Human epidermal growth factor receptor 2 (HER2) extracellular domain levels are associated with progression-free survival in patients with HER2-positive metastatic breast cancer receiving lapatinib monotherapy.

BACKGROUND: Changes in serum human epidermal growth factor receptor 2 (HER2) levels associated with clinical outcomes, including objective response rate, progression-free survival (PFS), and overall survival have been reported in patients with metastatic breast cancer (MBC) receiving trastuzumab and chemotherapy. This study investigated whether baseline or changes in serum HER2 correlated with overall response rate (ORR) and/or PFS in patients with MBC receiving first-line lapatinib monotherapy. METHODS: The EGF20009 study investigated lapatinib monotherapy in 138 HER2-positive patients with MBC previously untreated for their metastatic disease. Serum was collected and assessed at baseline and every 4 weeks for 16 weeks after treatment initiation. Disease assessment was performed at weeks 8 and 12 and every 12 weeks thereafter. A ≥ 20% decrease or increase in serum HER2 was defined as a significant change. RESULTS: Seventy-nine percent of patients had elevated baseline serum HER2. Baseline serum HER2 was associated with ORR (P = .043) but not PFS. Patients with a ≥ 20% decrease from baseline of serum HER2 at weeks 4, 8, 12, and 16 had a significantly increased ORR and prolonged PFS. Conversely, those with a ≥ 20% increase from baseline had a significantly lower ORR and shorter PFS. CONCLUSION: Significant decreases in serum HER2 levels during the first 16 weeks of lapatinib monotherapy were associated with better clinical outcome (longer PFS and increased ORR) in HER2-positive MBC patients.

Quality of life in hormone receptor-positive HER-2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib.

BACKGROUND: A phase III trial compared lapatinib plus letrozole (L + Let) with letrozole plus placebo (Let) as first-line therapy for hormone receptor (HR)(+) metastatic breast cancer (MBC) patients. The primary endpoint of progression-free survival (PFS) in patients whose tumors were human epidermal growth factor receptor (HER)-2(+) was significantly longer for L + Let than for Let (8.2 months versus 3 months; p = .019). This analysis focuses on quality of life (QOL) in the HER-2(+) population. METHODS: QOL was assessed at screening, every 12 weeks, and at withdrawal using the Functional Assessment of Cancer Therapy-Breast (FACT-B). Changes from baseline were analyzed and the proportions of patients achieving minimally important differences in QOL scores were compared. Additional exploratory analyses evaluated how QOL changes reflected tumor progression status. RESULTS: Among the 1,286 patients randomized, 219 had HER-2(+) tumors. Baseline QOL scores were comparable in the two arms. Mean changes in QOL scores were generally stable over time for patients who stayed on study. The average change from baseline on the FACT-B total score in both arms was positive at all scheduled visits through week 48. There was no significant difference between the two treatment arms in the percentage of QOL responders. CONCLUSION: The addition of lapatinib to letrozole led to a significantly longer PFS interval while maintaining QOL during treatment, when compared with letrozole alone, thus confirming the clinical benefit of the combination therapy in the HR(+) HER-2(+) MBC patient population. This all oral regimen provides an effective option in this patient population, delaying the need for chemotherapy and its accompanying side effects.

Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.

OBJECTIVE: To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)(+) human epidermal growth factor receptor (HER)-2(+) tumors receiving first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women (n = 1,286) with HR(+) MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2(+) tumors. The primary endpoint was progression-free survival (PFS) in HER-2(+) patients. RESULTS: Results in the HR(+) HER-2(+) population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53-0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2. CONCLUSIONS: The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2.

The Relative Bioavailability, Food Effect, and Drug Interaction With Omeprazole of Momelotinib Tablet Formulation in Healthy Subjects.

Momelotinib is a potent and selective small-molecule inhibitor of JAK1/2 that is under investigation for the treatment of myeloproliferative neoplasms. In a phase 1/2 study in myelofibrosis patients, once-daily dosing of a 300-mg momelotinib capsule was selected for further development based on a favorable benefit:risk profile. A tablet formulation was recently developed for further clinical evaluation. In this study, the relative bioavailability of the tablet formulation versus the initial capsule formulation and the effect of food and omeprazole on the pharmacokinetics of a single-dose momelotinib tablet were evaluated in healthy subjects. The momelotinib tablet, 200 mg, provided plasma exposure equivalent to the 300-mg capsule. Plasma exposure of momelotinib increased less than dose-proportionally from 100 to 800 mg. Food intake modestly increased Cmax (38% and 28% increase for low- and high-fat meals, respectively) and AUCinf (16% and 28% increase for low- and high-fat meals, respectively) for the momelotinib tablet. Omeprazole reduced the exposure of the momelotinib tablet by 36% for Cmax and 33% for AUCinf . Neither the food effect nor the omeprazole effect on momelotinib exposure was considered clinically meaningful because of the safety and efficacy profile of momelotinib.

Quality-adjusted survival analysis of first-line treatment of hormone-receptor-positive HER2+ metastatic breast cancer with letrozole alone or in combination with lapatinib.

AIM: Compare first-line lapatinib plus letrozole (L + Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2 + metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period. METHODS: The area under survival curves for each treatment group was partitioned into distinct health states of varying utility: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period following disease progression until death or end of follow-up (REL). The utility-weighted sum of the mean health state durations was derived for each group. The threshold utility analysis evaluates how varying utility values across the states affects Q-TWiST differences between groups, although the method is limited by not varying utilities within each health state. RESULTS: The primary analysis population was the HER2 + subgroup (n = 219). There was no significant difference between treatments in mean duration of grade 3/4 adverse events prior to progression (L + Let = 1.95 weeks; Let = 2.14 weeks; P = 0.90). Using utility weights of 0.5 for TOX and REL, L + Let was favored for quality-adjusted survival by 8.8 weeks (P = 0.09). The Q-TWiST difference between treatment groups ranged from 8 to 9.5 weeks, favoring combination therapy for all hypothetical utility levels, but none of the comparisons were statistically significant at P = 0.05. CONCLUSIONS: No significant differences were found between L + Let versus Let in mean duration of severe adverse events. Quality-adjusted survival was favored for the combination treatment arm for all utility levels examined when toxicity was defined by grade 3/4 AEs, but differences between groups were not statistically significant.

Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

PURPOSE: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION: This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.