Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients.

BACKGROUND: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744€ to 26,248€ in France). CONCLUSIONS: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.

Deep cutaneous mycoses in kidney transplant recipients: Diagnostic and therapeutic challenges.

Deep cutaneous mycoses (DCMs) are rare infections that extend throughout the dermis and subcutis, often occurring after inoculation with pathogenic fungi. Trends toward a growing incidence have been observed that may be partially related to an increasing population of solid organ transplant patients. The aim of this study is to describe the diagnostics and the outcomes of DCM among kidney transplant recipients so as to optimize their management. We performed a retrospective review of cases of DCM occurring among kidney transplant recipients in our institution over 12 years. Twenty cases were included. Lesions were only located on the limbs and presented mainly as single (10/20, 50%) nodular lesions (15/20, 75%), with a mean size of 3 cm. Direct mycological examination was positive for 17 patients (17/20, 85%) and the cultures were consistently positive. Thirteen different fungal species were observed, including phaehyphomycetes (n = 8), hyalohyphomycetes (n = 3), dermatophytes (n = 1), and mucorale (n = 1). The (1-3) beta-D-glucan antigen (BDG) was also consistently detected in the serum (20/20, 100%). Systematic imaging did not reveal any distant infectious lesions, but locoregional extension was present in 11 patients (11/14, 79%). Nineteen patients received antifungal treatment (19/20, 95%) for a median duration of 3 months, with surgery for 10 (10/20, 50%). There is a great diversity of fungal species responsible for DCMs in kidney transplant recipients. The mycological documentation is necessary to adapt the antifungal treatment according to the sensitivity of the species. Serum BDG positivity is a potentially reliable and useful tool for diagnosis and follow-up.

Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity.

While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

Which first-line treatment for cutaneous sarcoidosis? A retrospective study of 120 patients.

Sarcoidosis is a systemic disease that affects the skin in about 25% of patients. The treatment of cutaneous sarcoidosis is guided by the extent of lesions, associated symptoms and organ involvement. To evaluate rates of response to various potential first-line treatments for cutaneous sarcoidosis during the year following treatment initiation. This retrospective multicentre study included 120 patients with cutaneous sarcoidosis. Treatment response was assessed retrospectively from the patients' medical records. Univariate logistic regression analysis, with an estimation of unadjusted odds ratios (OR) and their 95% CI ,was performed to identify factors associated with complete cutaneous remission (CR), followed by multivariate logistic regression analysis. At one year, 43 of the 120 (36%) included patients had CR. The best response rates were obtained with oral corticosteroids (12/21, 57%), followed by a combination of hydroxychloroquine and topical steroids (6/13, 46%). In multivariate analysis, lupus pernio was the only predictor of a poor cutaneous response. We suggest the use of a combination of hydroxychloroquine and topical steroids as an optimal first-line treatment for cutaneous sarcoidosis, given the known adverse effects of systemic corticosteroids.

Abdominal metastases from Merkel cell carcinoma: Prevalence and presentation on CT examination in 111 patients.

