Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study.

BACKGROUND: Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. METHODS: From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. FINDINGS: Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. INTERPRETATION: Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. FUNDING: GlaxoSmithKline.

Adjunctive treatment for mood stabilization of patients with bipolar I disorder treated with lamotrigine.

OBJECTIVE: To describe the effect of supplemental psychotropic medications, specifically anxiolytics with sedative/hypnotics (ASH) combined with lamotrigine (LTG) on stabilization of symptoms in patients with bipolar I disorder. METHOD: Symptomatic patients participating in two LTG maintenance trials were classified post-hoc as those initiating LTG as monotherapy (n=313) or as adjunctive therapy (n=814) and further characterized by supplemental add-on therapies received during an open-label treatment phase. Patients were considered stabilized if they reached a stable dose of LTG monotherapy (100-200 mg/day) and had a Clinical Global Impressions-Severity scale score <3 for at least 4 weeks. Stabilization rates were compared across initial- and supplemental-treatment groups. RESULTS: Patients who initiated and were maintained on LTG monotherapy were stabilized at a slightly higher rate compared with those taking LTG adjunctive therapy (55% vs 48%; P=.080). Stabilization rates were numerically higher for LTG monotherapy patients who later received only ASH as supplemental medication compared with LTG monotherapy throughout, but this difference was not significant (66% vs 55%; P=.271). Stabilization rates were significantly higher for monotherapy patients who later received ASH alone versus other psychotropic medications (66% vs 28%; P=.001). For patients initiating LTG as adjunctive therapy, adding ASH alone resulted in significantly higher stabilization rates than adding another psychotropic medication (62% vs 33%; P<.001). CONCLUSION: LTG and adjunctive treatment with ASH may be useful in the treatment of acute mood symptoms in patients with bipolar I disorder.

The efficacy of intranasal fluticasone propionate in the relief of ocular symptoms associated with seasonal allergic rhinitis.

Intranasal corticosteroids have been shown to decrease ocular symptoms associated with allergic rhinitis as well as nasal symptoms. The primary objective of this retrospective analysis was to evaluate the efficacy of fluticasone propionate (FP) aqueous nasal spray in the treatment of ocular symptoms in patients with seasonal allergic rhinitis (SAR). We pooled efficacy data from seven multicenter, randomized, double-blind, placebo-controlled studies of similar design. Each study evaluated the efficacy of intranasal FP, 200 micrograms, given once daily in the treatment of nasal and ocular symptoms associated with SAR. At baseline and after 7 and 14 days of treatment, clinicians rated the severity of four individual ocular symptoms (itching, tearing, redness, and puffiness) via visual analog scales of 0-100, where 0 = no symptoms and 100 = worst symptoms. The four ratings were added to form the total ocular symptom score (TOSS). Patients rated the overall severity of their ocular symptoms (all symptoms evaluated with a single score) daily on diary cards in a similar fashion. The primary outcome was the mean change from baseline in the clinician-rated TOSS. A between-group difference of 25 points in the mean change from baseline TOSS by day 14 was considered clinically relevant. The FP group had greater mean changes from baseline in the TOSS and in all four individual symptom scores compared with placebo at days 7 and 14. At day 7, mean decreases from baseline in the TOSS were 76.0 points for the FP group and 50.9 points for the placebo group (p < 0.001), a difference between groups of 25.1. At day 14, mean decreases from baseline in the TOSS were 91.8 points for the FP group and 60.2 points for the placebo group (p < 0.001), a difference between groups of 31.6. Consistent with the clinician-rated data, patient-rated data showed a significantly greater reduction in the overall ocular symptom score for the FP group compared with placebo for both weeks 1 and 2 (p < 0.001). Intranasal FP provides safe and effective relief of ocular symptoms associated with SAR. Patients with allergic rhinitis who also have ocular symptoms as a component of their disease may benefit from intranasal FP monotherapy without the addition of topical ophthalmologic agents or oral antihistamines. Such an approach may have advantages regarding compliance and cost-effectiveness of treatment.

Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia.

BACKGROUND: Although response to intranasal corticosteroid therapy has been reported in patients with nonallergic rhinitis with eosinophilic syndrome (NARES), efficacy specifically in non-NARES patients has not been fully characterized. OBJECTIVE: To evaluate the efficacy of intranasal fluticasone propionate (FP) in the treatment of patients with perennial nonallergic rhinitis, with and without nasal eosinophilia. METHODS: Data from 983 patients in three randomized, double-blind, placebo-controlled PNAR trials were integrated. Patients received a total daily dose of FP 200 microg (n = 332), FP 400 microg (n = 325), or placebo (n = 326) for 28 days. Patients were > or =12 years of age with perennial rhinitis and negative skin tests to all allergens relevant to the geographic region. Nasal eosinophils were evaluated using a five-point scale. Patients were classified as non-NARES with a point score of 0 (n = 674; 69%); patients with a point score between I and 4 were classified as NARES (n = 309; 31%). Efficacy of FP was evaluated by the mean change in total nasal symptom score (TNSS), a sum of patient ratings of nasal obstruction, postnasal drip, and rhinorrhea. RESULTS: Patients with either NARES or non-NARES had similar statistically significant improvement with FP 200 microg or 400 microg compared with placebo; thus, the total group comprising both varieties of rhinitis responded to FP. In the total population, both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P < or = 0.002), with mean changes in TNSS for day 22 to day 28 ranging from -84 and -85 in the FP 200 microg and FP 400 microg groups, respectively, to -64 in the placebo group. The three study treatment groups had similar proportions of non-NARES (68 to 69%) and NARES (31 to 32%) patients at baseline. In the non-NARES subgroup, mean changes in TNSS for each treatment group were similar to changes seen in the total population. In the NARES subgroup, mean changes in TNSS for the FP 200 microg and placebo groups were similar to changes seen in the total population; mean change in TNSS for the FP 400 microg group was somewhat greater than changes seen in the total population. CONCLUSIONS: Intranasal FP is an effective treatment for perennial nonallergic rhinitis with or without nasal eosinophilia (NARES or non-NARES).