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 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).
Discussion
PRIMMO showed that pembrolizumab, SBRT, and an IDC produced a response in approximately 11–17% (depending on the criteria) of patients with persistent/recurrent/metastatic CC and EC, who had at least one previous line of chemotherapy. Whereas the study did not achieve its primary objective, predefined as an irORR with the lower bound of the 90% CI of > 10% in either cohort, and the data from this study are less impressive compared with results observed using other combinations (e.g., nivolumab/ipilimumab in CC and pembrolizumab/lenvatinib in EC) [7, 37], other endpoints, such as the early and durable responses and the stable HRQOL suggest benefits of this treatment in some patients. Despite inherent limitations of cross-study comparison, the observed response rates of this study are similar to those noted for single-agent anti–PD-(L)1. However, given that most patients (69.8%) were refractory to their most recent treatment, a setting marked by increased aggressiveness and resistance to single-agent ICI [38], this should be also appropriately considered when interpreting our results. Furthermore, many patients had other characteristics associated with a lower probability of response to single-agent ICI, such as non-squamous histology (33.3%) in the cervical cohort and p53abn (40.0%) in the endometrial cohort.
The literature on combined ICI and radiotherapy in CC and EC is scarce. In a phase I study (GOG-9929) of 21 patients with node-positive locally advanced CC, the use of ipilimumab sequentially after chemoradiotherapy has been shown to be safe and feasible (any grade, not reported; grade ≥ 3, 10%) [39]. A two-arm phase I study showed no apparent improvement to the response rate from adding radiotherapy (9Gyx3) to cemiplimab treatment versus single-agent cemiplimab (one PR in ten patients [10%] in both arms) in persistent/recurrent/metastatic CC patients who were resistant to or intolerant of platinum and taxane chemotherapy [40]. Both studies were not designed or powered to assess efficacy. To our knowledge, the combination of ICI and radiotherapy has not yet been investigated in EC. In the studies that evaluated the combination of ICI and radiotherapy among patients with other solid tumors, response rates varied widely. For instance, Luke et al. reported a modest 13% response rate in a phase I study of SBRT (dose varied by anatomic site) to two to four metastases followed by pembrolizumab in heavily pretreated patients with a variety of primary cancers [18], while Hammers, et al. reported an encouraging response rate of 56% in patients with metastatic clear cell renal cell carcinoma receiving dual anti-PD-1/cytotoxic T-lymphocyte-associated protein 4 with nivolumab/ipilimumab and concurrent, higher dose SBRT (10Gyx5) to only one or two metastases [19]. The reasons for the overall null findings in the present study are unclear but differences in technical aspects of treatment such as total dose, fractionation, dose heterogeneity, target site(s), volume of radiation (e.g., ablation of single metastasis, all, or as many as possible), and optimal sequencing in relation to ICI among different studies are likely to underlie the contradictory results [41]. Such radiotherapy differences could result in distinct immunomodulatory effects. Alternatively, a more nuanced explanation may relate to the heterogenous groups of patients under study or differences in tumor burden, tumor spread (oligometastatic or polymetastatic), total treatment duration, and type of ICI. While we recognize that significant work has been done to explain radiotherapy’s immunological impact, these and our data suggest that a more thorough understanding is needed to identify the radiotherapy schedule required to achieve an optimal immune response. Therefore, the widely adopted ‘one-size-fits-all’ strategy of 8Gyx3 is not always the optimal choice to combine with ICI, and both patient-specific and tumor-specific characteristics should determine whether and how radiotherapy should be combined with ICI.
Non-commercial repurposing of generic or off-patent drugs has increasingly become recognized as a cost-efficient way to develop new, widely available, and affordable cancer treatments [26]. Similar to our IDC (and radiotherapy) strategy, Herrera, et al. recently reported on a combined preclinical and phase I clinical study demonstrating that nivolumab, ipilimumab, low-dose radiotherapy, low-dose cyclophosphamide, and CD40ag/aspirin all contributed to a profound reprogramming of the TME in immune desert tumors. Although these results were widely appreciated as positive, the reported response rate (one PR in eight patients [12.5%]) was relatively low and comparable to that reported here [16]. The scientific rationale supporting our IDC originates from many sources mentioned in more detail in Supplemental Table S2 [28]. Despite the promising preliminary evidence, our results suggest that further study is warranted to translate this biological potential into clinical practice. One explanation for our lower than anticipated efficacy is that a fourth of patients experienced rapid progression and received only one or two pembrolizumab doses, which may reflect the aggressive biology and poor prognosis of non-immunoreactive tumors with escape mechanisms bypassing the PD-1/PD-L1 axis as well as the targeted immunomodulatory pathways [42]. Indeed, about half of our patients had a tumor with an immune desert phenotype characterized by scarce or absent sTILs. Another explanation is that we cannot exclude a negative impact of the IDC leading to accelerated tumor growth. For instance, recent studies across a broad variety of cancers have suggested that proton pump inhibitors could negatively affect outcomes in ICI-treated patients [43].
