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Breast Cancer

Lapatinib-Associated Toxicity and Practical Management Recommendations

Massachusetts General Hospital Cancer Center, Gillette Center for Women's Cancers, Boston, Massachusetts, USA

Key Words. Lapatinib • Dual tyrosine kinase inhibitor • Breast cancer • EGFR • ErbB-1 • ErbB-2 HER-2 • Toxicity

Correspondence: Beverly Moy, M.D., M.P.H., Massachusetts General Hospital Cancer Center, Gillette Center for Women's Cancers, 55 Fruit Street, Lawrence House, LRH 304, Boston, Massachusetts 02114, USA. Telephone: 617-726-4920; Fax: 617-643-0589; e-mail: bmoy{at}partners.org

Received March 28, 2007; accepted for publication May 7, 2007.

	Learning Objectives

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Discuss lapatinib-associated toxicities and provide practical management recommendations based on available data.
   
2. Describe the mechanism of action of lapatinib.
   
3. Discuss the breast cancer clinical trial data for lapatinib.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
Lapatinib is an oral receptor tyrosine kinase inhibitor, inhibiting both the ErbB-1 and ErbB-2 receptors. Lapatinib has been shown to have activity in ErbB-2–overexpressing breast cancer in several phase II and III clinical trials. Specifically, lapatinib is effective in patients with metastatic breast cancer, with inflammatory breast cancer, and possibly, with brain metastases. An ongoing clinical trial and another anticipated clinical trial will investigate lapatinib as adjuvant treatment in early-stage disease. Lapatinib has specific toxicities, the most common being diarrhea and rash. Cardiac toxicity is rarely seen with lapatinib. This paper reviews lapatinib-associated toxicities and provides practical management recommendations based on available data.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
Lapatinib ditosylate (GW572016/Tykerb®; GlaxoSmithKline, Research Triangle Park, NC) is an oral dual kinase inhibitor targeting both the ErbB-1 and ErbB-2 receptors. Increased expression and activation of ErbB-1 and ErbB-2 in breast cancer are associated with a high risk for recurrence after primary treatment and consequently a poor clinical outcome [1, 2]. ErbB-1 (or HER-1) is overexpressed in 27%–30% of breast tumors and ErbB-2 (or HER-2) is overexpressed in 20%–25% of the 1.5 million new breast cancers that are diagnosed annually worldwide [3–14].

Lapatinib reversibly binds to the intracellular cytoplasmic ATP-binding site of the tyrosine kinase domain and blocks receptor phosphorylation and activation, thereby blocking downstream signaling pathways, namely, simultaneous activation of extracellular signal–related kinase 1/2 and phosphatidylinositol 3' kinase/Akt (Fig. 1) [14–19].

View larger version (37K): [in this window] [in a new window]   Figure 1. Lapatinib binds to the tyrosine kinase (TK) domain, competitively blocking ATP binding, thus inhibiting the downstream cascade of events.

	LAPATINIB ACTIVITY IN ERBB-2–OVEREXPRESSING BREAST CANCER

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

In the lapatinib plus capecitabine arm, the median TTP was 8.4 months, versus 4.4 months in the capecitabine-alone arm (p < .001). The overall response rate was 22% in the lapatinib plus capecitabine group and 14% in the capecitabine-alone group (p = .09) in the independent intent-to-treat analysis. The addition of lapatinib to capecitabine significantly improves TTP and is an effective regimen for women with advanced ErbB-2 – positive breast cancer [27].

Central Nervous System Metastases
Because lapatinib is a small molecule able to penetrate the blood–brain barrier and because patients with ErbB-2–positive breast cancer have a higher risk for developing brain metastases [37], it is possible that lapatinib could be active in preventing or treating central nervous system (CNS) metastases. In the pivotal phase III trial, brain metastases as a site of progressive disease was a secondary outcome [27]. Four patients in the lapatinib plus capecitabine group developed CNS relapse compared with 11 patients in the capecitabine-alone group. At this point, the difference is not statistically significant (p = .10).

A phase II trial of lapatinib for ErbB-2 – positive patients with new or progressive brain metastases has been performed. Using the Response Evaluation Criteria in Solid Tumors (RECIST), two patients (5%) had a partial remission as the best CNS response [28]. Volumetric analysis, a three-dimensional measure of tumor size, showed more promising results than those as measured by RECIST. Thus, lapatinib may have CNS clinical activity [28].

