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

Emiel A De Jaeghere; Sandra Tuyaerts; An M T Van Nuffel; Ann Belmans; Kris Bogaerts; Regina Baiden-Amissah; Lien Lippens; Peter Vuylsteke; Stéphanie Henry; Xuan Bich Trinh; Peter A van Dam; Sandrine Aspeslagh; Alex De Caluwé; Eline Naert; Diether Lambrechts; An Hendrix; Olivier De Wever; Koen K Van de Vijver; Frédéric Amant; Katrien Vandecasteele; Hannelore G Denys

doi:10.1007/s00262-022-03253-x

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

Emiel A De Jaeghere, Sandra Tuyaerts, An M T Van Nuffel, Ann Belmans, Kris Bogaerts, Regina Baiden-Amissah, Lien Lippens, Peter Vuylsteke, Stéphanie Henry, Xuan Bich Trinh, Peter A van Dam, Sandrine Aspeslagh, Alex De Caluwé, Eline Naert, Diether Lambrechts, An Hendrix, Olivier De Wever, Koen K Van de Vijver, Frédéric Amant, Katrien VandecasteeleHannelore G Denys

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Samenvatting

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).

Originele taal-2	English
Pagina's (van-tot)	475-491
Aantal pagina's	17
Tijdschrift	Cancer Immunol Immunother
Volume	72
Nummer van het tijdschrift	2
Vroegere onlinedatum	12 aug. 2022
DOI's	https://doi.org/10.1007/s00262-022-03253-x
Status	Published - feb. 2023

Bibliografische nota

Funding Information:
MSD and Nutrisan provided material support by delivering study drugs pembrolizumab and curcumin, respectively, free of charge. Monetary support was provided by Kom op Tegen Kanker (Stand up to Cancer, the Flemish cancer society); de Nationale Loterij; and Anticancer Fund. Neither the funders nor the providers of medication had any role in study design (except Anticancer Fund), data collection, data analysis, data interpretation, or in the writing of the report. The first author (EAD) wrote the manuscript without industry medical-writing support. The first author, second author (ST), statisticians (AB and KB), and chief investigator (HD) had full access to all data in the study. The first author and chief investigator shared final responsibility for the decision to submit for publication.

Funding Information:
We thank all the women, their families, and their caregivers for participating in PRIMMO and all investigators and site personnel. The HIRUZ Clinical Trials Unit (Ghent, Belgium) ( https://hiruz.be ) contributed to the design, oversight, and conduct of the study. EAD and EN are supported by the Research Foundation-Flanders (FWO) ( https://www.fwo.be/en/ ) (Grant Nos. 1195919N and 1703020N, respectively). LL is supported by Kom op tegen Kanker (Stand up to Cancer, the Flemish cancer society) ( https://www.komoptegenkanker.be ). RB is supported by Kom Op Tegen Kanker (Grant Numbers ZKD5584 and RT0733), FWO (Grant No. T002218N), and ERA-NET-Transcan-2 (Grant No. G0H7516N).

Funding Information:
EAD: travel and accommodation expenses (institutional, not personal) from AstraZeneca, GSK, Pfizer, and PharmaMar. AMTV: became an employee for GSK during the publication development. PV: consulting or advisory role (personal) from Eli Lily and Company, MSD, Mundipharma, Novartis, Pfizer, and Roche; research funding from Tesaro. SH: consulting or advisory role (personal) from AstraZeneca, BMSi, Gilead Sciences, Merck, MSD Oncology, Novartis, and Sanofi. SA: consulting or advisory role (institutional, not personal) for MSD, Sanofi, Roche, BMS, and Pfizer; research funding (institutional, not personal) from Sanofi. AD: research funding (institutional, not personal) from AstraZeneca. EN: travel and accommodation expenses (institutional, not personal) from AstraZeneca, Novartis, Pfizer, PharmaMar, Roche, and Teva. DL: consulting or advisory role (institutional, not personal) for AstraZeneca, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly and Company, Hedera Dx, Montis Biosciences, MSD; consulting or advisory role (personal) for AstraZeneca, Biocartis, Montis Biosciences, and MSD. FA: consulting or advisory role (institutional, not personal) for MiMark. KV: travel and accommodation expenses (institutional, not personal) from PharmaMar. HGD: travel and accommodation expenses (institutional, not personal) from Amgen, AstraZeneca, Eli Lily and Company, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, Tesaro, and Teva; research funding (institutional, not personal) from Roche. ST, AB, KB, RB, LL, XBT, PAV, AH, OD, and KKV: declare no competing interests.

Publisher Copyright:
© 2022, The Author(s).

