Avelumab

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Jeffrey Schlom - One of the best experts on this subject based on the ideXlab platform.

  • interleukin 15 il 5 in combination with Avelumab in relapsed refractory mature t cell malignancies
    Blood, 2019
    Co-Authors: Milos D Miljkovic, Jeffrey Schlom, James L Gulley, Kevin C Conlon, Sigrid Dubois, Jennifer Hsu, Thomas A Waldmann
    Abstract:

    Background: Programmed death-ligand 1 (PD-L1) is expressed in many T-cell malignancies, including 75-100% of advanced cutaneous T-cell lymphomas, 75% of ALK-negaive anaplastic large cell lymphoma (ALCL), and 28% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). In 27% of patients with adult T-cell leukemia/lymphoma (ATLL) expression of PD-L1 is upregulated through 3'-UTR disruption; however, immune checkpoint inhibition has been associated with hyperprogression in three patients with indolent ATLL. In T-cell malignancies, PD-L1 expression was associated with worse outcomes. Avelumab is a fully human IgG1 anti-PD-L1 antibody which inhibits PD-1/PD-L1 interactions; unlike other approved immune checkpoint inhibitors, it also induces lysis of tumor cells in vitro via antibody-dependent cell-mediated cytotoxicity (ADCC). As ADCC is mediated by natural killer (NK) cells, agents which increase NK cell number and activity may act sinergistically with Avelumab. Administration of recombinant human (rh)IL-15 by continuous intravenous infusion (CIV) into adult cancer patients has produced a 15-75-fold expansion in the number of circulating NK cells at well-tolerated doses. Preclinical syngeneic and xenograft murine lymphoid malignancy models have shown increased efficacy with combined administration of IL-15 and anti-tumor antibodies compared to either alone. We therefore hypothesized that rhIL-15 may increase the efficacy of Avelumab in PD-L1 expressing T-cell malignancies, and are testing the combination in a phase I trial. Primary objective: determine the safety, toxicity profile and the maximum tolerated dose of CIV IL- 15 administration in combination with with a fixed dose of Avelumab. Secondary objectives: 1) determine the efficacy of combined CIV rhIL-15 and Avelumab treatment to patients with T-cell lymphomas other than ATL (overal response, duration of response, progression-free survival, event-free survival, and overall survival), 2) correlate response with level of PD-L1 expression in tumor cells ( Exploratory objectives: 1) assess the role of circulating tumor DNA (ctDNA) in T-cell malignancies, 2) assess the role of exosomes in T-cell malignancies, 3) identify other potential biomarkers of response, such as cytokine levels and T-cell clonality. Eligibility criteria: 1) age ≥18 years, 2) histologically proven PTCL-NOS, ALK-negative ALCL, or mycosis fungoides/Sezary syndrome that is refractory to at least one line of systemic treatment, 3) ECOG ≤1, 4) WBC count ≥ 3 ⨉ 109/L, with absolute neutrophil count ≥ 1.0 ⨉ 109/L, lymphocyte count ≥ 0.5 x 109/L, platelet count ≥ 100 ⨉ 109/L, and hemoglobin ≥ 9 gm/dL (may have been transfused), 5) no prior treatment with drugs targeting PD-1/PD-L1, or receipt of any organ transplantation including allogeneic stem cell transplantation. Study design: Open-label, single-center, non-randomized Phase 1 study with a 3+3 phase dose escalation design enrolling up to 30 patients. IL-15 will be administered by continuous intravenous infusion with a dose of 1 mcg/kg/day (DL1), 2 mcg/kg/day (DL2), 3 mcg/kg/day (DL3), or 4 mcg/kg/day (DL4) on days 1-5 of each cycle. Avelumab 10 mg/kg IV over 1 hour)will be administered on days 8 and 22 of the cycle. Treatment will continue for a maximum of 6 cycles, or until toxicity or progressive disease. Correlative studies: tumor (skin or lymph node) biopsy at baseline and before the second dose of Avelumab (C1D22); lymphocyte subset testing, ADCC capacity of ex vivo NK cells, ctDNA, exosomes, cell and plasma banking (days 1 and 8 of each cycle). One patients has been treated so far at DL1. Enrollment is ongoing. Download : Download high-res image (45KB) Download : Download full-size image Figure . Disclosures Waldmann: Bioniz: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Avelumab off-label use for treatment of T-cell malignancies.

