Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée).

BACKGROUND: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. MATERIALS AND METHODS: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). RESULTS: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. CONCLUSION: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.

Radiotherapy and prognostic factors in adnexal carcinomas: A retrospective study of 657 patients from the French CARADERM network.

BACKGROUND: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms. OBJECTIVES: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database. METHODS: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models. RESULTS: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS. CONCLUSIONS: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision.

Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases.

AIMS: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. METHODS AND RESULTS: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. CONCLUSION: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

BACKGROUND: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. PATIENTS AND METHODS: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. RESULTS: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). CONCLUSION: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Digital Papillary Adenocarcinoma in Nonacral Skin: Clinicopathologic and Genetic Characterization of 5 Cases.

Digital papillary adenocarcinoma (DPA) is a rare sweat gland neoplasm that has exceptionally been reported outside acral locations. Recently, human papillomavirus 42 was identified as the main oncogenic driver of DPA. Herein, we report 5 tumors arising in extra-acral locations predominantly in the female anogenital skin. Four patients were female and 1 patient was male. The mean age at the diagnosis time was 65 years (range: 55 to 82 y). Tumors were located on the vulva (n=3), perianal area (n=1), and forearm (n=1). Histologically, all tumors were lobular and mainly solid and composed of sheets of cells with rare focal papillae and frequent glandular structures in a "back-to-back" pattern and lined by atypical basophilic cells. Immunohistochemistry showed diffuse positivity for SOX10. Epithelial membrane antigen and carcinoembryonic antigen highlighted the luminal cells and staining for p63 and p40 revealed a consistent and continuous myoepithelial component around glandular structures. Follow-up was available in 3 cases (mean duration: 12 mo [range: 8 to 16 mo]). One patient developed local recurrence and 1 experienced regional lymph node metastases. HPV Capture Next-generation sequencing revealed the presence of the HPV42 genome in all samples. Viral reads distributions were compatible in the 5 cases with an episomal nature of the viral genome, with a recurrent deletion in the E1 and/or E2 open reading frames. In conclusion, this study demonstrates that digital DPA may rarely present in nonacral locations mainly in the female anogenital area, usually with a more solid pattern as compared with those cases presenting on the digits and it is also associated with HPV42.

Sweat Gland Tumors Arising on Acral Sites: A Molecular Survey.

Recurrent oncogenic drivers have been identified in a variety of sweat gland tumors. Recently, integration of human papillomavirus type 42 (HPV42) has been reported in digital papillary adenocarcinoma (DPA). The main objectives of the present study were (i) to provide an overview of the prevalence of previously identified oncogenic drivers in acral sweat gland tumors and (ii) to genetically characterize tumors in which no recurrent genetic alteration has been identified yet. Cases of acral sweat gland tumors were identified from the database of the French network CARADERM. After histologic review, the presence of previously identified genetic alterations was investigated in the entire cohort (n=79) using a combination of immunohistochemistry and targeted DNA and RNA sequencing. Tumor entities with no recurrent genetic alterations were submitted to whole-transcriptome sequencing. CRTC1::MAML2 fusion was identified in cases of hidradenoma and hidradenocarcinoma (n=9/12 and n=9/12). A p.V600E mutation of BRAF was observed in all cases of tubular adenoma (n=4). YAP1:MAML2 and YAP1::NUTM1 fusions were observed in poroid tumors (n=15/25). ETV6::NTRK3 and TRPS1::PLAG1 fusion transcripts were identified in secretory carcinoma (n=1/1) and cutaneous mixed tumors (n=3/4), respectively. The HPV42 genome was detected in most cases of DPA (n=10/11) and in 1 adnexal adenocarcinoma not otherwise specified. Finally, whole-transcriptome analysis revealed BRD3::NUTM1 or NSD3::NUTM1 fusions in 2 cases of NUT adnexal carcinoma and NCOA4::RET and CCDC6::RET fusion transcripts in 2 cystadenoma/hidrocystoma-like tumors. Our study confirms distinctive cytogenetic abnormalities in a wide number of acral adnexal neoplasms and supports the use of molecular analysis as a valuable aid in the diagnosis of these rare and often difficult to diagnose group of neoplasms.

Severity of Local Skin Reactions with 4% 5-Fluorouracil Plus Emollient versus 4% 5-Fluorouracil Alone in Patients with Actinic Keratosis: A Single-Blind Randomised Trial.

INTRODUCTION: Topical 5-fluorouracil (5-FU)-containing treatments are effective for actinic keratosis (AK); however, they frequently lead to transient local skin reactions (LSRs), which often result in treatment non-adherence. METHODS: The aim of this international, phase IV clinical trial was to investigate whether addition of an emollient to topical 4% 5-FU would reduce the frequency and severity of LSRs over 4 weeks of treatment (intervention group) compared with 4% 5-FU alone (control group) in patients with AK. The primary objective was to assess the severity of LSRs (i.e. erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) at week 4 of treatment (or before, in case of a major local reaction). Key secondary objectives were LSR total scores at weeks 2 and 8, the scores of individual LSR items at each visit, and the proportions of patients with 100% and ≥ 75% AK lesion clearance at week 8. RESULTS: In total, 141 patients were included in the efficacy analysis (71 in the intervention group and 70 in the control group). There were no statistically or clinically significant differences between the treatment groups in terms of LSR total score at week 4 (overall and by subgroups defined by the number of lesions and patient age at baseline), scores of individual LSR items at any time point, and AK lesion clearance rates at week 8. LSR scores with topical 4% 5-FU alone were lower than expected. Skin reactions were the most common treatment-emergent adverse events in both groups, leading to treatment discontinuation in nine patients (12.3%) in the intervention group and seven (9.9%) in the control group. No new safety signals were observed with the addition of an emollient to 4% 5-FU. CONCLUSIONS: Daily emollient applications during the 4-week treatment course did not impact the safety and efficacy profile of 4% 5-FU.

