Lapatinib Monotherapy Research Articles

In vitro and in vivo evidence that a combination of lapatinib plus S‐1 is a promising treatment for pancreatic cancer

Lapatinib is a small molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR). We investigated the effect of treatment with lapatinib alone or in combination with a fluoropyrimidine derivative S-1 against pancreatic cancer. The HER2/EGFR expression in each of the four pancreatic cancer cell lines MiaPaca-2, PANC-1, Capan-1 and Capan-2 was measured by flow cytometry. The anti-tumor effects of lapatinib (30 mg/kg) and/or S-1 (10 mg/kg) were evaluated using female BALB/c nude mice xenografts generated using these four cell lines. Synergy between lapatinib and S-1 was examined by median effect analysis in vitro. Resected pancreatic cancer tissues from 137 patients were immunohistochemically stained with anti-human HER2 and EGFR antibodies. The administration of lapatinib as a single agent substantially suppressed tumor growth in vivo of all pancreatic cancer cell lines examined. A strong correlation was observed between HER2 expression and the anti-tumor effect of lapatinib in vivo. Lapatinib synergized with S-1 to inhibit the tumor growth of MiaPaca-2 and PANC-1 xenografts. When used as a single agent in vitro, lapatinib barely inhibit the cell growth of any cell line. However, lapatinib synergized with the anti-tumor activity of the S-1 components 5-fluorouracil and 5-chloro-2,4-dihydrogenase against all cell lines. Immunohistochemical staining demonstrated that 70% of the pancreatic cancers overexpressed HER2 and/or EGFR. Both lapatinib monotherapy and combined treatment with S-1 may be promising treatments for patients with pancreatic cancers; the majority these cancers express lapatinib target molecules.

Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.

Abstract Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported.Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed.Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 61.

Biomarker Profiles in Trastuzumab (T) Refractory HER2+ Inflammatory Breast Cancer (IBC) That Predict for Survival Benefit from Lapatinib (L) Monotherapy.

Abstract Background:L is a reversible, oral small molecule inhibitor of EGFR and HER2. L demonstrated an objective response rate (ORR) of 39%, a median progression free survival (PFS) of 14.6 weeks and a median overall survival (OS) of 11.2 months in a monotherapy Phase II study of 126 patients (pts) with HER2+ IBC (Kaufman et al. Lancet Oncology, 2009). In the initial cohort of pts we reported an association between response to L and coexpression of pHER3 with pHER2 (Johnston et al, J Clin Oncol, 2008 26; 1066-72). In this study we measured a series of biomarkers in tumor biopsies obtained before the start of treatment and evaluated their association with parameters of clinical benefit to L in relation to prior T.Methods:Core needle biopsies were obtained pretreatment, preserved in phosphatase inhibitor buffer, fixed in formalin and embedded in paraffin. Baseline expression of total and activated EGFR, HER2, HER3 and downstream markers, as well as markers specific to IBC were determined by standard IHC techniques yielding manual and optical density (OD) scores. 94/126 pts received prior T treatment before beginning L treatment, while 32 patients were T naive. The baseline expression of each marker was tested for association with ORR, PFS and OS using proportional hazards and logistic regression models.Results:OD IHC data indicated pEGFR and TGFα had statistically significant association with OS and PFS in pts treated with prior T. pHER3 also appeared to be associated with OS, although was not statistically significant. Higher levels of these biomarkers were associated with decreased hazard of progression or death. Correlation between OD and manual scores (0,1,2,3) were highly significant for these markers (R=0.80, p<0.0001). These markers were not significant when tested against ORR.[table 1] OSPFSORRpEGFR (N=56)P<0.0001, HR=0.45P=0.0192,HR=0.66P=0.2721,OR=1.44pHER3 (N=71)P=0.0634, HR=0.74P=0.1256, HR=0.78P=0.0920, OR=1.72TGFα (N=57)P=0.0019, HR=0.95P=0.0386, HR=0.97P=0.8211, OR=1.05HR; Hazard Ratio, OR; Odds Ratio (odds of response)When we evaluated the same panel of biomarkers in T naïve pts, higher levels of HER2 expression were significantly associated with improved ORR (p=0.0186) and a trend towards significance with OS (p=0.0674). Furthermore, higher levels of pAKT (p=0.0068) and pERK (p=0.006) were significantly associated with improved OS.Discussion:L monotherapy is clinically active in the treatment of relapsed/refractory HER2+ IBC. Higher levels of pEGFR and TGFa by IHC are significantly associated with improved OS and PFS but not ORR in patients with prior T therapy. In contrast, T naïve pts, higher levels of pAKT and pERK showed a significant association with OS. Thus, different biomarker profiles may predict benefit in T naïve vs T-refractory pts benefiting from L monotherapy in HER2+ IBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 706.

