Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial

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Abstract

Background

We assessed the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with previously treated metastatic adrenocortical carcinoma (mACC).

Methods

In this phase 1b expansion cohort, patients with mACC and prior platinum-based therapy received avelumab at 10 mg/kg intravenously every 2 weeks. Continuation of mitotane was permitted; however, mitotane levels during the study were not recorded. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors v1.1.

Results

Fifty patients received avelumab and were followed for a median of 16.5 months. Prior treatment included ≥2 lines in 74.0%; mitotane was continued in 50.0%. The objective response rate (ORR) was 6.0% (95% CI, 1.3% to 16.5%; partial response in 3 patients). Twenty-one patients (42.0%) had stable disease as best response (disease control rate, 48.0%). Median progression-free survival was 2.6 months (95% CI, 1.4 to 4.0), median overall survival (OS) was 10.6 months (95% CI, 7.4 to 15.0), and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). In evaluable patients with PD-L1+ ( n = 12) or PD-L1− ( n = 30) tumors (≥5% tumor cell cutoff), ORR was 16.7% vs 3.3% ( P = .192). Treatment-related adverse events (TRAEs) occurred in 82.0%; the most common were nausea (20.0%), fatigue (18.0%), hypothyroidism (14.0%), and pyrexia (14.0%). Grade 3 TRAEs occurred in 16.0%; no grade 4 to 5 TRAEs occurred. Twelve patients (24.0%) had an immune-related TRAE of any grade, which were grade 3 in 2 patients (4.0%): adrenal insufficiency ( n = 1), and pneumonitis ( n = 1).

Conclusions

Avelumab showed clinical activity and a manageable safety profile in patients with platinum-treated mACC.

Trial registration

Clinicaltrials.gov NCT01772004; registered January 21, 2013.

Electronic supplementary material

The online version of this article (10.1186/s40425-018-0424-9) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 20

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Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

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Martin Fassnacht, Sarah Johanssen, Marcus Quinkler … (2009)

Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated. The German ACC Registry comprising 492 patients was searched for patients who were diagnosed between 1986 and 2007 with detailed information on primary diagnosis and a minimum follow-up of 6 months. Patients were assigned to UICC tumor stage, and disease-specific survival (DSS) was assessed. In addition, the contribution of potential risk factors for DSS was evaluated. In total, 416 patients with a mean follow-up of 36 months met the inclusion criteria (stage I, n=23 patients; stage II, n=176 patients; stage III, n=67 patients; stage IV, n=150 patients). Kaplan-Meier analysis revealed a stage-dependent DSS. However, DSS in patients with stage II ACC did not differ significantly from DSS in patients with stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16). Furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P=.004). An analysis of different potential risk factors for defining stage III ACC revealed important roles in DSS for tumor infiltration in surrounding tissue, venous tumor thrombus (VTT), and positive lymph nodes; whereas tumor invasion in adjacent organs carried a prognosis similar to that of infiltration in surrounding tissue only. The 2004 UICC staging classification for ACC has significant limitations. On the basis of the current analysis, a revised classification with superior prognostic accuracy is proposed (the European Network for the Study of Adrenal Tumors classification). In this system, stage III ACC is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or VTT; and stage IV ACC is restricted to patients with distant metastasis. Copyright (c) 2009 American Cancer Society.

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All references

Author and article information

Contributors

Christophe Le Tourneau: +33 144324675 , christophe.letourneau@curie.fr

Christopher Hoimes: Christopher.Hoimes@UHhospitals.org

Corrine Zarwan: corrine.zarwan@lahey.org

Deborah J. Wong: DeWong@mednet.ucla.edu

Sebastian Bauer: sebastian.bauer@uk-essen.de

Rainer Claus: Rainer.Claus@klinikum-augsburg.de

Martin Wermke: Martin.Wermke@uniklinikum-dresden.de

Subramanian Hariharan: s.hariharan@pfizer.com

Anja von Heydebreck: Anja.von.Heydebreck@merckgroup.com

Vijay Kasturi: vijay.kasturi@emdserono.com

Vikram Chand: vikramkchand@gmail.com

James L. Gulley: gulleyj@mail.nih.gov

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 22 October 2018

Publication date PMC-release: 22 October 2018

Publication date Collection: 2018

Volume: 6

Electronic Location Identifier: 111

Affiliations

[1 ]ISNI 0000 0004 0639 6384, GRID grid.418596.7, Department of Medical Oncology, , Institut Curie, ; 26, rue d’ulm, 75005 Paris & Saint-Cloud, France

[2 ]Versailles Saint Quentin en Yvenlines University, Montigny-le-Bretonneux, France

[3 ]INSERM U900 Research Unit, Saint-Cloud, France

[4 ]ISNI 0000 0004 0418 9795, GRID grid.473817.e, Case Western Reserve University and University Hospitals Seidman Cancer Center, ; Cleveland, OH USA

[5 ]ISNI 0000 0001 0725 1353, GRID grid.415731.5, Lahey Hospital and Medical Center, ; Burlington, MA USA

[6 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, UCLA Department of Medicine, ; California, Los Angeles USA

[7 ]ISNI 0000 0001 2187 5445, GRID grid.5718.b, Department of Medical Oncology, West German Cancer Centre, , University of Duisburg-Essen, ; Hufelandstraße, Essen, Germany

[8 ]ISNI 0000 0001 0262 7331, GRID grid.410718.b, German Cancer Consortium, , Partner Site University Hospital Essen, ; Essen, Germany

[9 ]Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

[10 ]Present address: Department of Hematology and Oncology, Augsburg Medical Center, Augsburg, Germany

[11 ]Early Clinical Trial Unit, University Cancer Center, Dresden, Germany

[12 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Pfizer, Inc, ; New York, NY USA

[13 ]ISNI 0000 0001 0672 7022, GRID grid.39009.33, Merck KGaA, ; Darmstadt, Germany

[14 ]ISNI 0000 0004 0412 6436, GRID grid.467308.e, EMD Serono Inc, ; Rockland, MA USA

[15 ]EMD Serono Research and Development Institute, Billerica, MA USA

[16 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, National Cancer Institute, National Institutes of Health, ; Bethesda, MD USA

Article

Publisher ID: 424

DOI: 10.1186/s40425-018-0424-9

PMC ID: 6198369

PubMed ID: 30348224

SO-VID: a32ed1b6-1cc8-464a-8c50-bba059e9827c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 April 2018

Date accepted : 7 October 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009945, Merck KGaA;

Funded by: FundRef http://dx.doi.org/10.13039/100004319, Pfizer;

Custom metadata

Keywords: avelumab,adrenocortical carcinoma,pd-l1,phase 1,javelin solid tumor,neuroendocrine tumors

Data availability:

Keywords: avelumab, adrenocortical carcinoma, pd-l1, phase 1, javelin solid tumor, neuroendocrine tumors