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Clinical Cancer Research 13, 4495-4502, August 1, 2007. doi: 10.1158/1078-0432.CCR-07-0004
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Phase I Pharmacokinetic Study of the Safety and Tolerability of Lapatinib (GW572016) in Combination with Oxaliplatin/Fluorouracil/Leucovorin (FOLFOX4) in Patients with Solid Tumors

Wandena S. Siegel-Lakhai1, Jos H. Beijnen1,3, Walter L. Vervenne2, Henk Boot1, Marianne Keessen1, Melissa Versola4, Kevin M. Koch4, Deborah A. Smith4, Lini Pandite4, Dirk J. Richel2 and Jan H.M. Schellens1,3

Authors' Affiliations: 1 The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital; 2 Academic Medical Center, Amsterdam, the Netherlands; 3 Faculty of Pharmaceutical Sciences, Division of Drug Toxicology, University Utrecht, Utrecht, the Netherlands; and 4 GlaxoSmithKline, Research Triangle Park, North Carolina

Requests for reprints: Wandena S. Siegel-Lakhai, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 316-223-16-504; E-mail: wan.les{at}quicknet.nl.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
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Purpose: This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib, oxaliplatin, and 5-FU when given alone and in combination were evaluated.

Experimental Design: This study was conducted in two parts. Part 1 was designed to determine the OTR and part 2 was the pharmacokinetic part of the study. Lapatinib was administered once daily for the entire duration of the study. Leucovorin and oxaliplatin were given concurrently over 2 h as an i.v. infusion, after which 5-FU was given as a bolus followed by continuous infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. Once the OTR was determined, it was to become the dose level for patients included in the pharmacokinetic part of the study.

Results: A total of 34 patients was treated in this study. No dose-limiting toxicities were observed and the OTR was established at 1,500 mg/d lapatinib in combination with the standard FOLFOX4 regimen. Nonhematologic toxicities consisted mainly of nausea, diarrhea, vomiting, fatigue, neuropathy, and mucositis. The most important hematologic toxicity was neutropenia. No drug-drug interactions between lapatinib and the FOLFOX4 regimen were observed.

Conclusion: Lapatinib can be safely administered in combination with the standard FOLFOX4 regimen. Further studies are warranted to explore the potential additive antitumor effect of lapatinib in combination with the FOLFOX4 regimen.

Molecular target-specific therapeutics have the potential to improve antitumor activity while minimizing toxicity to normal host cells. ErbB1 (epidermal growth factor receptor) and ErbB2 overexpression can promote tumor growth in a variety of epithelial tumors. In some tumors, such overexpression correlates with a poor clinical outcome, making these receptors attractive therapeutic targets (1–4). Kinase activation of the ErbB1 and ErbB2 receptors leads to interaction with other signal transduction molecules, initiating an intracellular signaling cascade, which promotes proliferation [mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) pathway] and survival (phosphatidylinositol 3-kinase pathway) of these tumors (5). Therapeutic monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting ErbB1 and/or ErbB2 have been developed. Monoclonal antibodies target the extracellular domain of the tyrosine kinase receptor, and small molecules compete with ATP for the ATP-binding pocket in the cytoplasmic domain of the receptor (6).

Lapatinib (GW572016) is an orally active small molecule that reversibly inhibits the phosphorylation of ErbB1 and ErbB2 tyrosine kinases. IC50 values against ErbB1 and ErbB2 are 10.2 and 9.8 nmol/L, respectively (7). Because ErbB2-containing heterodimers exert potent mitogenic signals, simultaneously interrupting both ErbB1 and ErbB2 signaling is an appealing therapeutic approach. Potent growth inhibition has been shown in both in vitro and in vivo models of ErbB1 and/or ErbB2 overexpression (7).

Phase I studies of single-agent lapatinib in cancer patients at oral doses up to 1,800 mg once daily are well tolerated when administered until disease progression (8). Drug-related adverse events observed were rash, diarrhea, nausea, vomiting, constipation, fatigue, and anorexia. These phase I lapatinib studies also showed evidence of clinical activity. In this study, the feasibility of combining lapatinib with the FOLFOX4 schedule was investigated. The FOLFOX4 schedule has proven to be effective in patients with advanced colorectal cancer (9–12). Major toxicities observed with the FOLFOX4 schedule were neutropenia, peripheral sensory neuropathy, diarrhea, stomatitis, nausea, and vomiting.

It is hypothesized that the inhibition of kinase activation of ErbB1 and ErbB2 by lapatinib contributes to the cytotoxic effects of the FOLFOX4 schedule. The objectives were (a) to determine the safety and tolerability of lapatinib in combination with FOLFOX4, (b) to determine the optimally tolerated regimen (OTR), (c) to determine the pharmacokinetic profile of lapatinib and oxaliplatin plus 5-fluorouracil (5-FU) when given alone and in combination, and (d) to assess preliminary antitumor activity.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
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Eligibility. Patients were eligible if they had a histologically or cytologically confirmed diagnosis of a locally advanced, recurrent, or metastatic solid tumor. Other eligibility criteria included a Karnofsky performance status of ≥70, anticipated life expectancy of at least 3 months, and age ≥18 years. Previous anticancer hormonal therapy, radiotherapy, or chemotherapy had to be discontinued for at least 4 weeks before entry into the study or 6 weeks in the case of nitrosourea or mitomycin C. All patients had to have acceptable bone marrow function, defined by platelets ≥100 x 109/L, absolute granulocyte count ≥1.5 x 109/L, and hemoglobin ≥9 g/dL, and adequate hepatic and renal function, defined as creatinine <1.5 mg/dL or estimated creatinine clearance >60 mL/min (calculated by Cockroft-Gault formula), total bilirubin <1.5 mg/dL, and aspartate aminotransferase and alanine aminotransferase ≤2 times the normal upper limit (or ≤5 times the normal upper limit in case of hepatic metastases). Additional eligibility criteria were a left ventricular ejection fraction (LVEF) of >40% at study entry and no evidence of neuropathy. The study protocol was approved by the Medical Ethics Committee of two hospitals, and all patients had to give written informed consent.

Treatment plan and study design. This study was conducted in two parts. Part 1 was designed to determine the OTR of lapatinib in combination with FOLFOX4 and part 2 was the pharmacokinetic part of the study. In part 1, lapatinib was administered once daily for the entire duration of the study and started the morning of the first day of treatment in cycle 1. The starting dose of lapatinib was 1,250 mg, once daily by oral administration. Leucovorin and oxaliplatin were given concurrently over 2 h by i.v. infusion followed by 5-FU as a bolus i.v. infusion (10 min) and immediately thereafter by continuous i.v. infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. The starting doses for oxaliplatin (68 mg/m2) and 5-FU (320 mg/m2 bolus; 480 mg/m2 infusion) constituted a 20% reduction in the standard FOLFOX4 dose used by de Gramont et al. (10). The leucovorin dose (200 mg/m2) administered as a 2-h i.v. infusion on days 1 and 2 remained unchanged during the study. An interpatient dose escalation scheme was used and at least three patients were treated at each dose level. If one of three patients experienced a dose-limiting toxicity (DLT) at a particular dose level, up to three additional patients were entered at that level. If no DLT occurred, a further three patients were entered at the next higher dose level and so forth until DLT was observed or the maximum dose level was reached in the absence of DLT. In this study, the maximum dose level consisted of the standard FOLFOX4 schedule (85 mg/m2 oxaliplatin on day 1, 200 mg/m2 leucovorin on days 1 and 2, and 400 mg/m2 bolus 5-FU followed by 600 mg/m2 infusional 5-FU on days 1 and 2) and 1,500 mg lapatinib once daily. The dose of lapatinib was not further escalated because trials of lapatinib in combination with paclitaxel or capecitabine have identified the OTR dose of lapatinib at 1,500 and 1,250 mg/d, respectively (13, 14).

In this study, the OTR was defined as the dose of lapatinib and FOLFOX4 at which no more than one of six patients experienced a DLT. Once the OTR was known, it was to become the dose level for patients included in the pharmacokinetic part of the study. These patients were randomized into three different treatment sequences to determine the pharmacokinetics of lapatinib alone, FOLFOX4 alone, and lapatinib in combination with FOLFOX4. Pharmacokinetic sampling occurred over three different 24-h periods in each treatment sequence (Table 1 ).