  • Safety and clinical activity of PD-L1 blockade in patients with aggressive recurrent respiratory papillomatosis
    Journal for ImmunoTherapy of Cancer, 2019
    Co-Authors: Clint T Allen, Jeffrey Schlom, Julius Strauss, Sunmin Lee, Damian Kovalovsky, Paul E Clavijo, Richard Schlegel, Scott M. Norberg, Siwen Hu-lieskovan, James L Gulley
    Abstract:

    Background Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-driven disorder that causes substantial morbidity and can lead to fatal distal airway obstruction and post-obstructive pneumonias. Patients require frequent surgical debridement of disease, and no approved systemic adjuvant therapies exist. Methods A phase II study was conducted to investigate the clinical activity and safety of programmed death-ligand 1 (PD-L1) blockade with Avelumab in patients with RRP. Results Twelve patients were treated. All patients with laryngeal RRP displayed improvement in disease burden, and 5 of 9 (56%) displayed partial responses. None of 4 patients with pulmonary RRP displayed a response. Using each patient’s surgical history as their own control, patients required fewer surgical interventions after Avelumab treatment ( p  = 0.008). A subset of partial responders developed HPV-specific reactivity in papilloma-infiltrating T-cells that correlated with reduced HPV viral load and an increased Tissue Inflammation Signature. Conclusions Avelumab demonstrated safety and clinical activity in patients with laryngeal RRP. Further study of immune checkpoint blockade for RRP, possibly with longer treatment duration or in combination with other immunotherapies aimed at activating antiviral immunity, is warranted. Trial registration NCT, number NCT02859454 , registered August 9, 2016.

  • safety and clinical activity of pd l1 blockade in patients with aggressive recurrent respiratory papillomatosis
    Journal for ImmunoTherapy of Cancer, 2019
    Co-Authors: Clint T Allen, Jeffrey Schlom, Julius Strauss, Sunmin Lee, Scott Norberg, Damian Kovalovsky, Paul E Clavijo, Siwen Hulieskovan, Richard Schlegel, James L Gulley
    Abstract:

    Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-driven disorder that causes substantial morbidity and can lead to fatal distal airway obstruction and post-obstructive pneumonias. Patients require frequent surgical debridement of disease, and no approved systemic adjuvant therapies exist. A phase II study was conducted to investigate the clinical activity and safety of programmed death-ligand 1 (PD-L1) blockade with Avelumab in patients with RRP. Twelve patients were treated. All patients with laryngeal RRP displayed improvement in disease burden, and 5 of 9 (56%) displayed partial responses. None of 4 patients with pulmonary RRP displayed a response. Using each patient’s surgical history as their own control, patients required fewer surgical interventions after Avelumab treatment (p = 0.008). A subset of partial responders developed HPV-specific reactivity in papilloma-infiltrating T-cells that correlated with reduced HPV viral load and an increased Tissue Inflammation Signature. Avelumab demonstrated safety and clinical activity in patients with laryngeal RRP. Further study of immune checkpoint blockade for RRP, possibly with longer treatment duration or in combination with other immunotherapies aimed at activating antiviral immunity, is warranted. NCT, number NCT02859454 , registered August 9, 2016.

  • pre existing antiacetylcholine receptor autoantibodies and b cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with Avelumab an immune checkpoint inhibitor targeting programmed death ligand 1
    Annals of the Rheumatic Diseases, 2019
    Co-Authors: Andrew L Mammen, Arun Rajan, Tanya J Lehky, Livia Casciolarosen, Renee N Donahue, Lauren M Lepone, Anastasia Zekeridou, Sean J Pittock, Raffit Hassan, Jeffrey Schlom
    Abstract:

    Immune checkpoint inhibitors enhance the immune response against tumours but may also trigger immune-related adverse events (IRAEs). Myositis is a rare IRAE. For example, creatine kinase (CK) elevations occurred in just 0.3% of those treated with Avelumab, an antiprogrammed death-ligand 1 antibody.1 Thymomas are the most common anterior mediastinal masses in adults. Since effective systemic therapies for thymic epithelial tumours are lacking, we included seven patients with recurrent thymoma and one patient with recurrent thymic carcinoma in a phase I trial of Avelumab (NCT01772004). Details regarding this trial have been published separately.2 Myasthenia gravis and myositis occur in up to 30% and 5% of patients with thymoma, respectively.3 Although no patient had a history of autoimmunity or weakness and each had normal baseline CK levels, four patients developed weakness and elevated CK levels, ranging from 762 IU/L to 16 037 IU/L, within 5 weeks of Avelumab administration (see online supplementary text and table 1). CK levels normalised in patients within weeks of stopping Avelumab and starting immunosuppressive therapy. Of note, …

