Pharmacotherapy for Cervical Cancer: Current Standard of Care and New Perspectives

Abstract

Introduction:

Cervical cancer, while highly preventable, remains an international public health challenge especially in under resourced regions. Although early-stage cervix confined cancers are often amenable to surgical resection, larger tumors deemed locally advanced cervical cancer (LACC) necessitate systemic therapy as part of chemoradiation therapy. Moreover, systemic therapy is the standard therapeutic approach for those presenting with primary metastasis or recurrence.

Areas covered:

While several agents have been approved to treat recurrent cervical cancer including checkpoint inhibitors as well as both biomarker agnostic and specific antibody drug conjugates, the development of agents added to chemoradiation has been less fruitful. Until recently, the addition of novel therapies to chemoradiation have been negative in terms of improving outcomes; however, results of a recent Phase III clinical trial (NCT 04221945) in LACC demonstrated that the addition of pembrolizumab to standard of care chemoradiation was associated with an improvement in progression-free survival and resulted in an FDA approval for this therapy. This observation led to the first change in treating LACC since the early 2000’s.

Expert Opinion:

Improvements in systemic therapy both alone and in combination with chemoradiation for cervical cancer have been realized. Ongoing research is needed for therapeutic options following immunotherapy.

1. Introduction

Cervical cancer is the third most common gynecologic malignancy in the United States, with an estimated 13,820 new cases and 4,360 deaths predicted for 2024 [1]. Unfortunately, due to persistent gaps in prevention and screening worldwide, cervical cancer remains a leading cause of cancer-related mortality, most pronounced in low- and middle-income countries where up to 85% of related deaths occur [2, 3]. While the global incidence of cervical cancer has declined over the past two decades, regional disparities persist in vaccine availability, education, and effective vaccination and screening programs [4, 5].

Understanding of cervical cancer biology and human papillomavirus (HPV) related oncogenesis has significantly evolved, informing worldwide preventative and screening strategies. Persistent infection with high-risk HPV subtypes is the cause of nearly all cervical cancers [6]. HPV 16 and 18 are estimated to cause 70% of all cervical cancers, while approximately 10 other high risk HPV strains cause the remaining 30% [7]. The second generation 9-valent vaccine was approved by the U.S. Food and Drug Administration (FDA) in 2014 to target 9 high risk HPV strains in males and females aged 9 through 26 years old [8]. This vaccine is currently recommended for men and women age 9-45, after an updated 2018 FDA approval, intended to prevent HPV-related diseases in a wider age range [8]. Implementation of vaccination programs and adherence to cervical cancer screening have decreased the prevalence of high-risk HPV infections and facilitated earlier detection of cervical dysplasia, where an excisional procedure can be curative and prevent the development of cervical cancer [9]. In August 2020, the World Health Organization (WHO) adopted a “90-70-90” global strategy for cervical cancer elimination. This strategy has three key pillars that should be met worldwide by 2030: 90% of girls fully vaccinated with the HPV vaccine by the age of 15, 70% of women screened using a high-performance test by the age of 35 and again by the age of 45, and 90% of women with pre-cancer treated and 90% of women with invasive cancer managed [10]. In addition to the important work being done to increase global rates of vaccination and high-quality cervical cancer screening, there remains a need for optimization of treatment strategies and to develop novel therapies for women with locally advanced, advanced, metastatic, and recurrent cervical cancer.

