Avelumab: clinical trial innovation and collaboration to advance anti-PD-L1 immunotherapy
2017; Elsevier BV; Volume: 28; Issue: 7 Linguagem: Inglês
10.1093/annonc/mdx170
ISSN1569-8041
AutoresKevin M. Chin, Vikram K. Chand, Dimitry S.A. Nuyten,
Tópico(s)Immunotherapy and Immune Responses
ResumoCancer development and progression are characterised by evasion of immune responses, including tumour escape mediated through immune checkpoint pathways [1.Dunn G.P. Bruce A.T. Ikeda H. et al.Cancer immunoediting: from immunosurveillance to tumor escape.Nat Immunol. 2002; 3: 991-998Crossref PubMed Scopus (3659) Google Scholar, 2.Schreiber R.D. Old L.J. Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.Science. 2011; 331: 1565-1570Crossref PubMed Scopus (4118) Google Scholar, 3.Hanahan D. Weinberg RA. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (43102) Google Scholar, 4.Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012; 12: 252-264Crossref PubMed Scopus (8958) Google Scholar]. Programmed death ligand-1 (PD-L1) is a suppressive immune checkpoint ligand that binds two receptors expressed on T cells—programmed death-1 (PD-1) and B7.1 (CD80)—to inhibit T-cell activation, proliferation, and cytotoxicity [5.Dong H. Strome S.E. Salomao D.R. et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.Nat Med. 2002; 8: 793-800Crossref PubMed Scopus (3777) Google Scholar, 6.Iwai Y. Ishida M. Tanaka Y. et al.Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.Proc Natl Acad Sci USA. 2002; 99: 12293-12297Crossref PubMed Scopus (2246) Google Scholar, 7.Latchman Y.E. Liang S.C. Wu Y. et al.PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells.Proc Natl Acad Sci U S A. 2004; 101: 10691-10696Crossref PubMed Scopus (489) Google Scholar, 8.Freeman G.J. Long A.J. 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A second checkpoint pathway ligand for PD-1, PD-L2, is expressed on various immune cells and may play a role in immune homeostasis [11.Latchman Y. Wood C.R. Chernova T. et al.PD-L2 is a second ligand for PD-1 and inhibits T cell activation.Nat Immunol. 2001; 2: 261-268Crossref PubMed Scopus (2174) Google Scholar, 12.Rozali E.N. Hato S.V. Robinson B.W. et al.Programmed death ligand 2 in cancer-induced immune suppression.Clin Dev Immunol. 2012; 2012: 656340Crossref PubMed Scopus (232) Google Scholar]. By overexpressing PD-L1, cancer cells exploit the PD-1/PD-L1 pathway to promote an immunosuppressive environment and allow tumour growth [5.Dong H. Strome S.E. Salomao D.R. et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.Nat Med. 2002; 8: 793-800Crossref PubMed Scopus (3777) Google Scholar, 13.Topalian S.L. Drake C.G. Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity.Curr Opin Immunol. 2012; 24: 207-212Crossref PubMed Scopus (1027) Google Scholar]. Blocking PD-L1 inhibitory signals can restore T-cell antitumour activity and thus represents a key therapeutic strategy [13.Topalian S.L. Drake C.G. Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity.Curr Opin Immunol. 2012; 24: 207-212Crossref PubMed Scopus (1027) Google Scholar, 14.Postow M.A. Callahan M.K. Wolchok JD. Immune checkpoint blockade in cancer therapy.J Clin Oncol. 2015; 33: 1974-1982Crossref PubMed Scopus (1841) Google Scholar]. Five checkpoint inhibitors are currently approved by the US Food and Drug Administration (FDA) for the treatment of cancer, including an anti-CTLA-4 antibody (ipilimumab), anti-PD-1 antibodies (pembrolizumab and nivolumab), and anti-PD-L1 antibodies (atezolizumab and avelumab). Avelumab (MSB0010718C) is a human immunoglobulin G1 (IgG1) anti-PD-L1 monoclonal antibody [15.Heery C.R. O'Sullivan-Coyne G. Madan R.A. et al.Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.Lancet Oncol. 2017; Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar] with the potential to utilise both adaptive and innate immune mechanisms to destroy cancer cells [5.Dong H. Strome S.E. Salomao D.R. et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.Nat Med. 2002; 8: 793-800Crossref PubMed Scopus (3777) Google Scholar, 15.Heery C.R. O'Sullivan-Coyne G. Madan R.A. et al.Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.Lancet Oncol. 2017; Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 16.Boyerinas B. Jochems C. Fantini M. et al.Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells.Cancer Immunol Res. 2015; 3: 1148-1157Crossref PubMed Scopus (338) Google Scholar]. Its ability to induce innate immune mechanisms against cancer cells, shown in preclinical studies [17.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=avelumab&Search=Search. Updated 2016 (20 December 2016, date last accessed).Google Scholar], makes avelumab unique among anti-PD-L1 or anti-PD-1 antibodies approved or in advanced clinical development. Avelumab is being evaluated in the international JAVELIN clinical trial programme across more than 16 different tumour types, both as monotherapy and in combination [17.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=avelumab&Search=Search. Updated 2016 (20 December 2016, date last accessed).Google Scholar]. This programme is sponsored by an alliance between two global companies, Merck KGaA, Darmstadt, Germany, and Pfizer, Inc., New York, NY. Evidence of promising antitumour activity and manageable adverse events has been demonstrated for multiple advanced malignancies [18.Gulley J.L. Rajan A. Spigel D.R. et al.Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.Lancet Oncol. 2017; Abstract Full Text Full Text PDF Scopus (231) Google Scholar, 19.Apolo A.B. Infante J.R. Balmanoukian A. et al.Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter phase 1b study.J Clin Oncol. 2017; Crossref Scopus (461) Google Scholar, 20.Chung H.C. Arkenau H.T. Wyrwicz L. et al.Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced gastric or gastroesophageal junction cancer from JAVELIN Solid Tumor phase 1b trial: analysis of safety and clinical activity.J Clin Oncol. 2016; 34Google Scholar, 21.Disis M.L. Patel M. Pant S. et al.Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase 1b trial: safety and clinical activity.J Clin Oncol. 2016; 34Google Scholar, 22.Dirix L.Y. Takacs I. Nikolinakos P. et al.Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase lb JAVELIN Solid Tumor trial.Cancer Res. 2016; 76Google Scholar, 23.Hassan R. Thomas A. Patel M. et al.Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase 1b trial: safety, clinical activity, and PD-L1 expression.J Clin Oncol. 2016; 34PubMed Google Scholar, 24.Kaufman H.L. Russell J. Hamid O. et al.Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 1374-1385Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar], leading to accelerated approval of avelumab by the US FDA in March 2017 for the treatment of metastatic Merkel cell carcinoma [25.Bavencio (avelumab) [package insert]. Darmstadt, Germany; Merck KGaA; March, 2017.Google Scholar]. Here, we provide an overview of avelumab's development from discovery to registrational studies in multiple tumour types. Avelumab was developed within Merck laboratories in 2006 based on a strategic vision for cancer immunotherapy as a pillar of the Merck oncology research and development programme. Preclinical studies of avelumab commenced in 2009, with more formal preclinical development starting in 2011 as part of Merck's translational innovation platform in immuno-oncology (Figure 1). Avelumab is thought to specifically bind to PD-L1, preventing the interaction between PD-L1 and the inhibitory T-cell receptor PD-1. PD-L1 blockade removes the suppression of T-cell activity, resulting in T-cell-mediated, adaptive antitumour immune responses, which can be measured by the effect of avelumab on interferon-γ release [26.Grenga I. Donahue R.N. Lepone L.M. et al.A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses.Clin Transl Immunol. 2016; 5: e83Crossref PubMed Google Scholar]. In addition, avelumab inhibits the interaction of PD-L1 with a second inhibitory receptor, B7.1, which may be expressed on APCs and T cells [9.Butte M.J. Keir M.E. Phamduy T.B. et al.Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.Immunity. 2007; 27: 111-122Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar]. Thus, avelumab may also potentiate T-cell reactivation and cytokine production by inhibiting the interaction with PD-1 and B7.1 on T cells with PD-L1 on APCs in the tumour microenvironment or lymph node [27.Brown J.A. Dorfman D.M. Ma F.R. et al.Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.J Immunol. 2003; 170: 1257-1266Crossref PubMed Scopus (789) Google Scholar]. Avelumab does not disrupt the interaction between PD-L1 and PD-L2, thereby allowing continuity of PD-L2-mediated homeostasis [12.Rozali E.N. Hato S.V. Robinson B.W. et al.Programmed death ligand 2 in cancer-induced immune suppression.Clin Dev Immunol. 