Safety and efficacy of nivolumab, an anti-PD1 immunotherapy, in patients with advanced basal cell carcinoma, after failure or intolerance to sonic Hedgehog inhibitors: UNICANCER AcSé NIVOLUMAB trial.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived. METHODS: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%). RESULTS: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction). CONCLUSION: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC.

Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma.

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

Impact of expert pathology review in skin adnexal carcinoma diagnosis: Analysis of 2573 patients from the French CARADERM network.

PURPOSE: To prospectively assess the impact of expert pathological review of skin adnexal carcinoma diagnosis in France. METHODS: From 2014 to 2019, 2573 samples from patients with newly diagnosed or suspected skin adnexal carcinomas were reviewed prospectively by expert pathologists through the national CARADERM (CAncers RAres DERMatologiques) network. Changes in diagnosis between referral and expert review were analysed regarding their potential impact on patient care or prognosis. RESULTS: The samples comprised 2205 newly diagnosed adnexal carcinomas, 129 benign adnexal tumours, 136 basal cell carcinomas, 74 squamous cell carcinomas, six cutaneous metastases and 13 other malignancies. There were 930 (42%) sweat gland carcinomas, of which porocarcinoma (261; 11.8%), microcystic adnexal carcinoma (125; 5.7%) and hidradenocarcinoma (109; 4.9%) were the most frequent subtypes; 778 (35%) hair follicle carcinomas, 238 (11%) sebaceous carcinomas and 212 (10%) extramammary Paget diseases/mammary-like anogenital gland adenocarcinomas. A diagnostic change between referral and expert review occurred in 503 (21.3%) patients, significantly higher for cases sent with a provisional diagnosis seeking an expert second opinion (45.7%) than for cases sent with a formal diagnosis (2.8%) (p < .0001). Sweat gland carcinomas were more prone to diagnostic discrepancies than other tumours (p < .0001), including 1.8% of patients with sweat gland carcinoma subtype misclassification with predicted clinical impact. Changes between benign and malignant conditions occurred in 117 samples (5% of patients). CONCLUSION: The study provides a unique description of the distribution of skin adnexal carcinomas and highlights the importance of expert review for these rare cancers. Optimal clinical management was impacted in a significant proportion of patients.

Effectiveness and safety of nivolumab in patients with advanced melanoma: A multicenter, observational study.

This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

A Multicenter Phase II Study of Pazopanib in Patients with Unresectable Dermatofibrosarcoma Protuberans.

Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01059656.

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer.

BACKGROUND: Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown. AIM: To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management. METHODS: Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up. RESULTS: Overall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low. CONCLUSION: The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient's quality of life appeared to be limited.

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 µg MAGE-A3 antigen plus 420 µg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network.

Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma.

Treatment patterns and outcomes for patients with locally advanced basal cell carcinoma before availability of Hedgehog pathway inhibitors: a retrospective chart review.

Understanding the molecular basis of basal cell carcinoma (BCC) has led to development of Hedgehog pathway inhibitors (HPIs) for patients with advanced forms of BCC (aBCC). A practical definition of aBCC as a distinct disease entity is unavailable, and epidemiological information is limited. To conduct the RONNIE study to describe characteristics, treatment patterns, and outcomes of patients with aBCC during the period preceding HPI introduction, as well as results from patients with locally advanced BCC (laBCC). A retrospective chart review was conducted using data from adult patients with a new diagnosis of laBCC between 1st January 2005 and 31st December 2010. The study period was 1st January 2005 to 31st December 2011 to allow for inclusion of at least 12 months of follow-up information for all patients. RESULTS: Treatment data were available for 106/117 patients. Radiation and excisional surgery were the most common first-line treatment options (43.4% and 23.5% of patients, respectively). Patients typically received multiple subsequent treatments; no apparent trend or pattern was observed. Complete visual response, partial visual response, and stable disease were obtained in 51.9%, 25.9%, and 11.1% of patients, respectively, after first-line surgery, and in 53.7%, 22.0%, and 9.8%, respectively, after first-line radiation. Median progression-free survival after first-line treatment was 32.1 months. Median overall survival was 78.8 months. These data represent a baseline for laBCC before HPIs became part of the treatment algorithm. The observed heterogeneity of treatment patterns highlights the lack of an established standard treatment for laBCC before HPIs were available.

Pattern and Severity of Psoriasiform Eruptions in Patients with Inflammatory Bowel Diseases, Arthritis or Skin Inflammatory Disorders Treated with TNF-alpha Inhibitors.

Psoriasiform eruptions are a classical adverse skin reaction of tumour necrosis factor (TNF)-α inhibitors. The aim of this study was to identify the association between the severity or pattern of psoriasiform reactions and the underlying disease. A retrospective study was conducted between January 2012 and May 2015. Adult patients who developed psoriasiform eruptions whilst being treated with TNFα inhibitors were included. For each patient, 3 independent blinded dermatologists graded twice the severity of the lesions according to 6 clinical psoriasiform eruption types. Inter- and intra-individual kappa tests were performed to evaluate the robustness of the scoring system. The association between severity score levels or the pattern of reactions and the underlying disease was assessed. The severity scoring system showed good inter- and intra-observer reproducibility. Women patients treated with TNFα inhibitors for inflammatory bowel diseases showed a higher risk of developing severe reactions with scalp and skin-fold involvement.