FIGO (International Federation of Gynecology and Obstetrics) staging guides treatment decisions for cervical cancer [9]. The current standard of care for early-stage disease is surgical excision either with cold knife conization, loop electrosurgical excision procedure, or simple hysterectomy [11]. In early stage patients with larger tumors (Stage IA2 to IB1), a radical hysterectomy with removal of the parametrium is and nodal assessment is indicated [11]. However, the SHAPE trial, published in February 2024, demonstrated that simple hysterectomy was not inferior to radical hysterectomy when evaluating 3-year incidence of pelvic recurrence in low-risk cervical cancer patients, specifically those with tumors ≤ 2cm and depth of invasion < 10mm among other criteria, who underwent simple hysterectomy were less likely to have postoperative urinary issues [12]. For almost 3 decades, chemoradiation consisting of weekly cisplatin with external beam radiation followed by intracavitary brachytherapy has been recommended for locally advanced cervical cancer (LACC) (Stage II-IVA) [11]. For these patients, surgery alone is unlikely to be curative and studies have demonstrated decreased complication rates with chemoradiation compared to surgical management followed by adjuvant radiation [13]. Finally, management of widespread metastatic cervical cancer is limited to systemic therapy, often cytotoxic chemotherapy, or palliative measures [9].

Approximately one-third of all patients with cervical cancer will experience recurrence within the first 2 years after initial treatment [14]. Specifically, early-stage disease is cured with primary treatment (surgery) approximately 95% of the time where patients treated for locally advanced disease have a 40-60% recurrence rate [15]. Recurrence is categorized into local or central-pelvic, regional, or distant [16]. Historically, platinum-based chemotherapy has been the predominant treatment for recurrent cervical cancer; however, depending on the site of recurrence, the patient’s treatment history, disease free interval, and overall health, treatment can also include radiation and surgical management with pelvic exenteration or a combination of these modalities [14]. Currently, pelvic exenteration represents the only surgical option with curative intent for limited, select cases of central recurrence after primary or adjuvant radiation and chemotherapy, though these procedures carry significant morbidity and mortality [14].

As discussed further in this review, therapeutic options for the management of advanced and recurrent cervical cancer have recently expanded with current indications for the use of biologic, targeted, and immunotherapeutic drugs [17]. A recent review comprehensively highlighted impactful clinical trial observations including the potential utility of anti-angiogenic therapy, immunotherapy and antibody drug conjugates among others [18]. Despite improvements, further research is warranted to optimize strategies for these patients, improve patient selection by using relevant biomarkers to guide treatment, and to develop new, effective therapies. The objective of this review is to describe the current landscape of cervical cancer pharmacotherapy with a focus on the use of anti-angiogenic drugs, immunotherapy, targeted therapy, and other novel agents for LACC and recurrent, progressive, or metastatic cervical cancer.

2. Anti-Angiogenic Therapy

Angiogenesis is a complex physiologic process essential for tumor invasion and metastasis [19, 20]. Development of effective anti-angiogenesis therapies has been a major focus of clinical research in cervical cancer [20]. In the context of cervical cancer, angiogenesis has been linked to HPV mediated expression of proangiogenic factors, including vascular endothelial growth factor (VEGF) [21, 22]. VEGF leads to neovascularization and enhanced vascular permeability of existing blood vessels and has been identified as an integral pro-angiogenic factor in cervical cancer [21, 22]. Furthermore, VEGF overexpression is associated with poor prognosis in cervical cancer [23].

The anti-VEGF monoclonal antibody bevacizumab is the preferred antiangiogenic therapy in the treatment of cervical cancer. GOG 227C, a phase II trial, demonstrated that single agent bevacizumab was well tolerated and active in pretreated patients with recurrent cervical cancer [24]. Subsequently GOG240, a phase III trial, demonstrated the addition of bevacizumab to combination chemotherapy (cisplatin and paclitaxel, or topotecan and paclitaxel) improved both progression-free survival (PFS) (8.2 vs 5.9 months; HR=0.67; CI 0.54-0.82) and overall survival (OS) (17.0 vs 13.3 months; HR 0.71; CI, 0.54-0.95) [25]. Although these trials demonstrated clinical benefit and were overall well tolerated, GOG240 investigators noted that patients treated with bevacizumab, compared to chemotherapy alone, experienced increased rates of grade 2 or higher HTN (25% vs. 2%, p<0.001), grade 3 or higher thromboembolic events (8% vs. 1%, p=0.001), and grade 3 or higher gastrointestinal fistulas (3% vs 0%, p=0.002) [25]. Following these results, in 2014, the FDA approved bevacizumab in combination with chemotherapy for patients with metastatic or recurrent cervical cancer [17], establishing bevacizumab with combination chemotherapy as the standard first-line therapy for metastatic or recurrent cervical cancer and marking the first new therapeutic approval for this patient population since 2006.

