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.     

Phase II trial of simple oral therapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: SWOG S0430

Background.

Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.

Methods.

The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.

Results.

In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.

Conclusions.

PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.     

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases �C the UK experience

Background:

The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab.

Methods:

Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented.

Results:

Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6–24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15–27%) and median TTP was 22 weeks (95% CI: 17–27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9–39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15–28).

Conclusions:

Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.     

Standard Versus Continuous Administration of Capecitabine in Metastatic Breast Cancer (GEICAM/2009‐05): A Randomized,Noninferiority Phase II Trial With a Pharmacogenetic Analysis

Background.

The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m² twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy.

Methods.

We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m² twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed.

Results.

The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of −2.0%; 95% confidence interval: −15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3–4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3–4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5′ untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival.

Conclusion.

Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.     

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Background:

HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients'' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies.

Methods:

In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab.

Results:

For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8–28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9–34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib.

Conclusion:

Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.     

Advances in first-line treatment for patients with HER-2+ metastatic breast cancer

Background.

The prognosis for breast cancer patients overexpressing human epidermal growth factor receptor (HER)-2 has changed with anti–HER-2–targeted therapy. Although anti–HER-2 therapy with trastuzumab and chemotherapy is the standard first-line treatment, the best therapeutic regimen has yet to be defined, and new strategies are evolving.

Methods.

A literature review of well-established and recently published trials, reviews, and ongoing clinical trials addressing first-line treatment for HER-2⁺ metastatic breast cancer patients was performed.

Results.

Taxanes are the agents most commonly used in combination with trastuzumab, but other chemotherapy drugs, such as anthracyclines, vinorelbine, and gemcitabine and triple-combination therapies including platinum compounds, capecitabine, and taxanes have been studied. The combination of aromatase inhibitors with anti–HER-2 therapies is a new therapeutic option for some patients who coexpress HER-2 and hormone receptors, although its activity observed in randomized clinical trials seems to be inferior to that of chemotherapy plus anti–HER-2 therapies. In addition, new anti–HER-2 therapies have shown activity in HER-2⁺ tumors, both alone and in combination with trastuzumab.

Conclusions.

Trastuzumab plus chemotherapy is the current standard of care for the upfront treatment of HER-2⁺ breast cancer patients, though other anti–HER-2–targeting agents may appear as new standards in the upcoming years.     

A phase II study of capecitabine and lapatinib in advanced refractory colorectal adenocarcinoma: A Wisconsin Oncology Network study

Background

Prognosis remains poor after progression on first-line chemotherapy for colorectal adenocarcinoma, and inactivation of the EGFR pathway with monoclonal antibodies is an effective treatment strategy in selected patients with metastatic disease. Lapatinib is an oral EGFR and HER-2 dual tyrosine kinase inhibitor that has not shown significant activity in metastatic colorectal cancer. However, lapatinib may act synergistically with capecitabine in anticancer effects.

Methods

This was an open-label, non-randomized phase II study of lapatinib 1,250 mg orally daily and capecitabine 2,000 mg/m² by mouth split into twice-daily dosing for 14 days of a 21 days cycle. Inclusion criteria included metastatic or locally advanced adenocarcinoma of the colon or rectum with progression by RECIST on or within six months of receiving a fluoridopyrimidine-, oxaliplatin- or irinotecan-containing regimen. Prior EGFR monoclonal antibody was permitted. K-ras testing was not routinely performed and was not a part of the study protocol.

Results

Twenty nine patients (16 M; 13 F) were enrolled in this study. There were no complete or partial responses. 41.4% of patients achieved stable disease as a best response. Median overall survival was 6.8 months, with a 1-year survival rate of 22%, and median progression-free survival was 2.1 months. The combination produced few grade 3 and no grade 4 toxicities. No grade 3 toxicity occurred in more than 10% of patients.

Conclusions

Although capecitabine and lapatinib is well tolerated, it is not an effective regimen in patients with refractory colorectal adenocarcinoma.Key Words: Colorectal cancer, capecitabine, lapatinib, EGFR, Her-2     

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.     

All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2-negative metastatic breast cancer: an International Phase II Trial

Background:

This multicentre, international phase II trial evaluated the efficacy and safety profile of a first-line combination of oral vinorelbine plus capecitabine for women with metastatic breast cancer (MBC).