Inflammatory Breast Cancer
A phase II trial of single-agent lapatinib for the treatment of relapsed or refractory ErbB-2–positive inflammatory breast cancer (IBC) demonstrated a 50% clinical response rate [32]. That trial failed to show response in ErbB-2 – negative IBC. Biomarker evaluation in the lapatinib monotherapy trial showed that ErbB-2 overexpression but not ErbB-1 expression alone, predicts for sensitivity to lapatinib in IBC and that high ErbB-2 and active phosphorylated HER-2 (p-ErbB-2) predict for clinical response to lapatinib monotherapy in this patient population [32]. Lapatinib in combination with paclitaxel for the neoadjuvant therapy of ErbB-2–positive IBC demonstrated a 77% clinical response rate and a 17% complete pathologic response rate seen at the time of surgery [33]. Lapatinib appears to have clinical activity in this aggressive subset of ErbB-2–positive IBC.

	LAPATINIB TOXICITY

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
Adverse Effects
There are considerable data regarding the safety and adverse effect profile of lapatinib. Like other small-molecule tyrosine kinase inhibitors, lapatinib is generally well tolerated. The most frequently reported drug-related adverse effects over a daily dosage range of 500–1,600 mg in the initial phase I lapatinib monotherapy trial were diarrhea (42%), rash (31%), nausea (13%), and fatigue (10%) [20]. In that study, 135 of 140 drug-related adverse events were mild or moderate (grade 1 or 2). Five of the 140 drug-related adverse events were severe (grade 3) and included diarrhea, abdominal cramping, rash, and gastroesophageal reflux disease, likely resulting from the large pill burden. The adverse effect profile of lapatinib in all published clinical trials is very similar. Grade 4 (life-threatening or disabling adverse events) or 5 (death due to adverse events) events secondary to lapatinib have been very rare.

Rash
A common toxicity associated with lapatinib is skin rash. In the initial phase I study of lapatinib monotherapy, rash was reported in 31% of patients [20]. Similar rates of rash have been reported across the lapatinib clinical trials [22–30]. In the large phase III trial of lapatinib plus capecitabine versus capecitabine alone, 28% of patients in the combination arm experienced rash, versus 15% in the capecitabine alone arm [27]. The vast majority of rash cases were mild to moderate (grade 1 or 2), with grade 3 rash seen in 1% of patients in both the combination arm and the capecitabine-alone arm.

The characteristic rash of lapatinib is shown in Figure 2. This rash has been seen as a class effect of drugs that target the ErbB-1 receptor. These targeted drugs also include the agents erlotinib, cetuximab, and gefitinib [38]. The drug-associated rash is characterized by inflammatory papules and pustules most often seen on the face, chest, and back and may resemble folliculitis or an acneiform drug eruption. The distribution is termed acneiform because the lesions are present at sites with large numbers of pilosebaceous units such as the scalp, face, neck, and upper trunk. However, the characteristic rash is different from classic acne vulgaris because of its lack of comedones. Histologic sections from patients who developed rashes while receiving cetuximab reveal suppurative folliculitis and superficial perifolliculitis as the most common histologic changes with microcomedones notably absent [39].

View larger version (79K): [in this window] [in a new window]   Figure 2. A typical papular eruption on the face following lapatinib therapy. (Photo courtesy of Nancy U. Lin, M.D., and Margaret A. Haldoupis, R.N.)

Diarrhea
Another common lapatinib-associated toxicity is diarrhea. In the initial phase I trial of lapatinib monotherapy [20], 42% of patients experienced diarrhea; all cases were mild to moderate (grades 1 or 2), except for two grade 3 diarrhea events. Mild diarrhea is consistently reported as a common toxicity across all clinical trials of lapatinib [22–31]. Prior to the initiation of the pivotal phase III trial [27], there was concern that lapatinib plus capecitabine therapy could cause higher rates of significant diarrhea because both therapeutic agents can commonly cause diarrhea. However, a phase I trial of 45 patients receiving lapatinib plus capecitabine showed that diarrhea occurred in 45% of patients, with only one grade 3 event [43]. The rate of diarrhea in the lapatinib plus capecitabine combination was felt to be similar to that expected from each drug individually [43].

In the phase III trial of lapatinib plus capecitabine versus capecitabine alone, rates of diarrhea were higher in the lapatinib plus capecitabine arm than in the capecitabine-alone arm. Sixty percent of patients experienced diarrhea in the combination arm (27% grade 1, 20% grade 2, 12% grade 3, and 1% grade 4), compared with 39% in the capecitabine-alone arm (14% grade 1, 14% grade 2, 11% grade 3) [27]. Grade 4 diarrhea occurred in two women in the lapatinib plus capecitabine combination group (1%). These rare severe diarrhea events led to discontinuation of lapatinib in these women. Guidelines for management of diarrhea were described in this protocol, including dose modifications for its severity and the use of antidiarrheals.

Cardiac Toxicity
The monoclonal antibody of ErbB-2, trastuzumab, has been associated with low rates of congestive heart failure (CHF), and in contrast, lapatinib appears to have lower rates of toxicity. Cardiac toxicity was an unexpected finding in the pivotal phase III trial of trastuzumab [44]. Most women with ErbB-2–overexpressing breast cancer have usually received both anthracyclines and trastuzumab, and therefore have had exposure to two potentially cardiotoxic drugs. Among metastatic breast cancer patients on trastuzumab, about 11% experience grade 3 cardiac toxicity but most cardiac symptoms improve with discontinuation of trastuzumab and initiation of appropriate cardiac medical therapy [45, 46]. The most recent results of the adjuvant clinical trials of trastuzumab following anthracycline-containing therapy have reported that the risk for severe CHF is approximately 0.5%–4% [47–49].

Because of the associated cardiac toxicity observed with trastuzumab, Perez and colleagues prospectively analyzed cardiac function in 3,558 patients treated with lapatinib in 18 phase I–III lapatinib clinical trials [50]. Ten of the trials involved lapatinib as monotherapy and eight included lapatinib in combination with capecitabine, letrozole, paclitaxel, cisplatin, or oxaliplatin/5-fluorouracil. A total of 3,558 patients who had received lapatinib were included in this analysis, including 2,008 breast cancer patients and 1,550 patients with other cancers (i.e., colorectal, non-small cell lung, renal, head and neck, scrotal, urothelial) [50]. Regarding prior therapy before receiving lapatinib, 598 received anthracyclines, 759 received trastuzumab with chemotherapy or after anthracyclines, and 2,201 received neither anthracyclines nor trastuzumab.

In the cardiac safety evaluation, lapatinib infrequently affected the left ventricular ejection fraction (LVEF), with only 1.6% of patients (58 of 3,558) experiencing a decrease in LVEF. The mean LVEF decrease was 18.7% (range, 11%–32%). The LVEF decrease was mostly asymptomatic (1.4% asymptomatic and 0.2% symptomatic). LVEF was similarly affected by lapatinib in both the breast cancer and non–breast cancer patients. Among 598 patients pretreated with anthracyclines but not trastuzumab, 1.2% had an LVEF decrease, of whom 0.3% were symptomatic. Among 759 patients pretreated with trastuzumab and chemotherapy, 1.7% had an LVEF decrease, of whom only 0.1% were symptomatic. Finally, in 2,201 anthracycline- and trastuzumab-naïve patients, 1.7% had an LVEF decrease, of whom 0.2% were asymptomatic [50].

Time to onset of an LVEF decrease occurred within 9 weeks of treatment in 34 patients, 10–16 weeks in eight patients, 17–24 weeks in eight patients, and >25 weeks in eight patients. The 0.2% of symptomatic patients with a decreased LVEF presented with dyspnea, palpitations, and signs of CHF. However, they responded promptly to standard cardiac management. The 1.6% incidence of symptomatic and asymptomatic decreases in LVEF in patients treated with lapatinib was less than that expected within a matched cohort of the general population (3%–6% incidence of asymptomatic LVEF decrease) and less than that of trastuzumab-treated breast cancer patients [50].

Potential cardiac risk factors were examined in 58 patients with decreased LVEF. The median age of these patients was 61 years (range, 31–81 years). Thirteen of these patients received prior or concurrent trastuzumab and 10 patients received prior anthracyclines. Fifteen patients received prior mediastinal or left-sided chest radiation. Twenty-six other patients had prior myocardial infarction, coronary artery disease, hypertension, and diabetes.

