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 numberNCT02155647

BackgroundAvelumab (anti-programmed death ligand 1 (PD-L1)) is approved in multiple countries for the treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. We report efficacy and safety data and exploratory biomarker analyses from a cohort of patients with mMCC treated with first-line avelumab in a phase II trial.MethodsPatients with treatment-naive mMCC received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was durable response, defined as objective response (complete or partial response; assessed by independent review) lasting ≥6 months. Additional assessments included progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses.ResultsIn 116 patients treated with avelumab, median follow-up was 21.2 months (range: 14.9–36.6). Thirty-five patients had a response lasting ≥6 months, giving a durable response rate of 30.2% (95% CI: 22.0% to 39.4%). The objective response rate was 39.7% (95% CI: 30.7% to 49.2%). Median PFS was 4.1 months (95% CI: 1.4 to 6.1) and median OS was 20.3 months (95% CI: 12.4 to not estimable). Response rates were numerically higher in patients with PD-L1+ tumors, Merkel cell polyomavirus (MCPyV)-negative tumors, and tumors with increased intratumoral CD8+ T-cell density. Exploratory analyses did not identify a biomarker that could reliably predict a response to first-line treatment with avelumab; however, a novel gene expression signature to identify the presence of MCPyV+ tumors was derived. Treatment-related adverse events (any grade) occurred in 94 (81.0%) patients, including grade 3/4 events in 21 (18.1%) patients; no treatment-related deaths occurred.ConclusionIn patients with mMCC, first-line treatment with avelumab led to responses in 40% and durable responses in 30%, and was associated with a low rate of grade 3/4 treatment-related adverse events.

Background and Objective Avelumab is approved for the treatment of metastatic Merkel cell carcinoma, a rare aggressive skin cancer with a poor prognosis. The aim of this qualitative study embedded in a clinical trial was to explore patient experiences while receiving avelumab. Methods All treatment-naïve patients with metastatic Merkel cell carcinoma entering part B of the phase II, open-label, international, JAVELIN Merkel 200 trial (NCT02155647) were invited to participate in optional semi-structured phone interviews before avelumab administration (baseline) and at weeks 13 and 25. Interviews were conducted by trained professionals, audio-recorded, transcribed and analysed. Key concepts identified at baseline were assessed during follow-up interviews. Results Twenty-nine patients completed the baseline interview; 19 had at least one follow-up interview. Baseline interviews described the patients' challenging journeys before being correctly diagnosed with Merkel cell carcinoma, the negative psychological burden of living with a symptomless disease and the hope for avelumab to be a successful therapy. During the trial, most patients reported an increased or continued sense of hope and willingness to fight metastatic Merkel cell carcinoma. Patients who self-reported disease improvement (n = 12) also reported stability or improvement in physical well-being and ability to do daily activities, having more energy, worrying less and being optimistic. Six patients who reported their condition as stable (n = 4) or worsened (n = 3) reported a worsening of physical well-being. Nine patients reported fatigue/ tiredness on the day of and after receiving avelumab. Baseline and longitudinal experiences were similar across countries. Conclusions This study suggests that patients experience perceptible benefits in physical and psychological well-being following treatment success with first-line avelumab in metastatic Merkel cell carcinoma.

PurposeTo report integrated electrocardiogram (ECG) summary and exposure–QTc analyses for avelumab, a human immunoglobulin G1 monoclonal antibody that binds programmed cell death 1 ligand 1, to assess potential effects on cardiac repolarization.MethodsData were pooled from three-phase 1/2 studies of patients with advanced solid tumors who received avelumab monotherapy (22,000 ECGs from 1818 patients). All analyses used 12-lead singlet ECGs taken using local ECG machines before and approximately 2 h after avelumab infusion on prespecified days. The exposure–QTc and outlier analyses used locally read ECGs; since larger variability is known to be associated with local reading, outlier ECGs were subsequently reevaluated by central read. QTc derived from Fridericia’s formula (QTcF) and a project-specific formula (QTcP) were analyzed. Multivariable linear mixed-effects models were used to describe the relationship between serum concentration of avelumab and QTc absolute value or change from baseline (ΔQTc).ResultsExposure–QTc models showed that the effect of avelumab on QTc or ΔQTc was minimal and not statistically significant for both QTcP and QTcF. In addition, models including avelumab concentration and diphenhydramine premedication use did not show a clinically meaningful effect on the QT interval. The frequency of QTc outliers in both short and long ranges was overestimated by local reads. Six patients (0.3%) were QTc outliers; all had either received concomitant medication known to cause QT prolongation or had a preexisting cardiac condition.ConclusionAvelumab does not have any clinically relevant effect on cardiac repolarization.

characteristics. Results: This study included 443 patients meeting both inclusion and exclusion criteria (304 patients in the powered stapler group and 139 patients in the manual stapler group). Based on the conducted multiple regression analyses, using powered stapler was associated with significantly shorter operation time (3.7 hours vs. 3.9 hours, p=0.010), significantly shorter post-surgery hospital stay length (7.9 days vs. 8.7 days, p=0.009) than using manual stapler. Additionally, using powered stapler was associated with lower total post-surgery drainage volume with approaching statistical significance (561.7 ml vs. 628.9 ml, p=0.074). The hospital costs associated with the two types of staplers were highly comparable (U65,449 vs. U64,757 CNY, p=0.488). Conclusions: Powered stapler gained more clinical benefits than manual stapler without increasing hospital costs inlobectomy conducted for lung cancer through VATS in a Chinese tertiary care hospital.