2012; 2012: 656340Crossref PubMed Scopus (232) Google Scholar]. Unlike other anti-PD-L1 or anti-PD-1 antibodies, avelumab has a wild-type IgG1 crystallizable fragment (Fc) region, which enables avelumab to engage with Fc-γ receptors on natural killer cells and induce tumour-directed antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro [16.Boyerinas B. Jochems C. Fantini M. et al.Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells.Cancer Immunol Res. 2015; 3: 1148-1157Crossref PubMed Scopus (338) Google Scholar, 28.Fujii R. Friedman E.R. Richards J. et al.Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab.Oncotarget. 2016; 7: 33498-33511Crossref PubMed Scopus (77) Google Scholar]. ADCC is a demonstrated mechanism of action for several approved anticancer monoclonal antibodies, including cetuximab, rituximab, and trastuzumab [29.Weiner L.M. Surana R. Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy.Nat Rev Immunol. 2010; 10: 317-327Crossref PubMed Scopus (912) Google Scholar]. Anti-PD-1 IgG4 antibodies (e.g. nivolumab or pembrolizumab) and engineered anti-PD-L1 IgG1 antibodies (e.g. atezolizumab or durvalumab) have been developed to minimise or disable ADCC, based on a theoretical potential for ADCC to deplete activated T cells [30.Herbst R.S. Soria J.C. Kowanetz M. et al.Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.Nature. 2014; 515: 563-567Crossref PubMed Scopus (3717) Google Scholar, 31.Khleif S.N. Lutsky J. Segal N. et al.MEDI4736, an anti-PD-L1 antibody with modified Fc domain: preclinical evaluation and early clinical results from a phase 1 study in patients with advanced solid tumors.Eur J Cancer. 2013; 49Google Scholar, 32.Gettinger S. Herbst RS. B7-H1/PD-1 blockade therapy in non-small cell lung cancer: current status and future direction.Cancer J. 2014; 20: 281-289Crossref PubMed Scopus (58) Google Scholar]. Importantly, preclinical and clinical studies showed minimal changes in immune cell subsets with avelumab treatment [26.Grenga I. Donahue R.N. Lepone L.M. et al.A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses.Clin Transl Immunol. 2016; 5: e83Crossref PubMed Google Scholar, 33.Donahue R.N. Lepone L.M. Grenga I. et al.Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody.J Immunother Cancer. 2017; 5: 20Crossref PubMed Scopus (67) Google Scholar]. PD-L1 blockade with avelumab therefore has the potential to both enhance tumour-specific effector T cell activity and induce ADCC-mediated lysis of tumour cells, representing a potential unique dual mechanism of action compared with other anti-PD-1/PD-L1 antibodies (Figure 2). The first-in-human trial of avelumab, which began in January 2013, has been carried out in partnership with the US National Cancer Institute. This phase 1 study, JAVELIN Solid Tumor (NCT01772004), evolved in size and scope to become a large dose-escalation and multicohort dose-expansion trial [15.Heery C.R. O'Sullivan-Coyne G. Madan R.A. et al.Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.Lancet Oncol. 2017; Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 17.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=avelumab&Search=Search. Updated 2016 (20 December 2016, date last accessed).Google Scholar] and is described in detail in the next section. In parallel, the JAVELIN Solid Tumor JPN (NCT01943461) trial, which included a dose-escalation cohort in patients with advanced tumours and a dose-expansion cohort in gastric cancer, was opened in Japan in September 2013 [17.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=avelumab&Search=Search. Updated 2016 (20 December 2016, date last accessed).Google Scholar, 34.Shitara K. Yamada Y. Yoh K. et al.Phase I, open-label, multi-ascending dose trial of avelumab (MSB0010718C), an anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors.J Clin Oncol. 2015; 33Crossref Google Scholar]. The first phase 2 study of avelumab, JAVELIN Merkel 200 (NCT02155647), was launched in July 2014 and enrolled patients with Merkel cell carcinoma (MCC) progressed after chemotherapy. MCC is a rare, aggressive, and highly immunogenic skin cancer [35.Agelli M. Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States.J Am Acad Dermatol. 