This chapter should be cited as follows:
Tse KY, Lin M, et al., Glob Libr Women's Med
ISSN: 1756-2228; DOI 10.3843/GLOWM.422043

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 13

Gynecological cancer

Volume Editors: Professor Hextan Ngan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong
Professor Karen Chan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong

Chapter

Systemic Treatment of Cervical Cancer

First published: May 2026

AUTHOR(S)

Ka Yu Tse

Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong SAR; Department of Obstetrics and Gynecology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China

Min Lin

Department of Obstetrics and Gynecology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China

Fang Li

Department of Obstetrics and Gynecology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

Sung Jong Lee

Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

Nozomu Yanaihara

Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan

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INTRODUCTION

In 2022, cervical cancer was the fourth most common cancer among women worldwide.¹ Disease stage and lymph node involvement are key prognostic factors. Accordingly, the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system incorporated retroperitoneal lymph node metastasis into cervical cancer staging.² Most patients are diagnosed at an early stage, when the disease can usually be managed effectively with surgery and/or chemoradiation. However, recurrence still occurs in about 11–22% of patients with Stage-IB–IIA disease.³ Patients with advanced metastatic, persistent or recurrent disease have poor prognosis, with historical 5-year overall survival (OS) rate of 5–17% once disease is no longer amenable to curative local therapy.⁴^,⁵ Traditionally, chemotherapy was the only systemic treatment for metastatic cervical cancer in both first-line as well as subsequent treatment settings. With more understanding of the biology of cervical cancer and advances in drug development, more treatment options have evolved, including targeted therapy, immunotherapy and antibody-drug conjugates (ADC). These therapies, either alone or in combination, have been proven to be superior to chemotherapy alone, revolutionizing the treatment landscape of this lethal condition.

In this chapter, the evidence on the use of systemic treatment in metastatic cervical cancer, and the role of predictive biomarkers, are discussed. The management of locally advanced cervical cancer is beyond the scope of this review.

CHEMOTHERAPY

Cisplatin has historically been the mainstay treatment in primary metastatic cervical cancer.⁶ The Gynecologic Oncology Group (GOG)-169 study showed that the addition of paclitaxel to cisplatin improved the objective response rate (ORR) from 19% to 36% (P = 0.002) and median progression-free survival (PFS) from 2.8 to 4.8 months (P < 0.001) compared to cisplatin alone.⁷ However, no improvement in OS was observed. Other agents have also been tested in combination with cisplatin, including vinorelbine, gemcitabine and topotecan, and there was a trend favoring cisplatin and paclitaxel in ORR, PFS and OS.⁸ The GOG-179 study compared cisplatin with and without topotecan⁹ and demonstrated that a combination of cisplatin and topotecan was associated with a superior median PFS (4.6 vs 2.9 months, P = 0.014) and median OS (9.4 vs 6.5 months, P = 0.017). However, hematologic toxicities have limited the use of this combination.

Carboplatin is associated with less nephrotoxicity, neuropathy, and nausea and vomiting than cisplatin. The JGOG0505 trial subsequently showed that paclitaxel plus carboplatin was non-inferior to paclitaxel plus cisplatin, with a median OS of about 18 months in both treatment arms.¹⁰ Therefore, paclitaxel combined with either cisplatin or carboplatin has remained a mainstay systemic treatment for primary advanced metastatic or recurrent cervical cancer.

Once first-line chemotherapy failed, the prognosis was historically poor. Various second-line chemotherapy agents, such as capecitabine, topotecan, gemcitabine, vinorelbine, etoposide and pemetrexed, have been evaluated.¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³ However, outcomes were modest with ORR ranging from 0–28%, stable disease rates of 11–53%, median PFS of 1.2–5.4 months and median OS of 3.5–11.7 months¹⁶^,²⁴^,²⁵^,²⁶ (Table 1). Irinotecan with mitomycin-C were shown to have an ORR of 33% in those who had prior therapy, but 59% of patients had Grade-3–4 neutropenia, thus limiting their widespread use.²⁷

Efficacy of selected second-line chemotherapy for recurrent cervical cancer.

Agent	Reference	Number of evaluable patients	ORR (%)	Stable disease rate (%)	Median PFS (months)
5-FU	⁹¹	43	14
Docetaxel	⁹²	23	8.7	34.8	3.8
Etoposide (oral)	²¹	42	11.9	42.9	3.1
Gemcitabine	¹⁷	22	4.5	36.4	2.1
Gemcitabine and docetaxel	⁹³	22	27.3	31.8	3.9
Irinotecan (CPT-11)	⁹⁴	45	13.3
Irinotecan and mitomycin-C	²⁷	51	33.3
Liposomal doxorubicin	⁹⁵	26	11.1	33.3	3.2
Nab-paclitaxel	⁹⁶	35	28.6	42.9	5
Oxaliplatin	⁹⁷	24	8.3	37.5
Oxaliplatin and paclitaxel	⁹⁸	32	22	25	4.6
Paclitaxel (weekly)	²⁴	15	6.7	53.3
Pemetrexed	⁹⁹	43	13.9	53.4	2.5
Topotecan	²⁶	43	18.6	32.6	2.4
Topotecan (weekly)	¹³	25	0	40	2.4
Topotecan and veliparib	¹⁰⁰	27	7.4	37	2
Vinblastine	¹⁰¹	33	0	60.6
Vinorelbine	¹⁰²	41	17	20	2.6

ORR, objective response rate; PFS, progression-free survival.

ANTI-ANGIOGENESIS

The limited survival benefit of cisplatin/carboplatin and paclitaxel compared to cisplatin alone highlighted the need for more effective treatments. Several targeted therapies have been investigated, particularly those targeting vascular endothelial growth factor (VEGF). A Phase-II study evaluating bevacizumab monotherapy in patients with persistent or recurrent cervical cancer reported a 6-month PFS rate of 23.9%, partial response rate of 10.9%, median PFS of 3.40 months (95% CI, 2.53–4.53 months) and median OS of 7.29 months (95% CI 6.11–10.41 months), respectively.²⁸ In the GOG-240 study, the addition of bevacizumab to platinum-based chemotherapy significantly improved the OS from 13.3 months to 17.0 months (hazard ratio (HR) for death, 0.71; 98% CI 0.54–0.95; P = 0.004, one-sided test), the PFS from 5.9 to 8.2 months (HR 0.67, 95% CI 0.54–0.82; P = 0.002, two-sided test), and the ORR from 36% to 48% (relative probability of a response, 1.35; 95% CI 1.08–1.68; P = 0.008, two-sided test).²⁹

Similarly, the Phase-II CIRCCa study, showed that the addition of cediranib, an oral tyrosine kinase inhibitor of VEGF1, VEGF2 and VEGF 3, to carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer improved median PFS from 6.7 months in the placebo arm to 8.1 months in the cediranib arm (P = 0.032).³⁰ However, cediranib has not yet been approved for the treatment of cervical cancer.

IMMUNOTHERAPY

The use of immune checkpoint inhibitors (ICIs) has been one of the most significant breakthroughs in the management of metastatic and recurrent cervical cancer. Among all the immune checkpoints, programmed cell death protein 1 and its ligand (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been the most studied therapeutic targets. Some immune checkpoints, including PD-1 and CTLA-4, are expressed on T-cells. When they bind to the corresponding ligands on tumor cells and/or antigen-presenting cells, as happens when PD-1 binds to PD-L1 and PD-L2, and CTLA-4 binds to CD80 (B7-1) and CD86 (B7-2), they can lead to immune evasion.³¹ By blocking these inhibitory pathways, ICIs can reinvigorate the immune system, enabling the T-cells to recognize and eliminate cancer cells.

There are several strong biological rationales for the use of ICIs in cervical cancer. First, up to 70% of cervical squamous cell carcinomas (SCC) exhibit amplification of CD274 and PDCD1LG2 genes, which encode PD-L1 and PD-L2, respectively.³²^,³³ Over half of cervical SCCs and approximately 10% of adenocarcinomas also express PD-L1.³⁴^,³⁵^,³⁶ Second, over 99% of cervical cancers are associated with persistent HPV infection. Integration of HPV into the host genome often leads to overexpression of the viral oncoproteins E6 and E7. While these proteins can suppress interferon responses, they also promote dendritic cells to present infected cells to cytotoxic T-lymphocytes.³⁷ Third, chronic HPV infection may further drive PD-L1 expression.³⁸^,³⁹ Lastly, it has been shown that, among all cancers, cervical cancer has a moderate tumor mutational burden (TMB) and neoantigen load.⁴⁰^,⁴¹ In addition, subsets of cervical cancer contain tumor-infiltrating immune cells, including activated memory CD4⁺ T cells, which can further modulate the tumor microenvironment.⁴²

Recurrent second-line therapy

In the KEYNOTE-028 study, pembrolizumab (10 mg/kg every 2 weeks) was used to treat patients with PD-L1-positive metastatic or recurrent cervical cancer after first-line treatment, for up to 24 months.⁴³ The ORR was 17% (95% CI, 5–37%), and the disease-control rate (DCR) was 30%.⁴³ The efficacy was subsequently confirmed by the Phase-II KEYNOTE-158 trial, which showed an ORR of 14.6% (95% CI, 7.8–24.2%), while the median duration of response was not reached (range, ≥ 3.7 to ≥ 18.6 months).⁴⁴ The Phase-III EMPOWER-CERVICAL 1/GOG-3016/ENGOT-cx9 study compared use of cemiplimab with conventional chemotherapy.³⁶ Treatment with cemiplimab significantly improved median OS (12.0 vs 8.5 months; HR 0.69; 95% CI 0.56–0.84), and median PFS to a lesser extent (2.9 months vs 2.8 months; HR 0.75; 95% CI 0.63–0.89).