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  		Table 1. Treatment sequences for the pharmacokinetic part of the study

 
Drug product. Lapatinib was supplied by GlaxoSmithKline as 250 mg tablets. Oxaliplatin, 5-FU, and leucovorin were supplied by the hospital pharmacy and used according to local regulatory requirements. Oxaliplatin is unstable in the presence of chloride and therefore precaution was taken to ensure that oxaliplatin did not make contact with chloride-containing solutions (e.g., normal saline) before infusion into patients. When oxaliplatin and leucovorin were administered concurrently, both drugs were diluted in 5% dextrose.

Patient evaluation and follow-up. Complete patient history, physical examination, hematology, chemistry, urinalysis, electrocardiogram, and a multiple-gated acquisition scan were done at baseline. Computed tomography or magnetic resonance imaging scans, chest X-rays, or clinical examination for superficial lesions was done to clearly document the location, size, and extent of the disease. Once on study, hematology and clinical chemistry were obtained once every week during cycles 1 and 2 and on day 1 of subsequent cycles. Vital signs were measured before dosing at the start of each treatment cycle. Multiple-gated acquisition scans and disease assessment were done every four treatment cycles and at the end of the study. Disease assessments were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria (15). Adverse events were evaluated throughout the study and graded according to the National Cancer Institute Common Toxicity Criteria version 2.0 (16). Approximately 28 days following the last dose of study medication or discontinuation from treatment, patients returned to the hospital for the final evaluation when it was possible. Follow-up assessments included physical examination, vital signs, hematology, clinical chemistry, pregnancy tests, performance status, and notification of adverse events.

DLTs were defined as any of the following events occurring during the first treatment cycle and related to study treatment: grade 3 or 4 nonhematologic toxicity (with the exception of untreated nausea or grade 2 alopecia); grade 3 or 4 clinically significant nausea, vomiting, or diarrhea in the presence of maximal supportive care; grade 4 granulocytopenia lasting ≥5 days with or without fever; grade 4 thrombocytopenia; or a required interruption of treatment >2 weeks due to toxicity.

Pharmacokinetic studies. Once the OTR was determined, additional patients were entered to further evaluate safety and tolerability (OTR expanding cohort) and at least 9 to 18 patients were to be enrolled in the pharmacokinetic part of the study. These patients were randomized into three different treatment sequences with at least three to six patients enrolled into each sequence. A summary of the different treatment sequences is shown in Table 1. When lapatinib was administered alone, 2 mL blood samples were taken before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. Immediately after collection, the samples were centrifuged at 4°C for 10 min at 3,000 rpm. The resulting plasma layer was stored at –20°C until analysis. The lapatinib plasma samples were analyzed using a solid-phase extraction method followed by liquid chromatography-tandem mass spectrometry analysis as described previously (17). When FOLFOX4 was administered alone, 4 mL blood samples for oxaliplatin analysis were taken before infusion and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after the start of the oxaliplatin infusion. Subsequently, the sample was centrifuged at 4°C for 10 min at 3,000 rpm. The resulting plasma layer was then removed and two 1.0 mL aliquots were transferred to a YM-30 Centricon filtration system equipped with 30-kDa cutoff filters. The loaded filter systems were immediately centrifuged at room temperature for 30 min at 3,500 rpm. The resulting plasma ultrafiltrate was immediately stored at –20°C until analysis. These samples were quantitatively analyzed for platinum by inductively coupled plasma-mass spectrometry. For 5-FU analysis, 3 mL blood samples were taken at 4, 5, 6, 8, 10, and 12 h after the start of the oxaliplatin infusion. The samples were immediately centrifuged at 4°C for 10 min at 3,000 rpm. The resulting plasma layer was stored at –20°C until analysis. These samples were analyzed for 5-FU by applying a validated quantitative assay using protein precipitation extraction followed by high-performance liquid chromatography-tandem mass spectrometry. When patients received lapatinib in combination with FOLFOX4, the blood sampling of lapatinib, oxaliplatin, and 5-FU as described above was combined.

Pharmacokinetic analysis. The following pharmacokinetic variables were determined using noncompartmental analysis with WinNonLin software (version 4.1; Pharsight Corp.): the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC), and the time to reach maximum plasma concentration (Tmax) for lapatinib and unbound (free) platinum. For lapatinib, the minimum plasma concentration (Cmin) and the lag time (Tlag) were also determined. For unbound platinum, the half-life (t1/2), volume of distribution at steady state (Vss), and clearance (CL) were also determined. In addition, the time-averaged concentration at steady state (Cave) and CL were determined for 5-FU.