Several additional clinical trials have explored the efficacy of similar agents in the class, either alone or in combination with other novel agents or with platinum based therapy (pazopanib and lapatinib [26], cediranib [27], sutinib [28]), though taken in sum these agents do not significantly improve clinical outcomes and can be associated with increased toxicity, including higher rates of fistula formation.

3. Immune Checkpoint Inhibitors (ICI)

Immunotherapeutic approaches for the treatment of cancer have dramatically grown over the past decade, relying on our understanding of how malignancies evade the host immune system and drive carcinogenesis through immune-mediated mechanisms. Of these, immune checkpoint inhibitors (ICI) have been the most prolific. HPV has several mechanisms to evade the immune system, persist, and drive the progression from cervical dysplasia to invasive cervical cancer. Importantly, pathologic PD-L1 expression related to persistent HPV infection plays an important role in creating a tumor environment with reduced immunity [29]. Up to 80% of squamous cell cancers have a high frequency of PD-L1 expression [30]. Widely accepted as a virally driven and highly immunogenic cancer, the development of immunotherapies to target these HPV and PD-L1 pathways to elicit an antitumor immune response holds much promise.

3.1. ICI Monotherapy

Anti-PD-1 directed therapy was first studied in cervical cancer in KEYNOTE-028, where pembrolizumab was administered to 475 patients with PD-L1 positive advanced solid tumors, including a cohort of 24 cervical cancer patients; ORR was 17% with a mDOR of 5.4months with 4 partial responses (PRs) (17%) and 3 patients with stable disease (SD) (13%) [31]. KEYNOTE-158, a phase II expansion trial investigating treatment with pembrolizumab in 98 patients with predominantly PD-L1 positive, advanced, squamous cell carcinoma, showed a 12.2% overall response rate (ORR) with 3 (complete responses) CRs and 9 PRs and a median duration of response (mDOR) not reached after 11 months of follow-up though 91% of patients responded to treatment for at least 6 months [32]. Importantly, all 12 responses were in patients with PD-L1 positive tumors [32]. In 2018 pembrolizumab received expedited approval from the FDA for the treatment of PD-L1-positive (PD-L1 combined positive score [CPS] ≥ 1) advanced cervical cancer with disease progression after chemotherapy [33].

Other PD-1-directed therapies have been studied in this population with mixed results. Nivolumab, an anti-PD-1 monoclonal antibody, was studied in 19 cervical cancer patients in the phase I/II CheckMate 358 study with an ORR of 26.3%, regardless of PD-L1 or HPV positivity [34]. In NRG-GY002, investigators reported low anti-tumor activity of nivolumab (ORR, 4%) in persistent and recurrent cervical cancer previously treated with platinum-based chemotherapy [35]. Finally, in GOG3016, patients treated with cemiplimab experienced increased median OS (12.0 vs. 8.5 months, p<0.001) and RR in 16.4% vs. 6.3% for patients treated with cemiplimab when compared to the chemotherapy group respectively. Importantly, this study also found that although patients with PD-L1 expression ≥ 1% had a higher objective response rate (18%) than in patients with PD-L1 expression < 1% (11%), responses were present in both groups [36].

Anti-CTLA-4 therapies have also been explored as immunotherapeutic agents in cervical cancer. A phase I study investigating ipilimumab, a CTLA-4 directed monoclonal antibody, following standard chemoradiation (CRT) for locally advanced cervical cancer demonstrated a 12 month OS of 90% and 12 month PFS of 81%, which is a modest improvement from historical data [37]. Ipilimumab monotherapy in metastatic or recurrent HPV-related cervical cancer by Lheureux et al. in 2018 demonstrated an ORR of 2.9% [38].

