Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, ave...

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-β (TGF-β) "trap."Experimental Design: In the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. Results:Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions STATEMENT OF TRANSLATIONAL RELEVANCEExcitement surrounding the durable benefits associated with PD-1/PD-L1-targeted therapy has been tempered somewhat by responses being confined to only a subset of patients.To increase the rate of response, many ongoing trials are evaluating anti-PD-1/PD-L1 agents in combination with other immunotherapies; however, these combination strategies have limitations and novel approaches are required. M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β "trap." We report the first clinical data for M7824 -including pharmacokinetics, safety, and efficacy findings -which derive from a phase 1 dose-escalation study in patients with advanced solid tumors. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β throughout the dosing period at a dose >1 mg/kg. M7824 appeared to have a manageable safety profile and early evidence of clinical efficacy -including 1 ongoing confirmed complete response and 2 durable confirmed partial responses -was demonstrated.

In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a-ribavirin.

Aim:Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with poor prognosis once metastasized. The aim of this study was to conduct a systematic literature review to assess clinical outcomes associated with chemotherapy regimens in metastatic MCC.>Materials & methods:Embase®, MEDLINE®, MEDLINE®-In-Process and CENTRAL were searched for studies published in January 2016.Results & conclusion:Overall, the literature on chemotherapy in patients with metastatic MCC is sparse, with most studies being case series/reports. Across all studies, response rates ranged from 20 to 61%, with higher response rates in first-line setting (53–61%) versus second-line setting (23–45%). Among responders, duration of response was short (≤8 months) in both first- and second-line settings. There is a need for novel agents that can induce durable responses in metastatic MCC.

aim: This retrospective study of patients in the USA with metastatic Merkel cell carcinoma (mMCC) aimed to assess patient responses to second-line and later (2L+) and first-line (1L) chemotherapy. Patients & methods: Out of 686 patients with MCC identified in The US Oncology Network, 20 and 67 patients with mMCC qualified for the 2L+ and 1L study, respectively; the primary analysis population was restricted to immunocompetent patients. Results: In the 2L+ primary analysis population, objective response rate (ORR) was 28.6%, median duration of response (DOR) was 1.7 months and median progression-free survival was 2.2 months. In the 1L primary analysis population, ORR was 29.4%, median DOR was 6.7 months and median progression-free survival was 4.6 months. conclusion: The low ORR and brief DOR underscore the need for novel therapies. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that occurs most frequently in elderly and immunocompromised patients [1][2][3]. There are approximately 1500 cases of MCC per year in the USA, and the incidence has dramatically increased over the last 20 years [4]. MCC typically presents as painless growths that are clinically unremarkable in appearance and are usually found on sun-exposed areas, such as the head and neck [2,3]. These tumors grow rapidly and tend to metastasize early and frequently to local regions of the body, leading to a relatively poor prognosis with this aggressive disease [2,3,5]. Among patients diagnosed with local or regional disease, the reported rates of recurrence range from 43 to 48% [6,7]. The 5-year overall survival (OS) rate is 40% [1] and the mortality rate with MCC is greater than that with other skin cancers, including melanoma [4].Recently, avelumab, a human IgG1 anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, was approved by the US FDA as the first and only approved treatment for patients with metastatic MCC (mMCC) [8]. Before this approval, there was no evidence-based standard therapeutic regimen for mMCC. The National Comprehensive Cancer Network treatment guidelines for mMCC [9] are based on those used for small cell lung cancer, as both are aggressive and poorly differentiated cancers [10]. Treatments typically include platinum agents, such as carboplatin or cisplatin with or without etoposide or topotecan, and are associated with high toxicity [9,11]. Although MCC is generally considered a chemosensitive tumor, responses to chemotherapy in metastatic disease are For reprint orders, please contact: reprints@futuremedicine.com

Background and aimsMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer; few treatments exist for patients with advanced disease. Once tumors metastasize to distant sites, patients generally receive chemotherapy, but response duration and progression-free survival (PFS) are typically short. Few studies have assessed the efficacy of second-line chemotherapy for metastatic MCC. Here, we studied outcomes in patients who received ≥ 2 lines of chemotherapy for metastatic MCC.Materials and methodsPatients in an MCC-specific registry diagnosed with stage IV MCC between November 1, 2004, and September 15, 2015, and treated with second-line or later chemotherapy were analyzed retrospectively. Patient records, including baseline characteristics, immunocompetent status, and responses to prior chemotherapy, were evaluated. Patients meeting eligibility criteria were followed through December 31, 2015.ResultsOf 29 patients with metastatic MCC and immunocompetent status who had received ≥ 2 lines of chemotherapy, 3 achieved a partial response, for an objective response rate (ORR) of 10.3% (95% CI, 2.2–27.4). In the overall population including patients with immunocompetent and immunocompromised status (n = 34), the ORR was 8.8% (95% CI, 1.9–23.7). The median duration of response was 1.9 months (range, 1.3–2.1 months; 95% CI, 1.3–2.1). In the immunocompetent population, median PFS and overall survival were 3.0 months (95% CI, 2.5–6.0) and 5.3 months (95% CI, 4.3–6.0), respectively.ConclusionsThe low response rates and limited durability confirm previous reports of the ineffectiveness of second-line or later chemotherapy in patients with metastatic MCC and provide a benchmark for assessing clinical benefit of new treatments.

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

ATV/RTV with Ortho Tri-Cyclen was well-tolerated and reductions in EE were not predicted to decrease contraceptive efficacy if the formulation contained ≥30 μg of EE.