To improve treatment efficacy, several Phase-II studies have investigated combining anti-PD1/PD-L1 with additional immune targets. In the CheckMate-358 trial, the NIVO1 plus IPI3 regimen (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles, followed by nivolumab 240 mg every 2 weeks) achieved an ORR of 40% in patients with HPV-positive or HPV-unknown cervical cancer, compared with 26% with nivolumab monotherapy.⁴⁵^,⁴⁶ The SKYSCRAPER-04 was an open-label, randomized Phase-II trial in patients with PD-L1-positive recurrent or persistent cervical cancer that compared atezolizumab monotherapy with atezolizumab plus the anti-TIGIT (T-cell immunoreceptor with Ig and ITIM domains antibody tiragolumab). The combination arm showed an ORR of 19.0% vs 15.6% with atezolizumab monotherapy, a numerical improvement that did not meet the prespecified statistical threshold.⁴⁷ Median PFS was 2.8 months with the combination and 1.9 months with atezolizumab alone, while median OS was 11.1 and 10.6 months, respectively.

First-line therapy

Following the encouraging response of ICIs in recurrent cervical cancer, their use with platinum-based chemotherapy was evaluated as a first-line treatment. KEYNOTE-826 was a Phase-III, randomized, double-blind trial evaluating pembrolizumab plus platinum-based chemotherapy (paclitaxel and cisplatin/carboplatin), with or without bevacizumab, vs placebo plus the same chemotherapy backbone as first-line therapy for persistent, recurrent or metastatic cervical cancer.⁴⁸^,⁴⁹ Median PFS in the pembrolizumab group was significantly longer than that in the placebo group (10.4 months vs 8.2 months; HR 0.61; 95% CI 0.50–0.74). Median OS was also significantly improved with pembrolizumab (26.4 months vs 16.8 months; HR 0.63; 95% CI 0.52–0.77). The benefits were consistent across PD-L1 combined positivity score (CPS) subgroups (≥ 1, ≥ 10 and overall population). Secondary endpoints, including ORR (66.2% vs 51.5%) and duration of response (18.0 months vs 10.4 months), also favored the pembrolizumab group.

The BEATcc (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030) was a Phase-III trial comparing atezolizumab plus bevacizumab and platinum-based chemotherapy with bevacizumab plus platinum-based chemotherapy in the first-line setting.⁵⁰ Similar to the KEYNOTE-826 study, it demonstrated significant improvement in median PFS (13.7 months vs 10.4 months; HR 0.62; 95% CI 0.49–0.78) and median OS (32.1 months vs 22.8 months; HR 0.68; 95% CI 0.52–0.88) in the atezolizumab group. Post-hoc analysis of 313 biomarker-evaluable patients showed benefits across PD-L1 CPS subgroups (< 1, ≥ 1, ≥ 10), independent of expression.

COMPASSION-16 was also a Phase-III trial that evaluated cadonilimab (a PD-1/CTLA-4 bispecific antibody) plus platinum-based chemotherapy with or without bevacizumab vs placebo plus the same chemotherapy regimen in first-line persistent, recurrent or metastatic cervical cancer.⁵¹ It showed that the combination of cadonilimab with chemotherapy led to significantly longer median PFS (12.7 months vs 8.1 months; HR 0.62; 95% CI 0.49–0.80) and median OS (not reached vs 22.8 months; HR 0.64; 95% CI 0.48–0.86) compared to chemotherapy alone, while the incidence of treatment-related adverse events (TRAEs) was similar between the groups.⁵¹

ANTIBODY–DRUG CONJUGATES

Antibody–drug conjugates (ADC) represent a relatively new treatment modality. They are composed of a fully humanized monoclonal antibody (mAb), a cytotoxic payload and linker that connects the two components.⁵² After the mAb binds to a tumor-associated surface antigen, the ADC is internalized into the cell by endocytosis. Within lysosomes, the linker is cleaved through mechanisms such as protease-sensitive peptides or disulfide bonds, releasing the active cytotoxic payload. Depending on the characteristics of the payload, the released drug can induce tumor cell death by disrupting DNA intercalation or causing microtubule disruption, ultimately leading to apoptosis. ADCs may also exert a ‘bystander effect’, in which the payload diffuses into neighboring antigen-negative tumor cells within heterogeneous tumors. Additionally, the antibody component can activate immune responses through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Currently there are two ADCs that have been approved as monotherapy for selected patients with recurrent or metastatic cervical cancer.

Tisotumab vedotin

Tisotumab vedotin (TV) comprises a human IgG1 mAb against tissue factor (TF) coupled to four molecules of monomethyl auristatin E (MMAE) via a protease-cleavable valine–citrulline linker.⁵³ TF, also known as platelet coagulation factor III, is a transmembrane glycoprotein mainly expressed in vascular endothelial subdural cells. It is highly expressed in about 34% of cervical cancers.⁵⁴ It can bind to coagulation factor VII/VIIa, inducing the production of pro-angiogenic factors, cytokines and adhesion molecules that promote tumor growth and metastasis.⁵⁵

The Phase-II single-arm InnovaTV 204/GOG-3023/ENGOT-cx6 study showed that TV led to ORR of 24% including 7% complete response (CR) in patients with recurrent cervical cancer.⁵⁶ In the Phase-III InnovaTV 301/ENGOT-cx12/GOG-3057 study, 502 patients with disease progressing after one or two prior systemic regimens were randomized to either TV or investigator’s-choice chemotherapy.⁵⁷ This study further demonstrated the efficacy of TV, with improved median OS in patients receiving TV (11.5 months vs 9.5 months, HR 0.70; 95% CI 0.54–0.89; P = 0.004), improved median PFS (4.2 months vs 2.9 months; HR 0.67; 95% CI 0.54–0.82; P < 0.001), and improved ORR (17.8% vs 5.2%; odds ratio (OR) 4.0; 95% CI 2.1–7.6; P < 0.0001), compared to chemotherapy. TV is now approved for use in patients with persistent, recurrent or metastatic cervical cancer who have progressed after first-line treatment. Currently, testing for TF expression is not required prior to treatment with TV. Therefore, further research is needed to identify biomarkers that may help select patients most likely to benefit from this therapy

In the TV group of the InnovaTV 301/ENGOT-cx12/GOG-3057 study, 52.8% experienced ocular events (conjunctivitis, keratitis, dry eye, blurred vision) (4.0% were Grade ≥ 3), 38.4% had peripheral neuropathy (5.6% Grade ≥ 3) and 42.0% reported bleeding events (2.4% Grade ≥ 3). In contrast, the chemotherapy group had lower rates of these TRAEs, i.e. 6.3% for ocular events (0% Grade ≥ 3), 4.2% for peripheral neuropathy (0.4% Grade ≥ 3) and 14.2% for bleeding (2.9% Grade ≥ 3). Given the risk of ocular complications, preventive measures are important, including baseline and pre-cycle eye examinations, use of steroid, vasoconstrictor and lubricating eye drops, cold eye compression masks, and avoidance of contact lenses.⁵⁸ If Grade-1–2 ocular AEs occur, TV should be withheld until resolution, and dose reduction should be considered. The drug should be permanently discontinued if there are Grade-3–4 or recurrent ocular (adverse events) AEs.

Trastuzumab deruxtecan

Trastuzumab deruxtecan (T-Dxd) is a human monoclonal IgG1 produced with the same amino acid sequence as trastuzumab targeted human epidermal growth factor receptor 2 (HER2), and is linked via a cleavable tetrapeptide linker to a membrane-permeable topoisomerase-I inhibitor (deruxtecan) with a high drug–antibody ratio of 8.⁵⁹ Using immunohistochemical staining (IHC), HER2 expression scores of IHC 2+ and 3+ are observed in 14–18% and 3–14% of cervical cancers, respectively. The reported proportions of IHC 2+ and 3+ in SCC were 14.1% and 2.7%, and those in adenocarcinoma were 18.2% and 11.0%, respectively.⁶⁰^,⁶¹

The main prospective efficacy data come from the Phase-II DESTINY-PanTumor02 trial which evaluated T-DXd at 5.4 mg/kg every 3 weeks in multiple HER2-expressing solid tumors (IHC ≥ 1+).⁶² In the cervical cancer cohort, including 40 patients of whom 85% received ≥ 2 prior lines of treatment, the ORR was 50% overall, and was 40.0% and 75.0% in patients with IHC 2+ and 3+, respectively. In patients with IHC 2+, the median PFS was 4.8 months and the median OS was 11.5 months. In patients with IHC 3+, the median PFS and OS were not reached. The US Food and Drug Administration (FDA) has approved T-Dxd for the treatment of HER2-positive (IHC 3+) solid tumors, while the National Comprehensive Cancer Network (NCCN) also include T-DXd as a treatment option for selected patients with HER2 IHC 2+ tumors.⁶³

The most frequently reported TRAEs in the overall study population were nausea, fatigue and hematological toxicity. Grade ≥ 3 TRAEs were predominantly neutropenia (19.1%) and anemia (10.9%). Notably, 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. Immunotherapy and smoking were risk factors for ILD.⁶⁴ Management of T-DXd-associated ILD involves routine monitoring and prompt investigation of respiratory symptoms such as dyspnea and cough. If there is clinical suspicion of ILD, high-resolution CT scan and multidisciplinary care are needed. Therapeutic strategies may include prompt initiation of corticosteroid therapy, supportive care, temporary treatment interruption and dose reduction. T-Dxd should be permanently discontinued in patients who develop recurrent or Grade ≥ 2 ILD.

The InnovaTV 205/GOG-3024/ENGOT-cx8 study evaluated combinations of T-Dxd with bevacizumab (Arm A), pembrolizumab (Arm B) and carboplatin (Arm C).⁶⁵ In the dose-expansion phase, the ORR for T-Dxd plus carboplatin as first-line treatment was 54.5%. The ORR for T-Dxd plus pembrolizumab was 40.6% in the first-line setting and 35.3% in the second- or third-line settings. However, each cohort included fewer than 40 patients, and further studies are required.