3.2. Immunotherapy Combinations

Based on the modest clinical activity noted with single agent immunotherapies, combination immunotherapy has emerged as a promising strategy to elicit anti-tumor activity for more patients, especially those with immunologically “cold” tumors [39]. For example, while ipilimumab monotherapy did not provide significant anti-tumor activity in recurrent or metastatic cervical cancer, the CheckMate 358 trial demonstrated more promising results with the combination regimen of nivolumab plus ipilimumab, as presented at ESMO congress in 2019 [40]. In the nivolumab plus ipilimumab arm, interim analysis results demonstrated an ORR of 46% in the chemo-naïve cohort vs. 36% in patients who had received previous systemic therapy with a mOS of 25.4 months in pretreated patients and mOS not reached in the chemo-naïve population. Two novel checkpoint inhibitors, balstilimab (anti- PD-1) and zalifrelimab (anti-CTLA-4), were evaluated in combination in a phase II trial that enrolled 155 women with recurrent and/or metastatic cervical cancer after prior platinum based therapy; this study reported an ORR of 25.6% (95% CI, 18.8-33.9), including 10 CRs and 22 PRs, with an overall disease control rate of 52% (95% CI, 43.3-60.6) [41]. Importantly, higher response rates were noted in PD-L1 positive tumors where ORR was 32.8% compared to 9.1% in the PD-L1 negative tumors [41]. These results support the rationale for further investigations of combination anti-CTLA-4 and anti-PD-1/PD-L1 directed therapies in cervical cancer.

Newer immunotherapeutic agents are being evaluated across several tumor types, including anti-T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitor motif domains (anti-TIGIT) [42]. In the phase II, SKYSCRAPER-04 study, investigators report combining tiragolumab (anti-TIGIT) with atezolizumab in PD-L1-positive, recurrent or persistent cervical cancer not amenable to curative therapy yielded an ORR of 19.0% with an ORR of 15.6% in the atezolizumab monotherapy arm [43]. While this study demonstrated an improvement in ORR, this did not reach statistical significance over the historical control ORR of 14.6% observed with pembrolizumab in KEYNOTE-158 for PD-L1 positive cervical cancer patients [32, 43]. While a strong biologic rationale exists for the combination of anti-TIGIT therapy with anti-PD-1/PD-L1 agents, further research will be needed to determine if clinical benefits exist for this population.

3.3. Checkpoint Inhibition in Combination with Active Systemic Regimens

While there are ongoing evaluations of novel agents alone and in combination, newer clinical trials have combined established active therapies with immunotherapy and have yielded largely promising results. Investigations of ICIs in recurrent, persistent and metastatic cervical cancer patients in combination with systemic platinum-based chemotherapy (with or without bevacizumab) have been explored in two notable trials KEYNOTE 826 and BEATcc [44, 45]. KEYNOTE 826 demonstrated a significant improvement in both PFS and OS with pembrolizumab, as compared to placebo, in chemo-naïve patients receiving concurrent chemotherapy, with or without bevacizumab. This effect persisted across prespecified strata by PD-L1 CPS score (CPS score ≥1: mPFS 10.4months (pembrolizumab) vs 8.2 months (placebo) and 24-month OS 53.0% vs 41.7%; CPS score ≥ 10: mPFS 10.4months vs 8.1 months and 24-month OS 54.4% and 44.6% [44]. The protocol-specified final OS analysis results of this study were published in 2023 and demonstrated the addition of pembrolizumab to chemotherapy significantly Improved OS and PFS in the CPS ≥10, CPS ≥1, and all comer populations, regardless of bevacizumab use [46]. Reductions in death were reported as 42%, 40%, and 37% in the CPS ≥10, CPS ≥1, and all comer cohorts, respectively [46]. Consistent with the previous results, these data support quadruplet therapy (pembrolizumab + platinum doublet chemotherapy +/− bevacizumab) as the new standard, first-line treatment for persistent, recurrent, or metastatic cervical cancer.

