Sintilimab plus HPV vaccine for recurrent or metastatic cervical cancer

Abstract

Purpose

Recurrent or metastatic cervical cancer (r/m CC) presents limited treatment options for patients failed or progressed quickly following first-line therapy. This study investigated the potential of sintilimab with a prophylactic human papillomavirus (HPV) quadrivalent vaccine as a second-line treatment for r/m CC.

Methods

In this phase 2 clinical trial, patients with r/m CC previously unresponsive or intolerant to standard treatments for metastatic or recurrent lesions were enrolled. Participants received sintilimab (3 mg/kg for body weight <60 kg; 200 mg for ≥60 kg) every 3 weeks until 24 months or 35 cycles and 3 doses of the HPV quadrivalent vaccine (initial dose prior to sintilimab initiation, with subsequent doses at 2 and 6 months). The primary endpoint was the objective response rate (ORR). A Simon two-stage optimal design was used.

Results

From October 2019 to October 2022, 13 patients with r/m CC were enrolled. ORR achieved 53.8% (95% CI 25.1% to 80.8%), and the disease control rate was 76.9% (95% CI 46.2% to 95.0%). Median follow-up duration was 16.07 months (range: 3.64–48.2 months), and median progressive free survival was 7.16 months (95% CI 1.91 –not applicable (NA)). The median overall survival (OS) was not reached (95% CI 9.89 –NA). Hypothyroidism (15.6%) was the most common treatment-related adverse event (AE). No grade 3 or above AEs were observed.

Conclusions

This study suggests the combination of sintilimab plus prophylactic HPV vaccine offers a potentially promising therapeutic strategy for patients with r/m CC unresponsive or intolerant to standard therapies.

Trial registration number

NCT04096911.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Sintilimab has been used in chemotherapy-resistant recurrent or refractory Hodgkin lymphoma but still needs further improvement in outcomes.

• Human papillomavirus (HPV) vaccines might stimulate B cell-driven humoral immunity, which might synergize with T cell-mediated antitumoral activity, enhancing the therapeutic outcomes of immunotherapy.

WHAT THIS STUDY ADDS

• The therapeutic of combining sintilimab with the HPV quadrivalent vaccine in patients with recurrent or metastatic cervical cancer (r/m CC) has promising results.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

• Combining immune checkpoint inhibitors with the prophylactic HPV vaccine might be a potential option for patients with r/m CC who don’t respond well to standard treatments.

Introduction

Cervical cancer (CC) stands as the predominant malignancy within the female reproductive system and ranks fourth in cancer-induced mortality among women globally, accounting for an alarming 311 000 fatalities each year.¹ Approximately half of these patients face recurrence or metastasis with just 2 years following their initial therapeutic intervention.² Such recurrent or metastatic CC (r/m CC) scenarios present an inferior prognosis, with a 5-year overall survival (OS) rate as low as 17%.³ In the past, the primary therapeutic approach for r/m CC involved taxanes like paclitaxel, topotecan, and platinum agents, notably cisplatin and carboplatin. Regrettably, these treatments yielded suboptimal results.4,7

The emergence of immune checkpoint inhibitors (ICIs) has opened up new treatment possibilities for r/m CC. Although the keynote158 trial showed that pembrolizumab alone in the treatment with PD-L1-positive r/m CC achieved an objective response rate (ORR) of 14.3% with a 3.2-month PFS,⁸ FDA approved it as the second-line treatment in patients with PD-L1-positive r/m CC. This unsatisfactory efficacy finding indicates that none of the monotherapies are satisfactory for r/m CC. To enhance efficacy, the current approach often involves combination therapy, such as pairing chemotherapy, radiotherapy, or antivascular therapy with immunotherapy. Notably, the KEYNOTE 826 trial has illuminated the enhanced efficacy of combining pembrolizumab with chemotherapy, optionally supplemented by bevacizumab, resulting in an extended OS by a notable 7.6 months.⁹ This combination has been endorsed as the primary therapeutic option by the National Comprehensive Cancer Network for PD-L1-positive r/m CC. Despite these advances, the therapeutic landscape remains barren for patients demonstrating progression post the first-line treatment, underscoring the pressing need for efficacious second-line treatments.¹⁰

Sintilimab is an innovative contender, a monoclonal antibody targeting PD-1, and rejuvenating the antitumor prowess of T cells. Its approval was for chemotherapy-resistant recurrent or refractory Hodgkin lymphoma in China in 2020.¹¹ Subsequent trials saw its deployment against diverse tumor types.¹² Intriguingly, a recent phase 2 clinical trial spotlighted the efficacy of sintilimab and anlotinib for PD-L1-positive r/m CC as a second or subsequent line of treatment. While the results boasted an impressive objective response rate (ORR) of 59.0% and a disease control rate (DCR) of 94.9%, the median progression-free survival (PFS) was a modest 4.95 months.¹³ Such outcomes underline the imperative for ongoing research to further refine and optimize treatment regimens for r/m CC.

