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.

Fig. 1

PRIMMO study design. A Study procedures. Consolidated Standards of Reporting Trials (CONSORT) diagram of B the cervical cohort and C the endometrial cohort. AE adverse event, CNS central nervous system, (e)FAS (extended) full analysis set, SBRT stereotactic body radiotherapy

Fig. 2

Antitumor activity to study treatment in the cervical cohort. A Combined waterfall and swimmer plot. Each row (i.e., response bar + characteristics + swimmer lane) corresponds to one patient. Waterfall plot showing best percentage change from baseline in the sum of diameters of the target lesions; best overall response is indicated by color coding of bars and includes assessment of target, nontarget, and new lesions. The dotted lines at − 30% and + 20% indicate thresholds for partial response and progressive disease (PD), respectively, per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Swimmer plot (event chart) for tumor response (response category indicated by color coding) and progressive disease per RECIST v1.1, safety, time on study, and death. The solid lines at week 3 and week 26 indicate the first pembrolizumab dose and the timing of the primary endpoint, respectively. B Spider plot. Dynamics of response according to best response (per RECIST v1.1). Circle indicates patients with new lesions or growth in non-target lesions (i.e., PD, even with a less than 20% change in the target lesions). Arrow indicates patients with an ongoing response at time of data cutoff. Square indicates patients with clinical progression (before an imaging scan was acquired). Patients with > 100% increase were truncated at 100% (indicated with a star). C Interval-censored progression-free survival per immune-related response criteria. AE adverse event, BOR best overall response, CR complete response, HPV human papillomavirus, PD progressive disease, PD-L1 programmed death ligand-1, PR partial response, RECIST v1.1 Response Evaluation Criteria in Solid Tumors, version 1.1, SD stable disease, sTILs stromal tumor-infiltrating lymphocytes

Fig. 2

Antitumor activity to study treatment in the cervical cohort. A Combined waterfall and swimmer plot. Each row (i.e., response bar + characteristics + swimmer lane) corresponds to one patient. Waterfall plot showing best percentage change from baseline in the sum of diameters of the target lesions; best overall response is indicated by color coding of bars and includes assessment of target, nontarget, and new lesions. The dotted lines at − 30% and + 20% indicate thresholds for partial response and progressive disease (PD), respectively, per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Swimmer plot (event chart) for tumor response (response category indicated by color coding) and progressive disease per RECIST v1.1, safety, time on study, and death. The solid lines at week 3 and week 26 indicate the first pembrolizumab dose and the timing of the primary endpoint, respectively. B Spider plot. Dynamics of response according to best response (per RECIST v1.1). Circle indicates patients with new lesions or growth in non-target lesions (i.e., PD, even with a less than 20% change in the target lesions). Arrow indicates patients with an ongoing response at time of data cutoff. Square indicates patients with clinical progression (before an imaging scan was acquired). Patients with > 100% increase were truncated at 100% (indicated with a star). C Interval-censored progression-free survival per immune-related response criteria. AE adverse event, BOR best overall response, CR complete response, HPV human papillomavirus, PD progressive disease, PD-L1 programmed death ligand-1, PR partial response, RECIST v1.1 Response Evaluation Criteria in Solid Tumors, version 1.1, SD stable disease, sTILs stromal tumor-infiltrating lymphocytes

Fig. 3

Antitumor activity to study treatment in the endometrial cohort. A Combined waterfall and swimmer plot. B Spider plot. C Interval-censored progression-free survival per immune-related response criteria. AE adverse event, BOR best overall response, CR complete response, MSI microsatellite instability, NOS not otherwise specified, NSMP no specific molecular profile, PD progressive disease, PR partial response, PTEN phosphatase and tensin homolog, RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1, SD stable disease, sTILs stromal tumor-infiltrating lymphocytes

Fig. 3

Antitumor activity to study treatment in the endometrial cohort. A Combined waterfall and swimmer plot. B Spider plot. C Interval-censored progression-free survival per immune-related response criteria. AE adverse event, BOR best overall response, CR complete response, MSI microsatellite instability, NOS not otherwise specified, NSMP no specific molecular profile, PD progressive disease, PR partial response, PTEN phosphatase and tensin homolog, RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1, SD stable disease, sTILs stromal tumor-infiltrating lymphocytes

Fig. 4

Local response to stereotactic body radiotherapy by disease cohort. A Cervical cancer cohort. B Endometrial cancer cohort. Bar plot showing the percent change from baseline (at the first imaging scan) in the largest diameter of the irradiated tumor lesion (short axis in case of a nodal lesion); best overall response per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) is indicated by color coding of bars and includes assessment of target, nontarget, and new lesions (excluding the irradiated tumor lesion). The dotted line at − 30% indicates the threshold for local response. Each column (i.e., response bar + case ID + location of irradiated tumor lesion) corresponds to one patient. CID case ID, RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1

Fig. 5

Differences in peripheral T cells between responders and nonresponders. Violin plot showing differences between responders (gray) and nonresponders (blue) in the proportion of peripheral A T cells, cytotoxic T cells, and B regulatory T cells, as well as in C the ratio helper to cytotoxic T cells. Patients were grouped according to their week 26 response per immune-related response criteria (irRC). The p values were obtained by the Mann–Whitney U/Wilcoxon Rank-Sum test. CR complete response, CTL cytotoxic T lymphocyte, irRC immune-related response criteria, PBMC peripheral blood mononuclear cell, PD progressive disease, PR partial response, SD stable disease