WHAT IS ALREADY KNOWN ON THIS TOPIC

Cervical cancer is the fourth most common cancer affecting women globally. When patients progress after initial therapy to recurrent or metastatic disease, treatment options are limited. The programmed cell death protein-1 (PD-1) inhibitors show potential for cervical cancer treatment.

WHAT THIS STUDY ADDS

This study is the first registration study in China to investigate a PD-1 monoclonal antibody in the treatment of patients with recurrent or metastatic, PD-L1-positive (combined positive score (CPS)≥1) cervical cancer that has progressed after first- or subsequent-line chemotherapy, and demonstrated promising results for zimberelimab in this population.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

This study provides clinical evidence for the application of zimberelimab in patients with recurrent or metastatic cervical cancer, offering additional treatment options for such patients. Based on this study, zimberelimab has been approved by the National Medical Products Administration (NMPA) for the treatment of patients with recurrent or metastatic cervical cancer.

Introduction

Cervical cancer is the fourth most common cancer affecting women globally and was responsible for approximately 342 000 deaths in 2020.1 According to GLOBOCAN 2020 data, there were approximately 1 10 000 cases of cervical cancer resulting in 59 000 deaths in China in 2020.2 For recurrent or metastatic cervical cancer, National Comprehensive Cancer Network guidelines currently recommend a three-drug combination of cisplatin, paclitaxel, and bevacizumab. In addition, pembrolizumab is recommended in combination with chemotherapy with/without bevacizumab as a first-line treatment for patients whose tumors express programmed death ligand-1 (PD-L1) with a combined positive score (CPS)≥1.3

The approval of pembrolizumab for metastatic cervical cancer is based on the KEYNOTE-158 and KEYNOTE-826 study results.4 5 The programmed cell death protein-1 (PD-1) inhibitors nivolumab and cemiplimab have also been studied in the setting of recurrent/metastatic cervical cancer.6–8 Furthermore, the PD-L1 inhibitor atezolizumab is currently being studied in combination with cisplatin, paclitaxel, and bevacizumab in the BEATcc trial in previously untreated patients with metastatic, recurrent, or persistent cervical cancer.9

When patients progress after initial therapy to recurrent or metastatic disease, treatment options are limited. Zimberelimab (GLS-010) is a fully human anti-PD-1 monoclonal antibody, with high affinity and selectivity, developed from an international transgenic rat platform (OmniRat).10 In a phase Ia/Ib study, zimberelimab treatment resulted in an objective response rate of 23.6% in 284 patients with advanced lymphoma or solid tumors and was associated with a favorable safety profile.11 In this study, the mean half-life of multiple doses of zimberelimab 240 mg once every 2 weeks was 303.3±41.4 hours.11

In a single-arm phase II study, zimberelimab was shown to be effective with a favorable safety profile in a population of Chinese patients with relapsed or refractory classical Hodgkin lymphoma. Overall, the objective response rate was 90.6%; 12-month progression-free survival and overall survival rates were 78% and 99%, respectively.12 Stage 1 of a multicenter, open-label, single-arm phase II trial evaluated zimberelimab in PD-L1-positive patients (22C3 assay; pharmDx, Agilent) with recurrent or metastatic cervical cancer. Eleven patients achieved partial response, corresponding to an objective response rate of 26.83%.13 Based on these findings, the National Medical Products Administration (NMPA) granted breakthrough therapy designation to zimberelimab for the treatment of patients with recurrent or metastatic, PD-L1-positive (CPS≥1) cervical cancer that has progressed after first- or subsequent-line chemotherapy. The study progressed to stage 2 as a registration study to evaluate zimberelimab in a larger cohort of patients. Here, we present interim results from stage 2 of patients with previously treated recurrent or metastatic cervical cancer with ≥1 line of platinum-based chemotherapy in the phase II YH-S001-05 study of zimberelimab (ClinicalTrials.gov identifier: NCT03972722).

MethodsStudy Design and Participants

The phase II, single-arm, open-label study using a Simon two-stage minimax design14 was planned to enroll 47 patients into stage 1, requiring a response in ≥3 patients in order to proceed to stage 2 (Figure 1A). Overall, 45 and 105 patients were enrolled in stages 1 and 2, respectively. This study is a registration clinical trial; stage 2 of the phase II study enrolled patients at 27 sites in China. The study was approved by the ethics committee at each participating center and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice for Drug Trials. All participants provided signed informed consent before any study procedure.