2003; 49: 832-841Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar, 36.Goh G. Walradt T. Markarov V. et al.Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.Oncotarget. 2016; 7: 3403-3415Crossref PubMed Scopus (253) Google Scholar, 37.Feng H. Shuda M. Chang Y. Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma.Science. 2008; 319: 1096-1100Crossref PubMed Scopus (2390) Google Scholar, 38.Lipson E.J. Vincent J.G. Loyo M. et al.PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.Cancer Immunol Res. 2013; 1: 54-63Crossref PubMed Scopus (285) Google Scholar]. Patients with advanced-stage MCC have a 5-year overall survival rate ranging from 0% to 18% [39.Lemos B.D. Storer B.E. Iyer J.G. et al.Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.J Am Acad Dermatol. 2010; 63: 751-761Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 40.Santamaria-Barria J.A. Boland G.M. Yeap B.Y. et al.Merkel cell carcinoma: 30-year experience from a single institution.Ann Surg Oncol. 2013; 20: 1365-1373Crossref PubMed Scopus (94) Google Scholar] and a mortality rate higher than that seen in patients with melanoma [41.Grabowski J. Saltzstein S.L. Sadler G.R. et al.A comparison of Merkel cell carcinoma and melanoma: results from the California Cancer Registry.Clin Med Oncol. 2008; 2: 327-333Crossref PubMed Google Scholar]. Patients with advanced MCC are typically treated with chemotherapy; however, there is no established standard of care [42.NCCN Clinical Practice Guidelines in Oncology. Merkel Cell Carcinoma. V1.2017.Google Scholar, 43.Lebbe C. Becker J.C. Grob J.J. et al.Diagnosis and treatment of Merkel cell carcinoma. European consensus-based interdisciplinary guideline.Eur J Cancer. 2015; 51: 2396-2403Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar] and responses are seldom durable [44.Iyer J.G. Blom A. Doumani R. et al.Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.Cancer Med. 2016; 5: 2294-2301Crossref PubMed Scopus (161) Google Scholar]. In 2015, preliminary efficacy and safety data from JAVELIN Merkel 200 led to avelumab receiving breakthrough, fast-track, and orphan-drug designations from the FDA and a positive opinion for orphan-drug status from the European Medicines Agency. Recently published data from the primary analysis of JAVELIN Merkel 200 showed that patients with distant metastatic MCC treated with avelumab (n = 88) had an objective response rate of 31.8% [95.9% CI (exact repeated), 21.9–43.1], including 9.1% achieving complete remission, with responses ongoing in 82% of responders at the time of analysis [6-month durable response rate of 29% (95% CI, 20–39)] and a 6-month progression-free survival (PFS) rate of 40% (95% CI, 29–50), demonstrating the efficacy of avelumab in this aggressive disease [24.Kaufman H.L. Russell J. Hamid O. et al.Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 1374-1385Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar]and leading to FDA approval of avelumab in this indication [25.Bavencio (avelumab) [package insert]. Darmstadt, Germany; Merck KGaA; March, 2017.Google Scholar]. JAVELIN Solid Tumor is an international, multicohort, open-label, single-arm, multiple-ascending-dose phase 1 study that is one of the largest phase 1 studies carried out to date (>1700 patients enrolled) [46.Kelly K. Heery C.R. Patel M.R. et al.Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced cancer: Safety data from 1300 patients enrolled in the phase 1b JAVELIN Solid Tumor trial.J Clin Oncol. 2016; 34Google Scholar]. This study has evolved beyond its initial design to comprise a dose-escalation part, plus 4 primary expansion cohorts, 8 secondary expansion cohorts, and 4 efficacy expansion cohorts in 12 tumour types (Figure 3) [17.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=avelumab&Search=Search. Updated 2016 (20 December 2016, date last accessed).Google Scholar, 46.Kelly K. Heery C.R. Patel M.R. et al.Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced cancer: Safety data from 1300 patients enrolled in the phase 1b JAVELIN Solid Tumor trial.J Clin Oncol. 2016; 34Google Scholar]. Its primary objectives are twofold: (i) assess the safety and tolerability and determine the maximum tolerated dose (MTD) of avelumab in patients with metastatic or locally advanced solid tumours; and (ii) evaluate best overall response (BOR) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 [47.Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18258) Google Scholar] in efficacy expansion cohorts. Secondary and exploratory objectives include assessment of BOR and PFS by RECIST v1.1, overall survival (OS), and clinical activity by modified immune-related response criteria (irRC) [48.Wolchok J.D. Hoos A. O'Day S. et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009; 15: 7412-7420Crossref PubMed Scopus (2520) Google Scholar]; characterization of pharmacokinetics (PK), target occupancy, and immunogenicity; and evaluation of PD-L1 expression and other potential biomarkers. In all cohorts, patients have been enrolled irrespective of PD-L1 expression status. The dose-escalation part of the trial used a 3 + 3 design, which established the dose level (10 mg/kg) and administration schedule (Q2W) for further studies based on observed safety, PK, and pharmacodynamics data. Of 53 patients enrolled in the dose-escalation part who received avelumab doses of 1–20 mg/kg Q2W, one dose-limiting toxicity occurred at 20 mg/kg in a patient with thymic cancer, and the MTD was not reached. Avelumab exhibited a linear PK profile over the investigational dose range, with maximum plasma concentrations reached within 1 h from the end of infusion and a half-life of ∼4 days seen at the highest doses [15.Heery C.R. O'Sullivan-Coyne G. Madan R.A. et al.Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.Lancet Oncol. 2017; Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar]. Analysis of patient samples showed that avelumab 10 mg/kg treatment resulted in >90% target occupancy at the end of the 2-week dosing interval [15.Heery C.R. O'Sullivan-Coyne G. Madan R.A. et al.Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.Lancet Oncol. 2017; Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar]. Following the dose-escalation part, 16 expansion cohorts were opened through stepwise protocol amendments and based on preliminary data analyses (Figure 3; Table 1). Tumour types were selected based on high unmet need, evidence of PD-L1 overexpression, and evidence for susceptibility to cancer immunotherapy, including in the JAVELIN Solid Tumor trial itself. In selected cohorts, planned enrolment was increased to further characterise clinical activity. The size of the four primary cohorts (n = 150) was chosen to explore the safety and efficacy of avelumab in specific indications, including subgroups defined by PD-L1 expression. The 4 efficacy cohorts included a primary endpoint of BOR adjudicated by blinded independent review.Table 1Key eligibility criteria for the JAVELIN Solid Tumor phase 1 trialInclusion criteriaExclusion criteria•Age ≥18 years•Histologically or cytologically confirmed locally advanced or metastatic advanced solid tumour•Biopsy material required (archival tissue acceptable if patient could not provide fresh or recent biopsy)•ECOG performance status score of 0–1 at study entry•Estimated life expectancy ≥3 months•Measurable lesion by RECIST v1.1 (except castration-resistant prostate cancer or metastatic breast cancer)•Adequate haematologic, hepatic, and renal function•Signed written informed consent•Concurrent treatment with an anticancer treatment or other non-permitted drug•Prior therapy with any drug targeting T-cell coregulatory proteins (patients with metastatic melanoma who had received prior treatment with an anti-CTLA-4 antibody were allowed)•Concurrent systemic therapy with corticosteroids or other immunosuppressive agents or use of any investigational drug within 28 days before starting trial drug; short-term administration of systemic steroids (for allergic reactions or management of immune-mediated adverse events) while on study is allowed•Active or history of central nervous metastases•Previous malignant disease (other than primary malignancy) within the last 5 years, except basal or squamous cell carcinoma of the skin or cervical carcinoma in situ•Prior organ transplantation, including allogenic stem-cell transplantation•Known history or testing positive for HIV/AIDS, HBV, or HCV (including acute and chronic infection)•Active or history of any autoimmune disease or immune deficiencies (patients with type 1 diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment were eligible)•Known monoclonal antibody hypersensitivity, history of anaphylaxis, or uncontrolled asthma•Persisting toxicity related