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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. 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. 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). Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Merck KGaA, Darmstadt, Germany.

Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Novartis Pharmaceuticals Corporation.

In this international, nonrandomized study, vismodegib, an oral inhibitor of the ligand that activates the hedgehog pathway, showed responses in patients with locally advanced or metastatic basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate. Basal-cell carcinoma is the most common cancer. It is estimated that more than 2.1 million new patients were treated for nonmelanoma skin cancer in 2006 in the United States 1 ; approximately 80% of nonmelanoma skin cancers are basal-cell carcinomas. Although most basal-cell carcinomas are readily treated by means of various surgical methods, these lesions occasionally progress to an advanced state that is no longer amenable to surgery or radiation therapy (locally advanced basal-cell carcinoma) or, more rarely, the lesions spread to distant sites (metastatic basal-cell carcinoma). When this study was designed, there was no approved therapy for advanced basal-cell carcinoma. . . .

Basal cell carcinoma (BCC) is the most common malignancy worldwide. Fortunately, most tumors are localized and easily amenable to surgical resection or locally destructive treatments. However, a subset of BCCs can become locally advanced or metastatic. The development of small-molecule inhibitors of smoothened, a protein in the hedgehog pathway, which is almost universally activated in BCCs, was a breakthrough in the treatment of patients with advanced BCC. However, these agents are associated with primary and secondary resistance and have a toxicity profile that makes long-term use difficult. The recent approval of cemiplimab for patients with advanced BCC who are resistant to or are intolerant of hedgehog inhibitor therapy fills a significant unmet need as these patients now have a viable, second-line systemic therapeutic option. This article summarizes the rationale and data leading to the approval for cemiplimab in advanced BCC.

Background Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab—a human anti–programmed death-ligand 1 (PD-L1) monoclonal antibody—showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease. Patients and methods Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Patients ( N  = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1–positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status. Conclusions With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy. Trial registration Clinicaltrials.gov identifier: NCT02155647.

BackgroundMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti–programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab.MethodsIn a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses.ResultsAs of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4–49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred.ConclusionsAvelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease.Trial registration number NCT02155647

BackgroundNemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8+ T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors.MethodsThis was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1–5 (21-day cycle) at 0.1–10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C).ResultsFrom July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 µg/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8+ T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3–4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs.ConclusionsNemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing.Trial registration numberNCT02799095.

Background We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS. Methods Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAF V600 -mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause. Results RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3–16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8–2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments. Conclusion A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).

Side population (SP) cells are identified as cells capable of excluding the fluorescent Hoechst dye and anticancer drugs, and it represents hematopoietic stem cells and chemoresistant cells from several solid tumors. In this study, we confirmed the presence of SP cells in tumors from melanoma patients. Melanoma SP cells overexpressed ATP-binding-cassette (ABC) transporters, ABCB1 and ABCB5. We generated a direct in vivo xenograft model, and demonstrated that SP cells were resistant to paclitaxel, a substrate of ABCB1, both in vitro and in vivo. However, melanoma SP cells were also resistant to temozolomide, which is not a substrate for ABC transporters, through IL-8 upregulation. In addition, gene profiling studies identified three signaling pathways (NF-κB, α6-β4-integrin, and IL-1) as differentially upregulated in melanoma SP cells, and there was a significant increase of PCDHB11 and decrease of FUK and TBX2 in these cells. Therefore, we provide evidence that SP is an enriched source of chemoresistant cells in human melanomas, and suggest that the selected genes and signaling pathways of SP cells may be a potential target for effective melanoma therapies. To our knowledge, this is a previously unreported study to isolate SP cells from melanoma patients and to investigate the gene expression profiling of these cells.

Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma. This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0–1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498. Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1–15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32–55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3–4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia. Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care. Regeneron Pharmaceuticals and Sanofi.