Abstract B250: Clinical benefit of lapatinib-based therapy in patients with HER2-positive breast tumors expressing p95HER2

Abstract Purpose: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain, retains kinase activity and correlates with intrinsic trastuzumab resistance. We tested the hypothesis that the small molecule lapatinib, an EGFR/HER2 dual tyrosine kinase inhibitor, would be active in these tumors. We studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinic [lapatinib monotherapy (Study EGF20009) or lapatinib in combination with capecitabine (Study EGF100151)]. Patients and Methods: Expression of p95HER2 in primary tumors was evaluated by immunofluorescence and correlated with clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) and progression-free survival using logistic regression and Cox-proportional hazard models. Results: Lapatinib was efficacious in inhibiting tumor growth and HER2 downstream signaling of p95HER2 expressing tumors in two different animal models. In human samples, expression of p95HER2 was evaluable in 76% (105/138) and 56% (223/399) of patients from EGF20009 and EGF100151 studies, respectively. The percentage of p95HER2 positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In neither study there was a statistically significant difference in progression-free survival between p95HER2-positive and p95HER2-negative patients. Similarly, in both studies the clinical benefit rate was not significantly associated with p95HER2 expression. Conclusions: Lapatinib as a monotherapy or in combination with capecitabine is equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B250.

Abstract B79: Antitumor activity of lapatinib as a single agent and in combination with capecitabine in a HER2-amplified human gastric tumor model

Abstract HER2 has been reported to be amplified or over-expressed in approximately 20% of gastric tumors and is an attractive target for treatment of gastric cancer. Lapatinib, a potent, oral, small-molecule, dual inhibitor of EGFR and HER2 tyrosine kinases, is approved in combination with capecitabine for the treatment of advanced HER2-positive metastatic breast cancer. It inhibits the phosphorylation of EGFR, HER2, HER3, down stream signaling pathways, and cell growth in HER2-amplified gastric tumor cells in vitro. The preclinical in vivo efficacy of lapatinib monotherapy and the combination of lapatinib with capecitabine, an oral prodrug of 5-fluorouracil was evaluated in the HER2-amplified N87 gastric xenograft model established in female SCID mice. Anti-tumor activities were determined from analyses of tumor growth inhibition (TGI), defined as the decrease in median tumor volume for treated versus vehicle control mice and tumor growth delay (TGD), defined as the increase in median time to end point in treated versus vehicle control mice. Twice daily oral administration of lapatinib resulted in 57% and 62% TGI and 111% and 113% TGD at 50 mg/kg and 65 mg/kg, respectively. Capecitabine monotherapy (dosed once daily at 350 mg/kg for 7 consecutive days, followed by 7 days off and repeated for 2 cycles) inhibited tumor growth by 57% and produced 159% TGD. The combinations of lapatinib (both 50 mg/kg and 65 mg/kg) with capecitabine (350 mg/kg) were well tolerated and resulted in significantly greater tumor volume reduction (71% and 74% TGI, respectively) and tumor growth delay (203% and 179%, respectively) compared to either single agent alone. These data demonstrate that lapatinib is highly efficacious as a single agent and combination of lapatinib with capecitabine is beneficial in HER2-positive gastric tumors, and support ongoing clinical trials of lapatinib, oxaliplatin, and capecitabine in patients with HER2-amplified gastric cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B79.

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Background:HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies.Methods:In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab.Results:For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8–28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9–34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib.Conclusion:Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

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]

Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study

Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. GlaxoSmithKline.

Decrease in serum extracellular domain of HER2 at 4 and 8 weeks is associated with prolonged progression-free survival on lapatinib monotherapy.