BEATcc, a phase III trial of atezolizumab combined with platinum doublet and bevacizumab for metastatic, persistent, or recurrent cervical cancer demonstrated that adding atezolizumab to first-line chemotherapy and bevacizumab improved dual primary endpoints of PFS and OS: mPFS 13.7 months (95% CI 12.3-16.6) with the addition of atezolizumab versus 10.4 months (9.7-11.7) with standard therapy (HR=0.62 [95% CI; 0.49-0.78; p<0.0001), mOS 32.1months (95% CI 25.3-36.8) vs 22.8months (20.3-28.0), respectively, (HR 0.68 [95% CI 0.52-0.88], p=0.0046) [47]. This trial again demonstrates the promising efficacy of immunotherapy in frontline management of advanced cervical cancer in chemo-naïve patients and suggests the addition of atezolizumab may be considered as an alternative first-line therapy option.

3.4. Immunotherapy and Chemoradiation

Research has demonstrated synergy between concurrent radiotherapy and immunotherapy [48–50]. Radioimmunotherapy has significantly improved the effective cure rate for patients in the clinical trial setting for other disease sites, namely lung cancer [51–53]. Radiotherapy can change the tumor microenvironment (TME) in several ways including endothelial damage and inflammation, release of tumor-specific antigens, and activation of immunosuppressive pathways leading to immune-mediated cell death [54]. These findings prompted several clinical trials to explore the role of ICIs combined with CRT in cervical cancer, with several ongoing [55–59].

CALLA, a phase III trial published in December 2023, revealed that durvalumab (a PD-L1 antibody) with and following CRT did not significantly improve PFS for locally advanced cervical cancer in a biomarker unselected population [55]. Future research exploring differences in clinical outcomes in cervical cancer patients treated with immunotherapy with concurrent chemoradiation, stratified by PD-L1 expression, could be warranted. Despite these negative results, KEYNOTE A18, a phase III trial, demonstrated a significant improvement in PFS and a favorable trend in OS in patients with high-risk, locally advanced cervical cancer treated with pembrolizumab with and following concurrent CRT versus placebo with and following concurrent CRT; 24-month PFS was 67.8% vs 57.3% with mPFS not reached in either group [59]. Based on this data, the FDA approved pembrolizumab in combination with CRT followed by pembrolizumab maintenance for FIGO 2014 Stage III-IVA cervical cancer [60]. While at the time of the original publication OS data was not mature, recent a MERCK announcement reported that pembrolizumab plus CRT showed a statistically significant and clinically meaningful improvement in OS; this the first immunotherapy-based regimen to demonstrate a statistically significant improvement in OS in newly diagnosed patients with high-risk locally advanced cervical cancer [61]. Questions remain regarding the sequencing of immunotherapeutic strategies in combination with traditional CRT with further research required to determine which agents and combination strategies will provide the most benefit.

3.5. Immune-Related Adverse Events (irAEs)

As with any treatment modality, associated risks of toxicity must be considered. ICIs have changed the landscape of therapy in gynecologic malignancies and use of these agents have rapidly expanded leading to a corresponding increase in immunotherapy-related adverse events (irAEs) [62]. ICIs increases the body’s tumor-directed T-cell response and suppression of the tumor microenvironment to facilitate destruction of cancer cells; this unique mechanism of action introduces new potential adverse events driven by the same immunologic processes by which they elicit anti-cancer effect. Importantly, these irAEs are significantly different from the toxicity profiles of traditional cytotoxic chemotherapies and careful attention to recognizing and managing these adverse events must be considered to ensure safety and efficacy.