  • adcc employing an nk cell line hank expressing the high affinity cd16 allele with Avelumab an anti pd l1 antibody
    International Journal of Cancer, 2017
    Co-Authors: Caroline Jochems, Kwong Y Tsang, James W Hodge, Massimo Fantini, James L Gulley, Amanda J Vandeveer, Jeffrey Schlom
    Abstract:

    NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety profile. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti-PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that Avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells. In the studies reported here, the ability of Avelumab to enhance the lysis of a range of human carcinoma cells by irradiated haNK cells via the ADCC mechanism is demonstrated; this ADCC is shown to be inhibited by anti-CD16 blocking antibody and by concanamycin A, indicating the use of the granzyme/perforin pathway in tumor cell lysis. Studies also show that while NK cells have the ability to lyse aNK or haNK cells, the addition of NK cells to irradiated haNK cells does not inhibit haNK-mediated lysis of human tumor cells, with or without the addition of Avelumab. Avelumab-mediated lysis of tumor cells by irradiated haNK cells is also shown to be similar to that of NK cells bearing the V/V Fc receptor high affinity allele. These studies thus provide the rationale for the clinical evaluation of the combined use of Avelumab with that of irradiated adoptively transferred haNK cells.

Sandra P Dangelo - One of the best experts on this subject based on the ideXlab platform.

  • first line Avelumab in a cohort of 116 patients with metastatic merkel cell carcinoma javelin merkel 200 primary and biomarker analyses of a phase ii study
    Journal for ImmunoTherapy of Cancer, 2021
    Co-Authors: Celeste Lebbe, Laurent Mortier, Andrew S Brohl, Nicola Fazio, Glenn J Hanna, Sandra P Dangelo, Jeanjacques Grob, Natalie Prinzi, Jessica C Hassel
    Abstract:

    Background Avelumab (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. Methods Patients 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. Results In 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. Conclusion In 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.

  • Avelumab in patients with previously treated metastatic merkel cell carcinoma long term data and biomarker analyses from the single arm phase 2 javelin merkel 200 trial
    Journal for ImmunoTherapy of Cancer, 2020
    Co-Authors: Omid Hamid, Andrew S Brohl, Shailender Bhatia, Patrick Terheyden, Sandra P Dangelo, Kent C Shih, Janice M Mehnert, Isaac Brownell, Celeste Lebbe
    Abstract:

    Background 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. Methods 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. Results 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. Conclusions 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. Trial registration number NCT02155647

  • 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
    JAMA Oncology, 2018
    Co-Authors: Celeste Lebbe, Jeffery Russell, Sandra P Dangelo, Jeanjacques Grob, Bartosz Chmielowski, Thilo Gambichler, Felix Kiecker, Guilherme Rabinowits, Patrick Terheyden
    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

  • updated efficacy of Avelumab in patients with previously treated metastatic merkel cell carcinoma after 1 year of follow up javelin merkel 200 a phase 2 clinical trial
    Journal for ImmunoTherapy of Cancer, 2018
    Co-Authors: Howard L Kaufman, Omid Hamid, Celeste Lebbe, Jeffery Russell, Shailender Bhatia, Patrick Terheyden, Sandra P Dangelo, Kent C Shih, Michele Milella, Isaac Brownell
    Abstract:

    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 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). 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. 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. Clinicaltrials.gov identifier: NCT02155647.