Overall, lapatinib-associated asymptomatic and symptomatic LVEF decreases are rare (1.4% and 0.2%, respectively) [50]. Of the seven total patients with symptomatic LVEF decreases, cardiotoxicity resolved in all but one patient. Notably, it appears that, unlike anthracycline-induced cardiac failure, the cardiac effects of lapatinib are generally reversible and nonprogressive. Anthracyclines generally cause irreversible ultrastructural changes to the myocardium, including vacuole formation, myofibrillar dropout, and myocyte necrosis [45, 46]. Thus far, it appears that the effect of lapatinib on the myocardium may be similar to the myocardial effect of trastuzumab in that cardiotoxicity is largely reversible, not cumulative or dose related, and ultrastructural myocardial changes are not generally seen [45, 46, 50]. Of note, many of the patients treated with lapatinib in the meta-analysis had not had prior exposure to anthracyclines and/or trastuzumab, which are cardiotoxic, so they may represent a select population. Therefore, the cardiac toxicity rates of lapatinib are not yet entirely clear. Ongoing cardiac evaluation is warranted in current and future lapatinib clinical investigations, but lapatinib-induced CHF, thus far, appears extremely rare.

	LAPATINIB DOSING SCHEDULE

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
A phase II trial comparing once-daily with twice-daily administration of lapatinib was performed in patients with advanced non-small cell lung cancer [51]. Patients were randomized to receive lapatinib at a dose of either 1,500 mg once daily or 500 mg twice a day. There were no grade 4 adverse events reported in the once-daily group compared with 13% (4 patients) experiencing grade 4 adverse events in the twice-daily group, including dyspnea, pulmonary embolism, acute respiratory distress syndrome, hypoxia, respiratory distress, and cerebrovascular accident. All these events were thought to be unrelated to lapatinib. Grade 3 adverse events were similar in both groups and included diarrhea, nausea, vomiting, and fatigue. One patient in the twice-daily dosing group had a grade 3 decrease in LVEF that resolved upon lapatinib discontinuation. Both schedules of lapatinib were generally well tolerated.

A randomized phase II trial compared once-daily lapatinib (1,500 mg/day) with twice-daily lapatinib (500 mg twice a day) as first-line treatment of patients with locally advanced or metastatic breast cancer. The target enrollment of 130 patients is complete. Preliminary results show a response rate of 35% across the trial and the adverse effect profiles are similar in both arms [29, 30]. Once-daily dosing has been used in subsequent clinical trials because of its ease of administration over twice-daily dosing [29, 30].

	PHARMACOLOGY

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
Lapatinib peak plasma levels occur 3–6 hours after oral administration. The effective plasma half-life is approximately 24 hours. The elimination of lapatinib occurs through hepatic metabolism primarily through cytochrome P450 (CYP)3A4 and excretion in feces.

Therefore, inducers and inhibitors of CYP3A4 may alter the metabolism of lapatinib. Given the significance of CYP3A4 in drug metabolism [52], 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 1 hour before and after lapatinib dosing. Lapatinib should also be used with great caution in patients with severe hepatic dysfunction. Table 2 lists the potential drug–drug interactions with lapatinib.

	PRACTICAL MANAGEMENT OF LAPATINIB TOXICITY

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
Rash
There are no clear evidence-based recommendations for management of lapatinib-associated rash. However, there is considerable experience in managing dermatologic eruptions from other ErbB-1–targeted agents. In most patients, rash attributable to lapatinib resolves during treatment, following a temporary interruption in treatment, or after treatment cessation. Clindamycin phosphate 1% gel can be used with good effect for inflammatory pustular lesions. A combination of clindamycin 1% and benzoyl peroxide 5% gel can also be effective. Oral antibiotics can also be used, including tetracycline (250 mg four times daily) or minocycline (100 mg two times daily). Colloidal oatmeal lotion has also been shown to be effective for this kind of rash [56]. Topical retinoids, like the antiacne medication tretinoin, are generally not recommended, because the rash seen with lapatinib has a different pathophysiology than acne vulgaris. The dry skin component of this rash responds well to emollients. Patients with extensive or persistent skin involvement should be referred to a dermatologist.

Diarrhea
Like lapatinib-associated rash, management of lapatinib-associated diarrhea is not evidence based. Practical management recommendations are similar to those that are given for capecitabine-associated diarrhea. If a patient experiences mild to moderate (grade 1 or 2) diarrhea, she should generally avoid all lactose-containing products, stay well hydrated, eat frequent small meals, and administer standard doses of antidiarrheals, such as loperamide. The standard dose of loperamide is an initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool and should be continued until the patient is free from diarrhea for at least 12 hours. This loperamide dosage regimen exceeds the usual dosage recommendations for loperamide [57].