Reported rates of irAEs vary widely in the literature, from 15-90% [63–65]. The majority of irAEs are mild to moderate though severe and potentially life-threatening irAEs are reported at rates of 0.5-13% and tend to occur more commonly with combination immunotherapy [64, 65]. While traditional cytotoxic therapies are most often associated by acute-onset emetic effects and myelosuppression, irAEs can be delayed and are often inflammatory or auto-immune in nature, affecting a variety of organ systems including skin, musculoskeletal, endocrine, GI and lung and less frequently, hematologic, renal, neurologic, cardiovascular, and ophthalmologic [63, 64]. While an in depth summary of irAEs is out of the scope of this review, several guidelines exist with recommendations for the diagnosis and management of irAEs: National Comprehensive cancer Network (NCCN) [64], Society for Immunotherapy of Cancer (STIC) [66], American Society of Clinical Oncology (ASCO) [67], European Society for Medical Oncology (ESMO) [68]. Importantly, we must consider that combining immunotherapy with systemic chemotherapies, targeted therapy, and radiotherapy may change the toxicity profile associated with immunotherapies and must be assessed in ongoing and future trials [69].

4. Antibody Drug Conjugates (ADCs)

4.1. Tisotumab Vedotin

Tisotumab vedotin is an antibody-drug conjugate (ADC) composed of tissue factor-directed antibody (tisotumab) covalently linked to a microtubule inhibitor (vedotin). This first in class drug was studied in the phase II innovaTV-204/GOG-3023/ENGOT-cx6 trial as a second-line therapy for recurrent or metastatic cervical cancer after disease progression on platinum doublet therapy [70]. This trial demonstrated an ORR of 24% (95 CI 16-33) with 17 (17%) PRs and 7 (7%) CRs among the 101 enrolled patients with a mDOR reported as 8.3 months (95% CI; 4.2-NR). It is important to recognize these findings in the context of historically used or recently approved therapies in this recurrent or metastatic cervical cancer population with overall poor ORR generally under 15%. Based on results from innovaTV-204/GOG-3023/ENGOT-cx6, in 2021, the FDA granted accelerated approval for the use of tisotumab vedotin for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [71].

The innovaTV-204/GOG-3023/ENGOT-cx6 trial investigators also reported the safety profile of tisotumab vedotin was manageable. While 92% of patients experienced TRAEs, the majority were mild to moderate in severity with no new safety signals. Grade 3 or worse TRAEs were reported in 28% of patients. Importantly, because significant ocular adverse events were observed in the first-in-human trial of tisotumab vedotin [72], a robust eye care plan was implemented in the study protocol. While 53% of patients had an ocular TRAE, these were grade 1 or 2 in 52 of 54 patients, most commonly conjunctivitis, dry eye, and keratitis, and most completely resolved. Investigators from this trial emphasize the importance of strict dose modification and preventative protocols for use of tisotumab vedotin, ultimately leading to lower rates of TRAEs of interest (peripheral neuropathy, ocular, and bleeding events) in this trial compared to the first-in-human study [72].

The 502 patient, confirmatory, phase III ENGOT-cx12/GOG-3057/innovaTV-301 trial recently published results demonstrating a statistically significant and clinically meaningful improvement in OS (11.5mo [95% CI 9.8-14.9] vs 9.5mo [95% CI, 0.54-0.82]), PFS (4.2mo [95% CI 4.0-4.4] vs. 2.9mo [95% CI 2.6-3.1] HR: 0.67 [95% CI, 0.54-0.82]; p<0.0001), and ORR (17.8% vs 5.2% (odds ratio: 4.0; 95% CI, 2.1-7.6; p<0.001) with tisotumab vedotin compared to investigator’s choice chemotherapy in patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [73]. Most recently, in April 2024, tisotumab vedotin received FDA approval for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, solidifying the previous accelerated approval [74]. Currently, these data support tisotumab vedotin as an FDA approved, PD-L1 agnostic, second-line treatment option for patients with recurrent and metastatic cervical cancer, a population without many other efficacious treatment options.

