and Safety of a Novel Irreversible HER2 Tyrosine Kinase Inhibitor Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer.

BackgroundAs a novel irreversible pan-ErbB inhibitor recently approved in China, pyrotinib has exhibited promising anticancer efficacy and acceptable safety profile in HER2-positive metastatic breast cancer (mBC). The aim of this retrospective study was to estimate the efficacy and safety of pyrotinib treatment in Chinese mBC patients.MethodsWe retrospectively reviewed the real-world clinicopathological and treatment data of HER2-positive mBC patients receiving pyrotinib-based treatment from August 2018 to July 2019 in Qilu Hospital of Shandong University and other medical centers of Shandong Province in China.ResultsA total of 64 patients treated with pyrotinib were included for analysis, and the median follow-up duration was 260 days (interquartile range, 199.0 to 339.0 days). Fifty-nine (92.2%) patients had been previously treated with trastuzumab and/or T-DM1, while 11 (17.2%) patients had been exposed to lapatinib. The objective response rate (ORR) of all patients was 73.4%, and the disease control rate (DCR) was 98.4%, with a clinical benefit rate (CBR) of 87.5%. Patients with exposure to lapatinib responded well to pyrotinib-based treatment, although the ORR was significantly lower compared with that of patients without exposure to lapatinib (44.1% vs 77.5%, p=0.037). Previous lapatinib exposure was negatively associated with the objective response of pyrotinib treatment (odds ratio [OR]=0.248, 95% confidence interval [CI] 0.063–0.970, p=0.045). The median progression-free survival (mPFS) for patients with previous lapatinib exposure and patients with visceral metastasis was 299 days (95% CI 240.1–357.9 days) and 359 days (95% CI 258.3–459.7 days), respectively. But the mPFS of the whole cohort has not been reached until the cut-off date. Cox multivariate analysis revealed that only visceral metastasis was an independent predictor of significantly shorter PFS (p=0.041) but not previous exposure to lapatinib (p=0.092). Diarrhea (28.1%), hand-foot syndrome (17.2%), and neutropenia (9.4%) were the most common grade 3 adverse events associated with pyrotinib treatment.ConclusionPyrotinib is highly beneficial to HER2-positive metastatic breast cancer patients, even in patients with previous lapatinib exposure. Pyrotinib is a feasible replacement of lapatinib in combination with chemotherapeutic drugs or as a monotherapy. Adverse effects are tolerable and easily manageable.

Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice

BackgroundAlthough chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER+ breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2+ breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure. The tolerance to high dose/long-term drug administration may hinder its potential in clinical settings. Therefore, we aimed to test a novel, short-term chemopreventative strategy using lapatinib during the premalignant risk window in MMTV-erbB-2 mice.MethodsWe initially treated cultured cells with lapatinib to explore the anti-proliferative effects of lapatinib in vitro. We used a syngeneic tumor graft model to begin exploring the in vivo anti-tumorigenic effects of lapatinib in MMTV-erbB-2 mice. Then, we tested the efficacy of brief exposure to lapatinib (100 mg/kg/day for 8 weeks), beginning at 16 weeks of age, in the prevention of mammary tumor development in MMTV-erbB-2 mice.ResultsIn the syngeneic tumor transplant model, we determined that lapatinib significantly inhibited tumor cell proliferation. Furthermore, we demonstrated that short-term lapatinib exposure resulted in life-long protective effects, as supported by increased tumor latency in lapatinib-treated mice compared to the control mice. We further established that delayed tumor development in the treated mice was preceded by decreased BrdU nuclear incorporation and inhibited mammary morphogenesis. Molecular analysis indicated that lapatinib inhibited phosphorylation and expression of EGFR, erbB-3, erbB-2, Akt1, and Erk1/2 in premalignant mammary tissues. Also, lapatinib drastically inhibited the phosphorylation and expression of ERα and the transcription of ER target genes in premalignant mammary tissues. We also determined that lapatinib suppressed the stemness of breast cancer cell lines, as evidenced by decreased tumorsphere formation and ALDH+ cell populations.ConclusionsTaken together, these data demonstrate that brief treatment with EGFR/erbB-2-targeting agents before the onset of tumors may provide lifelong protection from mammary tumors, through the concurrent inhibition of erbB-2 and ER signaling pathways and consequential reprogramming. Our findings support further clinical testing to explore the benefit of shorter lapatinib exposure in the prevention of erbB-2-mediated carcinogenesis.

