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Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

ABSTRACT: Importance:Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC). Objective:To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC. Design, Setting, and Participants:JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing. Interventions:Patients received avelumab, 10 mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred. Main Outcomes and Measures:Tumor status was assessed every 6 weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability. Results:As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing at the time of analysis. In responding patients, the estimated proportion with duration of response of at least 3 months was 93% (95% CI, 61%-99%); duration of response of at least 6 months, 83% (95% CI, 46%-96%). First-line avelumab treatment was generally well tolerated, and no treatment-related deaths or grade 4 adverse events occurred. Conclusions and Relevance:High rates of response to first-line avelumab therapy in patients with distant mMCC build on previously reported antitumor activity after second-line or later treatment, and maturing progression-free survival data suggest that responses are durable. These data further support avelumab's approval in the United States and European Union and use as a standard-of-care treatment for mMCC. Trial Registration:clinicaltrials.gov Identifier: NCT02155647.

SUBMITTER: D'Angelo SP

PROVIDER: S-EPMC5885245 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

D'Angelo Sandra P SP Russell Jeffery J Lebbé Céleste C Chmielowski Bartosz B Gambichler Thilo T Grob Jean-Jacques JJ Kiecker Felix F Rabinowits Guilherme G Terheyden Patrick P Zwiener Isabella I Bajars Marcis M Hennessy Meliessa M Kaufman Howard L HL

JAMA oncology 20180913 9

<h4>Importance</h4>Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC).<h4>Objective</h4>To evaluate the efficacy and safety of a ...[more]

PMID: 29566106

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Project description:INTRODUCTION:Complex underlying risk functions associated with immuno-oncology treatments have led to exploration of different methods (parametric survival, spline, landmark, and cure-fraction models) to estimate long-term survival outcomes. The objective of this study was to examine differences in estimated short- and long-term survival in previously treated metastatic Merkel cell carcinoma (mMCC) patients receiving avelumab, when using alternative extrapolation approaches. METHODS:Efficacy data from the phase 2 JAVELIN Merkel 200 trial (part A) with at least 12 months of follow-up were analyzed. Standard parametric survival analyses and analyses of overall survival (OS) as a function of surrogate outcomes comprised of response (landmark analyses) and progression-free survival plus post-progression survival (PFS?+?PPS) were used to project OS. Overall survival throughout lifetime was projected and compared with the observed OS data with at least 24 months of follow-up. RESULTS:Estimated OS from all three approaches provided a good fit to the observed OS curve from at least 12 months of follow-up. However, performance compared with OS data from at least 24 months showed that the landmark approach followed by PFS?+?PPS provided a better fit to the data as compared to standard parametric analysis. Mean life expectancy estimated with avelumab was 2.48 years with best-fitting parametric function (a log-normal distribution), 3.15 years with the landmark approach, and 3.54 years with PFS?+?PPS. CONCLUSION:Although standard parametric survival analysis may provide a good fit to short-term survival, it appears to underestimate the long-term survival benefits associated with avelumab in mMCC. Extrapolations based on surrogate outcomes of response or progression predict OS outcomes from longer follow-up better and appear to provide more clinically plausible projections. FUNDING:EMD Serono Inc, Rockland, MA, a business of Merck KGaA, Darmstadt, Germany.

Project description:BackgroundNivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.MethodsWe randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.ResultsAmong the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.ConclusionsNivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

Project description:BackgroundThe incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial. The global avelumab expanded access program (EAP) was designed to provide compassionate use of avelumab prior to approval for patients with mMCC who had limited treatment options. We report findings from a subgroup of Italian patients enrolled in the avelumab EAP.MethodsEligible patients had mMCC and progressive disease following ≥ 1 prior line of chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received avelumab 10 mg/kg intravenously every 2 weeks. Treating physicians were provided with an initial 3-month supply of avelumab; resupply was permitted if the patient achieved a complete response, partial response, stable disease, or other clinical benefit per physician assessment. Safety and efficacy data for the EAP were reported at the treating physician's discretion.ResultsBetween April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy, and 102 were approved. All but 1 of the approved patients had received ≥ 1 prior line of therapy. At data cutoff (March 22, 2019), 95 patients had been supplied with avelumab and response data were available for 55 patients. The objective response rate in response-evaluable patients was 29.1%, including 6 patients (10.9%) who achieved a complete response and 10 patients (18.2%) who achieved a partial response; in the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. The median duration of treatment in responding patients was 9.7 months (range, 3.5-41.7 months). The most frequently reported treatment-related adverse events were infusion-related reaction (single preferred term; n = 3 [3.2%]) and pyrexia (n = 2 [2.1%]).ConclusionsResults from Italian patients enrolled in the avelumab EAP are consistent with the findings of the JAVELIN Merkel 200 trial and confirm the efficacy and safety of avelumab treatment in this population.

Dataset Information

Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

Publications

Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

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