  • abstract ct079 durable responses to Avelumab anti pd l1 in patients with merkel cell carcinoma progressed after chemotherapy 1 year efficacy update
    Cancer Research, 2017
    Co-Authors: Howard L Kaufman, Omid Hamid, Celeste Lebbe, Shailender Bhatia, Patrick Terheyden, Sandra P Dangelo, Kent C Shih, Michele Milella, Jeffery S Russell, Isaac Brownell
    Abstract:

    Background: Merkel cell carcinoma (MCC), a rare, aggressive skin cancer, is a chemosensitive disease, but responses are seldom durable. Avelumab is a fully human anti-PD-L1 monoclonal antibody. In a phase 2 trial of Avelumab in patients with previously treated metastatic MCC (mMCC), the objective response rate (ORR) after ≥6 months of follow-up was 31.8%, including complete response (CR) in 9.1%, the estimated proportion with duration of response (DOR) ≥6 months was 92%, and the 6-month progression-free survival (PFS) rate was 40% (95% CI 29-50) (Kaufman et al., Lancet Oncol 2016). Here we present updated efficacy data with ≥1 year of follow-up in all patients. Methods: Patients with distant mMCC and prior progression on chemotherapy received Avelumab 10 mg/kg IV Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1 by independent review). ORR, DOR, PFS, and overall survival (OS) were evaluated. Time-to-event endpoints were analyzed using Kaplan-Meier methodology. Safety data were not analyzed for this update. Results: Patients with mMCC (N=88) were treated with Avelumab. Median age was 72.5 years (range 33-88), and 53% had visceral disease. As of Sep 3, 2016, median follow-up was 16.4 months (range 12.0-25.3), and treatment was ongoing in 22% (n=19); main reasons for discontinuations were disease progression (n=44; 50%), death (n=7; 8%), adverse event (n=7; 8%), or withdrawal (n=4; 5%). ORR was 33.0% (95% CI 23.3-43.8) with 10 (11.4%) CRs and 19 (21.6%) partial responses, including 1 new CR and 1 patient improving from PR to CR since the 6-month analysis. The 6-month durable response rate was 30.6% (95% CI 20.9-40.3). Median DOR has not been reached (range 2.8-23.3+ months; 95% CI 18.0-not estimable), and responses were ongoing in 21/29 patients (72.4%) at the time of analysis. The estimated proportion of responders with ≥1-year duration of response was 74% (95% CI 53-87). Estimated 1-year PFS rate was 30% (95% CI 21-41) and 1-year OS rate was 52% (95% CI 41-62). Median OS was 12.9 months (95% CI 7.5-not estimable). Conclusion: In longer-term follow-up from this study of Avelumab in patients with distant metastatic MCC progressed after chemotherapy, the majority of responses were durable beyond 1 year and 2 new CRs were reported. Maturing PFS and OS data suggest long-term benefit in a proportion of patients. Clinical trial information: NCT02155647. Citation Format: Howard L. Kaufman, Jeffery S. Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D’Angelo, Kent C. Shih, Celeste Lebbe, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Lisa Mahnke, Paul Nghiem. Durable responses to Avelumab (anti-PD-L1) in patients with Merkel cell carcinoma progressed after chemotherapy: 1-year efficacy update [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT079. doi:10.1158/1538-7445.AM2017-CT079

Manish R. Patel - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Avelumab for patients with recurrent or refractory ovarian cancer phase 1b results from the javelin solid tumor trial
    JAMA Oncology, 2019
    Co-Authors: Mary L Disis, Manish R. Patel, Michael Gordon, Karen Kelly, Thaddeus J Beck, Matthew H Taylor, Jorge Chaves, Kathleen M Moore, Haeseong Park, Alain C Mita
    Abstract:

    Importance Current treatment options for progressive ovarian cancer provide limited benefit, particularly in patients whose disease has become resistant to platinum-based chemotherapy. Objective To assess the efficacy and safety of Avelumab, an anti–programmed death-ligand 1 agent, in a cohort of patients with previously treated recurrent or refractory ovarian cancer. Design, Setting, and Participants In an expansion cohort of a phase 1b, open-label study (JAVELIN Solid Tumor), 125 patients with advanced ovarian cancer who had received chemotherapy including a platinum agent were enrolled between November 6, 2013, and August 27, 2015. Statistical analysis was performed from December 31, 2016, to October 9, 2018. Intervention Patients received Avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. Main Outcomes and Measures Prespecified end points in this cohort included confirmed best overall response (per Response Evaluation Criteria In Solid Tumors, version 1.1), immune-related best overall response, duration of response, progression-free survival, overall survival, results of programmed death-ligand 1 expression–based analyses, and safety. Results A total of 125 women (median age, 62.0 years [range, 27-84 years]) who had received a median of 3 prior lines of treatment (range, 0-10) for advanced disease were enrolled in the study. Patients received Avelumab for a median of 2.8 months (range, 0.5-27.4 months), with a median follow-up of 26.6 months (range, 16-38 months). A confirmed objective response occurred in 12 patients (9.6%; 95% CI, 5.1%-16.2%), including a complete response in 1 patient (0.8%) and a partial response in 11 patients (8.8%). The 1-year progression-free survival rate was 10.2% (95% CI, 5.4%-16.7%) and median overall survival was 11.2 months (95% CI, 8.7-15.4 months). Infusion-related reactions occurred in 25 patients (20.0%). Other frequent treatment-related adverse events (any grade event occurring in ≥10% of patients) were fatigue (17 [13.6%]), diarrhea (15 [12.0%]), and nausea (14 [11.2%]). Grade 3 or higher treatment-related adverse events occurred in 9 patients (7.2%), of which only the level of lipase increased (3 [2.4%]) occurred in more than 1 patient. Twenty-one patients (16.8%) had an immune-related adverse event of any grade. No treatment-related deaths occurred. Conclusions and Relevance Avelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer. Trial Registration ClinicalTrials.gov identifier:NCT01772004