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer

ImportanceEfficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed.ObjectiveTo determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer.Design, Setting, and ParticipantsIn the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region.InterventionsWomen received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory.Main Outcome and MeasuresThe primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety.ResultsThe intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed.Conclusions and RelevanceIn first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm.Trial Registrationclinicaltrials.gov Identifier: NCT00915018

Abstract P6-09-07: The development of a prediction tool for moderate to severe diarrhea in HER-2/hormone positive metastatic breast cancer (MBC) patients receiving lapatinib in combination with letrozole (L-L)

Abstract Background: For patients with HER-2/hormone positive MBC, the addition of lapatinib to letrozole is associated improvements in tumour response rates and a prolongation of progression free survival. However, moderate to severe diarrhea (≥ grade 2) is a potentially serious toxicity which can lead to dose reductions, delays, hospitalizations and even the premature discontinuation of treatment. Patient care could substantially be improved if these diarrhea events could be accurately predicted through the use of validated and easy-to-use mathematical models. In this study, the development of a repeated measures model to predict the risk of ≥ grade 2 diarrhea prior to each month of L-L therapy is described. Methods Data from 111 patients who received the L-L combination as part of a clinical trial were reviewed [Johnston, 2009]. Generalized estimating equations (GEE) were used to develop the final risk model using a backwards elimination process. Internal validation of the final regression coefficients was done using nonparametric bootstrapping. A risk scoring algorithm (range 0-250) was then derived from the final model coefficients. A receiver operating characteristic curve (ROC) analysis was then undertaken to measure the predictive accuracy of the final scoring algorithm. Results: Presence of skin and lung metastases at baseline, cumulative lapatinib dose and Hg level (nadir) were identified as being important predictors for ≥ grade 2 diarrhea. There was also a negative association between time on therapy and risk of diarrhea where a higher frequency was observed in the first few months. The ROC analysis indicated good predictive accuracy with an area under the curve of 0.80 (95%CI: 0.72 – 0.88). Prior to each new month of therapy, patients with risk scores > 125 units would be considered at high risk for developing ≥ grade 2 diarrhea. Conclusions: Risk of ≥ grade 2 diarrhea is associated with cumulative lapatinib exposure, disease related factors as well as Hg level. The planned external validation and eventual clinical application of this prediction tool will be an important source of risk information for the practicing oncologist and can enhance patient care by optimizing preventative therapies earlier in a proactive manner. Citation Format: George Dranitsaris, Mario E Locouture. The development of a prediction tool for moderate to severe diarrhea in HER-2/hormone positive metastatic breast cancer (MBC) patients receiving lapatinib in combination with letrozole (L-L) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-07.

Abstract P5-19-22: A phase I clinical trial of entinostat and lapatinib in patients with trastuzumab refractory HER2-positive metastatic breast cancer

