teaser
Lapatinib, as monotherapy or in combination, has shown impressive anti-tumour activity in HER2-positive mBC, even in patients with relapses after trastuzumab-based therapy
Hans-Peter Lipp
PharmD PhD
Department of Pharmacy
University Hospital of
Tubingen
Germany
Breast cancer represents the most frequently observed solid tumour worldwide. Most patients are diagnosed in a non-metastatic stage of disease, however, about 20% are first identified during tumour progression and metastases (mBC). Those patients with HER2-driven disease will have a poorer prognosis of survival based on the generally more aggressive course of disease and the increased risk for brain metastases affecting about 25-30% of women with HER2 overexpression.[1] With trastuzumab, a monoclonal antibody (MAB) targeting HER2 receptors, median overall survival time (OAS) could be successfully increased in patients with HER2 overexpressing tumours, but the use of a MAB is generally associated with some disadvantages:
- The protein can only be used via the parenteral route and this means frequent routine visits within the hospital or specialised outpatient settings.
- The need for an intravenous access is uncomfortable for the patient and increases the risk for infections especially in the case of central venous catheters (CVC).
- MABs are generally unable to pass the bloodbrain- barrier which limits their use in CNS-located tumours.
- Therapeutic drug levels may not be maintained by IV applications every 3 weeks.
Lapatinib is presented as the first long-awaited oral inhibitor of both tyrosine kinases HER1/neu (also called Erb1) and HER2/neu (also called Erb2) and is:
- Highly selective and potent against EGFR- and HER2-overexpressing tumours.
- Taken once daily on an empty stomach and associated with good tolerance and adherence in mBC patients.
- Is a small molecule (molecular weight: 925,46 g/mol), lipophilic and able to pass through the blood-brain-barrier.
- Provides a continuous drug exposure in plasma over time from daily intake.
These features combined may help to explain why lapatinib has been identified as active even in trastuzumab-refractory patients.
Dosage recommendations
The currently recommended dosage of lapatinib (Tyverb 250 mg) for pre-treated mBC patients is 1.25g once daily on days 1-21, given orally in combination with oral fluoropyrimidine capecitabine 2 g/m²/d (on days 1-14). Lapatinib should be taken on an empty stomach, 1hour before or at least 1 hour after a meal.[2] According to preliminary study results, the absolute bioavailability will be significantly increased, if given together with fat-containing meals. Based on the observation that the magnitude of inter-individual variability was much higher during intake with meals compared to administration on an empty stomach, the latter is preferred. Recent data confirmed these preliminary study results, when the mean lapatinibAUC was increased about 2.7-fold and 4.2-fold by a low-fat and high-fat containing breakfast, respectively(Table 1).[3]
According to a phase I pharmacokinetic study, a daily dose of 650 mg to 1000 mg resulted in lapatinib trough levels averaging 0.35 ug/ml (0.25-0.50) and 0.49 ug/ml (0.05-5.23), respectively. As most responders displayed Cmin values between 0.3 to 0.6 ug/ml, doses of 900 to 1200 mg daily have been advised for further clinical drug investigation to ensure geometric means about 0.5 ug/ml.[4] This is in accordance to preclinical pharmacological studies which indicated IC50 values of <0.16 uM (~0.16 ug/ml) to be highly effective for growth inhibition in EGFR or HER2 overexpressing human cancer cell lines.[5]
Pharmacokinetics and dosing
Lapatinib is extensively metabolised in the liver by cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 resulting in inactive metabolites. Very potent inhibitors of these isozymes (such astriazole antifungal agents) can result in severely increased drug levels in plasma and inducers (including rifamycins, several antiepileptic agents and St John’s wort) can cause subtherapeutic drug concentrations (Table 2).[6],[7]
Whenever possible, such co-medication should be avoided based on the experience that most of these agents can be substituted by drugs with similar efficacy but no obvious impact on Cyp3A.