Other ADCs

In addition to TV and T-Dxd, several ongoing trials are evaluating ADCs targeting other tumor-associated surface antigens. TROP2 is expressed in up to 90% of cervical cancers.⁶⁶ Several ADCs targeting TROP2 are currently being evaluated. For instance, in the Phase-II EVER-132–003 basket trial, sacituzumab govitecan was evaluated in Chinese patients with cervical cancer who were refractory to or intolerant of platinum- and taxane-based chemotherapy.⁶⁷ The study reported an ORR of 43% and a median PFS of 7.1 months. Among patients previously treated with ICIs, the response to sacituzumab goviteca was similar, with ORR of 48% and median PFS of 8.3 months. In another study evaluating SKB-264 (sacituzumab tirumotecan, Sac-TMT) plus pembrolizumab in 38 patients with recurrent or metastatic cervical cancer, the ORR was 57.9% and the median PFS was not reached.⁶⁸

Newer targets such as B7-H3, claudin-1, HER3 and mesothelin are also under investigation. A summary of selected studies is presented in Table 2.

Selected (as yet unpublished) clinical trials of antibody–drug conjugates in cervical cancer.

NCT number	Trial name(s)	Study title	Phase	Study design	Condition	Intervention	Target	Sample size	Study status
NCT06657222	5-STAR 1–01	First in Human Study of TUB-030 in Patients With Advanced Solid Tumors	I/II	Randomized	Advanced Solid Tumors	TUB-030	5T4	130	Recruiting
NCT02988817	GCT1021–0I/II016–002243–42/211258	Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors	I/II	Single-arm	Advanced Solid Tumors	Enapotamab vedotin (HuMax-AXL-ADC)	AXL	306	Completed
NCT06112704	HS-20093–203	HS-20093 in Patients with Advanced Esophageal Carcinoma and Other Advanced Solid Tumors	II	Non-randomized	Advanced Solid Tumor	HS-20093	B7-H3	220	Recruiting
NCT06057922	YL201-CN-101–01	A Study YL201 in Patients With Selected Advanced Solid Tumors	I/II	Non-randomized	Advanced Solid Tumor	YL201	B7-H3	990	Recruiting
NCT06953089	DB-1311–201	DB-1311 in Combination With BNT327 or DB-1305 in Advanced/Metastatic Solid Tumors	II	Randomized, open-labeled	Advanced Solid Tumors	DB-1311/BNT324, BNT327 (PD-L1 and VEGF-A bispecific Ab), DB-1305/BNT325	B7-H3: DB-1311/BNT324 TROP2: DB-1305/BNT325	492	Recruiting
NCT07205718	TAK-188–1501	A Study of TAK-188 in Adults With Advanced or Spreading Solid Tumors	I/II	Non-randomized	Advanced Solid Tumors	TAK-188	CCR8	223	Recruiting
NCT03543813	CTMX-M-2029–001	PROCLAIM-CX-2029: A Trial to Find Safe and Active Doses of an Investigational Drug CX-2029 for Patients With Solid Tumors or DLBCL	I/II	Non-randomized	Advanced Solid Tumors	CX-2029	CD71	133	Completed
NCT07169734	ALE.P03.0I/II025–521441–24–00	A Study to Investigate ALE.P03 as Monotherapy in Adult Patients With Selected Advanced or Metastatic CLDN1+ Solid Tumors	I/II	Non-randomized	Advanced Solid Tumors	ALE.P03	Claudin-1	180	Recruiting
NCT06747585	ALE.P02.0I/II024–515459–39–00	A Study to Investigate ALE.P02 as Monotherapy in Adult Patients With Selected CLDN1+ Solid Tumors	I/II	Randomized, open-labeled	Squamous Cell Carcinoma	ALE.P02	Claudin-1	170	Recruiting
NCT06003231	SGNDV-005/C5731005/2023–504445–31–00	A Study of Disitamab Vedotin in Previously Treated Solid Tumors That Express HER2	II	Single-arm	Advanced Solid Tumors	Disitamab vedotin	HER2	120	Active, not recruiting
NCT02465060	NCI-MATCH	Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)	II	Non-randomized	Advanced Solid Tumors	Multiple including Trastuzumab emtansine	HER2	6452	Active, not recruiting
NCT06155396	RC48-C030	A Study of RC48-ADC Combination With Zimberelimab Injection Therapies at Least First-line Platinum-containing Standard Therapy Failed With Recurrent or Metastatic Cervical Cancer	II	Single-arm	Cervical Cancer	Disitamab vedotin, Zimberelimab	HER2	116	Recruiting
NCT04965519	RC48-C018	A Study of RC48-ADC for the Treatment of HER2-expressing Gynecological Malignancies	II	Single-arm	Gynecological cancers	RC48-ADC	HER2	120	Unknown
NCT03602079	KlusPharma	Study of A166 in Patients With Relapsed/Refractory Cancers Expressing HER2 Antigen or Having Amplified HER2 Gene	I/II	Non-randomized	Advanced Solid Tumors	A166	HER2	49	Completed
NCT06016062	RC148-C001	A Study of RC148 As a Single Agent and Combination Therapy in Patients with Locally Advanced Unresectable or Metastatic Malignant Solid Tumors	I/II	Non-randomized	Advanced Solid Tumors	RC148 (PD-1/VEGF bispecific Ab), RC148+docetaxel , RC148+RC48 (Disitamab vedotin), RC148+RC88 (Misitatug blivedotin), RC148/Bevacizumab+RC88	HER2: RC48 Mesothelin: RC88	221	Recruiting
NCT04644068	D9720C0000I/II020–002688–77	Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies	I/II	Single-arm	Advanced Solid Tumors	AZD5305, Paclitaxel, Carboplatin, T- Dxd, Dato-DXd, Camizestrant	HER2: T-Dxd TROP2: Dato-Dxd	702	Active, not recruiting
NCT06107686	YL202-CN-201–01	A Study of YL202 in Selected Patients With Advanced Solid Tumors	II	Single-arm	Advanced Solid Tumors	YL202	HER3	200	Recruiting
NCT06941272	MK-9999–01C/LIGHTBEAM-U01	A Study of Patritumab Deruxtecan in Pediatric Participants With Relapsed or Refractory Solid Tumors (MK-9999–01C/LIGHTBEAM-U01)	I/II	Single-arm	Advanced Solid Tumors	Patritumab deruxtecan	HER3	50	Recruiting
NCT07070232	BNT326–0I/II024–517261–16–00/1011236	A Clinical Study to Test if an Investigational Treatment Called BNT326 is Safe and Potentially Beneficial When Used Alone or in Combination With Other Investigational Treatments Such as BNT327, for People With Advanced Malignant Tumors	I/II	Randomized, open-labeled	Advanced Solid Tumor	BNT326, Pumitamig (PD-L1 and VEGF-A bispecific Ab), Itraconazole, Paroxetine	HER3: BNT326	980	Recruiting
NCT04175847	RC88-C001	A Phase I/IIa Study of RC88-ADC in Subjects With Advanced Malignant Solid Tumors	I/II	Single-arm	Advanced Solid Tumors	RC88	Mesothelin	198	Completed
NCT06769152	HLX43-CC201	A Phase II Clinical Study to Evaluate the Efficacy and Safety of HLX43 (Anti-PD-L1 ADC) in Patients With Advanced Gynecological Malignant Tumors	II	Randomized, open-labeled	Cervical Cancer\|Ovarian Cancer	HLX43	PD-L1	130	Recruiting
NCT04925284	XB002–101	Study of XB002 in Subjects With Solid Tumors (JEWEL-101)	I	Randomized, open-labeled	Advanced Solid Tumors	XB002, Nivolumab, Bevacizumab	Tissue factor	269	Completed
NCT03438396	GCT1015–04/innovaTV 204	A Trial of Tisotumab Vedotin in Cervical Cancer	II	Single-arm	Cervical Cancer	Tisotumab vedotin	Tissue factor	102	Completed
NCT04697628	SGNTV-003/C5721002/2023–503813–31–01	Tisotumab Vedotin vs Chemotherapy in Recurrent or Metastatic Cervical Cancer	III	Randomized, open-labeled	Cervical Cancer	Tisotumab vedotin, topotecan, vinorelbine, gemcitabine, irinotecan, pemetrexed	Tissue factor	502	Active, not recruiting
NCT02552121	GEN702/innovaTV 202	Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors	I/II	Single-arm	Advanced Solid Tumors	Tisotumab vedotin (HuMax-TF-ADC)	Tissue factor	33	Completed
NCT02001623	GEN701/innovaTV 201	Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors	I/II	Single-arm	Advanced Solid Tumors	Tisotumab vedotin (HuMax-TF-ADC)	Tissue factor	195	Completed
NCT06459180	2870–020/MK-2870–020/TroFuse-020	A Study to Compare Sacituzumab Tirumotecan (MK-2870) Monotherapy Versus Treatment of Physician's Choice as Second-line Treatment for Participants With Recurrent or Metastatic Cervical Cancer (MK-2870–020/TroFuse-020/Gog-3101/ENGOT-cx20)	III	Randomized, open-labeled	Cervical Cancer	Sacituzumab tirumotecan, Tisotumab vedotin, Pemetrexed, Topotecan, Vinorelbine, Gemcitabine, Irinotecan	Tissue factor: TV TROP2: Sac-TMT	686	Recruiting
NCT05838521	2000023639	A Study of Sacituzumab Govitecan (IMMU-132) in Patients With Recurrent or Persistent Cervical Cancer	II	Single-arm	Cervical Cancer	Sacituzumab govitecan	TROP2	20	Recruiting
NCT07256236	SHINE	SKB264 Plus QL1706 in Recurrent or Metastatic Cervical Cancer	II	Single-arm	Cervical Cancer	Sacituzumab tirumotecan, QL1706	TROP2	89	Not yet recruiting
NCT05642780	SKB264-II-06	SKB264 in Combination With Pembrolizumab in Subjects With Selected Solid Tumors	II	Non-randomized	Advanced Solid Tumors	SKB264, Pembrolizumab	TROP2	240	Active, not recruiting
NCT05119907	EVER-132–003/CTR20210912	Study of Sacituzumab Govitecan in Patients With Solid Tumor	II	Non-randomized	Advanced Solid Tumors	Sacituzumab govitecan	TROP2	53	Active, not recruiting
NCT07216703	TroFuse-036/GOG-3123/ENGOT-cx22/jRCT2031250604	A Clinical Study of Sacituzumab Tirumotecan (MK-2870) in Combination With Pembrolizumab (MK-3475) as First-line Maintenance Treatment of Cervical Cancer (MK-2870–036/TroFuse-036/GOG-3123/ENGOT-cx22)	III	Randomized, single-blinded	Cervical Cancer	Pembrolizumab, Sacituzumab Tirumotecan, Bevacizumab, Paclitaxel, Cisplatin/Carboplatin	TROP2	1023	Recruiting
NCT05941507	LCB84–1001	A Study to Evaluate TROP2 ADC LCB84 Single Agent and in Combination With an Anti-PD-1 Ab in Advanced Solid Tumors	I/II	Non-randomized	Advanced Solid Tumors	LCB8, Anti-PD-1 monoclonal antibody	TROP2	300	Recruiting
NCT01631552	IMMU-132–01	Study of Sacituzumab Govitecan-hziy (IMMU-132) in Adults With Epithelial Cancer	I/II	Non-randomized	Advanced Solid Tumors	Sacituzumab govitecan	TROP2	515	Completed
NCT04152499	KL264–01	Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (KL264–01)	I/II	Non-randomized	Advanced Solid Tumors	SKB264	TROP2	1410	Active, not recruiting

