teaser
Beverly Moy
MD MPH
Medical Oncologist
Massachusetts General Hospital Cancer Center
Gillette Center for Women’s Cancers
Boston MA
USA
Lapatinib is an oral dual kinase inhibitor targeting both ErbB1 and ErbB2 receptors. Increased expression of ErbB1 and ErbB2 in breast cancer is associated with poor clinical outcome.(1,2) ErbB1 (or HER-1) is overexpressed in 27–30% of breast tumours and ErbB2 (or HER-2) in 20–25% of the 1.5 million new breast cancers which are diagnosed annually worldwide.(3–15)
Lapatinib reversibly binds to the intracellular cytoplasmic adenosine triphosphate-binding site of the tyrosine kinase domain and blocks receptor phosphorylation and activation, thereby blocking downstream signalling pathways, namely simultaneous activation of Erk1/2 and PI3K/Akt.(15–20)
Lapatinib activity in breast cancer
Phase II and III clinical trials conducted to date for the treatment of refractory and first-line metastatic breast cancer are summarised in Table 1.(21–35)
[[HPE33_table1_46USE]]
Refractory metastatic breast cancer
The pivotal phase III trial comparing lapatinib
+ capecitabine versus capecitabine alone was conducted in patients with trastuzumab-refractory ErbB2+ metastatic breast cancer.(25) Patients were randomised to receive either lapatinib + capecitabine or capecitabine alone. In the lapatinib + capecitabine arm, the median TTP was 8.4 months versus 4.4 months in the capecitabine-alone arm (p < 0.001). The overall response rate was 22% in the lapatinib + capecitabine group and 14% in the capecitabine-alone group (p = 0.09).(25)
Central nervous system (CNS) metastases
Since lapatinib is a small molecule able to penetrate the blood-brain barrier and since patients with ErbB2 + breast cancer have a higher risk of developing brain metastases,(36) lapatinib may be active in preventing or treating central nervous system (CNS) metastases. In the pivotal phase III trial, four patients in the lapatinib + capecitabine group developed CNS relapse compared with 11 patients in the capecitabine-alone group (p = 0.10).(25)
A phase II trial of lapatinib for patients with brain metastases demonstrated that, according to the response evaluation criteria in solid tumours (RECIST), two patients (5%) had a partial response as best CNS response.(27) Volumetric analysis showed more promising results than the results measured by RECIST.
Inflammatory breast cancer (IBC)
A phase II trial of single-agent lapatinib for the treatment of IBC demonstrated a 50% clinical response rate.(31) Lapatinib in combination with paclitaxel for neoadjuvant therapy of IBC demonstrated a 77% clinical response rate and a 17% complete pathological response seen at time of surgery.(32)
Lapatinib toxicity: adverse effects
Like other tyrosine kinase inhibitors, lapatinib is generally well tolerated. The most frequently reported drug-related adverse effects are diarrhoea, rash, nausea and fatigue. Life-threatening events secondary to lapatinib have been quite rare.
Rash
This is a common toxicity associated with lapatinib. In the initial phase I study of lapatinib monotherapy, it was reported in 31% of patients.(37) Similar rates have been reported across lapatinib clinical trials.(21–32)
The characteristic rash of lapatinib has been seen as a class effect of drugs that target the ErbB1 receptor, which also includes the agents erlotinib, cetuximab, and gefitinib.(38)
The rash is characterised by inflammatory papules and pustules most often seen on the face, chest and back, and may resemble folliculitis or an acneiform drug eruption.(39)
Diarrhoea
Mild diarrhoea is consistently reported as a common toxicity across all clinical trials of lapatinib.(21–32) In the phase III trial of lapatinib plus capecitabine versus capecitabine alone, rates of diarrhoea were higher in the lapatinib plus capecitabine arm compared with the capecitabine-alone arm. A total of 60% of patients experienced diarrhoea in the combination arm compared to 39% in the capecitabine-alone arm.(25) Life-threatening diarrhoea occurred in two women in the lapatinib plus capecitabine combination group (1%). These rare severe diarrhoea events led to discontinuation of lapatinib in these women.