Statistical analysis. Pharmacokinetic data from only those patients who provided complete pharmacokinetic profiles for all 3 days were included in the statistical analyses. The effects of FOLFOX4 on lapatinib and the effects of lapatinib on 5-FU and oxaliplatin (unbound platinum) were assessed. Log-transformed pharmacokinetic variables were compared using a mixed effect linear ANOVA model, including terms for subject within assigned sequence, period (time during which a treatment was administered), sequence, and treatment (combination versus alone). Period, sequence, and treatment were assumed to be fixed effects and subject within sequence was assumed to be a random effect. Least-squares geometric means and associated 95% confidence intervals were derived from the model to describe each treatment. The geometric mean least-squares ratios and the associated 90% confidence intervals were also derived from the model to compare between treatments. Tmax and Tlag were analyzed by a nonparametric method to determine the median difference between treatments and the associated 90% confidence interval. Tmax and Tlag were summarized for each treatment as median values with the associated range. The absence of an effect was concluded if the 90% confidence interval for the geometric least-squares mean included 1.00 or the 90% confidence interval for the median difference in Tmax and Tlag included 0.00. Statistical analyses were done using PROC MIXED within the SAS/STAT module version 8.02 of the SAS system (SAS Institute, Inc.).


   Results
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 Results
Discussion
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Patient characteristics. A total of 34 patients was treated in this study and their characteristics are presented in Table 2 . Ten patients were included in the dose escalation phase to determine the OTR. Once the OTR was determined, three additional patients were included at this dose level to confirm the OTR. Twenty-one patients were enrolled in the pharmacokinetic part of the study. The median age was 59.5 years (range, 39-73) and most patients had a good performance status. A total of 213 cycles was administered to the 34 patients. The median number was 5.5 (range, 1-13). The number of patients treated at each dose level is depicted in Table 3 . Three patients were treated at the starting dose and also three patients at dose level +1. Initially, three patients were treated at dose level +2. One patient received a wrong dose of oxaliplatin, different from the prescribed dose, and was replaced. No DLTs were observed during the first treatment cycle. The maximum dose level (+2) consisting of 1,500 mg/d lapatinib and the standard FOLFOX4 dose was the OTR. To further evaluate the safety and tolerability of the OTR, three additional patients were treated at dose level +2 (OTR expanding cohort). Subsequently, 21 patients were included in the pharmacokinetic part of the study and treated with the OTR. Therefore, the total number of patients treated at dose level +2 was 28.


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  		Table 2. Patient characteristics

 

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  		Table 3. Number of patients treated at each dose level

 
Adverse events. All patients were evaluable for safety. The treatment emergent nonhematologic and hematologic toxicities displayed by dose level and toxicity grade are presented in Table 4A and B . No DLTs were observed in the first treatment cycle up to a dose level of 1,500 mg lapatinib in combination with the standard FOLFOX4 dose.


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  		Table 4. Hematologic and nonhematologic toxicities observed during all cycles

 
The most important drug-related nonhematologic toxicities were nausea (86%), diarrhea (85%), vomiting (65%), fatigue (53%), neuropathy (53%), and mucositis (50%). Although no grade 4 nonhematologic toxicities were reported, diarrhea was a frequent problem. Twenty-nine patients had diarrhea, including seven patients with grade 3 diarrhea. The onset was frequent during cycle 1 or 2 and the duration of the episodes was often as long as the patient was treated with lapatinib. The diarrhea could be controlled in some patients by the concomitant use of loperamide, but six patients needed a dose reduction or temporary interruption of lapatinib and two patients had to stop lapatinib intake. Nine patients had a grade 1 to 2 decrease in LVEF. A summary is shown in Table 4C. Three of these nine patients had no poststudy evaluation. The decrease in ejection fraction was measured after 2 months of treatment with lapatinib. In four patients, this was a more or less reversible decline in function. Three patients still had a change of –23%, –11%, and –13% at poststudy evaluation. Only one patient experienced grade 2 dyspnea as a result of the decrease in ejection fraction. Four patients had increases in LVEF from baseline of 12%, 10%, 16%, and 15%.

The most important hematologic toxicities observed were leukopenia (36%), neutropenia (33%), and thrombocytopenia (33%), but none of these events was dose limiting. Neutropenia was the only grade 4 event reported. The grade 3 and 4 hematologic toxicities resolved after 1 or 2 weeks of delay of the next cycle.

