Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis.

BACKGROUND: The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily. METHODS: This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. RESULTS: Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). CONCLUSIONS: Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. TRIAL REGISTRATION: BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Response assessment and outcome of combining immunotherapy and radiosurgery for brain metastasis from malignant melanoma.

BACKGROUND: The optimal sequence of stereotactic radiotherapy (SRT) and immune checkpoint inhibition (ICI) and assessment of response in patients with brain metastases from melanoma remain challenging. METHODS: We reviewed clinical and neuroimaging data of 62 patients with melanoma, including 26 patients with BRAF-mutant tumours, with newly diagnosed brain metastases treated with ICI alone (n=10, group 1), SRT alone or in combination with other systemic therapies (n=20, group 2) or ICI plus SRT (n=32, group 3). Response was assessed retrospectively using response evaluation criteria in solid tumours (RECIST) V.1.1, response assessment in neuro-oncology (RANO) and immunotherapy RANO (iRANO) criteria. MRI follow-up from 43 patients was available for central review. RESULTS: Patients treated with ICI alone showed no objective responses and had worse outcome than patients treated with SRT without or with ICI. RECIST, RANO and iRANO criteria were concordant for complete response (CR) and partial response (PR). RANO called progression earlier than RECIST for clinical deterioration without MRI progression in some patients. Progression was called later when using iRANO criteria because of the need for a confirmatory scan. Pseudoprogression was documented in seven patients: three patients in group 2 and four patients in group 3. Radionecrosis was documented in seven patients: two patients in group 2 and five patients in group 3. Regression of non-irradiated lesions was seen neither in two patients treated with SRT alone nor in five patients treated with SRT plus ICI, providing no evidence for rare abscopal effects. CONCLUSIONS: Pseudoprogression is uncommon with ICI alone, suggesting that growing lesions in such patients should trigger an intervention. Pseudoprogression rates were similar after SRT alone or SRT in combination with ICI. Abscopal effects are rare or do not exist. Response assessment criteria should be considered carefully when designing clinical studies for patients with brain metastases who receive SRT.

Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma.

Sinonasal melanoma is a rare subtype of melanoma and little is known about its molecular fingerprint. Systemic treatment options are limited, as targetable BRAF mutations are rare compared to cutaneous melanoma. Currently, metastatic sinonasal melanoma is being treated according to the guidelines of cutaneous melanoma. In this study, we investigated the molecular profile of 19 primary sinonasal melanomas, using a novel customized melanoma-specific next generation sequencing (NGS) panel (MelArray) of 190 genes. Results were correlated to histological and clinical features to further characterize this rare, aggressive type of melanoma and screen for prognostic markers and possible treatment options. Molecular profiles encompassed predominantly mutations in NRAS (25%), whereas KIT or BRAF p.V600 mutations were not detected. Tumor mutational burden was overall low. High level of copy number variations (CNVs) were associated with alterations in DNA-repair genes and shorter distant metastasis-free survival (p = 0.005). Monomorphic (vs. pleomorphic) morphology was found to be significantly associated with worse disease-specific survival (p < 0.001), however no correlation between morphology and molecular aberrations was found. A variety of alterations in different pathways were detected, justifying molecular testing and opening potential personalized treatment options in current study or compassionate use settings.

Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management.

BACKGROUND: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. PATIENTS AND METHODS: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. RESULTS: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. CONCLUSION: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study.

Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.

BACKGROUND: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. METHODS AND FINDINGS: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patients delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. CONCLUSION: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Chemotherapy response assessment in stage IV melanoma patients-comparison of 18F-FDG-PET/CT, CT, brain MRI, and tumormarker S-100B.

PURPOSE: This study aims to compare the use of 18F-FDG-PET/CT, CT, brain MRI, and tumormarker S-100B in chemotherapy response assessment of stage IV melanoma patients. METHODS: In 25 patients with stage IV melanoma, FDG-PET/CT and S-100B after 2-3 months (three cycles) of chemotherapy was compared with baseline PET/CT and baseline S-100B. Retrospectively, the response was correlated with the outcome. In patients with clinical suspicion for brain metastases, MRI or CCT was performed. RESULTS: There was agreement between FDG-PET/CT and CT regarding response to chemotherapy in all patients. There was a clear trend to a longer OS of PET/CT responders (n=10) compared with PET/CT non-responders (n=15; p=0.072) with remarkably better 1-year OS of 80% compared to 40% (p=0.048). There was a significant longer PFS of PET/CT responders compared with PET/CT non-responders (p=0.002). S-100B was normal at baseline in eight of 22 patients where it was available. Chemotherapy response assessment with S-100B failed to show correlation with OS or PFS. Eleven patients developed brain metastases during treatment, first detected by PET/CT in two and by MRI or CCT in nine of 11 patients. Appearance of brain metastases was associated with a poor survival. CONCLUSIONS: 18F-FDG-PET/CT and CT alone are equally suitable for chemotherapy response assessment in melanoma patients and clearly superior to S-100B. PET/CT responders have better early survival, but this is shortlived due to late therapy failure--often with brain recurrence. Additional brain MRI for therapy response assessment in such high-risk patients is mandatory to detect brain metastases missed by PET/CT.