to prior therapy that was grade >1 according to NCI CTCAE v4.0; grade ≤2 sensory neuropathy was allowed•Clinically significant cardiovascular disease, or other diseases that in the investigator's opinion may influence the patient's tolerance of trial treatmentPrimary expansion cohorts (planned enrolment)NSCLC second line (n=150)•Stage IIIB or stage IV NSCLC progressed after one line of platinum-containing doublet chemotherapyNSCLC first line (n=150)•Stage IV or recurrent NSCLC•No activating EGFR mutation or ALK rearrangement•No prior treatment of metastatic or recurrent diseaseGastric and GEJ adenocarcinoma (n=150)•Unresectable locally advanced or metastatic adenocarcinoma of the stomach or GEJ, treated with first-line chemotherapy combination with or without disease progression•No prior trastuzumab treatment (HER2-positive status allowed)Breast cancer (n=150)•Locally advanced or metastatic breast cancer refractory to or progressive after standard-of-care therapy•≤3 prior lines of therapy for metastatic disease•Prior taxane and anthracycline treatment, unless contraindicatedSecondary expansion cohorts (planned enrolment)Ovarian cancer (n=120)•Recurrent or refractory, stage III-IV epithelial ovarian, fallopian tube, or peritoneal cancer progressed following adjuvant therapy or therapy for metastatic diseaseRenal cell carcinoma (n=20) with first-line expansion (n=60)•Metastatic RCC with a clear-cell componentAdrenocortical carcinoma (n=50)•Metastatic ACC•≥1 line of systemic therapy for metastatic disease (≥1 must be platinum based)•Patients receiving mitotane at enrolment were permitted to receive ongoing mitotane on studyMesothelioma (n=50)•Mesothelioma with unresectable disease progressed after either a platinum–pemetrexed-containing regimen or a platinum-containing regimen followed by pemetrexed after disease progressionMelanoma (n=50)•Stage IIIc or IV unresectable melanoma progressed after ≥1 prior standard therapy for metastatic diseaseUrothelial carcinoma (n=50)•Locally advanced or metastatic transitional cell carcinoma of the urothelium•Either ineligible for cisplatin-based chemotherapy or progressed after ≥1 platinum-containing regimenCastration-resistant prostate cancer (n=20)•Asymptomatic metastatic CRPC or minimally symptomatic with objective evidence of disease with stable, ongoing adequate testosterone suppression•Additional androgen blockade or treatment with an antiandrogen receptor was permittedColorectal cancer (n=20)•Recurrent or refractory metastatic CRC progressed after therapy containing oxaliplatin/fluoropyrimidine and/or irinotecan/fluoropyrimidine and, if eligible, cetuximab and bevacizumabEfficacy expansion cohorts (planned enrolment)Urothelial carcinoma (n=200)•Locally advanced or metastatic transitional cell carcinoma of the urothelium•Either ineligible for cisplatin-based chemotherapy or progressed after treatment with ≥1 platinum-containing regimenHead and neck cancer (n=150)•Recurrent or metastatic SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx progressed or recurrent within 6 months of the last dose of platinum-based chemotherapy given in the adjuvant, primary, recurrent, or metastatic setting, or platinum ineligibleGastric and GEJ adenocarcinoma (n=150)•Unresectable locally advanced or metastatic adenocarcinoma of the stomach or GEJ progressed after two lines of chemotherapy, including a ramucirumab-containing regimen in the second-line settingOvarian cancer, platinum resistant (n=100)•Confirmed, platinum-resistant (progression within 6 months of platinum-based therapy), stage III and IV epithelial ovarian, fallopian tube, or peritoneal cancer•≥1 line of prior platinum-based chemotherapy regimen and prior liposomal doxorubicin (monotherapy or combination)Target enrolment in expansion cohorts is shown.ACC, adrenocortical carcinoma; CRC, colorectal cancer; CRPC, castration-resistant prostate cancer; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; GEJ, gastro-oesophageal junction; HBV, hepatitis B virus; HCV, hepatitis C virus; HER2, human epidermal growth factor 2; HIV, human immunodeficiency virus; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors; SCCHN, squamous cell carcinoma of the head and neck. Open table in a new tab Target enrolment in expansion cohorts is shown. ACC, adrenocortical carcin
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