Ten patients went off-study because of drug-related adverse events. Drug-related adverse events leading to discontinuation included diarrhea (n = 2), fatigue (n = 2), elevated serum bilirubin, weight loss, decreased ejection fraction, malaise, hypersensitivity, and thrombocytopenia.

Response. The best response after initiation of therapy is shown in Table 5 . Thirty patients were evaluable for response. Four patients went off-study before response evaluation due to toxicity. Eight patients (23.5%) had a partial response as best response (includes two patients with confirmed partial response and six patients with unconfirmed partial response). Six of these patients were treated with the OTR. The patients with a partial response as best response had the following tumor types: carcinoma of the rectum (three patients), colon, esophagus, gall bladder, cholangiocarcinoma, and pancreas, respectively. The two patients with confirmed partial responses, one with colorectal cancer and one with cholangiocarcinoma, had a duration of response of 468 and 170 days, respectively. In addition to the 8 patients with a partial response, 14 patients (41%) had stable disease. The duration of stable disease varied between 1 and 9 months. Eight patients (23.5%) had progressive disease.


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  		Table 5. Best response during treatment

 
Pharmacokinetics. Twenty-one patients were included in the pharmacokinetic part of the study; 9 patients were assigned to sequence 1, 6 patients to sequence 2, and 6 patients to sequence 3. Plasma samples for pharmacokinetic studies were obtained from 19 patients for lapatinib, from 18 patients for 5-FU, and from 19 patients for unbound platinum.

The plasma pharmacokinetic variables are shown in Table 6 . There were no significant differences in AUC, Cmax, Cmin, or Tmax of lapatinib between combination with FOLFOX4 and monotherapy based on the inclusion of 1.00 in the 90% confidence intervals of the geometric least-squares mean ratios. Tlag was 0.42 h longer in the combination with FOLFOX4.


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  		Table 6. Pharmacokinetic variables

 
There were no statistically significant effects of lapatinib on the Cave or CL of 5-FU or the AUC, Cmax, Tmax, t1/2, CL, and Vss of unbound platinum.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The combination of lapatinib with the FOLFOX4 schedule was investigated in this study. The rationale for evaluating this combination was the good clinical activity shown with lapatinib and FOLFOX4 separately (8, 11) and the different mechanisms of action of lapatinib (ErbB1/ErbB2 inhibitor) and oxaliplatin/5-FU (DNA damaging). Phase I studies of lapatinib in patients with solid tumors indicated that doses up to 1,800 mg/d are well tolerated. In this study, the OTR was established at 1,500 mg/d lapatinib and the standard FOLFOX4 dose. No DLTs were observed during cycle 1 of dose escalation, but further dose escalation was not investigated because doses of single-agent lapatinib once daily in ongoing trials are dosed at 1,500 mg. This decision was also supported by results of concurrent trials of lapatinib in combination with paclitaxel or capecitabine (13, 14). In the combination trial of lapatinib and paclitaxel, the OTR was also established at 1,500 mg/d lapatinib and 175 mg/m2 paclitaxel (14). When lapatinib was combined with capecitabine, the OTR was defined as 1,250 mg/d lapatinib and 1,000 mg/m2 b.i.d. capecitabine (13).

Although no DLTs were observed with the current combination, diarrhea was a frequent and significant problem. In some patients, diarrhea could be controlled by the use of loperamide but other patients needed a dose reduction, dose interruption, or cessation of lapatinib treatment. Cells of the intestinal wall are rapidly dividing and express ErbB1 and ErbB2. Lapatinib could inhibit the proliferation of these cells, possibly resulting in decreased absorption. This could worsen the diarrhea induced by the FOLFOX4 schedule. To unravel the precise mechanism of action of lapatinib that causes diarrhea, further investigation is needed.

Lapatinib also induced a decline in ejection fraction, which was reversible in most patients. This same type of cardiac dysfunction was shown in clinical studies with trastuzumab (18). Trastuzumab is a monoclonal antibody targeting the extracellular domain of ErbB2. Studies in mice with a ventricular-restricted deletion of ErbB2 showed evidence of cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. This suggests that ErbB2 signaling is essential for preventing cardiotoxicity (19). Lapatinib also targets ErbB2 and can induce cardiotoxicity by inhibiting ErbB2 signaling. In a recent analysis of 3,127 cancer patients receiving lapatinib, a 1.3% incidence of decreased LVEF was reported (National Cancer Institute Common Toxicity Criteria grade 3 or 4 or asymptomatic LVEF decline of ≥20% relative to baseline and below the institutions lower limit of normal; ref. 20). Only 0.1% of patients had symptomatic LVEF dysfunction and this was generally reversible or nonprogressive.

