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Survival Analysis in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

ABSTRACT: 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.

SUBMITTER: Lanitis T

PROVIDER: S-EPMC6822847 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Survival Analysis in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

Lanitis Tereza T Proskorovsky Irina I Ambavane Apoorva A Hunger Matthias M Zheng Ying Y Bharmal Murtuza M Phatak Hemant H

Advances in therapy 20190726 9

<h4>Introduction</h4>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.<h4>Methods</ ...[more]

PMID: 31350728

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Project description:Merkel 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. In 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. As 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. Avelumab 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. NCT02155647.

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.

Project description: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.

Project description: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, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING:Merck KGaA, Darmstadt, Germany.

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Survival Analysis in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

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Survival Analysis in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

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