  • a review of Avelumab in locally advanced and metastatic bladder cancer
    Therapeutic Advances in Urology, 2019
    Co-Authors: Arpit Rao, Manish R. Patel
    Abstract:

    Urothelial carcinoma remains a devastating disease with a poor prognosis. Though immune therapy with Bacillus Calmette-Guerin (BCG) has been used for localized bladder cancer for years, only immune-checkpoint blockade with antiprogrammed cell-death 1 (anti-PD-1) and antiprogrammed cell-death ligand 1 (anti-PD-L1) inhibitors have demonstrated improvement in survival of patients with metastatic disease. Anti-PD-L1 antibody, Avelumab, was recently given United States Food and Drug Administration (FDA) accelerated approval for the treatment of recurrent/metastatic urothelial carcinoma after failure of first-line chemotherapy, marking the fifth immune checkpoint inhibitor to be given FDA approval for the treatment of metastatic urothelial cancer. The following manuscript will review Avelumab, its pharmacology, and the clinical experience that has led to its approval, as well as future plans for clinical development of Avelumab for the treatment or urothelial cancer.

  • A review of Avelumab in locally advanced and metastatic bladder cancer
    'SAGE Publications', 2019
    Co-Authors: Arpit Rao, Manish R. Patel
    Abstract:

    Urothelial carcinoma remains a devastating disease with a poor prognosis. Though immune therapy with Bacillus Calmette–Guérin (BCG) has been used for localized bladder cancer for years, only immune-checkpoint blockade with antiprogrammed cell-death 1 (anti-PD-1) and antiprogrammed cell-death ligand 1 (anti-PD-L1) inhibitors have demonstrated improvement in survival of patients with metastatic disease. Anti-PD-L1 antibody, Avelumab, was recently given United States Food and Drug Administration (FDA) accelerated approval for the treatment of recurrent/metastatic urothelial carcinoma after failure of first-line chemotherapy, marking the fifth immune checkpoint inhibitor to be given FDA approval for the treatment of metastatic urothelial cancer. The following manuscript will review Avelumab, its pharmacology, and the clinical experience that has led to its approval, as well as future plans for clinical development of Avelumab for the treatment or urothelial cancer

  • Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial
    The Lancet Oncology, 2018
    Co-Authors: Manish R. Patel, Raid Aljumaily, Keun Wook Lee, Carolyn D Britten, Luc Dirix, John Ellerton, Manish Agrawal, Jeffrey R Infante, Michael Gordon, Mathew Taylor
    Abstract:

    Background The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with Avelumab and to assess antitumour activity of this drug in post-platinum patients. Methods In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received Avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of Avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of Avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Findings Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with Avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with Avelumab, and one treatment-related death occurred (pneumonitis). Interpretation Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all Avelumab-treated patients. These data provide the rationale for therapeutic use of Avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Funding Merck KGaA, and Pfizer Inc.

  • safety profile of Avelumab in patients with advanced solid tumors a javelin pooled analysis of phase 1 and 2 data
    Journal of Clinical Oncology, 2017
    Co-Authors: Karen Kelly, Manish R. Patel, Jeffrey R Infante, Michael S Gordon, Matthew H Taylor, Deborah Jean Lee Wong, Nicholas Iannotti, Janice M Mehnert, Anja Loos, Helga Koch
    Abstract:

    3059Background: Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of Avelumab. Methods: Patients (pts) received Avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received ≥1 dose of Avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = ...

