Uncommon BRAF Mutations Associated with Durable Response to Immunotherapy in Patients with Metastatic Melanoma

Melanoma is a disease process which has been increasing in incidence over the past three decades and metastatic melanoma carries a poor prognosis. Through genetic studies of this disease, it has been determined that the BRAF V600 mutation plays a major role in the pathophysiology of the disease and this has led to the utilization of targeted therapy (BRAF and MEK inhibitors) in its treatment. Other BRAF mutations (non-V600 mutations) are rare in melanoma and targeted therapy is not indicated for patients with these mutations due to reduced response rates. An emerging option for metastatic melanoma with uncommon BRAF mutations is immunotherapy using checkpoint inhibitors such as PD-1 inhibitors or CTLA-4 inhibitors. Currently, it is unknown how patients with BRAF non-V600 mutations respond to immunotherapy. This report will examine the effect of immunotherapy on two distinct metastatic melanoma patients, each with uncommon BRAF mutations, occurring outside the V600 locus (E586K and G469E). These patients were noted to have a durable, complete response when treated with immunotherapy and continue to exhibit a response 9 and 15 months after discontinuing therapy. Further research and clinical trials are needed to study patients with uncommon BRAF mutations and the potential therapeutic benefit of immunotherapy

PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma

BACKGROUNDNo systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.METHODSWe report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.RESULTSIn the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.CONCLUSIONSAmong patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors

PArution: Jérémy Brunet, Quand la grande guerre s'invite à Brive, 1914-1917 (PULIM, 2014)

Les PULIM ont le plaisir de faire part de la parution de l’ouvrage   Jérémy Brunet Quand la grande guerre s’invite à Brive, 1914-1917 Histoire de deux hôpitaux de l’arrière Brive, dimanche 30 août 1914 : la population attend, fébrile, l’arrivée de « ses » premiers blessés de guerre. « Un spectacle à la fois pénible et grandiose » l’attend. Brive entrevoit les premiers indices du drame qui se joue déjà sur le front. Les hôpitaux corréziens accueillent des soldats martyrisés par l’armement mod..

A phase II trial of recombinant MAGE-A3 protein with immunostimulant AS15 in combination with high-dose Interleukin-2 (HDIL2) induction therapy in metastatic melanoma

Abstract Background HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma. Methods Patients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed. Results Eighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples. Conclusions The safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma. Trial registration ClinicalTrials.gov, NCT01266603. Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT0126660

Pelvic computed tomography scans for surveillance in patients with primary melanoma in the head and neck.

Although pelvic computed tomography (CT) scans are frequently performed as a part of routine surveillance, the evidence for or against the routine use of these scans in patients with primary melanoma in the head and neck is weak. We conducted a retrospective study to evaluate the value of pelvic CT scans as routine surveillance in patients with primary melanoma in the head and neck. We identified 146 patients with either primary or mucosal primary melanoma who had adequate follow-up evaluation for at least 5 years at our institution. Among them, 33 patients (23%) had stage III melanoma, and four (3%) had stage IV melanoma at the time of diagnosis. At a median follow-up duration of 49 months, 110 patients (75%) had developed recurrences, and the median time to the first recurrence was 13 months. A total of 82 (56%) patients had eventually developed distant metastases, but only 10 (7%) had developed metastases in the pelvis, and none had developed pelvic metastases as the first and the only site of recurrence. If the true rate of finding the pelvic metastasis as the first and the only recurrence was at least 3%, the probability of seeing 0 events of the 146 patients was 1.17%. This study, which is the largest series to evaluate the value of pelvic CT scans in this patient population to date, suggests that the routine use of a pelvic CT scan as a surveillance method does not have any impact on the management in patients with primary melanoma in the head and neck

Merkel Cell Polyomavirus Small T Antigen Activates Noncanonical NF-κB Signaling to Promote Tumorigenesis

Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT-expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth and in xenografts. We identify MCPyV sT-induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. IMPLICATIONS: This work is the first to identify the activation of ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis