gdc-0449 and Weight-Loss

Basal cell carcinoma (BCC) of the skin is the most common form of skin cancer in the United States. In life-threatening, advanced BCC, sonic hedgehog inhibitors (SSHis) remain a pre-eminent treatment option for locally advanced BCC and metastatic BCC.. In this updated systematic review and meta-analysis, we aimed to better characterize the efficacy and safety of SSHis by including final updates from pivotal clinical trials and additional new recent studies.. An electronic database search was performed for articles including clinical trials, prospective case series, and retrospective medical record reviews on human subjects. Overall response rates (ORRs) and complete response rates (CRRs) were the primary outcomes. For safety assessment, the prevalence of the following adverse effects was analyzed: muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, myalgias, vomiting, skin squamous cell carcinoma, increased creatine kinase, diarrhea, decreased appetite, and amenorrhea. Analyses were performed using R statistical software. Data were pooled using linear models with fixed effects meta-analysis for primary analyses, along with 95% confidence intervals (CIs) and p-values. Intermolecular differences were calculated using Fisher's exact test.. A total of 22 studies (N = 2384 patients) were included in the meta-analysis: 19 studies assessing both efficacy and safety, 2 studies assessing safety only, and 1 study assessing efficacy only. Overall, the pooled ORR for all patients was 64.9% (95% CI 48.2-81.6%), implicating there is at least a partial response (z = 7.60, p < 0.0001) in most patients receiving SSHis. The ORR for vismodegib was 68.5% and 50.1% for sonidegib. The most common adverse effects for vismodegib and sonidegib were muscle spasms (70.5% and 61.0%, respectively), dysgeusia (58.4% and 48.6%, respectively), and alopecia (59.9% and 51.1%, respectively). Patients were likely to experience weight loss (35.1%, p < 0.0001) from vismodegib. Alternatively, patients taking sonidegib experienced more nausea, diarrhea, increased creatine kinase levels, and decreased appetite compared with those receiving vismodegib.. SSHis are an effective treatment for advanced BCC disease. Given the high discontinuation rates, management of patient expectations is warranted for compliance and achieving long-term efficacy. It is essential to stay updated with the latest discoveries on the efficacy and safety of SSHis.

Topics: Alopecia; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Creatine Kinase; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Dysgeusia; Female; Hedgehog Proteins; Humans; Nausea; Retrospective Studies; Skin Neoplasms; Spasm; Weight Loss

Topics: Anilides; Antineoplastic Agents; Asthenia; Carcinoma, Basal Cell; Clinical Trials, Phase III as Topic; Disease Progression; Humans; Neoplasm Metastasis; Pyridines; Skin Neoplasms; Weight Loss

Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy.. The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients.

Topics: Alopecia; Anilides; Antineoplastic Agents; Asthenia; Biphenyl Compounds; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Pyridines; Signal Transduction; Spasm; Taste Disorders; Weight Loss

Vismodegib (Erivedge. This is a prospective cohort study in real-world practice. We included consecutive adult patients treated in Argentina with locally advanced or metastatic BCC not suitable for surgery or radiotherapy. Patients were followed until the end of the study, death, or loss to follow-up, whichever occurred first. Patients received 150 mg vismodegib PO daily.. We included in the analysis 63 patients who received treatment. Locally advanced BCC was present in 57 (90.4%) and metastatic disease in two (3.2%). ORR was observed in 46 patients (73%; 95% CI: 60.3-83.4), with partial response in 36 (57%; 95% CI: 44-69.5) and complete response in 10 (16%; 95% CI: 7.8-27.2). As to safety, 48 (76.2%) patients had at least one adverse event (AE). The most frequently observed AEs were muscular spasms in 25 (39.6%); dysgeusia in 23 (36.5%); alopecia in nine (14.2%); weight loss in seven (11.1%); and ageusia in (9.5%) patients. Serious AEs were observed in 11 (17%) patients with one episode of deep vein thrombosis and pulmonary embolism resulting in death.. Our study provides additional evidence of the efficacy and tolerability of vismodegib in patients with locally advanced or metastatic BCC in a real-world practice.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ageusia; Alopecia; Anilides; Antineoplastic Agents; Argentina; Carcinoma, Basal Cell; Dysgeusia; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Pyridines; Response Evaluation Criteria in Solid Tumors; Severity of Illness Index; Skin; Skin Neoplasms; Spasm; Venous Thrombosis; Weight Loss; Young Adult

Topics: Alopecia; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Creatine Kinase; Dysgeusia; Female; Hedgehog Proteins; Humans; Muscular Diseases; Ovarian Diseases; Pyridines; Skin Neoplasms; Weight Loss

Whereas vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management.. This prospective study included all patients who started vismodegib between October 2011 and May 2013 at Nantes University Hospital. Prior to July 2012, patients treated with vismodegib had not received any specific nutritional management (Historical cohort). Body weight and presence of dysgeusia were recorded monthly. Patients treated after July 2012 (Nutrition cohort) were evaluated by a physician of the Nutrition Support Unit and received dietary counseling at vismodegib initiation. A standardized nutritional management protocol was initiated in case of significant weight loss.. Forty-five patients (21 and 24 in the Nutrition and Historical cohort, respectively) were enrolled. In the Nutrition cohort, five patients (24 %) were undernourished at vismodegib initiation, and the 6-month cumulative incidence of dysgeusia was 71 %. Eight patients (38 %) and 13 patients (54 %) had a weight loss greater than 5 % in the Nutrition and Historical cohort, respectively (p = 0.3727).. The results of this pilot study suggest the benefit of early nutritional screening. The potential benefit of nutritional support in this setting warrants further investigation.

Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Cohort Studies; Dysgeusia; Female; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyridines; Skin Neoplasms; Weight Loss