Neratinib: an option for HER2-positive metastatic breast cancer.

Metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is currently incurable. The primary goals of treatment are to prolong survival while optimizing quality of life. Several agents are now available in this setting, including neratinib, tucatinib, ado-trastuzumab emtansine, and trastuzumab deruxtecan. Neratinib in combination with capecitabine was recently approved for the treatment of adult patients with advanced or metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. Neratinib is an oral pan-HER inhibitor that binds covalently to the kinase site, providing irreversible binding. Phase 3 data showed that the combination of neratinib plus capecitabine improved progression-free survival vs lapatinib plus capecitabine. The duration of response was longer among patients in the neratinib arm. Neratinib plus capecitabine was also active against brain metastases associated with refractory, HER2-positive breast cancer, and this combination is listed in guidelines from the National Comprehensive Cancer Network for this indication. When combined with fulvestrant, neratinib demonstrated efficacy in patients with HER2-positive breast cancer, regardless of their hormone receptor status. Ongoing trials are evaluating the ability of neratinib to treat brain metastases, as well as the efficacy and safety of the triplet combination of neratinib, fulvestrant, and trastuzumab in this setting.

Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer.

The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2-negative MBC.

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer.

Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

A phase II trial of pemetrexed and gemcitabine in patients with metastatic breast cancer who have received prior taxane therapy.

PURPOSE: This phase II trial assessed efficacy and safety of pemetrexed plus gemcitabine to treat metastatic or locally advanced breast cancer in patients previously treated with taxanes. PATIENTS AND METHODS: Eligible women with advanced breast cancer treated with taxanes in the adjuvant or metastatic setting received pemetrexed 500 mg/m2 on day 1 followed by gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle. Hematologic toxicities limiting day 8 gemcitabine dosing were observed in the first 20 patients, prompting a protocol amendment to evaluate pemetrexed 500 mg/m2 followed by gemcitabine 1500 mg/m2 on day 1 of a 14-day cycle. Patients received folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate (ORR). RESULTS: Between July 2003 and September 2006, 73 evaluable women (median age, 52.1 years; range, 28-73 years) were enrolled (21-day schedule: 21 patients, 52% estrogen receptor-positive, 24% HER2-positive; 14-day schedule: 52 patients, 58% ER-positive, 15% HER2-positive). For patients on the 21-day and 14-day schedules, median number of cycles was 4 (range, 1-8 cycles) and 5 (range, 1-38 cycles), respectively. The ORRs were 23.8% and 19.2%, respectively; median survival times were 16.2 months and 13.4 months. The most common grade 3/4 hematologic toxicities were neutropenia (71% vs. 33%) and leukopenia (24% vs. 14%); febrile neutropenia occurred in 10% and 6%. The most common grade 3/4 nonhematologic toxicity was fatigue (29% vs. 10%). CONCLUSION: Pemetrexed/gemcitabine given on a 21-day or 14-day schedule is active in patients with advanced breast cancer previously treated with taxanes. A 14-day schedule appears to result in fewer serious toxicities.

Phase II trial of capecitabine and weekly paclitaxel in patients with metastatic breast cancer previously treated with every-3-week taxane therapy.

PURPOSE: We conducted a multicenter phase II trial to determine the efficacy/safety of capecitabine and weekly paclitaxel, a combination with preclinical evidence of synergy, in patients with metastatic breast cancer (MBC) previously treated with a taxane. PATIENTS AND METHODS: Eligibility criteria included measurable MBC, history of every-3-week taxane therapy (adjuvant or for MBC), and no previous taxane on a weekly basis, capecitabine, or infusional 5-fluorouracil. Patients received capecitabine 825 mg/m2 per dose orally twice daily (1650 mg/m2 per day) on days 1-14 and weekly paclitaxel 80 mg/m2 intravenously on days 1 and 8, followed by a 1-week rest period (every-3-week cycle) until progression or intolerable toxicity. Fifty-four women were treated, most with previous every-3-week taxane exposure as adjuvant therapy (n=43) rather than for MBC (n=11). The median number of delivered cycles was 7, with dose modifications in 30 patients. The intent-to-treat objective response rate (primary study endpoint) was 59% (95% confidence interval, 46%-72%), including 7 complete and 25 partial responses. RESULTS: Three patients had stable disease for>or=6 months, for a clinical benefit rate of 65% (95% confidence interval, 51%-76%). Median objective response duration, time to progression, and overall survival were 8.1 months, 8.4 months, and 21.6 months, respectively. Grade 3/4 treatment-related adverse events consisted of neutropenia (13%), anemia (2%), hand-foot skin reaction (20%), fatigue (7%), diarrhea (4%), nausea/vomiting (4%), and pain (2%). No patients developed grade 3/4 neuropathy. CONCLUSION: Capecitabine and weekly paclitaxel were highly active with acceptable tolerability in patients with MBC previously treated with a taxane, consistent with our recently published experience in taxane-naive women with MBC.

Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer.