Methods:

Patients with measurable, HER2-negative disease received, as a first line in metastatic setting, 3-weekly cycles of oral vinorelbine 80 mg m⁻² (after a first cycle at 60) on day 1 and day 8, plus capecitabine 1000 mg m⁻² (750 if ⩾65 years of age) twice daily, on days 1–14. Treatment was continued until progression or unacceptable toxicity.

Results:

A total of 55 patients were enrolled and 54 were treated (median age: 58.5 years). Most (78%) had visceral involvement and 63% had received earlier (neo)adjuvant chemotherapy. The objective response rate (RECIST) in 49 evaluable patients was 51% (95% confidence interval (CI), 36–66), including complete response in 4%. The clinical benefit rate (response or stable disease for ⩾6 months) was 63% (95% CI, 48–77). The median duration of response was 7.2 months (95% CI, 6.4–10.2). After a median follow-up of 41 months, median progression-free survival was 8.4 months (95% CI, 5.8–9.7) and median overall survival was 29.2 months (95% CI, 18.2–40.1). Treatment-related adverse events were manageable, the main grade 3–4 toxicity was neutropaenia (49%); two patients experienced febrile neutropaenia and three patients had a neutropaenic infection (including one septic death). A particularly low rate of alopaecia was observed.

Conclusion:

These results show that the all-oral combination of oral vinorelbine and capecitabine is an effective and well-tolerated first-line regimen for MBC.     

Efficacy of capecitabine-based combination therapy and single-agent capecitabine maintenance therapy in patients with metastatic breast cancer

Objective

The purpose of this study was to observe the efficacy and toxicities of capecitabine-based chemotherapy and capecitabine monotherapy as maintenance therapy in the treatment of metastatic breast cancer (MBC).

Patients and methods

A total of 98 MBC patients were treated with capecitabine combined with vinorelbine (NX).

Results

The median number of treatment was 6 cycles (1-7 cycles). There were two cases of complete remission (CR), 58 partial remission, 27 stable disease (SD), 11 progression disease. The overall response rate (ORR) (CR + PR) was 61.2%. The clinical benefit rate (CBR) was 75.5%. Fifty of effective patients received with capecitabine monotherapy as maintenance therapy. The ORR (CR + PR) was 4%. The CBR was 48%. The median progression-free survival (PFS) was 12 months. In maintenance therapy or not, the median post metastasis survival rate (MSR) was 63 and 28 months, respectively. In the combination therapy group, the major grade 3/4 toxicities included hand-foot syndrome (3.1%), skin pigmentation (2.0%), diarrhoea and abdominal distension (5.1%), stomatitis (1.0%), and leukopenia (20.4%).

Conclusions

Capecitabine-based combination therapy and single-agent capecitabine maintenance therapy were well tolerated and effective to MBC.     

Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck

Background:

Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Methods:

In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2–6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity.

Results:

Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received ⩾4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib.

Conclusion:

Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.     

Phase I Study of Sunitinib in Combination With Gemcitabine and Capecitabine for First‐Line Treatment of Metastatic or Unresectable Renal Cell Carcinoma

Background.

The combination of gemcitabine plus capecitabine and sunitinib (GCS) shows activity in metastatic renal cell carcinoma (mRCC). We tested the multitargeted “chemo-switch” regimen as first-line treatment in patients with mRCC.

Methods.

We assessed the maximum tolerated dose and antitumor activity of GCS in treatment-naïve, advanced mRCC patients. Treatment consisted of intravenous gemcitabine on days 1 and 8, oral capecitabine twice daily on days 1–14, and oral sunitinib daily for six 21-day cycles, followed by sunitinib monotherapy at the investigator’s discretion. Dose level 0 (DL0) was gemcitabine 1,000 mg/m² per day plus capecitabine 650 mg/m² per 12 hours plus sunitinib 37.5 mg/day; DL1 was gemcitabine 1,000 mg/m² per day plus capecitabine 850 mg/m² per 12 hours plus sunitinib 37.5 mg/day.

Results.