Lapatinib and its metabolites are primarily excreted via bile and faeces. The elimination half-life (E1/2) of the parent compound has been estimated to average 24 hours during continuous drug administration.[2],[4],[8] Lapatinib itself should be categorised as a moderate Cyp3A4 and Cyp2C8-inhibitor. However, extended clinical drug interaction studies with Cyp3A4 substrates undergoing an extensive first-pass-effect (including simvastatin and everolimus) are still lacking.[9] In contrast, intravenous applied Cyp3A4 substrates (eg, docetaxel) do not appear to be changed in their clinical-pharmacokinetic behaviour by lapatinib.[8] In this regard, the observed increase of SN-38 levels during lapatinib/CPT-11 coadministration remains unclear.[10] Drug excretion is primarily mediated via bile and faeces. Whereas dose modification does not appear to be warranted in patients with renal dysfunction, caution is indicated in patients with mild to moderate hepatic dysfunction. It has been suggested that in chronic liver disease patients, with Child-Pugh score C, a lapatinib dose of 750 mg daily is sufficient, however, clinical trials proving this dosage to be efficacious and safe in those patients are needed.[2]
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Clinical trials overview
Based on very encouraging Phase II study results, three important Phase II studies were initiated to examine the current role of lapatinib in mBC patients:[11],[12]
- EGF100151 was intended to give answers to the question: Is there a beneficial role of additional lapatinib to capecitabine in heavily pretreated patients?
- EGF30001 should resolve the question: can lapatinib already be given as first-line agent together with paclitaxel in mBC and will a beneficial response be dependent on HER2 overexpression?
- EGF30008 examined the role of lapatinib in HER2- overexpressing and oestrogen-receptor-positive tumors in combination with letrozole without concomitant cytotoxic chemotherapy.
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Phase III study
EGF100151 was an open-label, randomised, controlled trial including patients with locally advanced or metastatic HER2-overexpressing breast cancer who had previously received anthracyclines, taxanes and trastuzumab.13 Patients pretreated with capecitabine were excluded. Patients in the ‘L+C Regimen’ received a combination based on lapatinib 1250 mg/d and capecitabine 1 g/m2 twice a day. Patient in the comparator group ‘C mono’. were treated with capecitabine 1.25 g/m2 twice a day. When the planned interim analysis revealed a significantly longer median time to progression (8.4 months versus 4.4 months) with L+C compared to the comparator group, the recruitment in this study was stopped and patients were offered a cross-over into the L+C arm. An updated analysis (Table 3) in women with HER2-positive mBC revealed a superior efficacy of lapatinib during combination concerning time to progression (TTP) and a trend toward improved survival (hazard ratio: 0.78, p=0.177). In addition, fewer cases with CNS involvement at first progression (4 vs 13, p=0.045) were observed during lapatinib.[14]
EGF30001 included 579 chemo-naive patients with advanced or metastatic breast cancer and HER2- negative as well as HER2-uncharacterised status.[15] They were randomly assigned to receive paclitaxel 175 mg/m2 IV every 3 weeks with either oral lapatinib 1500 mg daily or placebo. A preplanned retrospective evaluation of HER2-status was performed using fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC). The primary end point was TTP,
secondary end points included objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS) and overall survival (OS). In the intention-to-treat analysis (ITT), significant differences in ORR and CBR were achieved by the addition of lapatinib. However, retrospective evaluation of HER2 positive patients (15%) revealed a significant improvement of TTP, EFS, ORR as well as CBR by the addition of lapatinib in contrast to HER2-negative patients (Table 4).[16]
EGF30008 was a double-blind phase II trial in mBC patients with hormone-receptor positive (HR+) status and HER2+ expression within the tumour.[17] Arm A (L+L) received lapatinib and letrozole, Arm B (L+P) letrozole and placebo (L+P). The addition of lapatinib to letrozole resulted in a significant increase of PFS from 3 months (L+P) to 8.2 months (L+L) (p<0.02). As expected, patients with lower levels of HER2 overexpression (eg, borderline FISH, IHC 2+ or HER2 unknown status) did not benefit from the oral EGF/HER2-TKI. Whether a subgroup of these patients with lower levels (rather than higher levels) of oestrogen receptor expression may still benefit from lapatinib has to be elucidated in more detail.[18]
These study results clearly indicate lapatinib to be an encouraging agent for targeted therapy in HER2 overexpressing mBC.
Further experience
A recently published case report indicated lapatinibto be active in mBC with tumour progression into the CSF during treatment with trastuzumab. An mBC patient, who had received trastuzumab (2 mg/kg), paclitaxel (80 mg/m2) and carboplatin (AUC = 2) in weekly doses for six months based on tumour progression with pulmonary nodules and large pleural effusions, developed resolution of symptoms and disease stabilisation.
