Keywords
uterine cervical neoplasms - immunotherapy - data collection
Introduction
Despite screening exams and the implementation of human papillomavirus (HPV) vaccination
programs, cervical cancer is the fourth most common cancer in women worldwide, and
its incidence is especially high in low- and middle-income countries.[1] In Brazil, according to the National Cancer Institute (Instituto Nacional de Câncer,
INCA, in Portuguese), it represents the third most incident neoplasm in women (excluding
non-melanoma skin cancer) and the first cause of gynecologic cancer, with 17,010 new
cases estimated for 2024.[2]
In persistent, recurrent, or metastatic cervical cancer, the standard first-line treatment
is platinum-based chemotherapy. If the tumor expression of programmed cell death-ligand
1 (PD-L1) by combined positive score (CPS) is ≥ 1, the association of chemotherapy
with pembrolizumab is recommended, and, in case of no contraindication, bevacizumab
can also be included in the treatment regimen.[3]
After progression to platinum-based chemotherapy, trials[4] evaluating checkpoint inhibitors with anti-programmed death-1 (anti-PD-1) and anti-cytotoxic
T-lymphocyte-associated antigen 4 (anti-CTLA-4) agents have been conducted. Cemiplimab,[4] pembrolizumab,[5] and nivolumab,[6] anti-PD-1 agents, have demonstrated favorable outcomes in the scenario of platinum-resistant
disease in patients who have not received anti-PD-1 therapy combined with chemotherapy
in the first-line setting.[7]
[8]
These clinical trials were the key to advancing medical knowledge and improving the
care of patients with advanced cervical cancer. However, they are characterized by
methodological rigor to reduce bias, with strict inclusion and exclusion criteria
that often result in the inclusion of patients that differ significantly from those
seen in the clinical practice.[9] In this context, real-world studies have become increasingly important because they
pragmatically cover a representative proportion of the population,[10] providing information about the effectiveness and the reproducibility of the trial
results in a real-life population.[11]
The primary objective of the present study was to analyze the real-world outcomes
of patients with advanced cervical cancer from a Brazilian private healthcare network
treated with single-agent immunotherapy after progression to platinum-based chemotherapy.
Materials and Methods
The current was an observational, cohort study, with retrospective analysis of data
available in the Oncoclínicas&CO data lake, representing 70 clinical sites located
in 11 out of 27 federative units of Brazil. We combine longitudinal electronic health
record (EHR) data in a cloud-based platform, which includes structured elements (patient
demographics, disease stage, anticancer drug prescriptions) with elements from unstructured
sources (such as physician notes) using technology-based abstraction techniques. Trained
data curators qualify the data using predefined ontology and actively search for critical
outcomes in the patient's disease trajectory, including treatment line and intent.
External linkage to national death registries guarantees complete information of survival
endpoints. Manual data cleaning was performed to ensure validity and quality.
The eligible patients were 18 years of age or older, presented recurrent, persistent,
or metastatic disease not amenable to curative therapy, were exposed to immunotherapy
as a single agent, and had undergone at least 3 months of follow-up between the start
of immunotherapy and the last documented visit or death. The period for inclusion
was between July 2017 and January 2024. Patients treated with immunotherapy combined
with other systemic agents were excluded.
For the descriptive analysis, we expressed the categorical variables related to demographic
and clinicopathological characteristics as absolute and relative frequencies, and
values for the continuous variables, as median and range values. The time until treatment
discontinuation (TTD) was calculated as the time elapsed between the date of treatment
start and the date of discontinuation or death, while overall survival (OS) was estimated
from the time of the first treatment day until death from any cause using the Kaplan-Meier
method. Patients alive at the last available follow-up were censored. All data was
processed in the R programming environment (R Foundation for Statistical Computing,
Vienna, Austria), version 4.0.5.
Results
We included 60 patients with advanced cervical cancer who were treated with immunotherapy:
33 (55%) with cemiplimab, 26 (43.3%) with pembrolizumab, and only 1 (1.7%) with nivolumab.
The demographic and clinical characteristics of the patients are presented in [Table 1]. The median age was of 53 (range: 31–97) years. Most of the patients (73%) were
concentrated in the Southeastern region of Brazil, 7% in the Southern, and 10% in
the Midwestern and Northeastern regions. Most cases were metastatic de novo (60%),
and 85% of the patients received immunotherapy as the second-line treatment. Concerning
previous therapy for advanced disease, all patients received chemotherapy, in 23 (64%),
it was combined with bevacizumab. Information about subsequent therapy was available
for 19 patients (32%); all received chemotherapy, 2 of them in combination with bevacizumab
and, in 1 patient, immunotherapy (pembrolizumab) was maintained in association with
the chemotherapy and bevacizumab.
Table 1
Demographic and clinical characteristics of patients
|
Characteristic
|
Results
|
|
Patients – n (%)
|
60 (100)
|
|
Age (in years)
|
|
|
Median (range)
|
53 (31–97)
|
|
< 65–n. (%)
|
42 (70)
|
|
Metastasis at diagnosis – n (%)
|
|
|
Yes
|
36 (60)
|
|
No
|
15 (25)
|
|
Missing
|
9 (15)
|
|
Region of Brazil – n (%)
|
|
|
Southern
|
4 (7)
|
|
Southeastern
|
44 (73)
|
|
Midewestern
|
6 (10)
|
|
Northeastern
|
6 (10)
|
|
Line of immunotherapy – n (%)
|
|
|
Second line
|
51 (85)
|
|
Third line or more
|
9 (15)
|
|
Previous palliative therapy – n (%)
†
|
|
|
Anti-VEGF + chemotherapy
|
23 (64)
|
|
Chemotherapy
|
13 (36)
|
|
Subsequent therapy – no. (%)
‡
|
|
|
Anti-VEGF + chemotherapy
|
2 (11)
|
|
Chemotherapy
|
16 (84)
|
|
Immunotherapy + chemotherapy§
|
1 (5)
|
Abbreviation: VEGF, vascular endothelial growth factor.