Sixteen patients were enrolled. At DL1, two of four patients had dose-limiting toxicity (DLT; grade 3 diarrhea and grade 4 thrombocytopenia). The dose was reduced to DL0 when only 1 of 12 patients experienced DLT (grade 3 diarrhea, grade 3 mucositis, and grade 3 thrombocytopenia). Dose reductions were frequent (58% of patients), and only seven patients were able to receive the three drugs for more than three cycles. One patient achieved a complete response, three had partial responses, and the best response for four was stable disease.

Conclusion.

The safety profile of the combination does not seem manageable in this patient population. No further development of the combination is recommended.     

Trastuzumab beyond progression in HER2-positive advanced breast cancer: the Royal Marsden experience

Background:

Recent UK clinical guidance advises against continuing trastuzumab (T) beyond disease progression (PD) in the absence of brain metastases in patients with HER-2 positive (+ve) advanced breast cancer .We have retrospectively evaluated the outcome of patients with HER-2+ve locally advanced (LA) or metastatic breast cancer (MBC) who continued T beyond PD, treated in our unit.

Methods:

All HER-2+ve patients on our prospectively maintained database with LA or MBC who received T beyond PD after adjuvant or one line of T for advanced disease were assessed for response and outcome. From the timepoint of T continuation beyond PD, we calculated the overall disease control rate, time to progression (TTP), and overall survival (OS).

Results:

One hundred and fourteen patients with HER-2+ve LA or MBC treated with T beyond PD were identified. The main site of disease was visceral_in 84 (74%) patients. Seventy-six (66%) had one line of chemotherapy before continuation of T beyond PD and 21 (19%) had two or more. Post-progression, 66 (58%) received T combined with chemotherapy. Of the 93 (82%) patients with documented clinical or radiological response evaluation, 67 (59%) were considered as having stable disease or better. The median TTP was 24 weeks (95% CI: 21–28) and the median OS was 19 months (95% CI: 12–24).

Conclusion:

Our results from an unselected group of patients provide additional evidence that continuation of T beyond PD is of clinical benefit.     

First‐Line Treatment Patterns and Clinical Outcomes in Patients With HER2‐Positive and Hormone Receptor‐Positive Metastatic Breast Cancer From registHER

Background.

Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting.

Methods.

registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors.

Results.

HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89).

Conclusions.

These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.     

Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment

Background:

Platinum-based therapy (PBT) is the standard therapy for recurrent and/or metastatic head and neck cancer (HNC), but the incidence of recurrence remains high. This study evaluates the efficacy and tolerability of capecitabine as palliative monotherapy for recurrent HNC previously treated with PBT.

Methods:

Patients aged 18–75 years, with Eastern Cooperative Oncology Group performance status 0–2, squamous HNC with locoregional and/or metastatic recurrence previously treated with PBT and adequate organ functions, were included. Capecitabine (1.250 mg m⁻² BID) was administered on days 1–14 every 21 days for at least two cycles.

Results:

A total of 40 male patients with a median age of 58 years were analysed. All patients received a median number of four cycles of capecitabine (range: 1–9) and the median relative dose intensity was 91%. Seven patients were not evaluable for response. Overall response rate was 24.2%. Median time to progression and overall survival were 4.8 and 7.3 months, respectively. Haematological adverse events (AEs) grade 3/4 were reported in six patients. Most common grade 3/4 non-haematological AEs were asthenia (12.5%), palmar-plantar eritrodisestesia (10%), mucositis (10%), dysphagia (10%) and diarrhoea (7.5%).

Conclusions:

Capecitabine seems to be an active, feasible and well-tolerated mode of palliative treatment for advanced HNC patients who have previously received PBT schedules.     

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma

Background:

Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.

Methods:

Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg^–1 on day 1 and capecitabine 800 mg m^–2 twice daily on days 1–14 every 3 weeks as first-line therapy.

Results:

A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.

Conclusion:

The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.     

Moderate Immunohistochemical Expression of HER‐2 (2+) Without HER‐2 Gene Amplification Is a Negative Prognostic Factor in Early Breast Cancer

Background.

Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti–HER-2 treatment. However, commonly defined “HER-2⁻” tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm.

Methods.

We studied 1,150 women (median age, 58 years; range, 22–94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis.

Results.