It may be possible to control the episodes of diarrhea and cardiotoxicity by using a lower dose or another schedule of lapatinib treatment, but this needs further investigation.

No clinically significant drug-drug interactions between lapatinib and the FOLFOX4 schedule (oxaliplatin and 5-FU) were observed. This was as expected because lapatinib is primarily metabolized by CYP3A4.5 Oxaliplatin is mainly eliminated by the kidneys and 5-FU is catabolized by dihydropyrimidine dehydrogenase. Approximately 70% of these metabolites are excreted in urine (21).

The overall objective response rate in this study was 23.5%. The best responses were observed in patients with gastrointestinal malignancies. It is of interest to determine if the combination of lapatinib and the FOLFOX4 schedule has equal or greater effect than the standard treatment of the FOLFOX4 schedule alone. A previous trial investigated the clinical activity of FOLFOX4 alone in patients with metastatic colorectal cancer who progressed after treatment with one or more lines of chemotherapy (22). As second- and third-line treatment, FOLFOX4 achieved objective responses (partial response) in 18.2% and 23.5% of the patients, respectively. In our trial, most patients received more than one previous chemotherapy treatment. In another study that investigated the superiority of the FOLFOX4 schedule compared with oxaliplatin and 5-FU alone, partial responses were observed in 9.9% of the patients treated with the FOLFOX4 schedule (11). In our study, partial responses were observed in 23.5% of the patients. Therefore, it is of interest to investigate any additive effect of lapatinib in a controlled phase III setting.

In our study, the effect of lapatinib on markers of biological activity was not investigated. Recently, a pilot study has been done that examined biopsies obtained before treatment and during treatment in patients of various malignancies treated with lapatinib (23). This study showed that the tumor biopsies of responders exhibited variable levels of inhibition of phosphorylated ErbB1, phosphorylated ErbB2, phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated AKT, cyclin D1, and transforming growth factor-{alpha}. Partial responses occurred in patients with breast cancer. Increased tumor cell apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) occurred in patients with evidence of tumor regression but not in nonresponders (23). Furthermore, it was shown that clinical response was associated with increased pretreatment expression of ErbB2, phosphorylated ErbB2, extracellular signal-regulated kinase 1/2, phosphorylated extracellular signal-regulated kinase 1/2, insulin-like growth factor receptor-1, p70S6K, and transforming growth factor-{alpha} (23). The results generated in that study enhance possibly the ability to identify patients who are more likely to respond to lapatinib and provide information about markers that can be used to investigate the clinical effectiveness of lapatinib. The analysis of biological markers on archived tissue would not have contributed to the results of our study because the patients included had different tumor types and received various previous treatments. This could both affect the expression of ErbB1 and ErbB2. In addition, patients were not screened for ErbB1 and ErbB2 expression levels before start of the study.

The present trial showed that lapatinib in combination with the standard FOLFOX4 schedule is sufficiently safe and that major and clinically relevant drug-drug interactions were not evident. Consistent with this finding, the current regimen revealed signs of activity in patients with different tumor types, most often of gastrointestinal origin. There were eight partial responses (two confirmed and six unconfirmed) and 14 patients remained stable for 1 to 9 months. Because this study represents a combination of lapatinib with an effective cytotoxic regimen (FOLFOX4), the promising efficacy results documented in this study have to be interpreted with caution. Nonetheless, phase II and III studies of this combination are warranted. Additional investigation is needed to explore the potential additive affect of lapatinib in combination with the FOLFOX4 schedule and more information is needed about the mechanism of action of lapatinib that induces diarrhea and a decrease in LVEF. In view of the recent positive results of the addition of bevacizumab to FOLFOX4, investigation of the usefulness and feasibility of adding lapatinib to that combination may also be of interest.


   Footnotes
 
Grant support: GlaxoSmithKline.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

5 Unpublished data. Back

Received 1/ 3/07; revised 3/15/07; accepted 4/ 6/07.


   References
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 Materials and Methods
 Results
 Discussion
 References
 

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