PURPOSE: The taxanes and capecitabine have synergistic antitumor activity in preclinical models. This trial was designed to determine the efficacy and tolerability of weekly paclitaxel plus capecitabine as first-line treatment for metastatic breast cancer (MBC). PATIENTS AND METHODS: Participants had histologically proven breast cancer, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group. Exclusion criteria included prior taxane therapy or any prior capecitabine or infusional fluorouracil. Participants received capecitabine 825 mg/m2/dose orally bid (1,650 mg/m2/d) for days 1 to 14. Paclitaxel 80 mg/m2 was administered intravenously weekly on days 1 and 8. Cycles were repeated every 3 weeks. Responders (complete or partial) or those with stable disease were treated until progression of disease or intolerable toxicity. RESULTS: Fifty-five women were enrolled; 94% received study therapy as first-line treatment for MBC. In the intent-to-treat population, objective responses (partial) were achieved in 30 patients (55%; 95% CI, 40% to 69%), and six additional patients had stable disease for 6 months or longer (clinical benefit rate of 65%). The median duration of response was 10 months (range, 2.5 to 18.7 months). Dose modifications and reductions were common, particularly for capecitabine, leading to a delivered dose-intensity of 75% for capecitabine and 91% for paclitaxel. The most frequent grade 3 to 4 treatment-related adverse events were hand-foot skin reaction (n = 10); neutropenia (n = 7); fatigue (n = 4); and leukopenia, diarrhea, and pain (n = 3 each). CONCLUSION: Capecitabine in combination with weekly paclitaxel is an active and tolerable regimen as first-line therapy for women with MBC.

Capecitabine/Taxane combination therapy: evolving clinical utility in breast cancer.

Capecitabine is approved as a single agent and in combination with docetaxel for the treatment of metastatic breast cancer. Preclinical and clinical research suggests that the activity of capecitabine is enhanced in combination with taxanes and several biochemical mechanisms of synergy have been described. Recent data suggest that novel doses and schedules os capecitabine can improve safety without compromising efficacy. More than 50 publications and abstracts describing capecitabine/taxane combination therapy studies were reviewed to evaluate the available data on efficacy, safety, and quality of life for patients with breast cancer. Several ongoing randomized adjuvant and neoadjuvant clinical trials are assessing the clinical utility of capecitabine/taxane combinations in early-stage and locally advanced breast cancer.

Phase II study of pemetrexed in patients pretreated with an anthracycline, a taxane, and capecitabine for advanced breast cancer.

BACKGROUND: This phase II study evaluated the efficacy, safety, and health outcomes of pemetrexed treatment in heavily pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Women with metastatic breast cancer, Karnofsky performance status > or = 70, and previous treatment with > or = 3 regimens containing anthracyclines, taxanes, and capecitabine were eligible. Pemetrexed 500 mg/m2 intravenous infusion was administered on day 1 of a 21-day treatment cycle. RESULTS: Eighty patients were enrolled, and 60 received concurrent folic acid and vitamin B12 supplements per protocol amendment to minimize possible pemetrexed-related toxicity. The median numbers of cycles delivered were 3 for vitamin-supplemented patients and 2 for non-vitamin-supplemented patients. Regardless of vitamin supplementation, the overall response rate was 8% (95% CI, 3%-16.6%), stable disease was exhibited in 36% of patients, median time to disease progression was 2.9 months, and median survival was 8.2 months. Improvements in patient-reported symptoms ranged from 16.2% for pain intensity to 32.1% for nausea. Major grade 3/4 toxicities were hematologic, with grade 4 neutropenia in 10% of patients and grade 3 toxicities consisting primarily of neutropenia (29%) and leukopenia (21%). There were no clear trends of the effect of supplementation on toxicity. CONCLUSION: Pemetrexed has modest antitumor activity and is well tolerated in heavily pretreated patients with breast cancer. Further evaluation of this multitargeted antifolate in advanced breast cancer is warranted.

The evolving role of capecitabine in breast cancer.

Breast cancer is the most common cancer and the second greatest cause of cancer-related death among women in the United States. Capecitabine is a selectively tumor-activated fluoropyrimidine carbamate that is converted to 5-fluorouracil by the sequential activity of these enzymes, the final of which is thymidine phosphorylase, which is overexpressed in many human cancers. Capecitabine as a single agent and in combination with other drugs is efficacious in previously treated and untreated metastatic breast cancer (MBC). The integration of capecitabine, either as a single agent or in combination with docetaxel, into adjuvant breast cancer therapy is justified due to its high antitumor activity in previously treated and untreated MBC, its tolerability, lack of cross-resistance with the anthracyclines and taxanes, and because combined docetaxel/capecitabine improves the overall survival of patients with MBC. Capecitabine is being evaluated as preoperative therapy in patients with operable breast cancer, as adjuvant therapy in patients with high-risk node-negative or node-positive disease, and as oral single-agent therapy in women > or = 65 years of age. This article is an overview of published studies of capecitabine in MBC and the studies that are planned or have been proposed to evaluate capecitabine as adjuvant therapy for breast cancer.

Pemetrexed: a promising new treatment for breast cancer.

Metastatic breast cancer is a chemotherapy-responsive disease, and significant palliation of cancer-related symptoms can be achieved with effective treatment. New treatments are needed because patients with metastatic breast cancer commonly out-live the effectiveness of currently available cytotoxic and hormonal treatments. Pemetrexed is a novel antimetabolite that inhibits three enzymes critical in purine and pyrimidine biosynthetic pathways: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Several phase II studies of pemetrexed have showed objective response rates of more than 30% in minimally pretreated metastatic breast cancer patients and approximately 20% in more heavily pretreated patients. Pemetrexed is associated with limited toxicity when administered with folic acid and vitamin B(12) supplementation and is therefore a promising agent both for palliative treatment of metastatic disease and for incorporation into combination regimens for treating newly diagnosed metastatic and early-stage breast cancer.