PURPOSE: The purpose of this study was to report the prevalence and imaging features of abdominal metastases from Merkel cell carcinoma (MCC) on computed tomography (CT) examinations. MATERIALS AND METHODS: A total of 111 patients with MCC from two institutions were initially identified. Of these, 27 patients (27/111; 24.3%) had abdominal metastases from MCC present on CT examination. There were 19 men and 8 women with a mean age of 75  ± 10.8 (SD) years (age range: 46-92 years). CT examinations were retrospectively reviewed by two radiologists and analyzed quantitatively for the number and dimensions of abdominal metastases from MCC and qualitatively in terms of location, margins, contours, homogeneity, patterns of enhancement, vascular involvement and extension of metastases from MCC. RESULTS: Fifteen patients (15/27; 56%) had abdominal metastatic disease at initial diagnosis and twelve (12/27; 44%) developed abdominal metastases during the course of the disease. The mean number of locations of abdominal metastases was 2.1 ± 1.12 (SD) (range: 1-5). Abdominal metastases involved abdominal lymph nodes (16/27; 59%), adrenal glands/kidneys/retroperitoneum (14/27; 52%), mesentery/peritoneum (13/27; 48%), liver (7/27; 26%) and pancreas (7/27; 26%). Vascular involvement was found in association with peritoneal/mesenteric metastases in 6/13 (46%) patients with intraperitoneal metastases or in association with abdominal lymph nodes in 4/16 (25%) patients. Ureteral encasement and/or dilatation was found in 4/14 (28%) patients with retroperitoneal metastases and 3/16 (19%) patients with abdominal lymph nodes. Metastases to the liver, pancreas, peritoneum, retroperitoneum and adrenal glands displayed internal enhancement during the arterial phase in 1/2 (50%), 4/5 (80%), 4/7 (57%) and 5/8 (62%) patients for whom arterial phase was available, respectively. CONCLUSION: Metastases from MCC have a prevalence of 24.3% on CT examination and may involve a variety of abdominal organs, mainly lymph nodes, peritoneal and retroperitoneal structures, but also the liver and pancreas. CT features of abdominal metastases from MCC include hypervascularity during the arterial phase of enhancement and eventually vascular and ureteral involvement.

Simultaneous quantification of dabrafenib, hydroxy-dabrafenib and trametinib in human plasma by liquid chromatography-tandem mass spectrometry.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 µm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 µL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer.

Reintroduction of immune-checkpoint inhibitors after immune-related meningitis: a case series of melanoma patients.

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated antigen-4 and programmed cell death ligand-1) are associated with several immune-related neurological disorders. Cases of meningitis related to ICIs are poorly described in literature and probably underestimated. Several guidelines are available for the acute management of these adverse events, but the safety of resuming ICIs in these patients remains unclear. We conducted a retrospective case series of immune-related meningitis associated with ICIs that occurred between October 1 2015 and October 31 2019 in two centers: Saint-Louis and Cochin hospitals, Paris, France. Diagnosis was defined by a (1) high count of lymphocytes (>8 cells/mm3) and/or high level of proteins (>0.45 g/L) without bacteria/virus or tumor cells detection, in cerebrospinal fluid and (2) normal brain and spine imaging. Patients were followed-up for at least 6 months from the meningitis onset. Seven cases of immune-related meningitis are here reported. Median delay of meningitis occurrence after ICIs onset was 9 days. Steroid treatment was introduced in four patients at a dose of 1 mg/kg (prednisone), allowing a complete recovery within 2 weeks. The other three patients spontaneously improved within 3 weeks. Given the favorable outcome, ICIs were reintroduced in all patients. The rechallenge was well tolerated and no patients experienced meningitis recurrence. In conclusion, in our series, the clinical course was favorable and steroids were not always required. Resuming ICIs in these patients appeared safe and can thus be considered in case of isolated meningitis. However, a careful analysis of the risk/benefit ratio should be done on a case-by-case basis.

Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas.

PURPOSE: To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS: Patients, predominantly men, with their CSSCs' immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort's objective response rate at week 15 (ORRW15). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy-General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORRW15 difference between PD-L1+ and PD-L1- patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS: Median age of all patients was 79 years. The primary cohort's ORRW15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORRW15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1- patients (17%; P = .02). Responders' W15 total FACT-G score had improved (P = .025) compared with nonresponders. CONCLUSION: First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Increased risk of permanent stoma in Crohn's disease associated with hidradenitis suppurativa: a case-control study.