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

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De Jaeghere, E. A., Tuyaerts, S., Van Nuffel, A. M. T., Belmans, A., Bogaerts, K., Baiden-Amissah, R., Lippens, L., Vuylsteke, P., Henry, S., Trinh, X. B., van Dam, P. A., Aspeslagh, S., De Caluwé, A., Naert, E., Lambrechts, D., Hendrix, A., De Wever, O., Van de Vijver, K. K., Amant, F., ... Denys, H. G. (2023). 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. Cancer Immunol Immunother, 72(2), 475-491. https://doi.org/10.1007/s00262-022-03253-x

@article{b1786e46f94d4ce598b9cb6e2a90f910,

title = "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",

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).",

keywords = "Drug therapy, combination, Gynecologic neoplasms, Immunomodulation, Radioimmunotherapy, Tumor microenvironment",

author = "{De Jaeghere}, {Emiel A} and Sandra Tuyaerts and {Van Nuffel}, {An M T} and Ann Belmans and Kris Bogaerts and Regina Baiden-Amissah and Lien Lippens and Peter Vuylsteke and St{\'e}phanie Henry and Trinh, {Xuan Bich} and {van Dam}, {Peter A} and Sandrine Aspeslagh and {De Caluw{\'e}}, Alex and Eline Naert and Diether Lambrechts and An Hendrix and {De Wever}, Olivier and {Van de Vijver}, {Koen K} and Fr{\'e}d{\'e}ric Amant and Katrien Vandecasteele and Denys, {Hannelore G}",

note = "Funding Information: MSD and Nutrisan provided material support by delivering study drugs pembrolizumab and curcumin, respectively, free of charge. Monetary support was provided by Kom op Tegen Kanker (Stand up to Cancer, the Flemish cancer society); de Nationale Loterij; and Anticancer Fund. Neither the funders nor the providers of medication had any role in study design (except Anticancer Fund), data collection, data analysis, data interpretation, or in the writing of the report. The first author (EAD) wrote the manuscript without industry medical-writing support. The first author, second author (ST), statisticians (AB and KB), and chief investigator (HD) had full access to all data in the study. The first author and chief investigator shared final responsibility for the decision to submit for publication. Funding Information: We thank all the women, their families, and their caregivers for participating in PRIMMO and all investigators and site personnel. The HIRUZ Clinical Trials Unit (Ghent, Belgium) ( https://hiruz.be ) contributed to the design, oversight, and conduct of the study. EAD and EN are supported by the Research Foundation-Flanders (FWO) ( https://www.fwo.be/en/ ) (Grant Nos. 1195919N and 1703020N, respectively). LL is supported by Kom op tegen Kanker (Stand up to Cancer, the Flemish cancer society) ( https://www.komoptegenkanker.be ). RB is supported by Kom Op Tegen Kanker (Grant Numbers ZKD5584 and RT0733), FWO (Grant No. T002218N), and ERA-NET-Transcan-2 (Grant No. G0H7516N). Funding Information: EAD: travel and accommodation expenses (institutional, not personal) from AstraZeneca, GSK, Pfizer, and PharmaMar. AMTV: became an employee for GSK during the publication development. PV: consulting or advisory role (personal) from Eli Lily and Company, MSD, Mundipharma, Novartis, Pfizer, and Roche; research funding from Tesaro. SH: consulting or advisory role (personal) from AstraZeneca, BMSi, Gilead Sciences, Merck, MSD Oncology, Novartis, and Sanofi. SA: consulting or advisory role (institutional, not personal) for MSD, Sanofi, Roche, BMS, and Pfizer; research funding (institutional, not personal) from Sanofi. AD: research funding (institutional, not personal) from AstraZeneca. EN: travel and accommodation expenses (institutional, not personal) from AstraZeneca, Novartis, Pfizer, PharmaMar, Roche, and Teva. DL: consulting or advisory role (institutional, not personal) for AstraZeneca, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly and Company, Hedera Dx, Montis Biosciences, MSD; consulting or advisory role (personal) for AstraZeneca, Biocartis, Montis Biosciences, and MSD. FA: consulting or advisory role (institutional, not personal) for MiMark. KV: travel and accommodation expenses (institutional, not personal) from PharmaMar. HGD: travel and accommodation expenses (institutional, not personal) from Amgen, AstraZeneca, Eli Lily and Company, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, Tesaro, and Teva; research funding (institutional, not personal) from Roche. ST, AB, KB, RB, LL, XBT, PAV, AH, OD, and KKV: declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s). Copyright: Copyright 2022 Elsevier B.V., All rights reserved.",

year = "2023",

month = feb,

doi = "10.1007/s00262-022-03253-x",

language = "English",

volume = "72",

pages = "475--491",

journal = "Cancer Immunol Immunother",

issn = "0340-7004",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "2",

}

De Jaeghere, EA, Tuyaerts, S, Van Nuffel, AMT, Belmans, A, Bogaerts, K, Baiden-Amissah, R, Lippens, L, Vuylsteke, P, Henry, S, Trinh, XB, van Dam, PA, Aspeslagh, S, De Caluwé, A, Naert, E, Lambrechts, D, Hendrix, A, De Wever, O, Van de Vijver, KK, Amant, F, Vandecasteele, K & Denys, HG 2023, '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', Cancer Immunol Immunother, vol. 72, nr. 2, blz. 475-491. https://doi.org/10.1007/s00262-022-03253-x

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. / De Jaeghere, Emiel A; Tuyaerts, Sandra; Van Nuffel, An M T et al.
In: Cancer Immunol Immunother, Vol. 72, Nr. 2, 02.2023, blz. 475-491.