OTHER NOVEL THERAPIES

With advances in technology, Phase-I and -II trials are emerging on the use of newer treatment modalities.

Tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocyte (TIL) therapy involves harvesting tumor tissue from a patient, which is then enzymatically dissociated into individual cells. TILs are isolated from the tumor and then expanded ex vivo through cell-culture techniques. The patient subsequently receives lymphocyte-depleting chemotherapy, such as cyclophosphamide, or total body irradiation (TBI) to reduce endogenous lymphocytes. The cultivated TILs, along with high-dose IL-2, are then infused back into the patient to enhance the anti-tumor immune response.⁶⁹

Currently, there are scarce data on TILs in the treatment of cervical cancer. In a Phase-II study that investigated the role of TILs in HPV-related cancers, the ORR was 24.1% (7/29), including 27.8% (5/18) in the cervical cancer cohort.⁷⁰ Two patients who showed CR remained disease-free for a decade.⁷¹ Another Phase-II basket trial (NCT03108495) investigated autologous TILs (Lifileucel, LN-144) with and without pembrolizumab.⁷² The primary endpoint was the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs). Among the 14 Stage-IVb persistent, recurrent or metastatic cervical cancer patients receiving the combined treatment, the most common TEAEs were anemia (50%), thrombocytopenia (35.7%), neutropenic fever (35.7%) and neutropenia (28.6%). The ORR of the combination group was 57.1% with one CR (7.1%), and the disease-control rate was 92.9%.

Cancer vaccines

The association of HPV infection with cervical cancer provides the basis for using HPV therapeutic vaccines to treat recurrent and metastatic cervical cancer. These vaccines utilize modified, non-oncogenic E6/E7 proteins, which help activate CD8+ cytotoxic T-cells and CD4+ helper T-cells.⁷³ This immune response enables the body to recognize and eliminate HPV-infected cells expressing E6 and E7, while also promoting the presentation of these antigens through MHC class I molecules to facilitate tumor cell lysis.

In a two-stage Phase-II study, patients who had not responded to at least one previous treatment received Axalimogene filolisbac (ADXS-HPV), with up to three doses administered during the first stage, and continued treatment until disease progression in the second stage.⁷⁴ The median PFS was 2.8 months (95% CI, 2.6–3.0 months) and the median OS was 6.1 months (95% CI, 4.3–12.1 months). It was well tolerated, and the most common TRAEs were fatigue, chills, fever, nausea and anemia.

An open-label, single-arm Phase-II clinical trial published in 2024 investigated the combination of the therapeutic DNA vaccine GX-188E with pembrolizumab in patients with recurrent or advanced cervical cancer positive for HPV 16 or 18.⁷⁵ The treatment involved multiple doses of GX-188E alongside pembrolizumab every 3 weeks for 2 years or until disease progression. The results showed an ORR of 35% at 24 weeks, including five patients with CR (8.3%), and a disease-control rate of 56.7%. The median PFS was 4.4 months (95% CI, 2.1–8.3 months), and the median OS was 23.8 months (95% CI, 14.0 months to not reached). This combined treatment was also well-tolerated. The incidence of TRAEs of any grade was 33.8%, and Grade-3–4 TRAEs occurred in 6.2% with elevated AST/ALT, neutropenia and syncope.

Another Phase-II, multicenter, open-label, single-arm trial evaluated the combination of cemiplimab and peltopepimut-S, an HPV16-targeted vaccine, in patients with recurrent HPV16-positive cervical cancer who had progressed after platinum-based chemotherapy.⁷⁶ The treatment involved subcutaneous injections of peltopepimut-S on days 1, 29 and 50, combined with cemiplimab on days 8, 29 and 50, and cemiplimab was continued every 3 weeks until disease progression or withdrawal. The ORR was 16.8%, including three CR (2.7%), the median PFS was 3.0 months (95% CI, 1.7–4.0 months) and the median OS was 13.3 months (95% CI, 10.8–16.3 months). As exploratory endpoints, for patients with PD-L1 ≥ 1%, the ORR was 24.1% and the median PFS was 3.3 months (95% CI, 2.8–4.4 months), and the median OS was 14.3 months (95% CI, 10.5 months to not evaluable). The most common TEAEs were injection-site reaction (38.9%) and anemia (25.7%). Notably, six (5.3%) patients died from a TEAE.

CHALLENGES AND FUTURE PERSPECTIVES

PD-L1 expression is frequently used as a predictive biomarker for anti-PD1/PD-L1. However, there are several limitations with this biomarker.⁷⁷ First, different ICIs utilize different companion PD-L1 assays and scoring methods. For example, the KEYNOTE-826 study used CPS. Second, CPS is calculated by a cell-count method in which the number of PD-L1–positive tumor cells and immune cells is divided by the total number of viable tumor cells. This method could be subjective. Third, as PD-L1 CPS ≥ 1 is common in cervical cancer, it makes it difficult to identify patients who may benefit from ICIs. Some studies also explored different cut-off values. The tumor area positivity (TAP) score is determined by visual estimation of the proportion of tumor area occupied by PD-L1–positive tumor and immune cells. This method might have a higher concordance rate than the CPS score, but there is still no consensus on the best cut-off value.⁴⁷^,⁷⁸^,⁷⁹ In addition, although ADCs target specific tumor antigens, responses have been observed in tumors with low antigen expression due to the bystander effect. Therefore, further studies are required to explore the roles of additional biomarkers for ICIs, ADCs and combination therapies, including tumor histology, HPV status, MSI/MMR status, TMB and the tumor microenvironment.

With increasing evidence supporting novel therapies in the recurrent setting, the roles of neoadjuvant ICIs and ADCs are now being evaluated in the first-line setting. Emerging combination therapies are being investigated in early-phase studies, such as the combination of anti-PD-1/PD-L1 with chemotherapy,⁸⁰^,⁸¹ tyrosine kinase inhibitors,⁸²^,⁸³^,⁸⁴^,⁸⁵^,⁸⁶ poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), ADCs,⁶⁵ HPV vaccine⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰ and TILs.⁷² Other cellular approaches, including CAR-T and TCR-engineered T-cells targeting HPV antigens, are under investigation but remain at an exploratory stage.

Future research should focus on: identifying more reliable predictive biomarkers, determining the optimal timing of ICIs relative to conventional treatments in the first-line setting, evaluating the efficacy and safety of combined treatments involving ICIs and ADCs, elucidating their mechanisms of resistance, investigating optimal treatment after progression on ICIs and ADCs, and the possibility of rechallenge treatment. More real-world data are required to characterize the toxicities of these therapeutic agents and their management. Finally, given the rapid evolution of these novel treatments, patients with metastatic or recurrent cervical cancer should be encouraged to participate in clinical trials whenever feasible.

PRACTICE RECOMMENDATIONS

For patients with advanced, recurrent or metastatic cervical cancer, carboplatin/cisplatin, paclitaxel, anti-PD1/PD-L1, with or without bevacizumab, is the first-line treatment.
Patients with persistent, recurrent or metastatic cervical cancer who are immune checkpoint inhibitor (ICI)-naïve and have PD-L1 combined positivity score (CPS) ≥ 1 should consider using ICIs such as cemiplimab or pembrolizumab.
For patients with persistent, recurrent or metastatic cervical cancer who have received ICIs or have a contraindication to ICIs, tisotumab vedotin or trastuzumab deruxtecan (T-Dxd) can be considered. For the use of T-Dxd, target tumors should be either HER2 2+ or 3+ based on immunohistochemical staining.
Immune-related and ADC-related toxicities can occur. Multidisciplinary care and early intervention are required.
For patients with persistent, recurrent or metastatic cervical cancer who have received ICIs and/or ADCs, or have a contraindication to these drugs, second-line single-agent chemotherapy, such as topotecan, gemcitabine, pemetrexed or vinorelbine, can be considered, though objective response rate (ORR) tends to be poor.
Tumor-infiltrating lymphocytes, cancer vaccines and other novel therapeutic combinations are being investigated. Patients should be encouraged to join clinical trials.

CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

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REFERENCES

1.	International Agency for Research on Cancer. Global Cancer Observatory: Cancer Today. Lyon, France: World Health Organization; 2022. Available from: https://gco.iarc.fr
2.	Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cervix uteri. Int J Gynaecol Obstet. 2018;143 Suppl 2:22–36. doi: 10.1002/ijgo.12611. PubMed PMID: 30306584.
3.	Quinn MA, Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT, Heintz AP, Ngan HY, Pecorelli S. Carcinoma of the cervix uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95 Suppl 1:S43–103. doi: 10.1016/S0020-7292(06)60030-1. PubMed PMID: 17161167.
4.	Mackay HJ, Wenzel L, Mileshkin L. Nonsurgical management of cervical cancer: locally advanced, recurrent, and metastatic disease, survivorship, and beyond. Am Soc Clin Oncol Educ Book. 2015:e299–309. doi: 10.14694/EdBook_AM.2015.35.e299. PubMed PMID: 25993189; PMCID: PMC4920478.
5.	Gennigens C, Jerusalem G, Lapaille L, De Cuypere M, Streel S, Kridelka F, Ray-Coquard I. Recurrent or primary metastatic cervical cancer: current and future treatments. ESMO Open. 2022;7(5):100579. Epub 20220913. doi: 10.1016/j.esmoop.2022.100579. PubMed PMID: 36108558; PMCID: PMC9588874.
6.	Thigpen JT, Vance R, Puneky L, Khansur T. Chemotherapy as a palliative treatment in carcinoma of the uterine cervix. Semin Oncol. 1995;22(2 Suppl 3):16–24. PubMed PMID: 7537898.
7.	Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J, Miller DS, Olt G, King S, Boggess JF, Rocereto TF. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22(15):3113–3119. doi: 10.1200/JCO.2004.04.170. PubMed PMID: 15284262.
8.	Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(28):4649–4655. Epub 20090831. doi: 10.1200/JCO.2009.21.8909. PubMed PMID: 19720909; PMCID: PMC2754911.
9.	Long HJ, 3rd, Bundy BN, Grendys EC, Jr., Benda JA, McMeekin DS, Sorosky J, Miller DS, Eaton LA, Fiorica JV, Gynecologic Oncology Group S. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23(21):4626–4633. Epub 20050523. doi: 10.1200/JCO.2005.10.021. PubMed PMID: 15911865.
10.	Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, Nishimura S, Ushijima K, Takano M, Satoh T, Yoshikawa H. Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505. J Clin Oncol. 2015;33(19):2129–2135. doi: 10.1200/JCO.2014.58.4391. PubMed PMID: 25732161.
11.	Look KY, Blessing JA, Michener CM, Rubin S, Ramirez PT, Gynecologic Oncology Group S. Phase II evaluation of capecitabine in refractory nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2008;18(4):773–778. doi: 10.1111/j.1525-1438.2007.01080.x. PubMed PMID: 17892452.
12.	Jenkins AD, Ramondetta LM, Sun C, Johnston T, Wolf JK, Bodurka DC, Brown J, Atkinson EN, Levenback C. Phase II trial of capecitabine in recurrent squamous cell carcinoma of the cervix. Gynecologic oncology. 2005;97(3):840–844. doi: 10.1016/j.ygyno.2005.02.029. PubMed PMID: 15882895.
13.	Fiorica JV, Blessing JA, Puneky LV, Secord AA, Hoffman JS, Yamada SD, Buekers TE, Bell J, Schilder JM, Gynecologic Oncology G. A Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic oncology. 2009;115(2):285–289. doi: 10.1016/j.ygyno.2009.07.024. PubMed PMID: 19726073.
14.	Lorusso D, Mainenti S, Pietragalla A, Fusco E, Malaguti P, Masciullo V, Scambia G. Phase II study on weekly bolus topotecan in advanced or recurrent cervical cancer. Oncology. 2011;80(5–6):390–394. doi: 10.1159/000330537. PubMed PMID: 21829040.
15.	Coronel J, Cetina L, Candelaria M, Gonzalez-Fierro A, Arias D, Cantu D, Duenas-Gonzalez A. Weekly topotecan as second- or third-line treatment in patients with recurrent or metastatic cervical cancer. Medical oncology. 2009;26(2):210–214. doi: 10.1007/s12032-008-9108-5. PubMed PMID: 19016011.
16.	Schilder RJ, Blessing JA, Morgan M, Mangan CE, Rader JS. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a Phase II study of the gynecologic oncology group. Gynecologic oncology. 2000;76(2):204–207. doi: 10.1006/gyno.1999.5671. PubMed PMID: 10637071.
17.	Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecologic oncology. 2005;96(1):103–107. doi: 10.1016/j.ygyno.2004.09.027. PubMed PMID: 15589587.
18.	Muggia FM, Blessing JA, Waggoner S, Berek JS, Monk BJ, Sorosky J, Pearl ML. Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group Study. Gynecologic oncology. 2005;96(1):108–111. doi: 10.1016/j.ygyno.2004.09.028. PubMed PMID: 15589588.
19.	Muggia FM, Blessing JA, Method M, Miller DS, Johnson GA, Lee RB, Menzin A, Gynecologic Oncology Group s. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic oncology. 2004;92(2):639–643. doi: 10.1016/j.ygyno.2003.10.045. PubMed PMID: 14766259.
20.	Rose PG, Blessing JA, Van Le L, Waggoner S. Prolonged oral etoposide in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecologic oncology. 1998;70(2):263–266. doi: 10.1006/gyno.1998.5097. PubMed PMID: 9740702.
21.	Rose PG, Blessing JA, Buller RE, Mannel RS, Webster KD. Prolonged oral etoposide in recurrent or advanced non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic oncology. 2003;89(2):267–270. PubMed PMID: 12713990.
22.	Morris M, Brader KR, Burke TW, Levenback CF, Gershenson DM. A phase II study of prolonged oral etoposide in advanced or recurrent carcinoma of the cervix. Gynecologic oncology. 1998;70(2):215–218. doi: 10.1006/gyno.1998.5061. PubMed PMID: 9740693.
23.	Miller DS, Blessing JA, Ramondetta LM, Pham HQ, Tewari KS, Landrum LM, Brown J, Mannel RS. Pemetrexed and cisplatin for the treatment of advanced, persistent, or recurrent carcinoma of the cervix: a limited access phase II trial of the gynecologic oncology group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(25):2744–2749. doi: 10.1200/JCO.2013.54.7448. PubMed PMID: 25071133; PMCID: 4145184.
24.	McLachlan J, Boussios S, Okines A, Glaessgen D, Bodlar S, Kalaitzaki R, Taylor A, Lalondrelle S, Gore M, Kaye S, Banerjee S. The Impact of Systemic Therapy Beyond First-line Treatment for Advanced Cervical Cancer. Clinical oncology. 2017;29(3):153–160. doi: 10.1016/j.clon.2016.10.002. PubMed PMID: 27838135.
25.	Slayton RE, Blessing JA, Homesley HD. Phase II trial of etoposide in the management of advanced or recurrent non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Cancer treatment reports. 1984;68(12):1513–1514. PubMed PMID: 6509456.
26.	Muderspach LI, Blessing JA, Levenback C, Moore JL, Jr. A Phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecologic oncology. 2001;81(2):213–215. doi: 10.1006/gyno.2000.6024. PubMed PMID: 11354055.
27.	Umesaki N, Fujii T, Nishimura R, Tanaka T, Nishida M, Fushiki H, Takizawa K, Yamamoto K, Hasegawa K, Izumi R, Japan Gynecologic Oncology G. Phase II study of irinotecan combined with mitomycin-C for advanced or recurrent squamous cell carcinoma of the uterine cervix: the JGOG study. Gynecologic oncology. 2004;95(1):127–132. doi: 10.1016/j.ygyno.2004.06.044. PubMed PMID: 15385121.
28.	Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(7):1069–1074. doi: 10.1200/JCO.2008.18.9043. PubMed PMID: 19139430; PMCID: 2667811.
29.	Tewari KS, Sill MW, Long HJ, 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. The New England journal of medicine. 2014;370(8):734–743. doi: 10.1056/NEJMoa1309748. PubMed PMID: 24552320; PMCID: 4010094.
30.	Symonds RP, Gourley C, Davidson S, Carty K, McCartney E, Rai D, Banerjee S, Jackson D, Lord R, McCormack M, Hudson E, Reed N, Flubacher M, Jankowska P, Powell M, Dive C, West CM, Paul J. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Oncology. 2015;16(15):1515–1524. doi: 10.1016/S1470-2045(15)00220-X. PubMed PMID: 26474517; PMCID: 4705431.
31.	Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer. 2012;12(4):252–264. doi: 10.1038/nrc3239. PubMed PMID: 22437870; PMCID: 4856023.
32.	Howitt BE, Sun HH, Roemer MG, Kelley A, Chapuy B, Aviki E, Pak C, Connelly C, Gjini E, Shi Y, Lee L, Viswanathan A, Horowitz N, Neuberg D, Crum CP, Lindeman NL, Kuo F, Ligon AH, Freeman GJ, Hodi FS, Shipp MA, Rodig SJ. Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva. JAMA oncology. 2016;2(4):518–522. doi: 10.1001/jamaoncol.2015.6326. PubMed PMID: 26913631.
33.	Cancer Genome Atlas Research N, Albert Einstein College of M, Analytical Biological S, Barretos Cancer H, Baylor College of M, Beckman Research Institute of City of H, Buck Institute for Research on A, Canada's Michael Smith Genome Sciences C, Harvard Medical S, Helen FGCC, Research Institute at Christiana Care Health S, HudsonAlpha Institute for B, Ilsbio LLC, Indiana University School of M, Institute of Human V, Institute for Systems B, International Genomics C, Leidos B, Massachusetts General H, McDonnell Genome Institute at Washington U, Medical College of W, Medical University of South C, Memorial Sloan Kettering Cancer C, Montefiore Medical C, NantOmics, National Cancer I, National Hospital AN, National Human Genome Research I, National Institute of Environmental Health S, National Institute on D, Other Communication D, Ontario Tumour Bank LHSC, Ontario Tumour Bank OIfCR, Ontario Tumour Bank TOH, Oregon H, Science U, Samuel Oschin Comprehensive Cancer Institute C-SMC, International SRA, St Joseph's Candler Health S, Eli, Edythe LBIoMIoT, Harvard U, Research Institute at Nationwide Children's H, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins U, University of B, University of Texas MDACC, University of Abuja Teaching H, University of Alabama at B, University of California I, University of California Santa C, University of Kansas Medical C, University of L, University of New Mexico Health Sciences C, University of North Carolina at Chapel H, University of Oklahoma Health Sciences C, University of P, University of Sao Paulo RaPMS, University of Southern C, University of W, University of Wisconsin School of M, Public H, Van Andel Research I, Washington University in St L. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–384. doi: 10.1038/nature21386. PubMed PMID: 28112728; PMCID: 5354998.
34.	Heeren AM, Punt S, Bleeker MC, Gaarenstroom KN, van der Velden J, Kenter GG, de Gruijl TD, Jordanova ES. Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix. Mod Pathol. 2016;29(7):753–763. Epub 20160408. doi: 10.1038/modpathol.2016.64. PubMed PMID: 27056074; PMCID: PMC4931542.
35.	Enwere EK, Kornaga EN, Dean M, Koulis TA, Phan T, Kalantarian M, Kobel M, Ghatage P, Magliocco AM, Lees-Miller SP, Doll CM. Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer. Mod Pathol. 2017;30(4):577–586. Epub 20170106. doi: 10.1038/modpathol.2016.221. PubMed PMID: 28059093.
36.	Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouelian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Mackowiak-Matejczyk B, Guerra Alia EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A, Investigators for GOGP, En-Cx EP. Survival with Cemiplimab in Recurrent Cervical Cancer. The New England journal of medicine. 2022;386(6):544–555. doi: 10.1056/NEJMoa2112187. PubMed PMID: 35139273.
37.	Kobayashi O, Taguchi A, Nakajima T, Ikeda Y, Saito K, Kawana K. Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer. Taiwan J Obstet Gynecol. 2024;63(1):22–28. doi: 10.1016/j.tjog.2023.10.002. PubMed PMID: 38216264.
38.	Mezache L, Paniccia B, Nyinawabera A, Nuovo GJ. Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers. Mod Pathol. 2015;28(12):1594–1602. Epub 20150925. doi: 10.1038/modpathol.2015.108. PubMed PMID: 26403783.
39.	Yang W, Lu YP, Yang YZ, Kang JR, Jin YD, Wang HW. Expressions of programmed death (PD)-1 and PD-1 ligand (PD-L1) in cervical intraepithelial neoplasia and cervical squamous cell carcinomas are of prognostic value and associated with human papillomavirus status. J Obstet Gynaecol Res. 2017;43(10):1602–1612. Epub 20170817. doi: 10.1111/jog.13411. PubMed PMID: 28833798.
40.	Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR, Australian Pancreatic Cancer Genome I, Consortium IBC, Consortium IM-S, PedBrain I, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. Epub 20130814. doi: 10.1038/nature12477. PubMed PMID: 23945592; PMCID: PMC3776390.
41.	Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74. doi: 10.1126/science.aaa4971. PubMed PMID: 25838375.
42.	Wang J, Li Z, Gao A, Wen Q, Sun Y. The prognostic landscape of tumor-infiltrating immune cells in cervical cancer. Biomed Pharmacother. 2019;120:109444. Epub 20190925. doi: 10.1016/j.biopha.2019.109444. PubMed PMID: 31562978.
43.	Frenel JS, Le Tourneau C, O'Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, van Brummelen EMJ, Rugo HS, Thomas S, Saraf S, Rangwala R, Varga A. Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017;35(36):4035–4041. Epub 20171102. doi: 10.1200/JCO.2017.74.5471. PubMed PMID: 29095678.
44.	Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019;37(17):1470–1478. Epub 20190403. doi: 10.1200/JCO.18.01265. PubMed PMID: 30943124.
45.	Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, Lopez-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019;37(31):2825–2834. Epub 20190905. doi: 10.1200/JCO.19.00739. PubMed PMID: 31487218; PMCID: PMC6823884.
46.	Oaknin A, Moore K, Meyer T, Lopez-Picazo Gonzalez J, Devriese LA, Amin A, Lao CD, Boni V, Sharfman WH, Park JC, Tahara M, Topalian SL, Magallanes M, Molina Alavez A, Khan TA, Copigneaux C, Lee M, Garnett-Benson C, Wang X, Naumann RW. Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1–2, open-label, multicohort trial. Lancet Oncol. 2024;25(5):588–602. Epub 20240409. doi: 10.1016/S1470-2045(24)00088-3. PubMed PMID: 38608691.
47.	Salani R, McCormack M, Kim YM, Ghamande S, Hall SL, Lorusso D, Barraclough L, Gilbert L, Guzman Ramirez A, Lu CH, Sabatier R, Colombo N, Hu Y, Krishnan V, Molinero L, Feng Y, Kim N, Castro M, Lin YG, Monk BJ. A non-comparative, randomized, phase II trial of atezolizumab or atezolizumab plus tiragolumab for programmed death-ligand 1-positive recurrent cervical cancer (SKYSCRAPER-04). Int J Gynecol Cancer. 2024;34(8):1140–1148. Epub 20240805. doi: 10.1136/ijgc-2024-005588. PubMed PMID: 38858106.
48.	Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yanez E, Gumus M, Olivera Hurtado de Mendoza M, Samouelian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ, Investigators K-. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. The New England journal of medicine. 2021;385(20):1856–1867. Epub 20210918. doi: 10.1056/NEJMoa2112435. PubMed PMID: 34534429.
49.	Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yanez E, Gumus M, Olivera Hurtado de Mendoza M, Samouelian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D, Investigators K-. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023;41(36):5505–5511. Epub 20231101. doi: 10.1200/JCO.23.00914. PubMed PMID: 37910822.
50.	Oaknin A, Gladieff L, Martinez-Garcia J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Farinas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcon J, Follana P, Romero I, Lebreton C, Perez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM, Investigators EN-C-G-C-J-G-. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024;403(10421):31–43. Epub 20231201. doi: 10.1016/S0140-6736(23)02405-4. PubMed PMID: 38048793.
51.	Wu X, Sun Y, Yang H, Wang J, Lou H, Li D, Wang K, Zhang H, Wu T, Li Y, Wang C, Li G, Wang Y, Li D, Tang Y, Pan M, Cai H, Wang W, Yang B, Qian H, Tian Q, Yao D, Cheng Y, Wei B, Li X, Wang T, Hao M, Wang X, Wang T, Ran J, Zhu H, Zhu L, Liu X, Li Y, Chen L, Li Q, Yan X, Wang F, Cai H, Zhang Y, Liang Z, Liu F, Huang Y, Xia B, Qu P, Zhu G, Chen Y, Song K, Sun M, Chen Z, Zhou Q, Hu L, Abulizi G, Guo H, Liao S, Ye Y, Yan P, Tang Q, Sun G, Liu T, Lu D, Hu M, Wang ZM, Li B, Xia M. Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China. Lancet. 2024;404(10463):1668–1676. Epub 20241016. doi: 10.1016/S0140-6736(24)02135-4. PubMed PMID: 39426385.
52.	Colombo R, Tarantino P, Rich JR, LoRusso PM, de Vries EGE. The Journey of Antibody-Drug Conjugates: Lessons Learned from 40 Years of Development. Cancer Discov. 2024;14(11):2089–2108. doi: 10.1158/2159-8290.CD-24-0708. PubMed PMID: 39439290.