Figure 1

(A) Study design and (B) patient disposition. (Analysis cut-off date: April 29, 2022) *At least one line of chemotherapy in stage 1; at least one line of standard platinum-based chemotherapy in stage 2. AE, adverse event; CPS, combined positive score; CR, complete response; DCR, disease control rate; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival; PR, partial response; PS ; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response.

Eligible patients were women, aged 18–75 years, with histologically confirmed15 recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line platinum-containing standard chemotherapy. Tumor tissue from archival or newly obtained core or excisional biopsies was classified as positive for PD-L1 expression (CPS≥1) at the screening for each patient before enrollment. All patients had to have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and expected survival of >12 weeks. Patients also had to have adequate hematological, liver, and kidney function. Key exclusion criteria included previous treatment with antibodies to PD-1, PD-L1, PD-L2, CD137, or CTLA-4, treatment with any anti-tumor or investigational therapy in the 4 weeks before the start of study treatment, known allergy to any protein preparation or monoclonal antibody, treatment with immunosuppressive drugs within 14 days before enrollment, or the presence of meningeal or symptomatic central nervous system metastases.

All enrolled patients received intravenous zimberelimab 240 mg as monotherapy every 2 weeks until confirmed disease progression, intolerable adverse effects, or withdrawal from the study, for a maximum of 2 years. After 2 years of treatment, participants were permitted to enter an extended treatment period at the investigator’s discretion. Tumor assessments were performed by chest, abdomen, and pelvic CT scan/MRI every 8 weeks in the first year and every 12 weeks in the second year following treatment start. Imaging was conducted at least 4 weeks after the first assessment of complete response or partial response, and within the protocol-specified date of the next tumor assessment. If the patient had or was suspected to have bone metastases, a bone scan was performed. When baseline-proven skeletal lesions were not observed on the chest, abdomen, and pelvic CT (or MRI) scans at baseline, a localized CT, MRI, or X-ray examination was conducted.

PD-L1 Testing

PD-L1 testing was performed using two immunohistochemical assays: 22C3 and WD160 (WuXi Diagnostics). PD-L1-positivity was equivalent to CPS≥1 and PD-L1-negativity was equivalent to CPS<1. PD-L1-negative patients (CPS<1) tested by WD160 were excluded.

Efficacy and Safety Outcomes

The primary endpoint was the objective response rate, as determined by an independent review committee according to RECIST version 1.1 criteria. The independent review committee reviewed all study participants’ imaging data and provided an independent judgment on tumor response. Secondary endpoints included objective response rate as assessed by the investigators, duration of response and disease control rate as assessed by the independent review committee, progression-free survival, time to response as assessed by both the independent review committee and the investigators, and overall survival. Safety and tolerability were assessed by the number, severity, and duration of adverse events during treatment according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and coded using the Medical Dictionary for Regulatory Activities version 24.1. Treatment-emergent adverse events were defined as adverse events that occurred from the time of the first dose up to and including 90 days after the last dose. For this study, immune-related grade ≥3 adverse events were considered to be events of special interest.

Statistical Analysis

All statistical analyses were performed using SAS version 9.4 software. Assuming an objective response rate for zimberelimab of 20% in this study, the historical control objective response rate with chemotherapy is 10% as agreed with the Center for Drug Evaluation. With a one-sided significance level of 0.025, 94 participants are needed to provide 80% statistical power. Assuming a 10% non-evaluation rate, 105 participants were planned for enrollment.

For the primary endpoint of objective response rate, the number and percentage of participants achieving either complete response or partial response were calculated and 95% confidence intervals (CIs) were estimated using the Clopper–Pearson exact method. Results were tested against a 10% remission rate using the binomial exact model. Superiority of zimberelimab compared with historical controls was determined if a one-sided p value <0.025 was observed. The independent review committee- and investigator-assessed objective response rate was also evaluated in all the patients defined by age, baseline ECOG performance status, number of previous treatment lines, and PD-L1 expression level. Median duration of response, progression-free survival, time to response, and overall survival were calculated by the Kaplan–Meier method with two-sided 95% CIs estimated using the Brookmeyer and Crowley method. Disease control rate was calculated as the number and percentage of patients in remission (complete response or partial response) or with stable disease, with 95% CIs calculated using the Clopper–Pearson exact method.

ResultsPatients

Patient disposition is summarized in Figure 1B. Between June 11, 2020 and April 29, 2021, 194 patients were assessed for eligibility. Of these, 105 met the eligibility criteria at 27 sites in China and were assigned to receive treatment with zimberelimab. All patients received one or more doses of zimberelimab. As of April 29, 2022, data cut-off median follow-up time was 16.9 (range, 16.3–18.4) months. Over the study duration, 83 patients discontinued treatment, predominantly because of disease progression (n=56) or adverse events (n=14).