However, seven months later, she presented with signs of CNS tumour manifestation (diplopia and gait difficulties). Following MRT, brain metastases were evident. Whole-brain radiotherapy resulted in transient clinical improvement for about three months. Based on a further onset of CNS symptoms, a combination of lapatinib (1,250 mg daily) and capecitabine (2,000 mg/ m2/day on days 1-14 of a 21-day cycle) was initiated as salvage regimen. Four months later, a near complete resolution of brain metastases could be achieved confirmed by brain CT. However, the patient died from her
progressive systemic disease.[19]
Adverse effects
About 59% of patients receiving lapatinib monotherapy may develop diarrhoea (all grades), however, only 6% of patients may suffer from Grade >3 events (Table 5). The onset of this gastrointestinal discomfort is usually about 6 days after treatment initiation, the mean duration of this side effect may average 5 days.[11],[12] The incidence of diarrhoea has been shown to be significantly higher in patients receiving combination with a cytotoxic agent like paclitaxel or capecitabine.[13],[15] Supportive management is mainly based on the use of intensified loperamide with a loading dose of 4 mg followed by 2 mg every 4 hours. This dosage regimen should be maintained for at least up to 12hours after the last episode of diarrhoea. Further recommendations include the substitution of fluid, dextrose and electrolytes, empirical intake of antibiotics and the interruption of concomitant chemotherapy.
Meanwhile, 44 clinical trials including 3,689 patients could be evaluated to judge the cardiac safety of lapatinib. Grade 3 or 4 left ventricular systolic dysfunction according to NCI CTC could be observed in 60 patients (1.6%) who were pretreated with anthracyclines (n=12), trastuzumab (n=14) or neither (n=34). In most patients these cardiac events were rarely severe. The onset of LVEF dysfunction averaged 13 weeks after treatment initiation, the duration was assessed to be about 7.3 weeks. Despite the diagnosis of manifest LVEF decrease, 88% of patients had a partial or full recovery regardless of continuation or discontimation of lapatinib.[20]
Current analysis of the EGF30008 trial, which represents the first long-term evaluation of lapatinib on cardiac function revealed an incidence of cardiac events (Grade 3-4) following lapatinib to be only slightly higher compared to letrozole monotherapy (Table 6). Among 1,286 evaluable women, only one symptomatic grade 4 cardiac event could be observed with the letrozole/lapatinib combination. Median time to onset and duration of ejection fraction decrease was 21.8 and 8.1 weeks on lapatinib/letrozole combination, respectively.
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Further research
Lapatinib represents the very first dual tyrosine kinase inhibitor of EGFR/ErbB1 (HER1) and HER2/ErbB2 which is particularly active in HER2-positive locally advanced or metastatic breast cancer. A preplanned retrospective evaluation of the EGF30001 Trial (paclitaxel/ lapatinib versus Paclitaxel) revealed a significant increase in TTP, ORR and CBR by lapatinib.
Similar observations were published in the EGF30008 trial comparing lapatinib plus etrozole versus letrozole monotherapy. However, the encouraging study results of the EGF30001 trial in mBC patients with HER2 overexpression should be confirmed by a prospective randomised double-blind Phase-III -study.[21]
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A debate is ongoing about whether the optimal intake of lapatinib drug application is with or without food. One may argue that the drug intake with a lowfat breakfast results in a mean increase of lapatinib AUC by about 2.67″fold with an acceptable inter-and intraindividual variability of AUC and the perspective of a lower daily dose as well as reduced treatment
costs.[22]
In addition, preliminary data indicate that 500 mg twice-daily rather than a once-daily dosing of 1,500 mg may be associated with less variability of clinical pharmacokinetics, greater AUC values and comparable efficacy. [23] As a consequence, one may ask: will 500 mg lapatinib twice daily (or less) taken with low-fat meals be a useful regimen for the near future?
Based on the total number of patients treated so far with lapatinib, the incidence of adverse effects, especially cardiotoxicity, is impressively low. The incidence of symptomatic heart failure has been reported to be less than 0.5% with lapatinib. In comparison, study results with trastuzumab were associated with an incidence ranging from 4-7% which indicates that different effects of both agents on cardiac bioenergetics, cardiac ATP production and cardiac mitochondrial function may exist.[24]
Lapatinib offers promise in the treatment of HER2 overexpressing metastatic breast cancer which is in obvious competition to trastuzumab particularly as it offers more comfortable drug administration, better drug distribution into the CNS and potentially lower cardiotoxicity in long-term treatment. As a consequence, the results of the ongoing Phase II Trials EGF108919 (COMPLETE) and EGF111438 (CEREBEL) comparing lapatinib-containing protocols with trastuzumab-containing regimens in mBC are highly anticipated.
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