Abstract Abstract #3140 Background: The extracellular domain of the HER2 oncoprotein (ECD HER2) is shed into the serum and can be detected by ELISA. This study investigated whether baseline serum ECD HER2 level is associated with prolonged progression-free survival (PFS) on lapatinib monotherapy. Additionally, we analyzed whether change in serum ECD HER2 at week 4 and 8 after start of lapatinib therapy is associated with prolonged PFS.
 Methods: Study EGF20009 investigated lapatinib monotherapy in 138 HER2-positive patients with metastatic breast cancer who had not previously received chemotherapy or trastuzumab. Serum was collected at baseline and every 4 weeks after initiation of oral lapatinib (1,500 mg daily or 500 mg twice daily). Disease assessment was performed at week 8, 12 and every 12 weeks thereafter. Disease status was assessed by an independent radiology committee, and response was measured using RECIST. Serum ECD HER2 was measured using the ELISA from Siemens HealthCare DX/Oncogene Science. A serum ECD HER2 decrease or increase ≥ 20% from baseline was defined as a significant change.
 Results: Baseline ECD HER2 was not associated with PFS; however, a ≥ 20% decrease from baseline serum ECD HER2 was associated with prolonged PFS, and a ≥ 20% increase from baseline was associated with shorter PFS. Patients who experienced a ≥ 20% decrease from baseline serum ECD HER2 at week 4 had a median PFS of 199 days (95% confidence interval [CI] = 145, 253) compared with 135 days (95% CI = 104, 171) for patients who did not (p = 0.016). Similarly, patients who experienced a ≥ 20% increase from baseline serum ECD HER2 at week 4 had a median PFS of 113 days (95% CI = 59, 135) compared with 199 days (95% CI = 142, 253) for patients who did not (p < 0.001). Similar associations were observed for the week-8 changes in serum ECD HER2 levels.
 Conclusions: Baseline ECD HER2 was not associated with PFS, whereas a ≥ 20% decrease from baseline serum ECD HER2 at week 4 and 8 was associated with prolonged PFS on lapatinib monotherapy. Single-agent lapatinib could be considered for the subset of patients whose ECD HER2 declines in the first 8 weeks of therapy, whereas a combination of chemotherapy with anti-HER2 therapy may be more appropriate for the patients whose ECD increases by ≥ 20%. Identification of a subgroup of patients who may be able to avoid cytotoxic chemotherapy in the MBC setting is an attractive prospect in our quest to find suitable therapies for appropriate patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3140.

Lapatinib monotherapy in HER2+ relapsed or refractory inflammatory breast cancer (IBC): quality of life (QOL) assessment.

Abstract Abstract #4097 Background: IBC is a rare, clinically distinct and aggressive form of breast cancer characterized by severe pain and a poor prognosis. EGF103009 was a phase II, open-label, multicenter study that showed lapatinib monotherapy is clinically active in women with relapsed/refractory HER2+ IBC that progressed on prior therapy with anthracylines, taxanes, and trastuzumab. This analysis focuses on the impact of lapatinib on QOL and pain symptoms (endpoints added during a study amendment) in these patients.
 Methods: QOL was assessed using the EORTC QLQ C-30, a 30-item instrument that assesses 15 domains consisting of 5 functional scales (physical, role, emotional, cognitive, social) and 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global QOL item. A high score for a functional scale/global QOL indicates a high and healthy level of functioning/QOL whereas a high score for a symptom scale indicates a high level of symptoms/problems. Pain was specifically assessed using the Brief Pain Inventory-Short Form (BPI-SF), which includes 4 severity items and 7 items assessing pain interference with general activity, mood, work, walking ability, relations, sleep, and enjoyment of life. Scoring produces 4 scores: pain severity, overall pain interference, activity-related pain interference and mood-related pain interference. Higher scores indicate greater pain severity or pain interference. Both questionnaires were completed at baseline and every 4 weeks thereafter. Mean change in scores from baseline (with 95% CI) were provided by visit.
 Results: Because QOL/pain scales were added late in the study, only 33 of 126 patients in the HER2+ cohort completed at least one question in the health outcome questionnaires at baseline. At week 8, 64% (n=21) of patients completed assessments, and the results showed moderate improvement (10-20 points) in average EORTC QLC scores for global QOL, role functioning and social subscales. The physical function subscale also showed improvement (9 points). All symptom scales (except diarrhea) were lower than baseline at most scheduled visits indicating improvement in symptoms. Scores for all 4 summary pain scores of the BPI-SF at week 8 were also lower than baseline values suggesting improvement in pain severity and pain interference (decrease ranged from 1.3 to 2.7 points). Sixteen of the 33 patients (48%) had partial response to treatment and 9 had stable disease.
 Conclusions: Results suggest that lapatinib monotherapy may improve level of functioning/QOL and provide relief from most symptoms, including pain, in the short term. These QOL benefits add to the clinical improvement associated with lapatinib therapy in these heavily pre-treated patients with an aggressive form of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4097.