Notes:
†For those receiving palliative therapy in the metastatic setting; ‡38% of the patients who underwent single-agent immunotherapy had no record of subsequent
regimen use; §in association with anti-VEGF (bevacizumab).
With a median follow-up of 12 months, the median TTD was of 6.3 months (95% confidence
interval [95%CI]: 4.7–9.6) ([Fig. 1]) and the median OS was of 10.7 months (95%CI: 9.1–not reached [NR]) ([Fig. 2]).
Fig. 1 Time until treatment discontinuation.
Fig. 2 Overall survival.
Discussion
Patients with persistent, recurrent, or metastatic cervical cancer have a poor prognosis,
especially in the setting of platinum resistance. In this scenario, immunotherapy
has been shown to be a promising treatment, with improvements in progression-free
survival (PFS) and OS.
The efficacy of pembrolizumab in patients with previously-treated cervical cancer
was based on A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers
in Subjects with Advanced Solid Tumors (KEYNOTE-158),5 a phase-2 basket study that included several types of solid tumors that progressed
with the standard therapy. In the cervical cancer cohort, 98 patients were included,
83.7% of whom had PD-L1 positive tumors (CPS expression ≥ 1). In the PD-L1 positive
population, the response rate was of 14.6%, in addition to an estimated median PFS
of 2.1 months and a median OS of 11 months.[5]
Cemiplimab, a fully-human anti-PD1 monoclonal antibody, was approved after progression
to platinum-based chemotherapy according to An Open-Label, Randomized, Phase 3 Clinical
Trial of REGN2810 Versus Investigator's Choice of Chemotherapy in Recurrent or Metastatic
Cervical Carcinoma (EMPOWER CERVICAL-1).[4] Patients were randomized to receive cemiplimab or the investigator's choice of single-agent
chemotherapy (the options included pemetrexed, topotecan, gemcitabine, irinotecan,
or vinorelbine) regardless of PD-L1 status. The study met its primary endpoint, demonstrating
a statistically significant improvement in OS: of 12 months with cemiplimab versus
8.5 months with chemotherapy (hazard ratio [HR]: 0.69; 95%CI: 0.56–0.84; p < 0.001). Despite the fact that the median PFS was similar in the two groups (2.8
months with cemiplimab and 2.9 months with chemotherapy), the HR indicated a significantly
longer PFS with immunotherapy (HR: 0.75; 95%CI: 0.63–0.89; p < 0.001). The objective response rate (ORR) was of 16.4% with cemiplimab and of 6.3%
in the control arm, and the median duration of response (DOR) was also better with
the anti-PD1.[4]
Another checkpoint inhibitor evaluated as a monotherapy in this setting was nivolumab
in the phase-1/2 trial Non-Comparative, Open-Label, Multiple Cohort, Phase 1/2 Study
of Nivolumab Monotherapy and Nivolumab Combination Therapy in Subjects With Virus-Positive
and Virus-Negative Solid Tumors (CheckMate 358), in which patients with squamous cell
carcinoma of the cervix, vagina, or vulva received nivolumab 240 mg every 2 weeks.
Patients with HPV-negative tumors were not included. In total, 19/24 randomized patients
presented cervical neoplasms. Of these, 16 were quantified for PD-L1 expression through
evaluation of tumor cells, 10 of whom presented tumors with PD-L1 expression ≥ 1%.
In the cervical cohort, the response rate was of 26.3%, with a disease control rate
of 68.4%.[6] Considering these results, the National Comprehensive Cancer Network[12] (NCCN) also recommends nivolumab as a possible option for second-line or greater
in tumors with positive expression of PD-L1.
Some of the patients included in the present real-world study would not have met the
inclusion criteria of a clinical trial, such as upper age limits and other unmeasured
confounders. Despite this, a comparable median OS was found when compared to the KEYNOTE-158
and EMPOWER CERVICAL-1 trials: 10.7, 11, and 12 months respectively.
The current study has some limitations, since it was based on a small sample size
and retrospective analysis of EHR data, with missing information. Furthermore, it
was not possible to evaluate toxicity, and TTD is not necessarily associated with
disease progression, since the patient could have their treatment discontinued because
of adverse events.
A strength of the present work is that, although it portrays the reality of a single
private oncology center in Brazil, there are several clinics in this group distributed
across the various regions and cities of Brazil country, thus reflecting a diverse
population.
Conclusion
Real-world data are important because they reflect the efficacy of treatment outside
of the tightly-controlled environment of randomized clinical trials, considering a
more heterogeneous population. The current study demonstrated outcomes with immunotherapy
for advanced cervical cancer after platinum-containing therapy that are comparable
with those described in clinical trials. Despite the limitations, these results confirm
the effectiveness and reproducibility of this treatment in clinical practice.
Bibliographical Record
Giovanna Vieira Giannecchini, Rafael Duarte Paes, Christopher Lucas Negrete, Rodrigo
Dienstmann, Andreia Cristina de Melo. Outcome of Immunotherapy in Advanced Cervical
Cancer after Progression to Platinum-Based Therapy in the Real World. Brazilian Journal
of Oncology 2025; 21: s00451802966.
DOI: 10.1055/s-0045-1802966