4.2. HER2 Directed Therapy

While FDA approvals have moved pembrolizumab, with or without bevacizumab, into the first line for patients with persistent, recurrent, or metastatic cervical cancer with PD-L1 CPS score ≥1 and there is now a PD-L1 agnostic treatment for this population, tisotumab vedotin, given drug resistance and low response rates to single agent chemotherapy, there is a strong need for the continued development of novel treatment strategies for this population. Research investigating relevant clinical biomarkers in cervical cancer holds great potential in the pathway to identifying novel therapeutics.

HER2, human epidermal growth factor receptor 2, is a member of the receptor tyrosine kinase family and has been identified as a promising anticancer target [75]. Increased signaling by HER2, either by amplification of the HER2 gene or overexpression of the HER2 receptor, can drive tumor growth by promoting cellular proliferation, carcinogenesis, and cell survival [76]. Somatic HER2 mutations have been identified in a large variety of solid tumors, including gynecologic malignancies [77]. HER2 directed therapy has been well studied in other tumor types, notably breast, gastric, colorectal, and lung cancer, with multiple therapeutic agents FDA approved for standard of care indications [78–81]. Tumoral HER2 overexpression is associated with poor clinical outcomes including higher rates of recurrence, chemoresistance, and decreased overall survival [82–84]. While estimates vary widely in the literature, rates of HER2 positivity in cervical cancer are approximately 5% [85]. This represents a small but clinically important population of patients, often with aggressive tumor phenotypes and limited therapeutic options after standard therapy, and an opportunity to improve outcomes with HER2-targeted therapy.

SUMMIT was a phase II trial investigating the efficacy and safety of neratinib in HER2-mutant, persistent, metastatic, or recurrent cervical cancer with progression after platinum-based therapy [86]. Neratinib is an oral, pan-HER tyrosine kinase inhibitor with efficacy previously demonstrated in patients with HER2-positive breast cancer and evidence of anti-tumor activity in pre-clinical, HER2-mutant cervical cancer models [87–89]. In the final results from SUMMIT, of the 22 enrolled patients, four had confirmed PRs (ORR 18.2%, 95% CI 5.2-40.3) and six had stable disease ≥16 weeks (CBR 45.5%, 95% CI 24.4-67.8) with a median DOR of 7.6 months (95% CI 5.6-12.3) and median PFS of 5.1 months (95% CI 1.7-7.2) [90]. Of note, 18/22 (81.8%) of the enrolled patients had endocervical adenocarcinoma and all responses occurred in this cohort. In general, this therapy was well tolerated with the most common adverse event being diarrhea; for this reason, loperamide was mandatory during cycle 1. Overall, SUMMIT demonstrated that neratinib resulted in durable responses with a tolerable safety profile in patients with HER2-mutant, persistent, metastatic, or recurrent endocervical adenocarcinoma.

The DESTINY-PANTumor02 trial [91], published in January 2024, was a phase II basket trial evaluating trastuzumab deruxtecan (T-DXd), a HER2 directed ADC, in 7 tumor cohorts, including cervical cancer. At the time of publishing, T-DXd was approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer with a paucity of HER2 directed therapies available for other tumor types. This study enrolled 267 patients with HER2 IHC 3+/2+, locally advanced or metastatic disease who had received ≥1 prior line of therapy or without alternative treatment. The cervical cohort included 40 heavily pretreated patients, with 85% receiving ≥ 2 prior lines of therapy.

DESTINY-PANTumor02 demonstrated meaningful ORR, promising survival outcomes, and a tolerable safety profile consistent with previous trials investigating T-DXd. Importantly, the largest magnitude of benefit was observed in gynecologic malignancies and in the IHC3+ population. Specifically, the investigator assessed ORR for the cervical cohort was 50.0% (95% CI, 33.8-66.2) and 75.0% (95% CI, 34.9-96.8) in those with HER2 IHC 3+ expression. The median OS in this cohort was 13.6months with median OS not reached in the IHC3+ patients. Of note, the cervical cohort prospectively opened enrollment to patients with HER2 IHC 1+, and ultimately 12/40 patients in this cohort were identified as HER2 IHC 1+ or 0 on retrospective central testing. While T-DXd is FDA approved for HER2-low breast cancer [92], further studies are warranted to investigate the efficacy of this therapy in other HER2-low tumors.