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  • Efficacy and safety of first-line Avelumab in patients with advanced non-small cell lung cancer: results from a phase Ib cohort of the JAVELIN Solid Tumor study
    'BMJ', 2020
    Co-Authors: Jaafar Bennouna, Karen Kelly, Nicholas Iannotti, Marcis Bajars, Guy Jerusalem, David Spigel, Claire F Verschraegen, Edward F Mcclay, Charles H Redfern, Franklin L Chen
    Abstract:

    Introduction Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line Avelumab in advanced non-small cell lung cancer (NSCLC).Methods In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg Avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Results Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred.Conclusion Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of Avelumab in the phase III JAVELIN Lung 100 study.Trial registration details ClinicalTrials.gov NCT01772004; registered January 21, 2013

  • efficacy and safety of Avelumab for patients with recurrent or refractory ovarian cancer phase 1b results from the javelin solid tumor trial
    JAMA Oncology, 2019
    Co-Authors: Mary L Disis, Manish R. Patel, Michael Gordon, Karen Kelly, Thaddeus J Beck, Matthew H Taylor, Jorge Chaves, Kathleen M Moore, Haeseong Park, Alain C Mita
    Abstract:

    Importance Current treatment options for progressive ovarian cancer provide limited benefit, particularly in patients whose disease has become resistant to platinum-based chemotherapy. Objective To assess the efficacy and safety of Avelumab, an anti–programmed death-ligand 1 agent, in a cohort of patients with previously treated recurrent or refractory ovarian cancer. Design, Setting, and Participants In an expansion cohort of a phase 1b, open-label study (JAVELIN Solid Tumor), 125 patients with advanced ovarian cancer who had received chemotherapy including a platinum agent were enrolled between November 6, 2013, and August 27, 2015. Statistical analysis was performed from December 31, 2016, to October 9, 2018. Intervention Patients received Avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. Main Outcomes and Measures Prespecified end points in this cohort included confirmed best overall response (per Response Evaluation Criteria In Solid Tumors, version 1.1), immune-related best overall response, duration of response, progression-free survival, overall survival, results of programmed death-ligand 1 expression–based analyses, and safety. Results A total of 125 women (median age, 62.0 years [range, 27-84 years]) who had received a median of 3 prior lines of treatment (range, 0-10) for advanced disease were enrolled in the study. Patients received Avelumab for a median of 2.8 months (range, 0.5-27.4 months), with a median follow-up of 26.6 months (range, 16-38 months). A confirmed objective response occurred in 12 patients (9.6%; 95% CI, 5.1%-16.2%), including a complete response in 1 patient (0.8%) and a partial response in 11 patients (8.8%). The 1-year progression-free survival rate was 10.2% (95% CI, 5.4%-16.7%) and median overall survival was 11.2 months (95% CI, 8.7-15.4 months). Infusion-related reactions occurred in 25 patients (20.0%). Other frequent treatment-related adverse events (any grade event occurring in ≥10% of patients) were fatigue (17 [13.6%]), diarrhea (15 [12.0%]), and nausea (14 [11.2%]). Grade 3 or higher treatment-related adverse events occurred in 9 patients (7.2%), of which only the level of lipase increased (3 [2.4%]) occurred in more than 1 patient. Twenty-one patients (16.8%) had an immune-related adverse event of any grade. No treatment-related deaths occurred. Conclusions and Relevance Avelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer. Trial Registration ClinicalTrials.gov identifier:NCT01772004

  • safety profile of Avelumab in patients with advanced solid tumors a javelin pooled analysis of phase 1 and 2 data
    Journal of Clinical Oncology, 2017
    Co-Authors: Karen Kelly, Manish R. Patel, Jeffrey R Infante, Michael S Gordon, Matthew H Taylor, Deborah Jean Lee Wong, Nicholas Iannotti, Janice M Mehnert, Anja Loos, Helga Koch
    Abstract:

    3059Background: Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of Avelumab. Methods: Patients (pts) received Avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received ≥1 dose of Avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = ...

  • Avelumab an anti programmed death ligand 1 antibody in patients with refractory metastatic urothelial carcinoma results from a multicenter phase ib study
    Journal of Clinical Oncology, 2017
    Co-Authors: Andrea B Apolo, Manish R. Patel, Carolyn D Britten, Jeffrey R Infante, Ani Balmanoukian, Ding Wang, Karen Kelly, Anthony Mega, Alain Ravaud, Alain C Mita
    Abstract:

    Purpose We assessed the safety and antitumor activity of Avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received Avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with Avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.