Abstract Background: Our preclinical data show that entinostat enhances the efficacy of lapatinib in HER2 positive (HER2+) breast cancer cell lines via FOX-03-mediated Bim1 expression. In-vitro and in- vivo, the combination of entinostat and lapatinib enhanced apoptosis in lapatinib-resistant cells. We conducted a phase I study with the primary objective to determine the RP2D of entinostat plus lapatinib in patients with HER2+ metastatic breast cancer with progressive disease (PD) after trastuzumab treatment. Methods: This was a single-center, open-label study to evaluate the dose limiting toxicity (DLT) and determine the MTD of every-other-week entinostat plus daily lapatinib in 28-day cycles. Patients with locally recurrent or metastatic breast cancer in whom trastuzumab had failed were enrolled. DLT was defined as: any toxicity resulting in 14 or more days of treatment delay, febrile neutropenia (NTP), grade 4 NTP for over 7 days, any grade 3 or higher non-hematologic toxicity, grade 3 nausea, vomiting, diarrhea or electrolyte imbalance lasting over 48 hours despite adequate supportive care, or a platelet count less than 10,000. Grading was assigned according to common toxicity criteria (CTC 4). A standard 3+3 dose escalation design was used. Entinostat was given at 10 mg (level 0), 12 mg (level 1), or 15 mg (level 2) by mouth every 14 days. Lapatinib was given at 1250 mg by mouth daily. Toxicity was evaluated on day 15 and day 28 for C1 and C2, and at the end of each cycle thereafter. Results: Fifteen patients with HER2+ metastatic breast cancer were enrolled. Median age was 52 years (range 26-69), median of all prior systemic treatment was 4 (range 1- 12), and median prior trastuzumab-based regimens was 2 (range 1-6). Eight patients had prior lapatinib exposure. Seven patients had ER+/HER2+ tumors. Median number of cycles completed was 2 (range 1-13). DLT was observed in 0 of 3 patients at level 0, 1 of 6 at level 1, and 1 of 6 at level 2. 3 patients at level 1 had lapatinib dose reductions because of grade 3 rash (n=2) or grade 3 dyspnea (n=1) or grade 3 abdominal pain (n=1). 2 patients at level 2 had entinostat dose reductions because of grade 4 NTP in cycle 1 (n=1) or grade 3 NTP in cycle 5 and grade 4 neutropenia in cycle 6 (n=1). Five patients had SD (defined per 2009 RECIST guidelines): two at dose level 1 for 6 months and 13 months, three at level 2 for 3, 4, and 8 months. Median time to progression was 2 months (range 1-13). The most common treatment related adverse events were fatigue (n=15), myalgia (n=14), nausea (n=14), diarrhea (n=13), anemia (n=11), and rash (n=11). Conclusion: MTD was not reached. Cumulative toxicity of entinostat plus lapatinib was fairly well tolerated. The combination therapy suggests there was clinical activity in at-least 5 patients who had SD in this cohort of heavily pretreated trastuzumab-resistant MBC. Data from the EG104900 clinical trial showed that lapatinib plus trastuzumab significantly improved median overall survival compared with lapatinib alone. Therefore, this study was modified after 15 patients to add trastuzumab to the combination. We are currently conducting a phase 1b trial to determine the MTD of entinostat, trastuzumab and lapatinib. Citation Format: Jie Willey, Ricardo H Alvarez, Daniel J Booser, Sharon H Giordano, Ana M Gonzalez-Angulo, James L Murray, Vincente Valero, Jangsoon Lee, Naoto T Ueno, Summer A Jackson, Fahad A Faruqi. A phase I clinical trial of entinostat and lapatinib in patients with trastuzumab refractory HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-22.

Intermittent Dosing Increases Lapatinib Exposure

Abstract Systemic lapatinib exposure can be safely increased by intermittent dosing but ultimately plateaus.

Phase I Dose-Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer

The highly effective treatment of human epidermal growth factor receptor (HER) 2-amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis. We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring. Forty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL. Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.

Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours

To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC0-24 increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib Cmax increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %). Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.

Abstract P4-08-07: Novel insight into the tumor “flare” phenomenon and lapatinib resistance

Abstract BACKGROUND: Resistance to lapatinib generally develops in approximately half of patients within one year of initiating treatment. When lapatinib is withdrawn, there is often a rapid progression of disease which is associated with high mortality rates. This “flare” phenomenon has also been observed upon discontinuation of other tyrosine kinase inhibitors (TKIs) in lung cancer, renal cell carcinoma, and gastrointestinal stromal tumors. METHODS: Using the HER2+ cell lines SKBR3 and BT474, we developed both in vitro and in vivo models demonstrating lapatinib resistance and the tumor “flare” phenomenon. Parental HER2+ cell lines were gradually exposed to increasing doses of lapatinib (100nM to 5uM) to develop a lapatinib-resistant form which was ultimately maintained in 1uM of lapatinib. Lapatinib-”released” cell lines were developed by removing lapatinib exposure from resistant cell lines and allowing the cells to grow for at least two weeks. Cell lines were grown in vitro using traditional monolayer cell culturing techniques and mammosphere technology. A comprehensive analysis of parental, lapatinib-resistant, and lapatinib-released cell lines was performed using microscopy, protein/phosphoprotein analysis, cell cycle, cancer stem cell markers by FACS, and invasion assays. Parental cells served as the control in all experiments. In vivo models were performed by injecting 10,000 cells of parental, resistant, and released cell lines in the mammary fat pads of SCID mice. Tumors were surgically resected after approximately sixty days and volume recorded. All experiments were repeated three times and calculated for statistical significance. RESULTS: Cell cycle analysis and proliferation assays demonstrate that lapatinib-resistant and released cell lines continue to proliferate despite the addition of 1uM lapatinib. Released cells also demonstrate less of a response to retreatment with lapatinib. Tumor volume of lapatinib-released cell lines were significantly larger than parental and resistant counterparts [parental: 39.9mm3, SD 9.48; resistant: 71.8mm3, SD 62.33; released: 943.4mm3, SD 100.1] and this difference was statistically significant (p < 0.01). After three series of passages, mammosphere forming efficiency (MFE) was higher among lapatinib-released cell lines [parental: 1.03%; resistant: 1.93% released: 7.23%] and was statistically significant (p <0.01). Lapatinib-released mammosphere phenotypes appeared larger and less organized than the parental and resistant counterparts. MFE did not correlate with ALDH expression by FACS, and expression varied based on cell line. Western blot analysis revealed loss of E-cadherin among lapatinib-released cells which was not demonstrated in parental or resistant counterparts. Invasion assays demonstrated increased migration among resistant and released cell lines. CONCLUSIONS: We demonstrate the first in vitro and in vivo models of the tumor “flare” phenomenon using HER2+ breast cancer cell lines. This model demonstrates that lapatinib-resistant cells released from the exposure to lapatinib are propelled into a unique and more aggressive phenotype. This model has potential to elucidate new mechanisms of resistance to TKI therapy and provide novel preclinical data that may help in the understanding of disease progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-07.

Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines

BackgroundLapatinib, a tyrosine kinase inhibitor of HER2 and EGFR and is approved, in combination with capecitabine, for the treatment of trastuzumab-refractory metastatic breast cancer. In order to establish a possible gene expression response to lapatinib, a panel of breast cancer cell lines with varying sensitivity to lapatinib were analysed using a combination of microarray and qPCR profiling.MethodsCo-inertia analysis (CIA), a data integration technique, was used to identify transcription factors associated with the lapatinib response on a previously published dataset of 96 microarrays. RNA was extracted from BT474, SKBR3, EFM192A, HCC1954, MDAMB453 and MDAMB231 breast cancer cell lines displaying a range of lapatinib sensitivities and HER2 expression treated with 1 μM of lapatinib for 12 hours and quantified using Taqman RT-PCR. A fold change ≥ ± 2 was considered significant.ResultsA list of 421 differentially-expressed genes and 8 transcription factors (TFs) whose potential regulatory impact was inferred in silico, were identified as associated with lapatinib response. From this group, a panel of 27 genes (including the 8 TFs) were selected for qPCR validation. 5 genes were determined to be significantly differentially expressed following the 12 hr treatment of 1 μM lapatinib across all six cell lines. Furthermore, the expression of 4 of these genes (RB1CC1, FOXO3A, NR3C1 and ERBB3) was directly correlated with the degree of sensitivity of the cell line to lapatinib and their expression was observed to “switch” from up-regulated to down-regulated when the cell lines were arranged in a lapatinib-sensitive to insensitive order. These included the novel lapatinib response-associated genes RB1CC1 and NR3C1. Additionally, Cyclin D1 (CCND1), a common regulator of the other four proteins, was also demonstrated to observe a proportional response to lapatinib exposure.ConclusionsA panel of 5 genes were determined to be differentially expressed in response to lapatinib at the 12 hour time point examined. The expression of these 5 genes correlated directly with lapatinib sensitivity. We propose that the gene expression profile may represent both an early measure of the likelihood of sensitivity and the level of response to lapatinib and may therefore have application in early response detection.

P1-12-09: Safety and Efficacy of Neratinib in Combination with Capecitabine in Patients with ErbB2-Positive Breast Cancer.