Onderzoeksoutput: Article › peer review

TY - JOUR

T1 - Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma

T2 - Results of the phase II PRIMMO study

AU - De Jaeghere, Emiel A

AU - Tuyaerts, Sandra

AU - Van Nuffel, An M T

AU - Belmans, Ann

AU - Bogaerts, Kris

AU - Baiden-Amissah, Regina

AU - Lippens, Lien

AU - Vuylsteke, Peter

AU - Henry, Stéphanie

AU - Trinh, Xuan Bich

AU - van Dam, Peter A

AU - Aspeslagh, Sandrine

AU - De Caluwé, Alex

AU - Naert, Eline

AU - Lambrechts, Diether

AU - Hendrix, An

AU - De Wever, Olivier

AU - Van de Vijver, Koen K

AU - Amant, Frédéric

AU - Vandecasteele, Katrien

AU - Denys, Hannelore G

N1 - Funding Information: MSD and Nutrisan provided material support by delivering study drugs pembrolizumab and curcumin, respectively, free of charge. Monetary support was provided by Kom op Tegen Kanker (Stand up to Cancer, the Flemish cancer society); de Nationale Loterij; and Anticancer Fund. Neither the funders nor the providers of medication had any role in study design (except Anticancer Fund), data collection, data analysis, data interpretation, or in the writing of the report. The first author (EAD) wrote the manuscript without industry medical-writing support. The first author, second author (ST), statisticians (AB and KB), and chief investigator (HD) had full access to all data in the study. The first author and chief investigator shared final responsibility for the decision to submit for publication. Funding Information: We thank all the women, their families, and their caregivers for participating in PRIMMO and all investigators and site personnel. The HIRUZ Clinical Trials Unit (Ghent, Belgium) ( https://hiruz.be ) contributed to the design, oversight, and conduct of the study. EAD and EN are supported by the Research Foundation-Flanders (FWO) ( https://www.fwo.be/en/ ) (Grant Nos. 1195919N and 1703020N, respectively). LL is supported by Kom op tegen Kanker (Stand up to Cancer, the Flemish cancer society) ( https://www.komoptegenkanker.be ). RB is supported by Kom Op Tegen Kanker (Grant Numbers ZKD5584 and RT0733), FWO (Grant No. T002218N), and ERA-NET-Transcan-2 (Grant No. G0H7516N). Funding Information: EAD: travel and accommodation expenses (institutional, not personal) from AstraZeneca, GSK, Pfizer, and PharmaMar. AMTV: became an employee for GSK during the publication development. PV: consulting or advisory role (personal) from Eli Lily and Company, MSD, Mundipharma, Novartis, Pfizer, and Roche; research funding from Tesaro. SH: consulting or advisory role (personal) from AstraZeneca, BMSi, Gilead Sciences, Merck, MSD Oncology, Novartis, and Sanofi. SA: consulting or advisory role (institutional, not personal) for MSD, Sanofi, Roche, BMS, and Pfizer; research funding (institutional, not personal) from Sanofi. AD: research funding (institutional, not personal) from AstraZeneca. EN: travel and accommodation expenses (institutional, not personal) from AstraZeneca, Novartis, Pfizer, PharmaMar, Roche, and Teva. DL: consulting or advisory role (institutional, not personal) for AstraZeneca, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly and Company, Hedera Dx, Montis Biosciences, MSD; consulting or advisory role (personal) for AstraZeneca, Biocartis, Montis Biosciences, and MSD. FA: consulting or advisory role (institutional, not personal) for MiMark. KV: travel and accommodation expenses (institutional, not personal) from PharmaMar. HGD: travel and accommodation expenses (institutional, not personal) from Amgen, AstraZeneca, Eli Lily and Company, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, Tesaro, and Teva; research funding (institutional, not personal) from Roche. ST, AB, KB, RB, LL, XBT, PAV, AH, OD, and KKV: declare no competing interests. Publisher Copyright: © 2022, The Author(s). Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

PY - 2023/2

Y1 - 2023/2

N2 - 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).

AB - 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).

KW - Drug therapy, combination

KW - Gynecologic neoplasms

KW - Immunomodulation

KW - Radioimmunotherapy

KW - Tumor microenvironment

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U2 - 10.1007/s00262-022-03253-x

DO - 10.1007/s00262-022-03253-x

M3 - Article

C2 - 35960332

SN - 0340-7004

VL - 72

SP - 475

EP - 491

JO - Cancer Immunol Immunother

JF - Cancer Immunol Immunother

IS - 2

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De Jaeghere EA, Tuyaerts S, Van Nuffel AMT, Belmans A, Bogaerts K, Baiden-Amissah R et al. 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. Cancer Immunol Immunother. 2023 feb.;72(2):475-491. Epub 2022 aug. 12. doi: 10.1007/s00262-022-03253-x