Jeannie Hou

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).

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.

Metastatic basal cell carcinoma: Prognosis dependent on anatomic site and spread of disease

PURPOSE This review provides a description of the epidemiology and survival outcomes for cases with metastatic basal cell carcinoma (mBCC) based on published reports (1981-2011). METHODS A literature search (MEDLINE via PubMed) was conducted for mBCC case reports published in English: 1981-2011. There were 172 cases that met the following criteria: primary BCC located on skin, metastasis confirmed by pathology and metastasis not resulting from direct tumour spread. From these, 100 mBCC cases with explicit information on follow-up time were selected for analysis. Survival analysis was conducted using Kaplan-Meier methods. RESULTS Among 100 mBCC cases selected for analysis, including one case with Gorlin syndrome, 50% had regional metastases (RM) and 50% had distant metastases (DM). Cases with DM were younger at mBCC diagnosis (mean age, 58.0 versus 66.3 years for RM; P=0.0013). Among 93 (of 100) cases with treatment information for metastatic disease, more DM cases received chemotherapy (36.2% versus 6.5% for RM), but more RM cases underwent surgery (87.0% versus 40.4% for DM). Among all 100 cases, median survival after mBCC diagnosis was 54 months (95% confidence interval (CI), 24-72), with shorter survival in DM (24 months; 95% CI, 12-35) versus RM cases (87 months; 95% CI, 63-not evaluable). CONCLUSION Cases with RM and DM mBCC may have different clinical courses and outcomes. Based on published reports, DM cases were younger at mBCC diagnosis, with shorter median survival than RM cases. This study provides a historical context for emerging mBCC treatments.

A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma.

BACKGROUND Vismodegib is approved for treatment of advanced basal cell carcinoma. OBJECTIVE We sought to characterize vismodegib efficacy and safety in operable basal cell carcinoma. METHODS Patients with new, operable, nodular basal cell carcinoma received vismodegib (150 mg/d) followed by excision and Mohs micrographic surgery to ensure clear margins. Cohort 1 received vismodegib for 12 weeks; cohort 2 received vismodegib for 12 weeks, then 24 weeks of observation before excision; and cohort 3 received vismodegib for 8 weeks on/4 weeks off/8 weeks on. RESULTS In all, 24 patients enrolled in cohort 1, and 25 in cohorts 2 and 3. Complete histologic clearance was achieved by 42%, 16%, and 44% of patients in cohorts 1, 2, and 3, respectively. Muscle spasms (76%), alopecia (58%), and dysgeusia (50%) were the most frequent adverse events (AEs). Five (7%) patients discontinued treatment because of an AE. AE reversibility was evaluated in cohort 2 with 24 weeks of observation after treatment discontinuation. LIMITATIONS Nonrandomized, small cohort sizes, and short observation durations for some patients are limitations. CONCLUSION Primary efficacy end points were not met (predefined complete histologic clearance rate: >50% in cohorts 1 and 3; >30% in cohort 2). Safety was comparable when dosed continuously versus intermittently. Posttreatment reversibility of vismodegib-related AEs was demonstrated.

Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib

Background: Vismodegib is a first‐in‐class agent targeting the hedgehog signaling pathway for treatment of patients with locally advanced basal cell carcinoma (BCC) and metastatic BCC. There have been concerns about the development of squamous cell carcinoma (SCC) in patients treated with this drug. Objective: We sought to determine whether treatment with vismodegib is associated with an increase in the risk of cutaneous SCC. Methods: In this retrospective cohort study, patients treated with vismodegib as part of phase I and II clinical studies were compared with participants from the University of California, San Francisco, Nonmelanoma Skin Cancer Cohort who received standard therapy for primary BCC. In total, 1675 patients were included in the analysis, and the development of SCC after vismodegib exposure was assessed. Results: The use of vismodegib was not associated with an increased risk of subsequent development of SCC (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28‐1.16). Covariates including age, sex, history of previous nonmelanoma skin cancer, and number of visits per year were significantly associated with the development of SCC. Limitations: A limitation of the study was that a historic control cohort was used as a comparator. Conclusions: Vismodegib was not associated with an increased risk of subsequent SCC when compared with standard surgical treatment of BCC.

The incidence of metastatic basal cell carcinoma (mBCC) in Denmark, 1997–2010

BackgroundFew data exist on the occurrence of metastatic basal cell carcinoma (mBCC).ObjectiveTo identify all cases of mBCC in Denmark over a 14-year period.MethodsWe searched the Danish National Patient Registry covering all Danish hospitals, the Danish Cancer Registry, the National Pathology Registry and the Causes of Death Registry during the period 1997 to 2010 for potential cases of mBCC registered according to the International classification of diseases ICD-10 and the International Systemized Nomenclature of Medicine (SNOMED).ResultsWe identified 126,627 patients with a history of primary basal cell carcinoma (BCC) in the registries during the 14-year study period. Using case identifications from the four registries, a total of 170 potential mBCC cases were identified. However, after a pathology review, only five cases could be confirmed, of which three were basosquamous carcinomas. The 14-year cumulative incidence proportion of mBCC was 0.0039% (95% CI 0.0016–0.0083) among individuals with a history of previousBCC(n = 126,627) and 0.0001% (95% CI 0.0000–0.0002) in the general population.ConclusionMBCCis a rare disease and only a small proportion of potential cases identified in automated clinical databases or registries can be confirmed by pathology and medical record review.

The incidence of metastatic basal cell carcinoma (mBCC) in Denmark, 1997-2010 Incidence of metastatic BCC

BackgroundFew data exist on the occurrence of metastatic basal cell carcinoma (mBCC).ObjectiveTo identify all cases of mBCC in Denmark over a 14-year period.MethodsWe searched the Danish National Patient Registry covering all Danish hospitals, the Danish Cancer Registry, the National Pathology Registry and the Causes of Death Registry during the period 1997 to 2010 for potential cases of mBCC registered according to the International classification of diseases ICD-10 and the International Systemized Nomenclature of Medicine (SNOMED).ResultsWe identified 126,627 patients with a history of primary basal cell carcinoma (BCC) in the registries during the 14-year study period. Using case identifications from the four registries, a total of 170 potential mBCC cases were identified. However, after a pathology review, only five cases could be confirmed, of which three were basosquamous carcinomas. The 14-year cumulative incidence proportion of mBCC was 0.0039% (95% CI 0.0016–0.0083) among individuals with a history of previousBCC(n = 126,627) and 0.0001% (95% CI 0.0000–0.0002) in the general population.ConclusionMBCCis a rare disease and only a small proportion of potential cases identified in automated clinical databases or registries can be confirmed by pathology and medical record review.