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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).

SUBMITTER: De Jaeghere EA

PROVIDER: S-EPMC9870976 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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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 EA Tuyaerts Sandra S Van Nuffel An M T AMT Belmans Ann A Bogaerts Kris K Baiden-Amissah Regina R Lippens Lien L Vuylsteke Peter P Henry Stéphanie S Trinh Xuan Bich XB van Dam Peter A PA Aspeslagh Sandrine S De Caluwé Alex A Naert Eline E Lambrechts Diether D Hendrix An A De Wever Olivier O Van de Vijver Koen K KK Amant Frédéric F Vandecasteele Katrien K Denys Hannelore G HG

Cancer immunology, immunotherapy : CII 20220812 2

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 objectiv ...[more]

PMID: 35960332

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Project description:BackgroundLenvatinib plus pembrolizumab has demonstrated improved survival compared with doxorubicin or paclitaxel monotherapy in patients with advanced or recurrent endometrial cancers (ECs). However, response rates to monotherapy are poor in recurrent settings. Herein, we performed a retrospective analysis using real-world data to compare the outcomes of lenvatinib plus pembrolizumab, carboplatin plus paclitaxel (PT), and doxorubicin for patients with PT-pretreated, advanced, or recurrent ECs.MethodsWe performed a multi-institutional retrospective analysis using de-identified electronic health record database (TriNetX) to compare lenvatinib plus pembrolizumab, carboplatin plus paclitaxel (PT), and doxorubicin outcomes in patients with PT-pretreated, advanced, or recurrent ECs. A 1:1 propensity score matching (PSM) was conducted. The primary outcome was the overall survival (OS) among treatment groups. The secondary outcome was the adverse event profile.ResultsBetween January 2012 and September 2023, we identified 397 patients with PT-treated, advanced, or recurrent ECs who received lenvatinib plus pembrolizumab, and 469 patients receiving PT at a platinum-free interval of over 6 months. Following PSM, no significant difference in median OS was observed between the lenvatinib plus pembrolizumab and re-challenge PT groups (19.1 vs. 18.5 months, p = 0.60; hazard ratio: 1.08, 95% confidence interval 0.81-1.46). However, lenvatinib plus pembrolizumab provided better survival benefits than doxorubicin. Adverse event analysis showed more hypothyroidism, hypertension, and proteinuria with lenvatinib plus pembrolizumab, and more hematologic toxicities in both chemotherapy groups.ConclusionsLenvatinib plus pembrolizumab was not associated with improved survival when compared with re-challenge PT in patients with a platinum-free interval of over 6 months. Re-challenge PT remains a valid option for PT-treated, recurrent, or advanced ECs, especially in patients with a substantially long platinum-free interval.

Project description:IntroductionFirst-line treatment of persistent, recurrent, or metastatic (advanced) cervical cancer in patients who have a combined positive score (CPS) ≥ 1 with pembrolizumab + chemotherapy versus standard-of-care chemotherapy provides meaningful improvements in overall survival. We conducted a cost-effectiveness analysis from a US payer perspective. A societal perspective scenario was also considered, including productivity gains.MethodsThe cost-effectiveness of pembrolizumab + chemotherapy versus chemotherapy was assessed using a state-transition model comprising the health states "pre-progression," "post-progression," and "death," with a 1-week cycle length and 50-year time horizon. Patient-level KEYNOTE-826 data informed the efficacy, safety, and health-related quality of life of pembrolizumab + chemotherapy versus chemotherapy at first-line and subsequent treatments. Real-world data were sought to cost subsequent treatments according to US clinical practice. Transition probabilities were derived from parametric survival models fit to time-to-progression, progression-free survival, and post-progression survival patient-level KEYNOTE-826 data. Sensitivity analyses explored the impact on outcomes from variables such as bevacizumab use.ResultsAccording to the state-transition model, pembrolizumab + chemotherapy extended mean life expectancy versus chemotherapy from 1.8 to 6.7 life-years. The mean gain of 4.9 life-years/patient was mostly caused by pembrolizumab delaying progression. Total discounted quality-adjusted life-years (QALY) were 5.0 and 1.3 per patient for pembrolizumab + chemotherapy and chemotherapy, respectively (mean gain: 3.7 QALY/patient). Pembrolizumab + chemotherapy had comparable safety outcomes to chemotherapy alone. Total costs incurred were US $320,247 (pembrolizumab + chemotherapy) versus US $105,446 (chemotherapy; mean incremental costs: US $214,801/patient). The incremental cost-effectiveness ratio of pembrolizumab + chemotherapy versus chemotherapy was US $58,446/QALY. Sensitivity analyses showed results were insensitive to bevacizumab use. Including productivity gains led to an incremental cost-effectiveness ratio of US $58,385 per QALY.ConclusionsOur model-based analysis suggests that first-line treatment of pembrolizumab + chemotherapy in advanced cervical cancer with a CPS ≥ 1 offers a substantial clinical benefit over standard-of-care chemotherapy alone and is cost-effective at a willingness-to-pay threshold of US $150,000. The approximate doubling of life-years and QALYs associated with pembrolizumab + chemotherapy represents a step improvement in the treatment of advanced cervical cancer.Trial registrationClinicalTrials.gov Identification Number: NCT03635567.

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Dataset Information

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.

Publications

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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