Abstract Background: Neratinib (HKI-272) is an irreversible pan-ErbB receptor tyrosine kinase inhibitor that has shown antitumor activity in patients with ErbB2+ breast cancer. Capecitabine has demonstrated efficacy and tolerability in combination with lapatinib, a reversible dual ErbB1/ErbB2 kinase inhibitor, in patients with ErbB2+ advanced breast cancer. The current study evaluated the safety and clinical activity of neratinib in combination with capecitabine. Methods: In part 1 of this open-label, phase 1/2 study, the maximum tolerated dose (MTD) of neratinib in combination with capecitabine was determined in adults with advanced solid tumors. Part 2 of the study further evaluated the safety and clinical activity of neratinib plus capecitabine at the MTD in adults with confirmed ErbB2+ metastatic or locally advanced breast cancer (ECOG Performance Status of 0–2). Eligible patients had received prior taxane treatment and ≥1 prior trastuzumab-containing regimen for ≥6 weeks for metastatic or locally advanced disease. The primary endpoint of part 2 was objective response rate (ORR); tumor responses were assessed by investigators using modified RECIST version 1.0 guidelines every 6 weeks. Results: In part 1 (n = 33), the MTD was determined to be neratinib 240 mg/day plus capecitabine 750 mg/m2 twice daily on Days 1 to 14 of each 21-day cycle. In part 2, as of April 2011, 72 female patients (median age of 52 years [range, 33–79 years]) with ErbB2+ breast cancer were enrolled and treated at the MTD; 7 patients had prior lapatinib exposure and all had prior trastuzumab and taxane exposure. As of the snapshot date, 56% of patients at the MTD were still participating in the study. The most common drug-related adverse events (AEs) in part 2 were diarrhea (89%), palmar-plantar erythrodysesthesia (57%), nausea (33%), vomiting (26%), and decreased appetite (22%). Grade 3/4 drug-related AEs in ≥5% of patients were diarrhea (25%) and palmar-plantar erythrodysesthesia (13%). Eight patients withdrew from part 2 due to AEs, including 4 who withdrew due to diarrhea. Dose interruptions of neratinib and capecitabine, respectively, due to AEs were required by 19 and 29 patients; dose reductions due to AEs were required by 8 and 22 patients. As of June 2010 (interim analysis), 22 patients were evaluable for efficacy in part 2 of the study. Of these 22 patients, 11 achieved a partial response for an ORR of 50%. An additional 2 patients maintained stable disease for ≥24 weeks, resulting in a clinical benefit rate of 59%, and 8 patients had stable disease for <24 weeks. One patient had progressive disease without achieving a response or stable disease. Updated efficacy data will be presented. Conclusions: The results of this study indicate that neratinib combined with capecitabine is tolerable and has promising antitumor activity in patients with ErbB2+ metastatic or locally advanced breast cancer pretreated with trastuzumab. This study supports further evaluation of this combination in ErbB2+ breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-09.

Abstract P3-14-05: Safety and Efficacy of Neratinib (HKI-272) Plus Vinorelbine in the Treatment of Patients with ErbB2+ Metastatic Breast Cancer Pretreated with Anti-HER2 Therapy

Abstract Background: Neratinib (HKI-272) is an irreversible pan-ErbB tyrosine kinase inhibitor that blocks downstream signaling of the ErbB1, -2, and -4 receptors and has shown antitumor activity in patients with ErbB2+ breast cancer. Vinorelbine has shown synergistic antitumor activity in combination with trastuzumab, an ErbB2-specific monoclonal antibody. We report updated safety and efficacy data from this ongoing phase 1/2 study evaluating the combination of neratinib and vinorelbine in patients with solid tumors and ErbB2+ metastatic breast cancer. Material and Methods: In part 1 of this open-label, phase 1/2 study, patients with solid tumors underwent safety evaluations; the maximum tolerated dose (MTD) of oral neratinib administered as ascending multiple daily doses (160 mg, 240 mg) in combination with IV vinorelbine 25 mg/m2 (Days 1 and 8 every 3 weeks) was determined. In part 2, the clinical activity, safety, and pharmacokinetics of the combination was assessed in patients ≥18 years of age with ErbB2+ metastatic breast cancer (ECOG status of 0-2) who had received ≥1 prior treatment with a trastuzumab-containing regimen for ≥6 weeks for metastatic disease or relapse during adjuvant treatment, with or without prior lapatinib exposure. The primary endpoint is objective response rate (ORR). Tumor responses were assessed based on modified RECIST 1.0 criteria every 6 weeks. Results: In part 1 (n = 12), there were no dose-limiting toxicities observed in the neratinib 240-mg plus vinorelbine 25-mg/m2 cohort (full standard doses; defined as the MTD). In part 2, as of April 26, 2010, 77 patients with ErbB2+ metastatic breast cancer were enrolled and treated at the MTD (including 62 in the no prior lapatinib exposure cohort and 15 in the prior lapatinib exposure cohort). At the time of the data snapshot, 56.2% of patients treated at the MTD were still receiving neratinib. The most common drug-related treatment-emergent adverse events (TEAEs; all grades, ≥20% of patients) at the MTD were diarrhea (97.4%), nausea (48.1%), neutropenia (45.5%), vomiting (36.4%), fatigue (26.0%), decreased appetite (28.6%), leukopenia (26.0%), and abdominal pain (23.4%). Common drug-related grade ≥3 TEAEs (≥5% of patients) included neutropenia (36.0%), diarrhea (25.8%), and leukopenia (11.2%). One patient withdrew from the study at the MTD because of grade 3 diarrhea. Fifty-five patients from part 2 were evaluable for efficacy in the no prior lapatinib (n = 43) and prior lapatinib (n = 12) cohorts. ORR (based on investigator-assessed radiographic and clinical data) was 51% in the no prior lapatinib cohort and 42% in the prior lapatinib cohort. Discussion: The results of this study to date indicate that neratinib in combination with vinorelbine is tolerable and shows interesting antitumor activity in patients with ErbB2+ metastatic breast cancer pretreated with trastuzumab and lapatinib. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-05.