Patient baseline demographics and disease characteristics are shown in Table 1. Patients had a median age of 51 years and the majority had an ECOG performance status of 1 (63.8%). Most had a squamous carcinoma (87.6%) and 43.8% were in clinical stage II at diagnosis. As per the eligibility criteria, all patients had previously been treated with chemotherapy; the majority had also received surgery (71.4%) or radiotherapy (95.2%). Most patients had previously received chemotherapy once (61.0%) or twice (30.5%). Over one-third of patients (37.1%) had a PD-L1 CPS score of ≥20, with the other two-thirds having a score of 1 to <20.

Table 1

Baseline characteristics of patients (N=105)

Tumor Response

Results are based on an interim analysis of data, with a cut-off date of April 29, 2022. For the primary endpoint assessment, complete response and partial response were achieved by 6 (5.7%) and 23 (21.9%) patients (Table 2), corresponding to an objective response rate of 27.6% (95% CI: 19.34% to 37.20%; p<0.0001). Objective response rates were slightly lower using the investigator-assessed data (25.7%; 95% CI: 17.68% to 35.17%). In subgroup analyses, higher objective response rates were achieved in participants with an ECOG performance status of 0 compared with 1 (36.8% vs 22.4%), PD-L1 CPS≥20 compared with 1 to<20 (43.6% vs 18.2%), or following treatment with one compared with two previous chemotherapy treatments (29.7% vs 21.9%) (Online supplemental tables 1–4). Notably, of nine patients who had recurrent or metastatic cervical cancer despite receiving ≥3 previous lines of treatment, two achieved complete response, one achieved partial response and four had stable disease following treatment with zimberelimab. Overall, 58 patients had either complete response, partial response, or stable disease, giving a disease control rate of 55.2% (95% CI: 45.22% to 64.95%). The best change in target lesion size is illustrated in a waterfall plot in Figure 2A, with more than half of patients demonstrating a reduction in tumor size. Length of treatment exposure and independent review committee-assessed duration of response are captured in Figure 2B.

Figure 2

Efficacy of zimberelimab in the treatment of recurrent or metastatic cervical cancer. (A) Waterfall plot of independent review committee (IRC)-assessed best change in target lesion size from baseline; (B) Swimmer plot of treatment exposure and IRC-assessed duration of response. (C) Progression-free survival assessed by IRC. (D) Overall survival. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Table 2

Best overall response and objective response rate

Survival Analyses

As of April 29, 2022, 22 patients (21.0%) were still receiving treatment with zimberelimab. Median progression-free survival was 3.7 months and the 12- and 18-month progression-free survival rates were 28% (95% CI: 19% to 38%) and 22% (95% CI: 13% to 32%) as assessed by the independent review committee (Figure 2C). Similar progression-free survival results were observed using investigator-assessed data (Table 2). Median overall survival was 16.8 months (Figure 2D). The 12- and 24-month overall survival rates were 58% (95% CI: 48% to 67%) and 44% (95% CI: 31% to 55%), respectively. Median duration of response was not reached during the study (Table 2); 12- and 24-month duration of response rates were 74% (95% CI: 53% to 87%) and 55% (95% CI: 26% to 76%), respectively. Median time to response was 1.9 months (95% CI: 1.84 to 3.65) assessed by the independent review committee, similar to the investigator assessment.

Safety

Of the 105 participants included in the safety set, 102 (97.1%) experienced at least one treatment-emergent adverse event. Of these, 44 were considered to be grade ≥3 (41.9%). Treatment-related adverse events were experienced by 82 participants (78.1%), with hypothyroidism (26.7%) and anemia (19.0%) being the most frequently reported (Table 3). Grade ≥3 treatment-related adverse events were experienced by 26 participants (24.8%), including 8 (7.6%) who experienced a grade ≥3 treatment-related adverse event of anemia. Serious treatment-emergent adverse events, serious treatment-related adverse events, and immune-related adverse events were reported for 30 (28.6%), 16 (15.2%), and 48 (45.7%) participants, respectively. Treatment-related adverse events leading to treatment suspension or discontinuation, study withdrawal, or death were infrequent, affecting 11.4%, 9.5%, 2.9%, and 2.9% of participants, respectively. As of April 29, 2022, 52 (49.5%) patients in this study had died, including 39 (37.1%) who died from disease progression.