Four hundred-fifty seven (40%), 454 (39%), 116 (10%), and 123 (11%) patients were considered HER-2 0+, HER-2 1+, HER-2 2+/HER-2⁻ by FISH, and HER-2⁺ (3+ or HER-2⁺ by FISH), respectively. Compared with a HER-2 0 or 1+ status, a HER-2 2+/HER-2⁻ by FISH status was associated with a worse DFS outcome on multivariate analysis. Compared with a HER-2⁺ status, a HER-2 2+/HER-2⁻ status showed a time-dependent effect on the DFS probability, with an initial advantage that worsened every year by a factor of 1.649.

Conclusion.

A HER-2 2+/HER-2⁻ status is an adverse prognostic factor in patients with operable breast cancer. Because of suggestions from randomized trials that the benefits of adjuvant trastuzumab may not be limited to patients with HER-2⁺ tumors, patients with a HER-2 2+/HER-2⁻ status are ideal candidates for studies testing this hypothesis.     

An Open‐Label Safety Study of Lapatinib Plus Trastuzumab Plus Paclitaxel in First‐Line HER2‐Positive Metastatic Breast Cancer

Background.

Recent data support the hypothesis that combining lapatinib and trastuzumab with taxane chemotherapy may offer added clinical benefit to patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study examined the safety of the triplet combination in first-line HER2-positive MBC.

Patients and Methods.

Patients were enrolled into three sequential cohorts; the last two cohorts were added by protocol amendment following review of safety data from cohort 1. Patients in cohort 1 received lapatinib (1000 mg/day) plus paclitaxel (80 mg/m² per week, 3 of every 4 weeks); cohort 2 received lapatinib (1000 mg/day) plus paclitaxel (70 mg/m² per week, 3 of every 4 weeks); and cohort 3 received lapatinib (750 mg/day) plus paclitaxel (80 mg/m² per week, 3 of every 4 weeks). All received standard trastuzumab dosing. The primary objective was assessment of dose-limiting toxicities, safety, and tolerability of this combination.

Results.

The most frequent adverse events (AEs) for all cohorts were diarrhea (89%), rash (79%), fatigue (73%), alopecia (63%), nausea (63%), and vomiting (40%). In cohorts 1 and 2, the incidence of grade 3 diarrhea was 62% and 50%, respectively; in cohort 3, the incidence was 25% (with prophylactic loperamide). Dehydration was the most frequent serious AE (10%). Across cohorts, overall response rate was 75%.

Conclusions.

The dose-limiting toxicity of paclitaxel, trastuzumab, and lapatinib in first-line HER2-positive MBC was diarrhea. Of the triplet combinations tested, the cohort receiving 750 mg/day dose of lapatinib had the lowest incidence of diarrhea; therefore, this dose should be used in further studies on the treatment of MBC.     

Bevacizumab in combination with biweekly capecitabine and irinotecan, as first-line treatment for patients with metastatic colorectal cancer

Background:

Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treatment for metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the efficacy and safety of this regimen in combination with bevacizumab (BV), as first-line treatment for mCRC.

Patients and methods:

A total of 46 consecutive patients received a combination of BV (5 mg kg⁻¹, day 1), irinotecan (175 mg m⁻², day 1) and capecitabine (1000 mg m⁻² twice daily on day 2–8), every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary objective was to determine the progression-free survival (PFS) and safety profile.

Results:

The overall response rate (ORR) was 67.4%, with a disease control rate (ORR+stable disease) of 93.5%. Median PFS and overall survival (OS) were 12.3 months (95% confidence interval (CI): 6.5–18.1 months) and 23.7 months (95% CI: 16.7–30.6 months), respectively. The most frequent grade 3/4 treatment-related adverse events were asthenia (7%), diarrhoea (7%), nausea (9%) and vomiting (7%).

Conclusion:

Bevacizumab combined with biweekly XELIRI is a highly active first-line regimen for mCRC treatment, showing encouraging PFS, ORR and OS with a good tolerability.     

Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial

Background:

The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy.

Methods:

Patients with mCRC were randomised to cetuximab (400 mg m⁻², day 1, followed by 250 mg m⁻² weekly) plus CAPIRI (irinotecan 200 mg m⁻², day 1; capecitabine 800 mg m⁻², twice daily, days 1–14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m⁻², day 1; capecitabine 1000 mg m⁻², twice daily, days 1–14, every 3 weeks).

Results:

Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand–foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1–3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1–3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend.

Conclusion:

This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.