S-100B and FDG-PET/CT in therapy response assessment of melanoma patients.

OBJECTIVE: To compare the value of the tumor marker S-100B protein and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients treated for melanoma metastases. METHODS: In 41 patients with proven melanoma metastases, S-100B measurements and FDG-PET/CT were performed before and after therapy. The change of S-100B levels (DeltaS-100B) was assessed. In all patients, therapy response was assessed with PET/CT using visual criteria and change of maximal standard uptake value (DeltaSUV(max.)) or total lesion glycolysis (DeltaTLG). RESULTS: In 15 of 41 patients (37%), S-100B values were not suitable because they were normal before and after therapy. In 26 patients, S-100B was suitable for therapy response assessment. PET/CT was suitable for response assessment in all patients. Correlations between DeltaS-100B and DeltaTLG (r = 0.850, p < 0.001) and between DeltaS-100B and DeltaSUV(max.) (r = 0.818, p < 0.001) were both excellent. A complete agreement between S-100B and PET/CT response assessment was achieved in 22 of 26 patients. In 4 patients, therapy response differed between the S-100B and PET/CT findings, but subsequent S-100B measurements realigned the S-100B results with the later PET/CT findings. CONCLUSION: In a third of our patients with metastases, the S-100B tumor marker was not suitable for therapy assessment. In these patients, imaging techniques remain necessary, and FDG-PET/CT can be used for response assessment.

Tumour assessment in advanced melanoma: value of FDG-PET/CT in patients with elevated serum S-100B.

PURPOSE: To evaluate the usefulness of PET/CT in melanoma patients with an elevated serum S-100B tumour marker level. METHODS: Out of 165 consecutive high-risk melanoma patients referred for PET/CT imaging, 47 had elevated (>0.2 microg/l) S-100B serum levels and a contemporaneous 18F-FDG PET/CT scan. PET/CT scans were evaluated for the presence of metastases. To produce a composite reference standard, we used cytological, histological, MRI and PET/CT follow-up findings as well as clinical and S-100B follow-up. RESULTS: Among the 47 patients with increased S-100B levels, PET/CT correctly identified metastases in 38 (30 distant metastases and eight lymph node metastases). In one patient with cervical lymph node metastases, PET/CT was negative. Eight patients had no metastases and PET/CT correctly excluded metastases in all of them. Overall sensitivity for metastases was 97% (38/39), specificity 100% (8/8) and accuracy 98% (46/47). S-100B was significantly higher in patients with distant metastases (mean 1.93 microg/l, range 0.3-14.3 microg/l) than in patients with lymph node metastases (mean 0.49 microg/l, range 0.3-1.6 microg/l, p=0.003) or patients without metastases (mean 0.625 microg/l, range 0.3-2.6 microg/l, p=0.007). However, 6 of 14 patients with a tumour marker level of 0.3 microg/l had no metastases. CONCLUSION: In melanoma patients with elevated S-100B tumour marker levels, FDG-PET/CT accurately identifies lymph node or distant metastases and reliably excludes metastases. Because of the significant number of false positive S-100B tumour marker determinations (17%), we recommend repetition of tumour marker measurements if elevated S-100B levels occur before extensive imaging is used.

Weight of decision-making impairs clinical assessment of melanocytic lesions.

BACKGROUND AND OBJECTIVE: We studied the weight of decision-making on clinical assessment of melanocytic lesions judging benign, atypical, and malignant lesions; common mistakes; and total removal rates, comparing dermatologists with nondermatologists. METHODS: Of 11,246 histopathology specimens, 3,768 had a clinical assessment of melanocytic lesions. Histopathologic diagnosis served as the gold standard. RESULTS: Benign nevi were assessed most accurately (77%). Dermatologists assessed benign nevi better (p < .0001). The accuracy of clinical assessment in atypical nevi and melanoma was lower (23% and 42%, respectively). Seborrheic keratosis was the most common mistaken diagnosis. Complete removal of clinically benign nevi, atypical nevi, and melanoma was 84%, 90%, and 89%. Decision-making impaired clinical assessement of melanocytic lesions by 5% for dermatologists and 9% for nondermatologists. CONCLUSION: The accuracy of clinical assessment of melanocytic lesions is high for benign nevi, with dermatologists outperforming nondermatologists. Clinicians overestimated malignant potential. Complete removal was more frequent in suspicious lesions. Clinical decision-making impaired assessment by 5 to 9%.

Emerging drugs in cutaneous T-cell lymphomas.

Cutaneous T-cell lymphomas are a heterogeneous group of rare lympho-proliferative disorders. In most cases, they are characterised by the accumulation of clonal CD4+ lymphocytes in the skin. Extracutaneous involvement is present in late stages only. Unfortunately, only few drugs are registered for these disfiguring diseases. Skin-directed therapies using topical formulations are the preferred first-line modalities for cutaneous lesions in early stages. In this field there are interesting developments using topical retinoids and gene therapy products, such as adeno-IFN-gamma. Systemic treatment uses biologicals, such as fusion molecules, monoclonal antibodies and immune response modifiers (IFNs, retinoids), and well-tolerated antiproliferative drugs, such as histone deacetylase inhibitors or liposomal doxorubicin.