Current hypotheses posit that prophylactic preventive human papillomavirus (HPV) vaccines might stimulate B cell-driven humoral immunity. This immune response could, in theory, synergize with T cell-mediated antitumoral activity, enhancing the therapeutic outcomes of anti-PD-1/PD-L1 modalities.¹⁴ Although theoretically appealing, clinical validations of this synergy are limited. To address this gap, we initiated a single-center, phase 2 clinical trial to evaluate the combined efficacy and safety of sintilimab and a prophylactic HPV vaccine for treating patients with r/m CC resistant or intolerant to standard first-line therapies.

Methods

Study design and participants

This is a single-arm, single-center, pilot phase 2 clinical trial involving patients with r/m CC who have failed previous lines of therapy. Patients eligible for inclusion were those aged 18 years or older, with histologically confirmed cervical cancer, who had previously failed or were intolerant to first-line or above standard treatment for metastatic or recurrent lesions. Further inclusion criteria encompassed the presence of at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1, an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–1 and a PD-L1 Combined Positive Score (CPS) of ≥1. Exclusions from the study were applied to patients with a history of other active malignant tumors within the past 5 years, uncontrolled infections, active or historical autoimmune diseases, current use of immunosuppressants, receipt of live vaccines within 28 days preceding the administration of the study drug, previously received prophylactic HPV vaccine or ICIs and known allergies to any drug or vaccine ingredient. A comprehensive list of inclusion and exclusion criteria is available in online supplemental table S1).

This clinical trial is registered with ClinicalTrials.gov under the identifier NCT04096911.

Treatment and assessments

All eligible patients received sintilimab plus HPV quadrivalent vaccine. Sintilimab was administrated based on body weight: those under 60 kg received 3 mg/kg, while those 60 kg or above were given a fixed 200 mg. The drug was administered intravenously infusion on the second day of each 21-day cycle. Treatment persisted until disease progression, intolerable toxicity, initiation of another antitumor treatment, withdrawal of informed consent, loss to follow-up, death, or if the investigator deemed discontinuation necessary. The maximum treatment duration was set at 24 months or 35 cycles. Alongside sintilimab, patients received three doses of the prophylactic HPV quadrivalent vaccine (4vHPV; GARDASIL, Merck Sharp Dohme) 0.5 mL subcutaneous injection: the first dose 1 day before starting sintilimab, followed by doses at 2 and 6 months postinitial administration. The HPV infection status of the patient was detected by PCR. The tumor mutational burden (TMB) of the patient was detected by next-generation sequencing using the “Shihe-1” large panel genetic testing kit, which has a cut-off value of 10 mutations/Mb for TMB detection.

Postinitiation of the study regimen, tumor evaluations were scheduled every 6 weeks (±7 days) for the initial 48 weeks, transitioning to a 12-week interval (±7 days) subsequently. Assessments relied on CT or MRI scans of the chest, abdomen, pelvic region, and any potential tumor sites. Clinical response of the tumor is evaluated by the investigator according to RECIST V.1.1. Depending on clinical exigencies, the frequency of these evaluations can be augmented. If any patient showed disease progression (PD), a follow-up imaging should be mandated about 6 weeks (2 cycles of therapy) later to affirm the diagnosis of PD.

Once the study treatment concluded or was terminated, a safety follow-up was conducted 30 days (±7 days) after the final treatment. This involved monitoring survival status, recording adverse events (AEs), and executing essential laboratory evaluations. After this phase, patients’ survival was periodically checked via phone every 12 weeks (±7 days).

