gdc-0449 and Dysgeusia

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

Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between sonidegib and vismodegib is their respective pharmacokinetic profiles with sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of sonidegib and vismodegib based on published literature to date. J Drugs Dermatol. 2021;20(2):156-165. doi:10.36849/JDD.5657\ \ THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Topics: Alopecia; Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials, Phase II as Topic; Dysgeusia; Hedgehog Proteins; Humans; Multicenter Studies as Topic; Progression-Free Survival; Pyridines; Randomized Controlled Trials as Topic; Signal Transduction; Skin Neoplasms; Spasm

Sonic hedgehog inhibitors (SHHis) provide an additional treatment option for basal cell carcinomas (BCCs), especially for metastatic or locally advanced BCC. However, studies have been heterogeneous and lacked direct comparisons between molecules.. To determine the efficacy and safety of the class of molecules SHHi for treating BCC and to compare them individually.. We performed a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review of studies followed by a meta-analysis.. Eighteen articles were included in our meta-analysis; 16 articles were combined for efficacy and 16 for safety. In locally advanced BCC, overall response rates (ORRs) were similar for vismodegib and sonidegib (69% vs 57%, respectively) but not complete response rates (31% vs 3%, respectively). In metastatic disease, the ORR of vismodegib was 2.7-fold higher than the ORR of sonidegib (39% vs 15%, respectively). For side effects affecting a majority of patients, prevalences for muscle spasms (67.1%), dysgeusia (54.1%), and alopecia (57.7%) were in similar proportions for sonidegib and vismodegib. Patients receiving sonidegib experienced more upper gastrointestinal distress than patients receiving vismodegib.. SHHis induce a partial response to locally advanced BCC disease. Side effects are common, similar across molecules, associated with high discontinuation rates, and warrant discussion beforehand.

Topics: Alopecia; Anilides; Antineoplastic Agents; Biphenyl Compounds; Carcinoma, Basal Cell; Clinical Trials as Topic; Dysgeusia; Gastrointestinal Diseases; Hedgehog Proteins; Humans; Muscular Diseases; Neoplasm Proteins; Prospective Studies; Pyridines; Skin Neoplasms

Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the development of targeted anti SMO drugs inactivating the pathway. Two molecules have become available following Phase I and II studies: vismodegib (Erivedge®) the first in class indicated for locally advanced and metastatic BCC and sonidegib (Odomzo®) indicated only for locally advanced BCC. The pharmacokinetic profiles of sonidegib and vismodegib showed several differences. No head to head comparative studies are available between these two drugs. Their pivotal phase II studies had similar study designs and endpoints. The objective response rate (ORR) by central review for vismodegib was 47.6% (95% CI 35.5-60.6) at 21 months follow-up. The ORR for sonidegib according to central review at 18 months follow-up is 56.1% (95% CI 43.3-68.3). Although both treatments share a similar adverse event profile with possible numerically differences in incidence, most patients will discontinue hedgehog inhibitors treatment in the long term because of side effects. Some resistant cases to these drugs have been described but are rather rare. In case of resistance or bad tolerability to the drug future hopes rely on immunotherapy currently under investigation. © 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Prise en charge des carcinomes basocellulaires difficiles à traiter réalisé avec le soutien institutionnel de Sun Pharma.

Topics: Alopecia; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Basal Cell Nevus Syndrome; Biphenyl Compounds; Carcinoma, Basal Cell; Cisplatin; Clinical Trials as Topic; Drug Resistance, Neoplasm; Dysgeusia; Fluorouracil; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Multicenter Studies as Topic; Muscle Cramp; Mutation; Neoplasm Proteins; Patched-1 Receptor; Patched-2 Receptor; Pyridines; Signal Transduction; Skin Neoplasms; Smoothened Receptor