The observed toxicity profile was less favorable than what has previously been reported with combined PD-1 inhibitors and radiotherapy in other tumor types, although these studies cannot be compared in a formal manner [44]. Patients in both cohorts experienced frequent (any grade, 83.7%; grade ≥ 3, 44.2%), but not unexpected, TRAEs consisting mainly of mild to moderate gastrointestinal toxicities and fatigue. Although no DLTs were noted within the 7-week safety run-in period, grade ≥ 3 TRAEs occurring beyond this window were rather frequent. In particular, grade ≥ 3 colitis affected 14% of patients. Possible explanations for this are that patients may have developed aspirin-mediated intestinal epithelial dysfunction [45], had their gut microbiome disrupted by the IDC [46], and often underwent pelvic surgery and/or radiotherapy. In addition, grade ≥ 3 anemia and lymphopenia were observed in 9.3% and 14.0% of patients, respectively. This is higher than what would be expected (< 5%) [47], a result with no clear explanation of the mechanism. It is important to note that the higher incidence of grade ≥ 3 TRAEs was not reflected in a higher pembrolizumab discontinuation rate (4.7%). This may, however, be due to the limited drug exposure of the subgroup of patients who experienced rapid progression. Nonetheless, our results suggest that the study treatment had little adverse impact on HRQOL.
Subgroup analyses showed no consistent pattern of benefit with study treatment, including not in PD-L1–positive (cervical cohort) or MSI-H (endometrial cohort) tumors, although these were neither powered nor corrected for multiple comparisons and should be interpreted with caution. Particular caution should be warranted due to our very small number of MSI-H tumors (n = 8) and wide confidence intervals. Similarly, the presented translational work should be interpreted as exploratory. Nonetheless, our results suggest that peripheral T cells could be a valuable marker of response to the study treatment.
There are limitations to this study. The main limitations include the small number of patients in each disease cohort and the lack of a randomly allocated control group, combined with the broad historic response rates to single-agent anti-PD-1 in both diseases (0–57%, depending on biomarker profiles), which became apparent during the conduct of this study. Second, although the concurrent assessment of seven therapy components allowed parallel focus on multiple immunomodulatory mechanisms, incremental stepwise assessment would have made it easier to unveil the individual contributions of the components. Because of the clinical pressure for achieving response in the studied populations and the lower overall costs we favored the concurrent assessment. Third, tumor response assessments were not independently reviewed.
In conclusion, the combination of pembrolizumab, SBRT, and an IDC was justified by preclinical evidence but did not meet expectations of clinical activity in both cohorts; however, some patients may have derived benefit from treatment, with durable responses in difficult-to-treat patients. It is therefore worth to further investigate ICIs, either alone in biomarker-enriched populations or in novel combinations in persistent/recurrent/metastatic CC or EC, as evidenced by recent successes [5,6,7, 10].
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Change history
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01 September 2022
There was an unusual spacing in Table 1 and it has been corrected.
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Acknowledgements
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
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.
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Contributions
EAD: methodology, validation, formal analysis, investigation, resources, data curation, writing (original draft), visualization, and project administration. ST: conceptualization, methodology, investigation, resources, data curation, writing (review and editing), project administration, and funding acquisition. AMTV: conceptualization, methodology, writing (review and editing), and funding acquisition. AB and KB: methodology, software, validation, formal analysis, resources, writing (review and editing), and visualization. RB, LL, PV, SH, XBT, PAV, SA, AD, EN, DL, AH, and OD: resources and writing (review and editing); KKV: validation, investigation, and writing (review and editing). FA and KV: conceptualization, methodology, investigation, resources, writing (review and editing), project administration, and funding acquisition. HGD: conceptualization, methodology, validation, investigation, resources, data curation, writing (review and editing), supervision, project administration, and funding acquisition.
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Conflict of interest
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.
Ethical approval and consent to participate
The study protocol and amendments were approved by the independent ethics committee or review board at each participating institution (Ghent University Hospital ethics committee, identifier EC/2017/0304); all patients provided written informed consent. The study was conducted in compliance with local and national regulations and in accordance with the Declaration of Helsinki and the International Council for Harmonization Guidelines for Good Clinical Practice. The findings have been reported according to the (applicable parts of) Consolidated Standards of Reporting Trials guidelines.
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