Endpoints

The primary endpoint was the ORR, defined as the proportion of subjects achieving either complete response (CR) or partial response (PR). Secondary endpoints encompassed duration of response (DOR), DCR, PFS, and OS. The DCR was the percentage of patients who achieved CR, PR, or stable disease (SD) for at least 12 weeks. DOR was the time from the first documented response to PD or death, whichever came first. PFS was the time from the first vaccine to the detection of PD or death, and OS was from the first vaccine to death. For safety, all AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) V.5.0. AEs related to the study drug and those causing treatment modification or discontinuation were documented.

Specific antibodies detection

We detected anti-HPV 16 L1 IgG in blood samples using the Human Anti-HPV16L1 IgG ELISA Kit (Alpha Diagnostic Intl, Texas, USA) and Human Anti-HPV18L1 IgG ELISA Kit (Alpha Diagnostic Intl, Texas, USA) by blood sampling the patients before the first dose of HPV vaccination and the third cycle of sintilimab, respectively.

Statistical analysis

Employing the Simon two-stage optimal design, the sample size was calculated based on the ORR.

A response rate of ≤14.3% was considered to be of no clinical interest (based on the results of the KEYNOTE158⁸). Available studies^{15 16} have reported response rates of approximately 30%–40% for combination therapies with therapeutic HPV vaccines for r/m CC. Based on this possible existence of new mechanisms, we believe that a higher response rate is needed to support it, so we set a response rate of ≥50% which was considered to be clinically relevant. The null hypothesis that the true response rate was 14.3% was tested against a one-sided alternative. Based on these assumptions, three patients would be initially enrolled in the study’s first stage. If any response was noted, the trial proceeded, incorporating an additional eight patients during its second stage. If 4 or more among these 11 patients showed a response, the null hypothesis could be rejected. This design yields a type I error rate of 2.5% and a power of 80% to reject the null hypothesis when the true response rate is 50%. The sample size was 4 for the first stage and 13 for all of the first and second stages, considering a dropout rate of 10%.

Statistical analysis was performed using R software V.3.4.1. Continuous data that conformed to normal distribution were represented as mean±SD, otherwise as median and range. Categorical data such as ORR, DCR, and AEs were delineated by frequency and percentage. Time-to-event outcomes including DOR, PFS, and OS were assessed using the Kaplan-Meier method, with the corresponding KM curves being constructed. Median values for DOR, PFS, and OS, complemented by their 95% CIs, were ascertained.

Patient and public involvement

No patient was involved in the development of the research questions and outcome measures, study design or recruitment, and in the conduct of this study.

Results

Patient demographics and clinical characteristics

Of the 35 patients with r/m CC initially screened, 13 were enrolled between October 2019 and October 2022. All 13 patients underwent treatment combining HPV vaccine and sintilimab and subsequently were included in the efficacy analysis (figure 1). The median age of the patients was 55 years, with an age range spanning from 52 to 83 years. When first diagnosed, one patient (7.6%) presented with International Federation of Gynecology and Obstetrics (FIGO) stage I, seven (53.8%) with FIGO stage II, and four (30.8%) with FIGO stage III. All the participants demonstrated an ECOG PS of 1. Among them, one patient (7.6%) was diagnosed with adenocarcinoma, while the remainder had squamous cell carcinoma. Detailed baseline characteristics are presented in table 1. With the data cut-off on February 28, 2024, patients received immunotherapy with sintilimab for a median of 11 cycles (range: 3–36 cycles) in a median treatment duration of 7.41 months (range: 2.1–24.9 months). Three (23.1%) patients completed only two doses of HPV vaccine due to the progression of the disease during the therapy, while 11 (76.9%) completed three doses.

Figure 1. Flowchart of patients.

Table 1. Baseline characteristics of patients.

Variables	All (n=13)
Age, years, median (range)	55 (52–83)
FIGO stage at initial diagnosis, n (%)
I	1 (7.6)
II	7 (53.8)
III	4 (30.8)
Unknown	1 (7.6)
ECOG performance status, n (%)
0	0
1	13 (100)
Histology, n (%)
Squamous cell carcinoma	12 (92.3)
Adenocarcinoma	1 (7.6)
HPV type, n (%)	13 (100)
16	2 (15.4)
18	1 (7.6)
33	1 (7.6)
Other type	1 (7.6)
Negative	8 (61.5)
Local recurrence plus distant metastasis, n (%)	1 (7.6)
Local recurrence only, n (%)	1 (7.6)
Distant metastasis only, n (%)	12 (92.3)
Lymph node metastasis	4 (30.8)
Organ metastasis	11 (84.6)
Liver	2 (15.4)
Lung	6 (46.2)
Others	6 (46.2)
Target lesion size, mm, median (range)	32 (10–56)
Previous radiotherapy, n (%)	13 (100)
Time since last radiotherapy, months, n (%)
<12	6 (46.2)
≥12	7 (53.8)
Previous systemic therapy lines, n (%)
1	12 (92.3)
2	1 (7.6)
Previous platinum, n (%)	12 (92.3)
PD-L1 expression status (CPS), n (%)
<10	10 (76.9)
≥10	3 (23.1)
TMB status, n (%)
High (≥10 mutations/Mb)	6 (46.2)
Low (<10 mutations/Mb)	6 (46.2)
Without somatic mutation	1 (7.6)