Cardiac toxicity
Cardiac toxicity was an unexpected finding in the pivotal phase III trial of trastuzumab, the monoclonal antibody of ErbB2.(40) Due to the associated cardiac toxicity observed with trastuzumab, a prospective analysis of the cardiac function in 3,558 patients treated with lapatinib in 18 phase I to III lapatinib clinical trials was performed.(41) Lapatinib infrequently affected the left ventricular ejection fraction (LVEF), with only 1.6% of patients experiencing a decrease in LVEF. Decrease in LVEF was mostly asymptomatic (1.4% asymptomatic and 0.2% symptomatic). The incidence of LVEF decreases in patients treated with lapatinib was less than that expected within a matched cohort of the general population and less than that of trastuzumab-treated breast cancer patients.(41) Ongoing cardiac evaluation is warranted in future lapatinib clinical investigations but lapatinib-induced congestive heart failure, thus far, appears extremely rare.
Lapatinib dosing schedule
A randomised phase II trial compared once-daily lapatinib (1,500 mg) versus twice-daily lapatinib (500 mg) as first-line treatment of patients with locally advanced or metastatic breast cancer. The target enrolment of 130 patients is complete. Preliminary results show a response rate of 35% across the trial and the adverse effect profile is similar in both arms.(28,29) Once-daily dosing has been used in subsequent clinical trials due to its ease of administration over twice-daily dosing.(28,29)
Pharmacology
Lapatinib peak plasma levels occur between three and six hours of oral administration. The effective plasma half-life is about 24 hours. The elimination of lapatinib occurs through hepatic metabolism, primarily through CYP3A4 and excretion in faeces.
Therefore, inducers and inhibitors of CYP3A4 may alter the metabolism of lapatinib. Given the significance of CYP3A4 in drug metabolism,42 lapatinib should be used with caution when used concurrently with medications that are CYP3A4 substrates until further data are available. Additionally, antacids that modify gastric pH may affect absorption of lapatinib and should generally be avoided for one hour before and after lapatinib dosing. Table 2 lists the potential drug-drug interactions with lapatinib.
[[HPE33_table2_47USE]]
Few data are available on drug-drug interactions with lapatinib and other anticancer agents. A phase I study evaluated use of lapatinib with fluorouracil, leucovorin and irinotecan, and while this combination is tolerable, a 50% increase in the SN-38 active metabolite of irinotecan was noted and 30% and 14% increases were seen for lapatinib in Cmax and AUC, respectively, requiring reduction in the dose of irinotecan and lapatinib.(43) The interaction between lapatinib and irinotecan may be due to irinotecan’s partial metabolism by CYP3A4.(44) Additional trials examining concurrent use of lapatinib with other anticancer agents have shown that dosing adjustment is not necessary when lapatinib is used in combination with trastuzumab or letrozole, suggesting a lack of interaction between these medications.(45) Regarding dosing of lapatinib with other anticancer agents, to date dosage adjustment has only been necessary when administered with irinotecan.
Conclusions
Lapatinib is an active and well-tolerated oral dual tyrosine kinase inhibitor for the treatment of breast cancer. Efficacy of lapatinib is limited only to the treatment of ErbB2-overexpressing breast cancer. Lapatinib is active in refractory and first-line metastatic breast cancer patients and has potential benefit in patients with brain metastases. Lapatinib appears to have a very low incidence of cardiotoxicity.
The most frequently reported adverse events include rash, diarrhoea, nausea and fatigue. Severe toxicities are rare and most adverse events associated with lapatinib are mild to moderate. Lapatinib offers convenient once-daily dosing but may interact with drugs metabolised by CYP3A4. Improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes of breast cancer allows us to bring patient-specific novel therapies such as lapatinib to the clinic. Results from ongoing and future clinical trials of lapatinib in early-stage breast cancer are eagerly anticipated.
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