Safety and Efficacy of Neratinib (HKI-272) in Combination with Vinorelbine in ErbB2+ Metastatic Breast Cancer.

Abstract Background: The irreversible pan-ErbB tyrosine kinase inhibitor neratinib (HKI-272) potently blocks downstream signaling of the ErbB1, -2, and -4 receptors and has demonstrated antitumor activity in patients with ErbB2+ breast cancer (BC). Vinorelbine has shown synergistic antitumor activity in combination with the ErbB2-specific monoclonal antibody trastuzumab. The objective of this ongoing phase 1/2 study is to evaluate the safety and efficacy of neratinib in combination with vinorelbine in patients with solid tumors and ErbB2+ metastatic BC.Material and Methods: This open-label, 2-part, phase 1/2 study enrolled patients with solid tumors (part 1) to evaluate safety and determine the maximum tolerated dose (MTD) of neratinib administered as ascending multiple daily oral doses (160 mg, 240 mg) in combination with IV vinorelbine 25 mg/m2 (days 1 and 8 every 3 weeks). In part 2, the clinical activity, safety, and pharmacokinetics (PK) of the combination will be assessed in patients ≥18 years of age with ErbB2+ metastatic BC (Eastern Cooperative Oncology Group status of 0 to 2) who had received ≤2 prior treatments with a trastuzumab-containing regimen for ≥6 weeks, with or without prior lapatinib exposure. The primary endpoint is objective response rate. Tumor responses are assessed by modified RECIST criteria every 6 weeks.Results: In part 1 (n = 12), no dose-limiting toxicities were observed in the neratinib 240-mg–vinorelbine 25-mg/m2 cohort (full standard doses; defined as the MTD). Two patients withdrew from the study because of adverse events (1 case each of neuropathy and progression of non-small cell lung cancer). As of the 1 May 2009 data cutoff, 1 patient with gastric cancer had received treatment with neratinib 160 mg plus vinorelbine for 183 days and 1 patient with BC had received treatment with neratinib 240 mg plus vinorelbine for 259 days. In part 2, as of 1 May 2009, 14 patients with ErbB2+ metastatic BC were enrolled and treated at the MTD (including 11 in the no prior lapatinib exposure cohort and 3 in the prior lapatinib exposure cohort; 100% were female). The median duration of treatment with neratinib was 5.9 weeks (range, 0-26). The most common drug-related treatment-emergent adverse events (all grades, ≥10% of patients) included diarrhea (86%), vomiting (36%), nausea (29%), fatigue (29%), headache (14%), and neutropenia (14%). No cases of rash were observed. The most common adverse events leading to dose reductions were diarrhea (n = 2) and vomiting (n = 1). One patient withdrew from the study because of diarrhea. Six patients from part 2 are evaluable for efficacy, all in the no prior lapatinib cohort. Among these 6 patients, best overall responses (based on investigator-assessed radiographic and clinical data) included 1 partial response and 4 cases of stable disease <24 weeks.Discussion: Preliminary results of this study show that the combination of neratinib and vinorelbine is tolerable and demonstrates promising antitumor activity in patients with ErbB2+ metastatic BC. Updated efficacy and safety data are forthcoming, as well as PK results. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5095.