53.	Hong DS, Concin N, Vergote I, de Bono JS, Slomovitz BM, Drew Y, Arkenau HT, Machiels JP, Spicer JF, Jones R, Forster MD, Cornez N, Gennigens C, Johnson ML, Thistlethwaite FC, Rangwala RA, Ghatta S, Windfeld K, Harris JR, Lassen UN, Coleman RL. Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;26(6):1220–1228. Epub 20191203. doi: 10.1158/1078-0432.CCR-19-2962. PubMed PMID: 31796521.
54.	Zhao X, Cheng C, Gou J, Yi T, Qian Y, Du X, Zhao X. Expression of tissue factor in human cervical carcinoma tissue. Exp Ther Med. 2018;16(5):4075–4081. Epub 20180911. doi: 10.3892/etm.2018.6723. PubMed PMID: 30402151; PMCID: PMC6200962.
55.	Zhai C, Cui Y, Guo L, Chen C, Song Y, Zhong J, Wang Y. Progress in the study of antibody-drug conjugates for the treatment of cervical cancer. Front Oncol. 2024;14:1395784. Epub 20240606. doi: 10.3389/fonc.2024.1395784. PubMed PMID: 38903711; PMCID: PMC11187480.
56.	Coleman RL, Lorusso D, Gennigens C, Gonzalez-Martin A, Randall L, Cibula D, Lund B, Woelber L, Pignata S, Forget F, Redondo A, Vindelov SD, Chen M, Harris JR, Smith M, Nicacio LV, Teng MSL, Laenen A, Rangwala R, Manso L, Mirza M, Monk BJ, Vergote I, innova TVGOGE-cC. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609–619. Epub 20210409. doi: 10.1016/S1470-2045(21)00056-5. PubMed PMID: 33845034.
57.	Vergote I, Gonzalez-Martin A, Fujiwara K, Kalbacher E, Bagameri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM, innova TVE-cGOGC. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. The New England journal of medicine. 2024;391(1):44–55. doi: 10.1056/NEJMoa2313811. PubMed PMID: 38959480.
58.	Kim SK, Ursell P, Coleman RL, Monk BJ, Vergote I. Mitigation and management strategies for ocular events associated with tisotumab vedotin. Gynecologic oncology. 2022;165(2):385–392. Epub 20220308. doi: 10.1016/j.ygyno.2022.02.010. PubMed PMID: 35277279.
59.	Tsurutani J, Iwata H, Krop I, Janne PA, Doi T, Takahashi S, Park H, Redfern C, Tamura K, Wise-Draper TM, Saito K, Sugihara M, Singh J, Jikoh T, Gallant G, Li BT. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discov. 2020;10(5):688–701. Epub 20200325. doi: 10.1158/2159-8290.CD-19-1014. PubMed PMID: 32213540; PMCID: PMC8292921.
60.	Liu W, Wang X, Cui Y, Song K, Lin W, Lei X, Weng X, Shen W, Liu J, Zhang L, Miao W, Ye J, He T, Xu Q, Hu D. HER2 expression in cervical squamous cell carcinoma: high prevalence of HER2-low/ultralow and spatiotemporal heterogeneity across tumor evolution. NPJ Precis Oncol. 2025;9(1):410. Epub 20251128. doi: 10.1038/s41698-025-01189-w. PubMed PMID: 41315811; PMCID: PMC12753676.
61.	Shi H, Shao Y, Lu W, Lu B. An analysis of HER2 amplification in cervical adenocarcinoma: correlation with clinical outcomes and the International Endocervical Adenocarcinoma Criteria and Classification. J Pathol Clin Res. 2021;7(1):86–95. Epub 20201022. doi: 10.1002/cjp2.184. PubMed PMID: 33089969; PMCID: PMC7737776.
62.	Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, Gonzalez-Martin A, Jung KH, Lugowska I, Manso L, Manzano A, Melichar B, Siena S, Stroyakovskiy D, Fielding A, Ma Y, Puvvada S, Shire N, Lee JY. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42(1):47–58. Epub 20231023. doi: 10.1200/JCO.23.02005. PubMed PMID: 37870536; PMCID: PMC10730032.
63.	National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer 2.2026.
64.	Antonarelli G, Milano M, Andreon C, Gandini S, Pellizzari G, Trapani D, Dellapasqua S, Marra A, Zagami P, Valenza C, Colleoni M, Munzone E, Curigliano G. Real-world safety and efficacy profiles of trastuzumab deruxtecan in patients with advanced breast cancer. ESMO Open. 2025;10(11):105847. Epub 20251015. doi: 10.1016/j.esmoop.2025.105847. PubMed PMID: 41101156; PMCID: PMC12550575.
65.	Vergote I, Van Nieuwenhuysen E, O'Cearbhaill RE, Westermann A, Lorusso D, Ghamande S, Collins DC, Banerjee S, Mathews CA, Gennigens C, Cibula D, Tewari KS, Madsen K, Kose F, Jackson AL, Boere IA, Scambia G, Randall LM, Sadozye A, Baurain JF, Gort E, Zikan M, Denys HG, Ottevanger N, Forget F, Mondrup Andreassen C, Eaton L, Chisamore MJ, Viana Nicacio L, Soumaoro I, Monk BJ. Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study. J Clin Oncol. 2023;41(36):5536–5549. Epub 20230831. doi: 10.1200/JCO.23.00720. PubMed PMID: 37651655; PMCID: PMC10730069.
66.	Chiba Y, Kojima Y, Yazaki S, Yoshida H, Takamizawa S, Kitadai R, Saito A, Okuma HS, Nishikawa T, Shimoi T, Sudo K, Noguchi E, Uno M, Ishikawa M, Kato T, Fujiwara Y, Yonemori K. Trop-2 expression and the tumor immune microenvironment in cervical cancer. Gynecologic oncology. 2024;187:51–57. Epub 20240508. doi: 10.1016/j.ygyno.2024.04.022. PubMed PMID: 38723340.
67.	An J, Li G, Zhang Y, Feng M, Kong W, Jiang H, Luo S, Li W, Xu C, Han L, Chen Y, Mocci S, Yan Y, Wu L. Sacituzumab govitecan in Chinese patients with recurrent/metastatic cervical cancer: Results from the phase 2 EVER-132-003 basket study (NCT05119907). Gynecologic oncology. 2025;202:33–40. Epub 20250918. doi: 10.1016/j.ygyno.2025.09.001. PubMed PMID: 40972504.
68.	Wang J, An R, Huang Y, Zhang J, Goh JCH, Jiang K, Yu G, Chen L, Provencher DM, Tang Y, Li G, Qiu H, Akala B, Chartash E, Zhou Y, Jin X, Ge J, Wu X. 716MO Efficacy and safety of sacituzumab tirumotecan (sac-TMT) plus pembrolizumab in patients with recurrent or metastatic cervical cancer. Annals of Oncology. 2024;35:S548-S9. doi: 10.1016/j.annonc.2024.08.778.
69.	Zhang J, Wang Y, Li H. Research progress of adoptive tumor infiltrating lymphocyte therapy for cervical cancer. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2026;172(1):104–114. Epub 20250710. doi: 10.1002/ijgo.70360. PubMed PMID: 40637256.
70.	Stevanovic S, Helman SR, Wunderlich JR, Langhan MM, Doran SL, Kwong MLM, Somerville RPT, Klebanoff CA, Kammula US, Sherry RM, Yang JC, Rosenberg SA, Hinrichs CS. A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus-associated Epithelial Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;25(5):1486–1493. Epub 20181205. doi: 10.1158/1078-0432.CCR-18-2722. PubMed PMID: 30518633; PMCID: PMC6397671.
71.	Norberg SM, Doran S, Subramanian K, Joshi R, Biswas A, Chang Y-C, Radford S, Cao L, Kang Z, Gulley JL, Montagna C, Cao J, Hinrichs CS. 377 Decade-long epithelial cancer remissions from cellular therapy. Journal for ImmunoTherapy of Cancer. 2025;13(Suppl 2). doi: 10.1136/jitc-2025-SITC2025.0377.
72.	O’Malley D, Lee S, Psyrri A, Sukari A, Thomas S, Wenham R, Gogas H, Jazaeri A, Monk BJ, Rose P, Reuda A, Finckenstein FG, Jagasia M, Fiaz R, Garelik B, Shi W, Desai A, Sulur G, Chen G, Wu X, Jimeno A. 492-Phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers. Journal for ImmunoTherapy of Cancer. 2021;9(Suppl 2):A523-A4. doi: 10.1136/jitc-2021-SITC2021.492.
73.	Alouini S, Pichon C. Therapeutic Vaccines for HPV-Associated Cervical Malignancies: A Systematic Review. Vaccines (Basel). 2024;12(4). Epub 20240417. doi: 10.3390/vaccines12040428. PubMed PMID: 38675811; PMCID: PMC11054545.
74.	Huh WK, Brady WE, Fracasso PM, Dizon DS, Powell MA, Monk BJ, Leath CA, 3rd, Landrum LM, Tanner EJ, Crane EK, Ueda S, McHale MT, Aghajanian C. Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: An NRG oncology/gynecologic oncology group study. Gynecologic oncology. 2020;158(3):562–569. Epub 20200706. doi: 10.1016/j.ygyno.2020.06.493. PubMed PMID: 32641240; PMCID: PMC7487015.
75.	Lim MC, Choi YJ, Hur SY, Kim YM, No JH, Kim BG, Cho CH, Kim SH, Jeong DH, Lee JK, Kim JH, Choi YJ, Woo JW, Sung YC, Park JS. GX-188E DNA vaccine plus pembrolizumab in HPV 16- and/or 18-positive recurrent or advance cervical cancer: a phase 2 trial. EClinicalMedicine. 2024;74:102716. Epub 20240713. doi: 10.1016/j.eclinm.2024.102716. PubMed PMID: 39823099; PMCID: PMC11736335.
76.	Lorusso D, Oaknin A, Borges GS, Damian F, Ottevanger N, Van Gorp T, Paiva CE, Kroep JR, Kim YM, Kim HS, Lee JK, Denys H, Lalisang R, De Melo AC, Redondo A, Reyners AKL, Mora P, Closset C, Melief CJM, Hooftman L, Jamil S, Boersma L, Yoo SY, Seebach F, Lowy I, Fury MG, Mathias M, Colombo N. Cemiplimab plus peltopepimut-S vaccine in recurrent cervical cancer: A phase 2 clinical trial. Gynecologic oncology. 2025;196:28–35. Epub 20250327. doi: 10.1016/j.ygyno.2025.03.019. PubMed PMID: 40154184.