CPS, Combined Positive Score; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; HPV, human papillomavirus; TMB, tumor mutational burden

Efficacy endpoints

The treatment outcomes for the 13 patients who underwent efficacy analysis are depicted in both the swim-lane and waterfall charts (figure 2A and B). Notably, five patients (38.5%) exhibited a CR, while two patients (15.4%) showed PR and three (23.1%) showed SD. Only three patients (23.1%) had PD. The ORR was 53.8% (95% CI 25.1% to 80.8%), and the DCR was 76.9% (95% CI 46.2% to 95.0%) (table 2).

Figure 2. (A) Treatment exposure and response duration; (B) the best percentage changes from baseline in target lesions; (C) K-M curve of progression-free survival; and (D) K-M curve of overall survival. CR, complete response; PD, progressive disease; PR, partial response; K-M, Kaplan-Meier; SD, stable disease.

Table 2. Efficacy endpoints.

Variables	All (n=13)
Best overall response
CR, n (%)	5 (38.5)
PR, n (%)	2 (15.4)
SD, n (%)	3 (23.1)
PD, n (%)	3 (23.0)
ORR, n (%)	7 (53.8)
95% CI	25.1% to 80.8%
DCR, n (%)	10 (76.9)
95% CI	46.2% to 95.0%
DOR, months, median	NA
95% CI	3.09–NA
PFS, months, median	7.16
95% CI	1.91–NA
OS, months, median	NA
95% CI	9.89–NA

ORR, objective response rate; DCR, disease control rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; DOR, duration of response; PFS, progression-free survival; OS, overall survival; NA, not applicable

With a median follow-up duration of 16.07 months (range: 3.64–48.2 months), the median DOR was not reached. PFS events emerged in seven patients, with a median PFS of 7.16 months (95% CI: 1.91–not applicable (NA)) (figure 2C). The PFS rates at 6 and 12 months were 53.8% (95% CI 0.326 to 0.891) and 46.2% (95% CI 0.257 to 0.830), respectively. Regarding OS, events were noted in six patients, resulting in a median OS that was not reached (95% CI 9.89–NA), with a 6-month OS rate of 92.3% (95% CI 0.789 to 1.000) and a 12-month rate of 61.5% (95% CI 0.4 to 0.946) (figure 2D, table 2).

There was no statistical difference in PFS between the patients with low PD-L1 expression (CPS <10, mPFS=6.85 months (95% CI 1.05–NA)) and high PD-L1 expression (CPS ≥10, mPFS=NA (95% CI 1.91–NA)) (p=0.4). There was no statistical difference in PFS among the patients with low TMB (<10 mutations/Mb, mPFS=4.24 (95% CI 1.05–NA)) and high TMB (≥10 mutations/Mb, mPFS=12.71 (95% CI 1.91–NA)) (p=0.3).

Safety profile

During the study, patients exhibited a median treatment duration of 7.41 months, ranging between 2.1 and 24.7 months. Among these, 6 patients (46.2%) encountered treatment-emergent AEs, while there were no reported vaccine complications. The most common treatment-related AEs identified was hypothyroidism (15.6%) (table 3). Notably, there were no AEs of grade 3 or higher. One patient discontinued sintilizumab for synovitis after CR and subsequently received low-dose glucocorticoid for synovitis.

Table 3. Treatment-related adverse events.