Lapatinib is active in patients with HER2-amplified breast tumors expressing p95HER2.

Abstract Abstract #708 Background: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain and retains kinase activity. Tumors expressing p95HER2 have a worse clinical outcome and are resistant to trastuzumab therapy (Scaltriti M. et al, JNCI 2007). The hypothesis that lapatinib, a small molecule inhibitor that targets the intracellular kinase domain of EGFR and HER2, would be active in these tumors was tested by correlating p95HER2 expression with clinical response to lapatinib in EGF20009, a lapatinib monotherapy study
 Methods: Archival tumor blocks were obtained from patients (pts) participating in study EGF20009. In this study, pts with untreated locally advanced or metastatic HER2 amplified breast tumors either received lapatinib 1500mg daily or 500mg BID (H.L. Gomez et al, J Clin Oncol 2008). Pre-treatment samples were analyzed for p95HER2 expression by immunofluorescence using 2 antibodies against HER2, binding to the intracellular and extracellular domain, respectively, plus a pan-cytokeratin antibody. Tumors were scored as p95HER2 positive (p95HER2+) [if any cytoplasmic staining was detected with the intracellular HER2 antibody and this staining co-localized with the pan-cytokeratin antibody], negative (p95HER2-) [no intracellular HER2 cytoplasmic staining) or non-evaluable (N/E) [no cytokeratin or HER2 staining by immunofluorescence]. The presence of p95HER2 was then correlated with response rate (RR), stable disease for over 100 days (SD) and progression-free survival (PFS) to lapatinib. A Cox-proportional hazards model was used to compare the groups. In order to correlate the presence of p95HER2 with HER2 extracellular domain in the serum, a quantitative determination of the 105 kD ECD level in serum (Oncogene Science HER2/neu Microtiter ELISA) has also been performed.
 Results: 68/105 tumors were evaluable for p95HER2 expression. Fourteen were p95HER2+ (20.5%) and 54 were p95HER2- (79.5%). The observed percentage of p95HER2+ tumors is concordant with published reports. Among the 14 pts with p95HER2+ tumors, 7 responded (RR: 50%) and 1 had SD for > 100 days for an overall clinical benefit rate of 57% (RR+SD). In the p95HER2- population (N=54), 24 pts responded (RR: 44.4%) and 16 pts had SD >100 days for an overall clinical benefit rate of 56% (RR+SD). PFS was similar in both groups, with a median PFS of 24 wks in pts with p95HER2+ and p95HER2- tumors (p=0.97, HR 1.1). These findings compare with the median PFS of 20.7 wks for the entire population in the trial (N=138pts). Further correlation of p95 status and HER2 ECD status of the tumors will be presented.
 Conclusion: These data demonstrate that lapatinib has similar activity in pts with p95HER2+ or p95HER2-, HER2 amplified breast tumors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 708.

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.

Analysis of dermatologic events in patients with cancer treated with lapatinib

Dermatologic events (DEs) in patients with cancer treated with lapatinib, a small-molecule dual tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR [ErbB1]) and HER2 (ErbB2), were characterized. Nine clinical trials of metastatic cancer were included in this analysis. Lapatinib was administered at doses ranging from 1000 to 1500 mg/day as monotherapy (n=928) or in combination with paclitaxel or capecitabine (n=491). Patients not treated with lapatinib comprised the control group. Dermatologic events included hand-foot syndrome, rash, hair disorder, dry skin, pruritus/urticaria, skin disorder, skin infection, and nail disorder; DEs were characterized based on type, time to onset, severity, duration, and required interventions. Fifty-eight percent of patients treated with lapatinib monotherapy, 74% treated with lapatinib plus paclitaxel or capecitabine, and 53% in the control group developed DEs. Among patients receiving lapatinib monotherapy, 55% experienced grade 1/2 DEs, 3% had grade 3 DEs, and no grade 4 DEs were observed. The most common DE was rash (43%); all other events occurred in <or=8% of patients. Most DEs developed between days 1 and 14 of starting treatment, with a median duration of 29 days. Three percent of DEs led to lapatinib dose reduction, 7% resulted in dose interruption, and 1% led to drug discontinuation. Most DEs in lapatinib-treated patients present early, are mild to moderate in severity, and infrequently require dose modification or treatment interruption. Lapatinib-associated DEs appear to differ clinically from those associated with EGFR TKIs in both frequency and severity.