Vismodegib is a novel hedgehog pathway inhibitor approved to treat advanced and metastatic basal cell carcinoma (BCC) in the United States. Several studies have demonstrated efficacy for treatment of new and existing BCC in both basal cell nevus syndrome (BCNS) and non-BCNS patients. However, severe and numerous adverse events are associated with vismodegib use. Therefore, we have also examined all of the currently published clinical trials and tabulated the available adverse events for review. The most frequently reported adverse events include muscle spasms (53.4%), dysgeusia/ageusia (49.3%), alopecia (38.8%), fatigue (32.0%), nausea (28.4%), weight loss (24.2%), and decreased appetite (16.5%).. We report a case of a previously healthy 72-year-old male with a history of innumerable BCCs who developed severe nausea, jaundice, and cholestasis with significantly elevated BUN, creatinine, and liver enzymes one month after starting vismodegib. The patient began using over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) to treat severe, vismodegib-induced myalgia. No other new medications were started. Our patient had no history of liver disease.. Herein, we describe a potential serious adverse effect associated with vismodegib use. Whether the illness is directly attributable to the medication or the result of drug-drug interactions between vismodegib and NSAIDs, practitioners should be aware of the possibility of hepatic injury in patients on vismodegib. Furthermore, patients need to be informed of the potential risks of vismodegib and should be monitored closely to ensure that life-threatening complications of treatment are avoided.

Topics: Aged; Anilides; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Carcinoma, Basal Cell; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Interactions; Dysgeusia; Humans; Male; Myalgia; Naproxen; Pyridines; Skin Neoplasms

Vismodegib demonstrated 60% response rates in the ERIVANCE trial. Basal cell carcinoma has various histopathologies. Their effect on response is unclear.. The purpose of this study was to determine whether basal cell carcinoma histopathology affected vismodegib response.. This phase 2b, single-center, prospective case series study compared the efficacy of vismodegib in infiltrative, nodular, and superficial basal cell carcinomas treated for 12 or 24 weeks in 27 patients. Patients had 1 target lesion and up to 3 nontarget lesions.. Twenty-seven patients were enrolled, with 65 tumors (27 target lesions/38 nontarget lesions). At 24 weeks, most basal cell carcinomas achieved histologic clearance, with positive biopsy results in 10.5% of target lesions, 30.4% of nontarget lesions, and 21.4% overall. No statistical differences were observed between histopathologic subtypes. One hundred percent of patients experienced an adverse event, 94% grade 1 or 2. The most common adverse events were dysgeusia/loss of taste (86%), muscle spasms (82%), and alopecia (71%). Clinically progressive disease during treatment was low (1.5%). Two patients had recurrence within 1 year of treatment.. Limitations included sample size of basal cell carcinoma histopathologic subtypes, sampling punch biopsies, and short follow-up.. Basal cell histopathologic subtype did not significantly affect response to vismodegib. Each subtype was observed to completely respond at 12 weeks of therapy, 24 weeks, or both.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Alopecia; Anilides; Antineoplastic Agents; Biopsy; Carcinoma, Basal Cell; Drug Administration Schedule; Dysgeusia; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Pyridines; Skin; Skin Neoplasms; Spasm; Treatment Outcome

Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib.. We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options.. This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0.. A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events.. Abbreviated follow-up time because of study termination upon FDA approval was a limitation.. This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.

Topics: Adult; Aged; Aged, 80 and over; Alopecia; Anilides; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Basal Cell; Diarrhea; Disease Progression; Dysgeusia; Female; Humans; Male; Middle Aged; Pyridines; Skin Neoplasms; Spasm; Treatment Outcome; Young Adult

Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis.. We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant vismodegib.. This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability.. Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4±2 months of vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, vismodegib reduced the surgical defect area by 27% (95% confidence interval -45.7% to -7.9%; P=.006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery.. Short follow-up time and no placebo control are limitations.. Neoadjuvant vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.

Topics: Adult; Aged; Aged, 80 and over; Alopecia; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Chemotherapy, Adjuvant; Dysgeusia; Female; Humans; Male; Middle Aged; Mohs Surgery; Muscle Cramp; Neoadjuvant Therapy; Pyridines; Skin Neoplasms; Tumor Burden

Topics: Aged; Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Dysgeusia; Female; Humans; Male; Middle Aged; Muscle Cramp; Nausea; Pyridines; Skin Neoplasms

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