77.	Yanaihara N, Tse KY, Lee SJ, Yoo JG, Wilailak S. Immune checkpoint inhibitors in gynecologic oncology: Current status and perspectives. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2025;171 Suppl 1(Suppl 1):166–188. doi: 10.1002/ijgo.70280. PubMed PMID: 40908776; PMCID: PMC12411819.
78.	Liu C, Fang F, Kong Y, ElGabry EA. Tumor Area Positivity (TAP) score of programmed death-ligand 1 (PD-L1): a novel visual estimation method for combined tumor cell and immune cell scoring. Diagn Pathol. 2023;18(1):48. Epub 20230419. doi: 10.1186/s13000-023-01318-8. PubMed PMID: 37076889; PMCID: PMC10114344.
79.	Monk BJ, Toita T, Wu X, Vazquez Limon JC, Tarnawski R, Mandai M, Shapira-Frommer R, Mahantshetty U, Del Pilar Estevez-Diz M, Zhou Q, Limaye S, Godinez FJR, Oppermann Kussler C, Varga S, Valdiviezo N, Aoki D, Leiva M, Lee JY, Sulay R, Kreynina Y, Cheng WF, Rey F, Rong Y, Ke G, Wildsmith S, Lloyd A, Dry H, Tablante Nunes A, Mayadev J. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(12):1334–1348. Epub 2023/12/02. doi: 10.1016/S1470-2045(23)00479-5. PubMed PMID: 38039991.
80.	Wang Y, Zhao J, Liang H, Liu J, Huang S, Zou G, Huang X, Lan C. Efficacy and safety of sintilimab plus albumin-bound-paclitaxel in recurrent or metastatic cervical cancer: a multicenter, open-label, single-arm, phase II trial. EClinicalMedicine. 2023;65:102274. Epub 20231024. doi: 10.1016/j.eclinm.2023.102274. PubMed PMID: 38106561; PMCID: PMC10725023.
81.	An J, Li X, Wang J, Zhu L, An R, Jiang K, Huang Y, Wang K, Li G, Wang C, Yuan J, Hou X, Yang G, Li J, Wang Q, Zhu J, Wu L. Efficacy and safety of serplulimab plus nab-paclitaxel in previously treated patients with PD-L1-positive advanced cervical cancer: a phase II, single-arm study. Front Immunol. 2023;14:1142256. Epub 20230421. doi: 10.3389/fimmu.2023.1142256. PubMed PMID: 37153587; PMCID: PMC10161140.
82.	Lan C, Shen J, Wang Y, Li J, Liu Z, He M, Cao X, Ling J, Huang J, Zheng M, Zou G, Yan H, Liu Q, Yang F, Wei W, Deng Y, Xiong Y, Huang X. Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial. J Clin Oncol. 2020;38(34):4095–4106. Epub 20201014. doi: 10.1200/JCO.20.01920. PubMed PMID: 33052760; PMCID: PMC7768345.
83.	Lan C, Lu H, Zhou L, Liao K, Liu J, Xie Z, Liang H, Zou G, Yang T, Xu Q, Huang X. Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study. Cancer Commun (Lond). 2024;44(6):654–669. Epub 20240513. doi: 10.1002/cac2.12547. PubMed PMID: 38741375; PMCID: PMC11194449.
84.	Wu X, Wang D, Wang J, Huang Y, Yi T, Li G, Zhang J, Wang K, Kang Y, Liu A, Han X, Lu P, Shi H, Tan P, Fan S, Shi M, Su W. 289MO Fruquintinib plus sintilimab in advanced cervical cancer (CC) patients (pts): Results from a multicenter, single-arm phase II study. Annals of Oncology. 2023;34:S1587. doi: 10.1016/j.annonc.2023.10.411.
85.	Xu Q, Liu J, Chang L, Zhu F, Zhu M, Zhang H. Sintilimab and anlotinib combination therapy in PD-L1-positive recurrent/metastatic cervical carcinoma: A 3-year follow-up of ALTER-C201 study. Journal of Clinical Oncology. 2024;42(16_suppl):e17526-e. doi: 10.1200/JCO.2024.42.16_suppl.e17526.
86.	Tse KY, Chu MMY, Ngu SF, Kwok GST, Lau LSK, Wei N, Chan WS, Liu SS, Siu SWK, Yeung ANY, Soong IS, Lee EYP, Ip PPC, Cheung ANY, Ngan HYS, Chan KKL. Avelumab with axitinib in persistent or recurrent cervical cancer after platinum-based chemotherapy (ALARICE study). Journal of Clinical Oncology. 2024;42(16_suppl):5540-. doi: 10.1200/JCO.2024.42.16_suppl.5540.
87.	Berg KCG, Bousquet P, Blaga M, Bello T, Arabpour M, Pedersen MW, Schjetne K. Abstract A003: High-throughput TCR sequencing demonstrates induction of long-lasting HPV16-specific T cell responses in VB10.16 vaccinated advanced cervical cancer patients. Cancer Immunology Research. 2023;11(12_Supplement):A003-A. doi: 10.1158/2326-6074.Tumimm23-a003.
88.	Wang B, Liang Y, Wu Y, Li Q, Zeng Y, Liu L, Cao W, Geng X, Huang Y, Wu Y, Pan J, Zhang X, Gu JJ. Sintilimab plus HPV vaccine for recurrent or metastatic cervical cancer. J Immunother Cancer. 2024;12(11). Epub 20241127. doi: 10.1136/jitc-2024-009898. PubMed PMID: 39608975; PMCID: PMC11603683.
89.	Lorusso D, Oaknin A, Borges GS, Damian F, Ottevanger PB, Van Gorp T, Paiva CE, Kroep JR, Kim YM, Kim HS, Lee JK, Melief CJM, Hooftman L, Jamil S, Yoo SY, Seebach FA, Lowy I, Fury MG, Mathias MD, Colombo N. Combination of cemiplimab and ISA101b vaccine for the treatment of recurrent/metastatic HPV16 cervical cancer. Journal of Clinical Oncology. 2024;42(16_suppl):5522-. doi: 10.1200/JCO.2024.42.16_suppl.5522.
90.	Youn JW, Hur SY, Woo JW, Kim YM, Lim MC, Park SY, Seo SS, No JH, Kim BG, Lee JK, Shin SJ, Kim K, Chaney MF, Choi YJ, Suh YS, Park JS, Sung YC. Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial. Lancet Oncol. 2020;21(12):1653–1660. doi: 10.1016/S1470-2045(20)30486-1. PubMed PMID: 33271094.
91.	Look KY, Blessing JA, Valea FA, McGehee R, Manetta A, Webster KD, Andersen WA. Phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent adenocarcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic oncology. 1997;67(3):255–258. doi: 10.1006/gyno.1997.4886. PubMed PMID: 9441772.
92.	Garcia AA, Blessing JA, Vaccarello L, Roman LD, Gynecologic Oncology Group S. Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. American journal of clinical oncology. 2007;30(4):428–431. doi: 10.1097/COC.0b013e31803377c8. PubMed PMID: 17762444.
93.	Symonds RP, Davidson SE, Chan S, Reed NS, McMahon T, Rai D, Harden S, Paul J, Scottish Gynaecological Cancer Trials Group BWoSCC. SCOTCERV: a phase II trial of docetaxel and gemcitabine as second line chemotherapy in cervical cancer. Gynecologic oncology. 2011;123(1):105–109. doi: 10.1016/j.ygyno.2011.06.001. PubMed PMID: 21723596.
94.	Look KY, Blessing JA, Levenback C, Kohler M, Chafe W, Roman LD. A phase II trial of CPT-11 in recurrent squamous carcinoma of the cervix: a gynecologic oncology group study. Gynecologic oncology. 1998;70(3):334–338. doi: 10.1006/gyno.1998.5129. PubMed PMID: 9790784.
95.	Rose PG, Blessing JA, Lele S, Abulafia O. Evaluation of pegylated liposomal doxorubicin (Doxil) as second-line chemotherapy of squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecologic oncology. 2006;102(2):210–213. doi: 10.1016/j.ygyno.2005.11.048. PubMed PMID: 16478630.
96.	Alberts DS, Blessing JA, Landrum LM, Warshal DP, Martin LP, Rose SL, Bonebrake AJ, Ramondetta LM. Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study. Gynecologic oncology. 2012;127(3):451–455. doi: 10.1016/j.ygyno.2012.09.008. PubMed PMID: 22986144; PMCID: 4459779.
97.	Fracasso PM, Blessing JA, Wolf J, Rocereto TF, Berek JS, Waggoner S. Phase II evaluation of oxaliplatin in previously treated squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecologic oncology. 2003;90(1):177–180. PubMed PMID: 12821360.
98.	Kuo DY, Blank SV, Christos PJ, Kim M, Caputo TA, Pothuri B, Hershman D, Goldman N, Ivy PS, Runowicz CD, Muggia F, Goldberg GL, Einstein MH. Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: a New York Cancer Consortium Study. Gynecologic oncology. 2010;116(3):442–446. doi: 10.1016/j.ygyno.2009.10.082. PubMed PMID: 19931137; PMCID: 2822050.
99.	Lorusso D, Ferrandina G, Pignata S, Ludovisi M, Vigano R, Scalone S, Scollo P, Breda E, Pietragalla A, Scambia G. Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 2010;21(1):61–66. doi: 10.1093/annonc/mdp266. PubMed PMID: 19605508.
100.	Kunos C, Deng W, Dawson D, Lea JS, Zanotti KM, Gray HJ, Bender DP, Guaglianone PP, Carter JS, Moore KN. A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2015;25(3):484–492. doi: 10.1097/IGC.0000000000000380. PubMed PMID: 25594147; PMCID: 4336206.
101.	Sutton GP, Blessing JA, Barnes W, Ball H. Phase II study of vinblastine in previously treated squamous carcinoma of the cervix. A Gynecologic Oncology Group study. American journal of clinical oncology. 1990;13(6):470–471. PubMed PMID: 2239800.
102.	Lhomme C, Vermorken JB, Mickiewicz E, Chevalier B, Alvarez A, Mendiola C, Pawinski A, Lentz MA, Pecorelli S. Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: an EORTC Gynaecological Cancer Cooperative Group Study. European journal of cancer. 2000;36(2):194–199. PubMed PMID: 10741277.

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