Table 3

Treatment-related adverse events occurring in ≥5% of patients at any grade

DiscussionSummary of Main Results

In this study, zimberelimab demonstrated encouraging therapeutic activity in Chinese patients with recurrent or metastatic PD-L1-positive (CPS≥1) cervical cancer. Zimberelimab could confer longer-term benefits compared with other agents available for PD-L1-positive Chinese cervical cancer patients. Subgroup analyses indicated that zimberelimab may be more effective in patients with better functional status and who are less heavily pre-treated, with the highest objective response rates achieved in patients with an ECOG performance status of 0 and treatment with only one prior chemotherapy line. In addition, higher PD-L1 expression appeared to correlate with greater efficacy in this population.

Results in the Context of Published Literature

Although this was a single-arm study and head-to-head data are not available, the objective response rate of 27.6% achieved with zimberelimab may be higher than previously reported in studies investigating PD-1 or PD-L1 inhibitors as monotherapy in patients with recurrent/metastatic cervical cancer and PD-L1 CPS≥1. For example, 14.6% was achieved with pembrolizumab in KEYNOTE-158,4 18.3% with cemiplimab in EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9,8 20.0% with nivolumab in CheckMate-358,6 and 5.9% with nivolumab in NRG-GY002.7

The median overall survival in this study was 16.8 months. In comparison, median overall survival of 11.0, 13.9, and 19.9 months was estimated for patients with PD-L1-positive cervical cancer treated with pembrolizumab, cemiplimab, and nivolumab monotherapy, respectively.4 6 8 The median progression-free survival in this study (3.7 months) compared favorably with that achieved with monotherapy with pembrolizumab (2.1 months)4 or cemiplimab (3.0 months)8 in patients with PD-L1-positive cervical cancer. In studies evaluating nivolumab monotherapy or atezolizumab in combination with bevacizumab, median progression-free survival values of 3.5 months7 and 5.1 months6 were reported; however, these were determined in the overall patient population, irrespective of PD-L1 status.

Hypothyroidism, anemia, and hyperthyroidism were the most common treatment-related adverse events reported in the study (26.7%, 19.0%, and 12.4%, respectively). The safety profile of zimberelimab was consistent with that reported in a previous study12 and was broadly similar to that observed for other PD-1/PD-L1 inhibitors used as monotherapy.4 6 8 Nevertheless, it is important to note that these studies constitute a variety of designs, patient numbers, and patient populations. Conclusive comparisons cannot be made with other PD-1 or PD-L1 inhibitors used in this setting.

Strengths and Weaknesses

This study is the first registration study in China to investigate a PD-1 monoclonal antibody in the treatment of patients with recurrent or metastatic cervical cancer and showed promising results for zimberelimab in this population. Based on this study, zimberelimab has been approved by the NMPA for the treatment of patients with recurrent or metastatic PD-L1-positive (CPS≥1) cervical cancer that has progressed after first- or subsequent-line chemotherapy on June 30, 2023. Weaknesses of this study include the single-arm design with no control group. Additionally, the study was performed in a population of Chinese patients and therefore may not be generalizable to a broader population.

Implications for Practice and Future Research

In this phase II study, the novel PD-1 inhibitor zimberelimab exhibited promising results in Chinese patients with recurrent or metastatic cervical cancer. The objective response rate of 27.6%, demonstrates significant efficacy compared with historical controls and compares favorably in indirect comparisons with other PD-1/PD-L1 inhibitors in this population. Overall survival results suggest that a survival benefit might be achieved with this drug. These results provide clinical evidence for the application of zimberelimab in patients with recurrent or metastatic cervical cancer, offering additional treatment options for such patients.

Longer-term follow-up of the patients treated in this study and subsequent controlled trials will be required to gain further insights into the benefits of zimberelimab as a treatment for recurrent or metastatic cervical cancer. A phase III randomized controlled trial was started in 2023 to verify the efficacy and safety of zimberelimab plus platinum-containing chemotherapy with/without bevacizumab as first-line treatment for recurrent, persistent, or metastatic cervical cancer (NCT05798819).

Conclusions

Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with recurrent or metastatic cervical cancer. Therefore, zimberelimab could be considered an optimal treatment choice for such patients.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

This study involves human participants and was approved by the ethics committee of Fudan University Shanghai Cancer Center (1901196-7-2105C). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

Zimberelimab is being developed by Guangzhou Gloria Biosciences Co., Ltd. We thank Steph Carter of Edanz (www.edanz.com) for providing medical writing assistance with earlier drafts of the manuscript, which was funded by Guangzhou Gloria Biosciences Co., Ltd.