Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial

Heery, Christopher R.; Coyne, Geraldine Helen O'Sullivan; Madan, Ravi A.; Cordes, Lisa; Rajan, Arun; Rauckhorst, Myrna; Lamping, Elizabeth; Oyelakin, Israel; Marté, Jennifer L.; Lepone, Lauren M.; Donahue, Renee N.; Grenga, Italia; Cuillerot, Jean-Marie; Neuteboom, Berend; Heydebreck, Anja von; Chin, Kevin M.; Schlom, Jeffrey; Gulley, James L.

doi:10.1016/s1470-2045(17)30239-5

Cited by 272 publications

(289 citation statements)

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“…51 The avelumab dose of 10 mg/kg every 2 weeks was selected based on adequate safety and tolerability, as well as PK and target occupancy data. 52 No MTD was reached with doses up to 20 mg/kg. Mean target occupancy was 90% or higher at doses of 3 and 10 mg/kg.…”

Section: Dose Selectionmentioning

confidence: 99%

“…[30][31][32]40,41,44,46,51,52,[56][57][58][66][67][68][69][70][71][72][73] PK characteristics listed and described here are not an exhaustive characterization of each agent. Characteristics were linear over at least a part of the dose ranges tested for all 6 agents, although the PK for pembrolizumab, durvalumab, and avelumab was nonlinear at doses of <0.1, 46 <3, 32 and <10 mg/kg, 52 respectively. As expected for these mAbs, all had a relatively low distribution (volumes of distribution of 4.72 to 6.9 L).…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

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Section: Dose Selectionmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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“…Avelumab, a human anti–PD‐L1 immunoglobulin (Ig) G1 antibody that specifically inhibits PD‐L1/PD‐1 interactions,4 is approved in the United States and European Union for the treatment of metastatic Merkel cell carcinoma (mMCC),5, 6 in Japan for the treatment of MCC that cannot be completely cured with surgery, and in the United States for the treatment of locally advanced or metastatic urothelial carcinoma (UC) that has progressed during or after platinum‐containing chemotherapy 5…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Doses ≤20 mg/kg every 2 weeks (Q2W) were safely administered during the dose‐escalation phase 4. Based on pharmacokinetic, target occupancy, and safety analyses, a dose of 10 mg/kg Q2W was selected for further study 4. Objective responses and disease stabilization with avelumab have been reported in several tumor types, including non‐small cell lung cancer (NSCLC), UC, gastric and ovarian cancer, and mesothelioma,7, 8, 9, 10, 11 and pooled safety data have been presented previously in 1300 patients 12.…”

Section: Introductionmentioning

confidence: 99%

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Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Kelly

Infante

Taylor

et al. 2018

Cancer

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BACKGROUNDAntibodies targeting the programmed death‐ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy.METHODSPatients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti–PD‐L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment‐related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune‐related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion‐related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms.RESULTSOf the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%).CONCLUSIONSAvelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010‐7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Efficacy and Safety of Avelumab Treatment in Patients With Advanced Unresectable Mesothelioma

et al. 2019

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IMPORTANCE Patients with malignant mesothelioma whose disease has progressed after platinum and pemetrexed treatment have limited options. Anti-programmed cell death 1 (PD-1) antibodies have antitumor activity in this disease, but little is known about the activity of anti-programmed cell death ligand 1 (PD-L1) antibodies in patients with mesothelioma. OBJECTIVE To assess the efficacy and safety of avelumab in a cohort of patients with previously treated mesothelioma. DESIGN, SETTING, AND PARTICIPANTS Phase 1b open-label study (JAVELIN Solid Tumor) in patients with unresectable mesothelioma that progressed after platinum and pemetrexed treatment, enrolled at 25 sites in 3 countries between September 9, 2014, and July 22, 2015. INTERVENTIONS Participants 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 included confirmed best overall response based on Response Evaluation Criteria In Solid Tumors, version 1.1; duration of response; progression-free survival (PFS); overall survival (OS); PD-L1 expression-based analyses; and safety. RESULTS Of 53 patients treated with avelumab, the median age was 67 (range, 32-84) years; 32 (60%) were male. As of December 31, 2016, median follow-up was 24.8 (range, 16.8-27.8) months. Twenty patients (38%) had 3 or more previous lines of therapy (median, 2; range, 1-8). The confirmed objective response rate (ORR) was 9% (5 patients; 95% CI, 3.1%-20.7%), with complete response in 1 patient and partial response in 4 patients. Responses were durable (median, 15.2 months; 95% CI, 11.1 to not estimable months) and occurred in patients with PD-L1-positive tumors (3 of 16; ORR, 19%; 95% CI, 4.0%-45.6%) and PD-L1-negative tumors (2 of 27; ORR, 7%; 95% CI, 0.9%-24.3%) based on a 5% or greater PD-L1 cutoff. Disease control rate was 58% (31 patients). Median PFS was 4.1 (95% CI, 1.4-6.2) months, and the 12-month PFS rate was 17.4% (95% CI, 7.7%-30.4%). Median OS was 10.7 (95% CI, 6.4-20.2) months, and the median 12-month OS rate was 43.8% (95% CI, 29.8%-57.0%). Five patients (9%) had a grade 3 or 4 treatment-related adverse event, and 3 (6%) had a grade 3 or 4 immune-related, treatment-related adverse event. There were no treatment-related deaths. CONCLUSIONS AND RELEVANCE Avelumab showed durable antitumor activity and disease control with an acceptable safety profile in a heavily pretreated cohort of patients with mesothelioma. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01772004

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Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial

Abstract: National Cancer Institute and Merck KGaA.

Cited by 272 publications

References 34 publications

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Efficacy and Safety of Avelumab Treatment in Patients With Advanced Unresectable Mesothelioma

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