James A. Solomon

Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma

BACKGROUND Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib.

BACKGROUND 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. OBJECTIVE We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. METHODS 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. RESULTS 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. LIMITATIONS Abbreviated follow-up time because of study termination upon FDA approval was a limitation. CONCLUSION 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.

Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC

BACKGROUND Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. OBJECTIVE An efficacy and safety analysis was conducted 12 months after primary analysis. METHODS This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. RESULTS After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. LIMITATIONS Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. CONCLUSION The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.

Safety and efficacy of therapies for skin symptoms of psoriasis in patients with psoriatic arthritis: a systematic review

Numerous guidelines and recommendations exist for the treatment of psoriasis in various populations. One important population is patients with psoriatic arthritis (PsA) who have symptoms of both joint and skin disease. In patients with both facets of psoriatic disease, skin and joints must be treated separately, but also simultaneously. As several systemic therapies are approved for either one or both, the concept of treating both facets with the same drug is feasible. This review summarizes evidence from studies in patients with PsA on the efficacy of these drugs on psoriatic skin disease in these patients.

Safety and efficacy of vismodegib in patients aged ≥65 years with advanced basal cell carcinoma

Because many patients with unresectable basal cell carcinoma (BCC) are aged ≥65 years, this study explores the efficacy and safety of vismodegib in these patients with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC) in the ERIVANCE BCC trial and the expanded access study (EAS).We compared patients aged ≥65 years to patients aged <65 years taking vismodegib 150 mg/day, using descriptive statistics for response and safety. Patients aged ≥65 years (laBCC/mBCC) were enrolled in ERIVANCE BCC (33/14) and EAS (27/26). Investigator-assessed best overall response rate in patients ≥65 and <65 years was 46.7%/35.7% and 72.7%/52.6% (laBCC/mBCC), respectively, in ERIVANCE BCC and 45.8%/33.3% and 46.9%/28.6%, respectively, in EAS. These differences were not clinically meaningful. Safety was similar in both groups, although those aged ≥65 years had a higher percentage of grade 3-5 adverse events than those aged <65 years. Vismodegib demonstrated similar clinical activity and adverse events regardless of age.

Comparing Demographic Characteristics and Adverse Event Rates at Two Dermatologic Surgery Practices

Background: Patient demographics and operative techniques may contribute to adverse events after surgeries. Objective: To identify differences in adverse event rates between different dermatologic surgery centers and potential contributing features affecting these rates. Methods: Data regarding demographics, procedure type, and adverse events were collected at two dermatologic surgery centers. Results: The most common adverse event at both sites was infection: 2.1% at site 1 versus 0.5% at site 2 (p < .001). Using multivariate logistic regression, procedure type (Mohs surgery), geographic location (being at site 1), older age, and anatomic location of surgery were associated with a higher risk of infection. Conclusion: Adverse event rate appears to correlate with patient demographics, procedure type, and setting of surgery more than use of prophylactic antibiotics. Identification of differences in adverse event rates and potential contributing variables at different practices may allow for identification of opportunities to prevent adverse events.

Ixekizumab treatment shows a neutral impact on cardiovascular parameters in patients with moderate-to-severe plaque psoriasis: Results from UNCOVER-1, UNCOVER-2, and UNCOVER-3

Background: The impact of ixekizumab treatment for psoriasis on cardiovascular‐related parameters in patients is unknown. Objective: To investigate cardiovascular‐related parameters in patients with psoriasis treated with ixekizumab. Methods: In phase 3 trials, patients with moderate‐to‐severe psoriasis were randomized and treated with placebo, ixekizumab, or etanercept during the induction period (weeks 0‐12; UNCOVER‐1, UNCOVER‐2, and UNCOVER‐3). At week 12, responders were rerandomized to receive placebo or ixekizumab through the maintenance period (weeks 12‐60; UNCOVER‐1 and UNCOVER‐2). Laboratory measures (fasting lipid profiles, glucose level, or high‐sensitivity C‐reactive protein [hsCRP] level), weight, blood pressure, and electrocardiograms were obtained through 60 weeks. Results: Baseline parameters were within normal ranges with the exception of elevated triglyceride and hsCRP levels. After maintenance dosing, no significant changes were observed versus placebo for total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, very‐low‐density lipoprotein cholesterol, triglyceride, apolipoprotein A1, apolipoprotein B, or fasting glucose levels or for systolic/diastolic blood pressure at 60 weeks. Importantly, low‐density lipoprotein–to–high‐density lipoprotein ratios remained stable during the induction and maintenance periods. HsCRP concentrations were significantly reduced versus placebo at 12 weeks and remained reduced at 60 weeks, although not significantly. Although transient changes were observed for some parameters during the induction period, these changes did not persist into the maintenance period. Limitations: A lack of echocardiogram evaluations. Conclusions: Ixekizumab had a neutral impact on cardiovascular‐related parameters in patients with psoriasis.

Gaps in the understanding and treatment of skin cancer in people of color

People of color are at significantly higher risk in mortality from skin cancers, such as melanoma, than Caucasians. Around 4,500,000 people of color are affected by skin cancer The five-year survival rates from melanoma are 81.1% for Hispanics, 80.2% for Asians, 72.2% for African- Americans, and 89.6% for Caucasians. For this reason, it is important to ensure the scientific literature reflects the most up to date recommendations and treatment for blacks regarding skin cancer. Therefore the authors conducted a “gap analysis” on the current treatment of skin cancer in people of color. Three major areas of deficiency were identified. The first major gap identified is the lack of a clear definition of people of color in the literature. The vast majority of current studies utilize the terms Hispanic, Asian, and African-American as if they were all-inclusive, homogenous groups. The second gap identified is the widespread false assumption among dermatologists that people of color do not participate in tanning activities or at risk for UV induced skin cancer. The third gap identified is the false belief among people of color that darker pigmentation confers a “total immunity” against skin cancer. Hopefully raising awareness for these issues will eventually lead to appropriate research and solutions from the medical community as well as the population at risk to lead to the closure of these gaps.

Prevalence of pediatric alopecia areata among 572,617 dermatology patients

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Patient Research Partners: Lessons Learned from OMERACT Applied to Dermatology:

Across medicine, vocal, educated patients are collaborating with researchers to generate clinical trial outcome measures that matter to the patient yet remain scientifically sound. Medical literature refers to these people as “patient research partners,” “patient experts,” “patient representatives,” or “patient stakeholders.” Spearheaded by the rheumatology-based Outcome Measures in Rheumatology group, the medical community has learned the value of allowing patients to be involved actively in outcome measure creation. This paper discusses the history, education, utilization, recruitment, and expanding role of patient experts in dermatology. This information was collected through literature searches and the meetings of outcome measure groups such as Harmonizing Outcome Measures for Eczema, Acne Core Research Network, and International Dermatology Outcome Measures. It was found that over the past several years, patient experts have been helping develop dermatology outcome measures through these groups, leading to major trial design changes.