  • Avelumab an anti programmed death ligand 1 antibody in patients with refractory metastatic urothelial carcinoma results from a multicenter phase ib study
    Journal of Clinical Oncology, 2017
    Co-Authors: Andrea B Apolo, Manish R. Patel, Carolyn D Britten, Jeffrey R Infante, Ani Balmanoukian, Ding Wang, Karen Kelly, Alain Ravaud, Anthony E Mega, Alain C Mita
    Abstract:

    PurposeWe assessed the safety and antitumor activity of Avelumab, a fully human anti–programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma.MethodsIn this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received Avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1–associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells.ResultsForty-four patients were treated with Avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of an...

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  • first line Avelumab in a cohort of 116 patients with metastatic merkel cell carcinoma javelin merkel 200 primary and biomarker analyses of a phase ii study
    Journal for ImmunoTherapy of Cancer, 2021
    Co-Authors: Celeste Lebbe, Laurent Mortier, Andrew S Brohl, Nicola Fazio, Glenn J Hanna, Sandra P Dangelo, Jeanjacques Grob, Natalie Prinzi, Jessica C Hassel
    Abstract:

    Background Avelumab (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. Methods Patients 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. Results In 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. Conclusion In 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.

  • health related quality of life trajectory of treatment naive patients with merkel cell carcinoma receiving Avelumab
    Future Oncology, 2020
    Co-Authors: Murtuza Bharmal, Sandra Nolte, Celeste Lebbe, Laurent Mortier, Andrew S Brohl, Nicola Fazio, Jeanjacquez Grob, Sara Pusceddu, Glenn J Hanna, Jessica C Hassel
    Abstract:

    Aim: To evaluate changes in health-related quality of life (HRQoL) in a Phase II trial (NCT02155647) of treatment-naive patients with metastatic Merkel cell carcinoma treated with Avelumab (15-month follow-up). Materials & methods: Mixed-effect Models for Repeated Measures were applied to HRQoL data (FACT-M; EQ-5D-5L) to assess changes over time. Clinically derived progression-free survival was compared with HRQoL deterioration-free survival. Results: Overall, we saw relative stability in HRQoL among 116 included patients, with nonprogression associated with statistically and clinically meaningful better HRQoL compared with progressive disease. Deterioration-free survival rates (49-72% at 6 months, 40-58% at 12 months) were consistently higher/better compared with progression-free survival rates (41/31% at 6/12 months). Conclusion: These findings show unique longitudinal HRQoL data for treatment-naive metastatic Merkel cell carcinoma patients treated with Avelumab. Clinical trial registration: NCT02155647 (ClinicalTrials.gov).

  • Avelumab in patients with previously treated metastatic merkel cell carcinoma long term data and biomarker analyses from the single arm phase 2 javelin merkel 200 trial
    Journal for ImmunoTherapy of Cancer, 2020
    Co-Authors: Omid Hamid, Andrew S Brohl, Shailender Bhatia, Patrick Terheyden, Sandra P Dangelo, Kent C Shih, Janice M Mehnert, Isaac Brownell, Celeste Lebbe
    Abstract:

    Background 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. Methods 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. Results 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. Conclusions 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. Trial registration number NCT02155647

  • 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
    JAMA Oncology, 2018
    Co-Authors: Celeste Lebbe, Jeffery Russell, Sandra P Dangelo, Jeanjacques Grob, Bartosz Chmielowski, Thilo Gambichler, Felix Kiecker, Guilherme Rabinowits, Patrick Terheyden
    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

  • updated efficacy of Avelumab in patients with previously treated metastatic merkel cell carcinoma after 1 year of follow up javelin merkel 200 a phase 2 clinical trial
    Journal for ImmunoTherapy of Cancer, 2018
    Co-Authors: Howard L Kaufman, Omid Hamid, Celeste Lebbe, Jeffery Russell, Shailender Bhatia, Patrick Terheyden, Sandra P Dangelo, Kent C Shih, Michele Milella, Isaac Brownell
    Abstract:

    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 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). 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. 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. Clinicaltrials.gov identifier: NCT02155647.

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