A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

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Abstract

Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

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Most cited references 25

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Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

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Author and article information

Contributors

Rahul Aggarwal:

ORCID: http://orcid.org/0000-0001-7003-7982

Rahul.Aggarwal@ucsf.edu

Journal

Journal ID (nlm-ta): NPJ Precis Oncol

Journal ID (iso-abbrev): NPJ Precis Oncol

Title: NPJ Precision Oncology

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2397-768X

Publication date (Electronic): 5 August 2021

Publication date PMC-release: 5 August 2021

Publication date Collection: 2021

Volume: 5

Electronic Location Identifier: 74

Affiliations

[1 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Mayo Clinic, ; Rochester, MN USA

[2 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[3 ]GRID grid.280502.d, ISNI 0000 0000 8741 3625, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, ; Baltimore, MD USA

[4 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Massachusetts General Hospital, ; Boston, MA USA

[5 ]GRID grid.65499.37, ISNI 0000 0001 2106 9910, Dana-Farber Cancer Institute, ; Boston, MA USA

[6 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Washington University School of Medicine, ; St. Louis, MO USA

[7 ]GRID grid.50956.3f, ISNI 0000 0001 2152 9905, Cedars-Sinai Medical Center, ; Los Angeles, CA USA

[8 ]GRID grid.461341.5, ISNI 0000 0004 0402 4392, University of Kentucky Chandler Medical Center, ; Lexington, KY USA

[9 ]GRID grid.240531.1, ISNI 0000 0004 0456 863X, Earle A. Chiles Research Institute, Providence Cancer Institute, ; Portland, OR USA

[10 ]GRID grid.470142.4, ISNI 0000 0004 0443 9766, Mayo Clinic, ; Phoenix, AZ USA

[11 ]GRID grid.5386.8, ISNI 000000041936877X, Weill Cornell Medicine, ; New York, NY USA

[12 ]GRID grid.430503.1, ISNI 0000 0001 0703 675X, University of Colorado Denver, ; Aurora, CO USA

[13 ]GRID grid.418204.b, ISNI 0000 0004 0406 4925, Banner MD Anderson Cancer Center, ; Gilbert, AZ USA

[14 ]GRID grid.468198.a, ISNI 0000 0000 9891 5233, H Lee Moffitt Cancer Center, ; Tampa, FL USA

[15 ]GRID grid.431072.3, ISNI 0000 0004 0572 4227, AbbVie, Inc, ; North Chicago, IL USA

[16 ]GRID grid.511215.3, ISNI 0000 0004 0455 2953, UCSF Helen Diller Family Comprehensive Cancer Center, ; San Francisco, CA USA

Author information

Aaron S. Mansfield http://orcid.org/0000-0002-9483-6903

Himisha Beltran http://orcid.org/0000-0003-3259-2226

Alan H. Bryce http://orcid.org/0000-0002-0206-3895

Scott T. Tagawa http://orcid.org/0000-0003-2777-8587

Rahul Aggarwal http://orcid.org/0000-0001-7003-7982

Article

Publisher ID: 214

DOI: 10.1038/s41698-021-00214-y

PMC ID: 8342450

PubMed ID: 34354225

SO-VID: d4c0e889-59bf-4804-a0ee-c06fbfd8e7b2

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 October 2020

Date accepted : 14 July 2021

Funding

Funded by: FundRef https://doi.org/10.13039/100006483, AbbVie (AbbVie Inc.);

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Keywords: phase ii trials,targeted therapies,phase i trials

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Keywords: phase ii trials, targeted therapies, phase i trials

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A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

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Abstract

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Gamma Delta T cells

Most cited references 25

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

Pembrolizumab versus Ipilimumab in Advanced Melanoma.

Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.

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Cited by 17

Most referenced authors 732