BACKGROUND: Crohn's disease (CD) and hidradenitis suppurativa (HS), a chronic inflammatory skin disease, induce similar inflammatory lesions of the groin and gluteal area. Both diseases are characterised by an inadequate immune response to commensal bacteria in genetically predisposed subjects and can be associated. AIM: To assess whether HS was associated with clinical and prognostic factors in CD. METHODS: A retrospective case-control study included 4645 patients with CD referred to Saint-Antoine Hospital gastroenterology tertiary care centre between 2003 and 2016. Matching variables were sex, age, age and the presence of perianal lesions at CD diagnosis, follow-up quality. HS was confirmed by dermatological examination; location, phenotype and severity (Hurley staging) were recorded. RESULTS: Hidradenitis suppurativa prevalence was 0.95% (44 cases); 80% of patients displayed Hurley stage II or III disease. CD preceded HS in 70% of cases with a median interval of 9 years (IQR 5.25-12.75). CD with HS was more active (56% vs 40% years with active disease, P < 0.001) and required more anti-TNF agents (39% vs 23% years spent with anti-TNF treatment, P < 0.001) than CD without HS. HS was associated with a higher risk of permanent stoma, 16.8% (IQR 7.5-33.3) vs 2.5% (IQR 0.8-7.4) in the control group (P = 0.002). Multivariate analysis confirmed HS as independent risk factor for permanent stoma (odds ratio 6.19; 95% CI, 2.30-38.33; P < 0.001). CONCLUSIONS: Hidradenitis suppurativa is associated with worse CD prognosis, more active disease and increased risk of permanent stoma, despite a higher use of anti-TNF agents.

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma.

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUCOHD/AUCDAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); p = 0.023 and 10.61 (2.34-48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); p = 0.032 and HR = 1.23 (1.35-10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUCOHD/AUCDAB deserves more investigation in a larger cohort of MM patients.

Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: a monocentric retrospective study.

Combined BRAF and MEK inhibition is one of the first-line treatment strategies for patients with advanced BRAF-mutant melanoma. Sarcoid-like reactions (SLRs) have occasionally been described with melanoma systemic treatments such as immunotherapy or the BRAF inhibitor vemurafenib, but very few cases have been reported with dabrafenib and trametinib. Our aim was to better characterize SLR induced by this combination. We conducted a monocentric retrospective observational study among patients treated with dabrafenib and trametinib for BRAF-mutant advanced melanoma from January 2015 to March 2019. Patients presenting with histologically proven SLR were included. We also searched Medline database for all reported cases of SLR induced by targeted therapy. Of 63 patients on dabrafenib/trametinib combination, seven were diagnosed with a SLR. They all had specific cutaneous involvement, and one also displayed mediastinal and salivary glands involvement. None required systemic corticosteroids or dabrafenib/trametinib discontinuation. Three of them (43%) reached melanoma complete remission and are still on targeted therapy; and four patients progressed and died. A literature review yielded 22 additional cases of SLR induced by targeted therapy: the main affected organ was the skin, 11 patients (50%) had systemic involvement, five patients (23%) required systemic corticosteroids to reach partial or complete remission of SLR, 12 (55%) reached partial or complete response of melanoma while six (27%) progressed. BRAF and MEK inhibitors are potential triggers of SLR, although pathological mechanisms remain unclear. The mainstay of treatment is systemic or topical corticotherapy; targeted therapy discontinuation is usually not necessary.

Deep cutaneous fungal infections in solid-organ transplant recipients.

BACKGROUND: Deep cutaneous fungal infections (DCFIs) are varied in immunosuppressed patients, with few data for such infections in solid-organ transplant recipients (s-OTRs). OBJECTIVE: To determine DCFI diagnostic characteristics and outcome with treatments in s-OTRs. METHODS: A 20-year retrospective observational study in France was conducted in 8 primary dermatology-dedicated centers for s-OTRs diagnosed with DCFIs. Relevant clinical data on transplants, fungal species, treatments, and outcomes were analyzed. RESULTS: Overall, 46 s-OTRs developed DCFIs (median delay, 13 months after transplant) with predominant phaeohyphomycoses (46%). Distribution of nodular lesions on limbs and granulomatous findings on histopathology were helpful diagnostic clues. Treatments received were systemic antifungal therapies (48%), systemic antifungal therapies combined with surgery (28%), surgery alone (15%), and modulation of immunosuppression (61%), leading to complete response in 63% of s-OTRs. LIMITATIONS: Due to the retrospective observational design of the study. CONCLUSIONS: Phaeohyphomycoses are the most common DCFIs in s-OTRs. Multidisciplinary teams are helpful for optimal diagnosis and management.