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

BackgroundThe efficacy and tolerability of the epidermal growth factor receptor/human epidermal growth factor receptor type 2 (HER2) tyrosine kinase inhibitor lapatinib in refractory metastatic breast cancer were assessed. Patients and methodsIn a phase II, open-label study, patients with previously treated HER2-positive (n=140) or HER2-negative (n=89) metastatic breast cancer received once-daily oral lapatinib 1500 mg/day. ResultsMost (76%) patients had received four or more lines of prior therapy. The response rate in the HER2-positive cohort was 4.3% by investigator assessment and 1.4% by independent assessment. Both assessments established that ∼6% of HER2-positive patients derived clinical benefit from lapatinib, being progression free for ≥6 months. No objective tumor responses occurred in the HER2-negative cohort. Independent review assessments of median time to progression and median progression-free survival were similar in the HER2-positive and HER2-negative cohorts (9.1 and 7.6 weeks, respectively). All responders exhibited HER2 overexpression (3+ by immunohistochemistry), and five of six responders were HER2 amplified by FISH. Lapatinib-related adverse events, including diarrhea (54%), rash (30%), and nausea (24%), were primarily mild to moderate in severity. ConclusionsLapatinib monotherapy had modest clinical activity in HER2-positive metastatic breast cancer that progressed on prior trastuzumab regimens. No apparent clinical activity was observed in chemotherapy-refractory, HER2-negative disease.

Clinical activity of lapatinib monotherapy in patients with HER2+ relapsed/refractory inflammatory breast cancer (IBC): Final results of the expanded HER2+ cohort in EGF103009

636 Background: IBC is an uncommon (∼2–6%) form of breast cancer with a significantly worse prognosis than non-IBC. Lapatinib is a reversible, oral small molecule inhibitor of EGFR and HER-2/neu tyrosine kinases (also known as ERBB1 and ERBB2, respectively). EGF103009 was initially designed as a two stage, Green-Dahlberg study of lapatinib monotherapy in 30 subjects in each of two cohorts, HER2+ and EGFR+/HER2-. Following a 50% response rate in the first 30 HER2+ patients, this cohort was expanded to 120 patients in order to improve the precision of estimated ORR; this represents the only prospective clinical study ever conducted in HER2+ IBC. Methods: Patients with HER2+ (IHC 3+ / FISH Ampified) IBC that was refractory to anthracyclines, taxanes, and trastuzumab (where available) were enrolled. Pretreatment and day 28 fresh biopsies were collected for each subject to assay for relevant biomarkers. Patients received lapatinib daily (1,500 mg/d). Skin lesions were assessed at 4 week intervals and RECIST-measurable disease if present was assessed at 8 week intervals. Results: One hundred twenty-six HER2+ patients were treated continuously with once-daily lapatinib (1,500 mg). Final analysis is currently underway and preliminary data suggest a response rate of approximately 40%; responses were also seen in the ∼50% of patients who were trastuzumab-refractory. Most frequent toxicity was Grade I/II diarrhea and skin rash. Biomarker analyses of pretreatment tumor biopsies confirmed a molecular phenotype consistent with IBC (i.e., RhoC- and E-cadherin-overexpression); co-expression of pHER2 and pHER3 were predictive of lapatinib response. Conclusions: Lapatinib monotherapy is active in the treatment of relapsed / refractory HER2+ IBC where few effective therapies are available, and is well tolerated. Within this group, tumors that have an activated HER2/HER3 pathway appear to be more likely to respond. Final analysis of responses and their durability as well as of biomarkers predictive of responses will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Novartis, Pfizer GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline, Novartis, Roche GlaxoSmithKline

Mathematics in the Realm of Lapatinib: 500 + 500 = 1,500?

Mathematics in the Realm of Lapatinib: 500 + 500 = 1,500?