Events, n (%)	Any grade	Grade 1	Grade 2	Grade 3
Hypothyroidism	2 (15.4)	1 (7.6)	1 (7.6)	0
Fever	1 (7.6)	0	1 (7.6)	0
Immune encephalitis	1 (7.6)	0	1 (7.6)	0
Synovitis	1 (7.6)	0	1 (7.6)	0
Proteinuria	1 (7.6)	1 (7.6)	0	0

Specific antibodies

No significant correlation was found between anti-HPV 16 L1 IgG (online supplemental figure S1) or anti-HPV 18 L1 IgG (online supplemental figure S2) results with tumor response in 13 patients.

Discussion

Our study exploring the therapeutic potential of combining sintilimab with the HPV quadrivalent vaccine in patients with r/m CC has produced promising results. Within the cohort of 13 participants, who had either failed to respond to or could not tolerate standard first-line treatments, the observed ORR was an encouraging 53.8%, with a DCR of an appreciable 76.9%. Impressively, five patients (38.5%) exhibited CR, a rarity in treatments for r/m CC. The recorded PFS was 7.16 months, and the median OS was not reached. During our study with a median follow-up spanning 16.07 months, the median DOR was not reached, suggesting a sustained therapeutic benefit in patients who showed a response to the combined treatment approach. Throughout the treatment and follow-up phases, no AEs of grade 3 or higher were detected. The combination of sintilimab with the HPV quadrivalent vaccine demonstrates not only significant efficacy but also a commendable safety profile, offering a potential new therapeutic avenue for recurrent or patients with r/m CC who are resistant or intolerant to conventional treatments. The therapeutic landscape of r/m CC has long struggled with the challenge of developing effective second-line treatments. Conventional treatments often yield suboptimal outcomes, highlighting the need for innovative approaches. Trials like KEYNOTE-028 and KEYNOTE-158, investigating pembrolizumab for advanced cervical tumors, saw modest success, with ORRs of 17% and 14.3%, and limited PFS of 2–3 months.^{8 17} Despite this, the FDA endorsed pembrolizumab as a second-line therapy for r/m CC. Another phase 3 study with cemiplimab reported an ORR of 16.4% and OS of 12.0 months post-platinum-based chemotherapy.¹⁸ These results, though slightly better, emphasize the enduring challenges. Interestingly, amid modest outcomes from ICI monotherapies, research is pivoting toward combination therapies, with some exploring immunization alongside antiangiogenic agents,^{13 19} as radiation²⁰ or chemotherapy. The ORRs have been marginally better, but still not ideal.²¹ The KEYNOTE-826 trial, testing pembrolizumab with chemotherapy in r/m CC, saw a 66.2% ORR and 22.7% CR rate.²² In contrast, our study, centered on single-agent immunotherapy using sintilimab, unveiled a remarkable ORR of 53.8% and, achieved an unprecedentedly high DCR of 76.9%, meanwhile 38.5% of the patients achieved CR. Given these promising results, our treatment approach may offer even greater benefits if used as a first-line therapy. Further large-scale studies are required to confirm these findings and understand their implications for the broader patient population with r/m CC . The etiology of cervical cancer is deeply linked to persistent infections of high-risk HPV strains.²³ The persistent infection activates HPV oncogenes E6 and E7, crucial for deactivating proteins like p53 and retinoblastoma. This leads to genomic instability and initiates carcinogenesis.²⁴ Parallelly, the E6 and E7 oncoproteins have been found to amplify the expression of PD-L1, a mechanism involving the suppression of p53 and Rb.²⁵ This combined modality appears particularly effective in a niche cohort doubly expressing HPV and PD-L1. Illustratively, a regimen involving nivolumab coupled with ISA 101, an HPV-16-specific synthetic long peptide vaccine, exhibited an ORR of 33% in patients previously treated for recurrent HPV-16 positive malignancies,¹⁵ with a median OS of 15.3 months.²⁶ Another noteworthy investigation demonstrated an ORR of 42% in patients with advanced or recurrent cervical cancer following combined treatment with pembrolizumab and GX-188E.¹⁶ Moreover, the blend of MEDI0457, a therapeutic DNA vaccine, and durvalumab showed promise, yielding an ORR of 21% and a DCR of 37% when administered to patients with recurrent or metastatic HPV-16/18 cervical cancer, or in rare cases of HPV-associated cancers like anal and penile cancers.²⁷ These findings underscore the potential benefits of such combination approaches. Remarkably, our study highlights the potential of the traditionally preventive quadrivalent vaccine, rather than a therapeutic HPV-specific vaccine, to achieve unexpectedly strong therapeutic responses. These results suggest that combining preventive HPV vaccines with PD-1 inhibitors can enhance significant synergistic effects against HPV. Instead of restricting tumor immunization strategies solely to T cell-centric cellular immunity, our data suggest a collaborative effect between B and T cells in promoting robust antitumor responses.