If a patient experiences moderate to severe diarrhea or has complicating features, such as severe cramping, severe nausea or vomiting, fever, or dehydration, further doses of lapatinib should be held; i.v. fluids and inpatient hospitalization should be considered. Repeat administration of lapatinib should be delayed until the patient recovers and subsequent doses should be decreased or held indefinitely.

Cardiac Toxicity
Any surveillance recommendations for cardiac toxicity associated with the ErbB-2–directed therapies trastuzumab and lapatinib are not directly evidence based. However, given the confusion and uncertainty for clinicians surrounding cardiac safety recommendations, a Cardiac Guidelines Consensus Committee was established to provide practitioners with some guidance regarding the management of cardiac events during adjuvant trastuzumab therapy [58]. Given the similarities between trastuzumab- and lapatinib-induced cardiac toxicity, these consensus guidelines can serve as a basis for patients on lapatinib therapy (Figs. 3 and 4, adapted with permission by Michael S. Ewer, M.D.). Within the context of these guidelines, it is important to individualize patients when weighing the benefit of lapatinib versus the rare risk for cardiotoxicity. This weighing of the risk/benefit ratio is particularly important in the treatment-refractory metastatic breast cancer setting.

View larger version (20K): [in this window] [in a new window]   Figure 3. Suggested cardiac criteria for initiating lapatinib. Abbreviations: LVEF, left ventricular ejection fraction; MUGA, multigated acquisition. Adapted from Ewer MS, Perez EA, Baselga J et al. Cardiac safety guidelines for the adjuvant use of trastuzumab (Herceptin) in HER2-positive early breast cancer. The Breast 2007;16(suppl 1):S63, with permission by Michael S. Ewer, M.D.

View larger version (23K): [in this window] [in a new window]   Figure 4. Management of asymptomatic decreases in LVEF occurring during lapatinib therapy. Abbreviations: LLN, lower limit of normal; LVEF, left ventricular ejection fraction. Adapted from Ewer MS, Perez EA, Baselga J et al. Cardiac safety guidelines for the adjuvant use of trastuzumab (Herceptin) in HER2-positive early breast cancer. The Breast 2007;16(suppl 1):S63, with permission by Michael S. Ewer, M.D.

If a patient develops symptomatic CHF, lapatinib should be held, LVEF measurement should be performed, and input from a cardiologist should be sought.

Cardiac surveillance in an asymptomatic patient on lapatinib is more controversial. It seems prudent to perform serial screening of LVEF while a patient is on lapatinib, perhaps on an every several months basis. Across the clinical trials of lapatinib, if a patient's LVEF fell below the institution's lower limit of normal or decreased >20% from baseline, lapatinib was held and repeat cardiac evaluation was performed 1 month later. While this is a generally recommended approach, the decision of whether or not to continue therapy with a patient, particularly if it is controlling the disease, should carefully be made on an individual basis.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
In conclusion, lapatinib is an active and well-tolerated oral dual tyrosine kinase inhibitor for the treatment of breast cancer. Clinical efficacy of lapatinib is limited only to the treatment of ErbB-2–overexpressing breast cancer. Lapatinib is active in refractory metastatic breast cancer patients and as a first-line metastatic treatment, with potential benefit in patients with brain metastases. Importantly, lapatinib has demonstrated efficacy in combination with capecitabine in patients with refractory ErbB-2–overexpressing breast cancer. Lapatinib appears to have a very low incidence of cardiotoxicity. The most frequently reported adverse events include rash, diarrhea, nausea, and fatigue. However, severe (grades 3 and 4) toxicities are rare, and most adverse events associated with lapatinib are mild to moderate (grade 1–2). Generally, lapatinib-associated toxicity can be easily managed. Upcoming clinical investigations with other HER-2–directed compounds such as the irreversible ErbB-1/ErbB-2 inhibitors HKI-272 (Wyeth, Madison, NJ) and BIBW 2992 are eagerly anticipated. The planned adjuvant lapatinib and/or trastuzumab treatment optimization trial comparing 1 year of trastuzumab versus 1 year of lapatinib versus 1 year of trastuzumab plus lapatinib versus 3 months of trastuzumab followed by 9 months of lapatinib will also be of great interest. This information can guide practitioners and help them inform their patients about what to expect when they receive lapatinib.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 
B.M. has acted as a consultant to Genentech and GlaxoSmithKline.

	REFERENCES

Top Learning Objectives Abstract Introduction Lapatinib Activity in ErbB-2... Lapatinib Toxicity Lapatinib Dosing Schedule Pharmacology Practical Management of... Conclusions Disclosure of Potential... References

 

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