Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study

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Abstract

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders ( p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.

Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-022-03253-x.

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Most cited references 47

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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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Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Aurélien Marabelle, Dung Le, Paolo Ascierto … (2019)

Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

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Author and article information

Contributors

Emiel A. De Jaeghere: emiel.dejaeghere@ugent.be

Sandra Tuyaerts: sandra.tuyaerts@uzbrussel.be

An M. T. Van Nuffel: anvannuffel@gmail.com

Ann Belmans: ann.belmans@kuleuven.be

Kris Bogaerts: kris.bogaerts@kuleuven.be

Regina Baiden-Amissah: reginaesimensimah.baidenamissah@kuleuven.be

Lien Lippens: lien.lippens@ugent.be

Peter Vuylsteke: peter.vuylsteke@uclouvain.be

Stéphanie Henry: stephanie.henry@uclouvain.be

Xuan Bich Trinh: xuanbich.trinh@uza.be

Peter A. van Dam: peter.vandam@uza.be

Sandrine Aspeslagh: sandrine.aspeslagh@uzbrussel.be

Alex De Caluwé: alex.decaluwe@bordet.be

Eline Naert: eline.naert@ugent.be

Diether Lambrechts: diether.lambrechts@kuleuven.be

An Hendrix: an.hendrix@ugent.be

Olivier De Wever: olivier.dewever@ugent.be

Koen K. Van de Vijver: koen.vandevijver@uzgent.be

Frédéric Amant: f.amant@nki.nl

Katrien Vandecasteele: katrien.vandecasteele@uzgent.be

Hannelore G. Denys: hannelore.denys@ugent.be

Journal

Journal ID (nlm-ta): Cancer Immunol Immunother

Journal ID (iso-abbrev): Cancer Immunol Immunother

Title: Cancer Immunology, Immunotherapy

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0340-7004

ISSN (Electronic): 1432-0851

Publication date (Electronic): 12 August 2022

Publication date PMC-release: 12 August 2022

Publication date (Print): 2023

Volume: 72

Issue: 2

Pages: 475-491

Affiliations

[1 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, Department of Medical Oncology (Route 535), , Ghent University Hospital, ; C. Heymanslaan 10, 9000 Ghent, Belgium

[2 ]GRID grid.510942.b, Cancer Research Institute Ghent (CRIG), ; Ghent, Belgium

[3 ]GRID grid.5342.0, ISNI 0000 0001 2069 7798, Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, , Ghent University, ; Ghent, Belgium

[4 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Gynaecologic Oncology, Department of Oncology, , KU Leuven, ; Leuven, Belgium

[5 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Leuven Cancer Institute, ; Leuven, Belgium

[6 ]GRID grid.411326.3, ISNI 0000 0004 0626 3362, Department of Medical Oncology, , University Hospital Brussels, ; Brussels, Belgium

[7 ]GRID grid.8767.e, ISNI 0000 0001 2290 8069, Laboratory for Medical and Molecular Oncology (LMMO), , VUB, ; Brussels, Belgium

[8 ]GRID grid.491191.5, Anticancer Fund (ACF), ; Strombeek-Bever, Belgium

[9 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Biostatistics and Statistical Bioinformatics Centre (L-BioStat), , KU Leuven, ; Leuven, Belgium

[10 ]GRID grid.7942.8, ISNI 0000 0001 2294 713X, Department of Hemato-Oncology, , Centre Hospitalier Universitaire Université Catholique de Louvain Namur (Sainte-Elisabeth), ; Namur, Belgium

[11 ]GRID grid.411414.5, ISNI 0000 0004 0626 3418, Department of Gynecologic Oncology and Senology, , University Hospital Antwerp, ; Edegem, Belgium

[12 ]GRID grid.411414.5, ISNI 0000 0004 0626 3418, Multidisciplinary Oncologic Centre Antwerp (MOCA), , University Hospital Antwerp, ; Edegem, Belgium

[13 ]Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Edegem, Belgium

[14 ]GRID grid.418119.4, ISNI 0000 0001 0684 291X, Department of Radiation Oncology, , Jules Bordet Institute, ; Brussels, Belgium

[15 ]Department of Radiation Oncology, General Hospital Sint-Maarten, Mechlin, Belgium

[16 ]GRID grid.511459.d, VIB–KU Leuven Center for Cancer Biology, ; Leuven, Belgium

[17 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, Department of Pathology, , Ghent University Hospital, ; Ghent, Belgium

[18 ]GRID grid.430814.a, ISNI 0000 0001 0674 1393, Center for Gynecologic Oncology Amsterdam (CGOA), , Netherlands Cancer Institute and Amsterdam Medical Center, ; Amsterdam, The Netherlands

[19 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of Gynecology and Obstetrics, , University Hospitals Leuven, ; Leuven, Belgium

[20 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, Department of Radiation Oncology, , Ghent University Hospital, ; Ghent, Belgium

Article

Publisher ID: 3253

DOI: 10.1007/s00262-022-03253-x

PMC ID: 9870976

PubMed ID: 35960332

SO-VID: f6d6465c-2c9e-48bd-92f1-b9ff8aff4f25

License:

Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 March 2022

Date accepted : 4 July 2022

Funding

Funded by: Fonds Wetenschappelijk Onderzoek

Award ID: 1195919N

Award ID: T002218N

Award Recipient : Emiel A. De Jaeghere Regina Baiden-Amissah

Funded by: Kom op tegen Kanker

Award ID: ZKD5584

Award Recipient : Regina Baiden-Amissah

Funded by: ERA-NET-Transcan-2

Award ID: G0H7516N

Award Recipient : Regina Baiden-Amissah

Funded by: Nationale Loterij

Award ID: SW/OPS/SUB 11719-0001

Award Recipient : Regina Baiden-Amissah

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: radioimmunotherapy,drug therapy, combination,gynecologic neoplasms,immunomodulation,tumor microenvironment

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: radioimmunotherapy, drug therapy, combination, gynecologic neoplasms, immunomodulation, tumor microenvironment

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study

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Abstract

Supplementary Information

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Most cited references 47

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

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

RECIST 1.1-Update and clarification: From the RECIST committee.

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