gdc-0449 and Bone-Neoplasms

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

The use of 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) in subjects with advanced basal cell carcinoma (BCC) has not been fully explored due to the rarity of disease presentation. This study evaluated PET/CTs from subjects with advanced BCC participating in a phase I dose-escalation clinical trial of vismodegib. Fourteen subjects with BCC were imaged with 18-FDG PET/CT for lesion identification and response categorizing (European Organisation for Research and Treatment for Cancer [EORTC] and PET response criteria in solid tumors [PERCIST] 1.0). Several parameters including metabolic activity of target lesions, site of disease presentation and spread, treatment response, and prognostic significance of metabolic activity following therapy were evaluated. All subjects exhibited at least one hypermetabolic lesion. Most subjects had only four organ systems involved at study enrollment: skin-muscle (93%), lung (57%), lymph nodes (29%), and bone (21%). SUVmax measured across all lesions decreased (median 33%, SD ± 45%) following therapy with metabolic activity normalizing or disappearing in 42% of lesions. No significant difference was observed between EORTC and PERCIST 1.0. Subjects that demonstrated at least a 33% reduction in SUVmax from baseline had a significantly longer progression-free survival (PFS) (median 17 months, 95% confidence interval [CI] ±4 months vs. 9 months, 95% CI ±5 months, P = 0.038) and overall survival (OS) (median 24 months, 95% CI ±4 months vs. 17 months, 95% CI ±13 months, P = 0.019). BCC lesions are hypermetabolic on 18-FDG PET/CT. A decrease in SUVmax was associated with improved PFS and OS. These results further support the incorporation of 18-FDG PET/CT scans in advanced BCC management.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Basal Cell; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Multimodal Imaging; Muscle Neoplasms; Positron-Emission Tomography; Pyridines; Skin Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

Canine osteosarcoma (OSA), the most common canine primary bone malignancy, has a highly aggressive biologic behavior. Despite current standard of care therapies, including amputation and adjuvant chemotherapy, most dogs still succumb to metastatic disease. Further investigations into molecular mechanisms and pathways driving OSA are needed to improve therapeutic options. The Hedgehog (HH) cell-signaling pathway has demonstrated involvement in human OSA. Several studies in canine OSA have found changes in expression of some HH pathway genes and demonstrated a role for HH transcription factors. However, the role of this pathway as well as the translational value of its targeting in canine OSA are still undefined. The objectives of this study were to determine the expression of HH components directly in canine OSA tissues and to evaluate the biologic impact of HH signaling inhibition in canine OSA cells. In situ hybridization was used to detect HH family mRNA expression in archived canine OSA tissues and revealed variable expression levels of these mRNAs in canine OSA tissues. The effect of a commercially available Smoothened inhibitor, vismodegib, was studied in established canine OSA cell lines. Alterations in cellular growth as well as assessment of downstream HH targets were evaluated. Although changes in cell growth were noted following Smoothened inhibition, inconsistent decreases in target gene expression were found. While treatment with vismodegib had a negative impact on canine OSA cell growth and viability, the mechanism remains unclear. Further studies are warranted to evaluate the clinical significance of canonical HH signaling in canine OSA.

Topics: Anilides; Animals; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dogs; Gene Expression Profiling; Hedgehog Proteins; Osteosarcoma; Pyridines; RNA, Messenger; Signal Transduction; Smoothened Receptor

Vismodegib (GDC-0449, Genentech, USA), a small molecule inhibitor of the Hedgehog signalling pathway, has potent anti-tumour activity in advanced basal cell carcinoma (BCC). We report a case of a 67-year-old Australian man with metastatic BCC including pulmonary disease with malignant effusion who showed a dramatic complete response to vismodegib but subsequently experienced a recurrence of pulmonary disease, indicative of chemoresistance to vismodegib. This case is the first to illustrate chemoresistance in a patient with metastatic BCC, and demonstrates the need for closely monitoring metastatic BCC patients even after an apparently complete response.

Topics: Aged; Anilides; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Pyridines; Ribs; Signal Transduction; Skin Neoplasms

Topics: Adult; Anilides; Antineoplastic Agents; Bone Neoplasms; Cerebellar Neoplasms; Humans; Male; Medulloblastoma; Pyridines; Radionuclide Imaging; Remission Induction; Time Factors; Treatment Outcome