Future options in the treatment of ErbB2 (HER2)-positive breast cancer

This article overviews future trends for the treatment of ErbB2 (HER2)-positive breast cancer. It is based on a presentation given at the ECCO 14 congress, September 2007. Novel ErbB2-targeted agents and/or treatment combinations have shown promise in treating ErbB2-positive metastatic breast cancer. Combinations include two agents that both inhibit ErbB2 and existing/novel ErbB2 inhibitors with chemotherapy and/or vascular endothelial growth factor (VEGF)- and VEGF receptor (VEGFR)-targeted agents. Early data suggest lapatinib (an ErbB1/2 inhibitor that recently received European approval) may be valuable in treating and/or preventing brain metastases secondary to ErbB2-positive breast cancer. Furthermore, based on promising data in metastatic disease, adjuvant and neoadjuvant lapatinib monotherapy and combination therapy trials are ongoing in early disease. Translational research will become increasingly important with new/novel agents to optimize outcomes through individualized treatment. In summary, novel targeted agents/combinations may fulfill unmet treatment needs in ErbB2-positive breast cancer; ongoing research will confirm therapeutic potential.

Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy

Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.

Pooled analysis of diarrhea events in patients with cancer treated with lapatinib

To characterize diarrhea events in patients with cancer treated with lapatinib as monotherapy or in combination with capecitabine or taxanes. Eleven clinical trials (phase I, II, or III) in patients with metastatic cancer were analyzed. Lapatinib was administered at doses ranging from 1,000 to 1,500 mg/day as monotherapy (n = 926) or in combination with capecitabine (n = 198) or taxanes (n = 687). Diarrhea events were characterized based on severity, time to onset, duration, required interventions, and clinical outcomes. In the pooled analysis of nine studies, diarrhea occurred in 55% of lapatinib-treated patients and 24% of patients not receiving lapatinib. All grade diarrhea occurred in 51% of patients treated with lapatinib monotherapy and 65% treated with lapatinib plus capecitabine. In a separate analysis, 48% of patients treated with lapatinib plus a taxane experienced diarrhea. Overall, most diarrhea events were grade 1/2. Grade 3 events occurred in <10% of patients and grade 4 events were rare (<or=1%). Most diarrhea events resolved with conventional approaches and without dose modification. Approximately 40% of patients treated with lapatinib monotherapy or combination therapy experienced a first diarrhea event within 6 days of treatment initiation, with a median duration of 7-9 days. Lapatinib-containing chemotherapy regimens do not cause severe diarrhea when proactive monitoring and intervention is introduced. Most diarrhea events in lapatinib-treated patients are low grade, requiring infrequent lapatinib dose modification or interruption. Proactive management of diarrhea is crucial to prevent more serious complications in lapatinib-treated patients.

Autoresistance to ErbB2 kinase inhibitors: Elucidating mechanisms and identfying strategies to prevent its onset in breast cancer

2075 Background: Clinical efficacy of ErbB1/ErbB2 kinase inhibitors is limited by the development of acquired autoresistance. Developing clinically relevant models to study the mechanism(s) of acquired autoresistance will identify therapeutic strategies to prevent its onset. Methods: BT474 cells, an ErbB2-overexpressing/ER+ breast cancer line sensitive to lapatinib-induced apoptosis were chronically exposed to lapatinib, simulating chronic administration of lapatinib in the clinic. Lapatinib-resistant cells (rBT474) and single cell clones were established. Baseline gene expression in parental BT474 and rBT474 cells was compared using Human Affymetrix oligonucleotide arrays. Sequential tumor biopsies were analyzed by quantitative IHC as part of a clinical trial using lapatinib monotherapy (1500mg/d) in patients with metastatic breast cancer. Results: Gene expression and protein analysis indicates that acquired resistance to lapatinib is mediated by increased estrogen receptor (ER) signaling rather than loss of ErbB2 expression or insensitivity of the ErbB2-MAPK-PI3K pathways to lapatinib. Activation of ER signaling results from de-repression of FOXO3a and transient up-regulation of caveolin-1, both facilitating ER transcriptional activity. Gene interference studies confirm that acquired resistance involves a switch in survival dependence and regulation of survivin from ErbB2 to ER. Since ErbB2 signaling is operative in rBT474 cells, treating parental BT474 cells with lapatinib plus (i) fulvestrant, or (ii) estrogen deprivation prevents the onset of acquired lapatinib resistance compared with either therapy alone. Importantly, increased ER signaling occurs in patients with ErbB2-overexpressing/ER+ breast cancers treated with lapatinib monotherapy, consistent with changes in cell lines. Conclusions: Chronic lapatinib monotherapy induces a shift in the dependence of cell survival from ErbB2 to ER. Combining lapatinib with selected anti-estrogens prevents its onset in cell lines and warrants clinical validation. Establishing models of acquired resistance simulating the clinic provides a tool to identify strategies to improve treatment options for patients with ErbB2-overexpressing breast cancers. [Table: see text]