The specific antibody detection results for anti-HPV 16 L1 IgG and anti-HPV 18 L1 IgG did not correlate with tumor response. This suggests that B-cell and T-cell therapy interaction may involve new pathways of autocrine or paracrine cytokines. Indicators such as elevated IL-14α levels in effectively treated patients further cement the participatory role of B cells in tumor immunity.

The prophylactic HPV vaccine effectively mobilizes B cells to enhance antitumor immunity alongside T cells, contrasting with the previous low efficacy of PD-1/PD-L1 therapy, which relied solely on T cells. Solely targeting PD-L1 for cervical cancer treatment has shown limited efficacy, potentially due to impaired endogenous T cell responses in tumor hosts.²⁸ Our study achieved outstanding efficacy by combining a prophylactic HPV vaccine with mono immunotherapy, marking a significant breakthrough in addressing the low efficiency of mono immunotherapy. However, understanding the specific mechanisms of B cell involvement remains a key focus. The safety of ICI for r/m CC has been confirmed in previous research. In the KEYNOTE-028 trial, 21% of participants experienced grade 3 AEs, with rash and fever being the most common. No grade 4 treatment-related AEs or fatalities were observed. The KEYNOTE-158 trial reported treatment-related AEs in 65.3% of patients, with hypothyroidism, decreased appetite, and fatigue being predominant. Grade 3 to 4 AEs occurred in 12.2% of the cohort. In the KEYNOTE-826 trial, 82.4% of participants experienced grade ≥3 AEs with pembrolizumab.^{8 17 22}

In contrast, our study combining ICIs with the vaccine showed a reassuring safety profile. The most common treatment-related AE was hypothyroidism, occurring in 15.6% of participants. Importantly, no grade 3 or above AEs were reported. Overall, our study’s safety profile closely aligns with what is typically observed with sintilimab monotherapy.29,31

Furthermore, while the prophylactic HPV vaccine is currently age-restricted (20–45 years) in China, our cohort’s median age suggests that age should not unduly limit its use alongside ICIs for cervical cancer therapy. It is noteworthy that while all patients in this study were PD-L1-positive, the majority had low PD-L1 expression (CPS <10), and some patients had either high or low TMB. Despite these variations, both groups benefited significantly from the combination of immunotherapy with the HPV prophylactic vaccine. This finding raises the possibility that this therapeutic approach may have broader applicability, potentially benefiting patients with low PD-L1 expression who are traditionally less responsive to ICIs. Additionally, although the current data hint at some efficacy in patients with high-TMB, the evidence remains insufficient to form definitive conclusions due to the small sample size. Given the known limitations of PD-L1 and TMB as reliable biomarkers, our results further emphasize the need for novel or more effective biomarkers to guide immunotherapy in r/m CC. Future studies involving larger cohorts are required to fully understand the implications of this observation and to validate whether this combination therapy could serve as an effective option for patients with low PD-L1 expression.

While our study highlights the promising combination of sintilimab and an HPV vaccine for patients with r/m CC, it’s important to acknowledge its limitations. The modest sample size may limit the generalizability of our findings, and the wide CIs observed for ORR and DCR reflect the inherent uncertainty of small sample sizes. While the results are encouraging, larger studies are required to provide more precise estimates and validate these findings. Future research should focus on enrolling larger patient cohorts to further assess the potential of this therapeutic approach. This study is the first to investigate a prophylactic HPV vaccine in combination with ICI without restrictions based on HPV infection status, a relevant consideration given the high HPV infection rate among Chinese patients with cervical cancer. A subsequent phase III multicenter clinical trial to further explore the combination of the HPV vaccine with ICI will be conducted. Due to the limited availability of the nine-valent HPV vaccine in China, we employed the quadrivalent vaccine in this study. However, the potential benefits of the nine-valent vaccine warrant further exploration in future studies.³²

In this initial study, combining sintilimab with the prophylactic HPV vaccine shows promise for treating patients with r/m CC who don’t respond well to standard treatments. Despite the small sample size, the therapy proves effective and safe.

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.