Pulmonary adverse events, notably interstitial lung disease (ILD)/pneumonitis, are an established risk with T-DXd therapy and occurred in 28 (10.5%) of patients enrolled in the DESTINY-PANTumor02 trial. Though most of these drug-related pulmonary adverse events were low grade and manageable, there was one (0.4%) grade 3 event and three (1.1%) drug-related ILD/pneumonitis-related death. In the cervical cohort, there was a 32.5% rate of drug-related adverse events leading to dose modification, 7.5% leading to discontinuation, and no associated deaths. T-DXd related ILD/pneumonitis is an important consideration when prescribing this therapy and multidisciplinary guidelines on diagnosis and management exist recommending a high level of clinical suspicion and that suspected cases being managed by multidisciplinary team including the oncologist, pulmonologist, pharmacist, infectious disease specialist, and radiologist [93].

Based on this trial, on April 5, 2024, the FDA granted accelerated, tumor agnostic approval for the use of T-DXd in patients with unresectable or metastatic HER2 IHC3+ solid tumors who have received previous systemic therapy or who have no satisfactory alternative treatments [92]. DESTINY-PANTumor02 represents the first reported investigation of a HER2 directed ADC in gynecologic cancer and provides data supporting the use of T-DXd in this cohort of patients with limited treatment options and an overall low response to these therapies. Table 1 summarizes the important clinical trials which have informed modern cervical cancer management including the patients’ studied and outcomes from the referenced trials, while Figure 1 depicts applicable regulatory approval of reviewed agents, and which are now commercially available.

Table 1 –

Clinical trials with novel pharmacotherapies informing current clinical practice for both primary locally advanced as well as recurrent cervical cancer.

	Patient Population	Agent (s)	Results	Conclusions
Anti-Angiogenesis
GOG 240	recurrent, persistent, or metastatic	Bevacizumab + combination chemotherapy (cisplatin and paclitaxel or topotecan and paclitaxel)	PFS: 8.2 vs. 5.9 months; HR 0.67; CI 0.54-0.82	Improvement in PFS and OS with addition of bevacizumab to chemotherapy.
			OS: 17.0 months vs. 13.3 months; HR 0.71; CI 0.54-0.95
ICI Monotherapy
KEYNOTE-158	PD-L1 positive, progression during or after chemotherapy	pembrolizumab	12.2% ORR, 3 CR, 9 PR, CI 6.5-20.4	Pembrolizumab monotherapy has durable antitumor activity in PD-L1 positive, advanced cervical cancer with disease progression after chemotherapy
ICI + Chemotherapy +/− Anti-Angiogenesis
KEYNOTE 826	first line, recurrent, persistent, or metastatic	pembrolizumab + chemotherapy +/− bevacizumab	PFS: 10.4 months vs. 8.2 months, HR 0.65; CI, 0.53-0.79	Improvement in PFS and OS with addition of pembrolizumab to chemotherapy +/− bevacizumab
			OS (24 month): 50.4% vs 40.4%, HR 0.67;+D6:D9 CI 0.54-0.84
BEATcc	first line, recurrent, persistent, or metastatic	atezolizumab + chemotherapy + bevacizumab	PFS: 13.7 months vs 10.4 months, HR 0.62; CI 0.49-0.78	Improvement in PFS and OS with addition of atezolizumab to chemotherapy + bevacizumab
			OS: 32.1 months vs 22.8 months, HR 0.68; CI 0.52-0.88
ICI + Chemoradiation
CALLA	first line, locally advanced	durvalumab with and following chemoradiation	PFS (24 month): 67.8% vs 57.3%; HR 0.84; CI 0.65-1.08	No improvement in PFS with addition of durvalumab to chemoradiation and as maintenance, in a biomarker unselected population
KEYNOTE A18	first line, locally advanced	pembrolizumab with and following chemoradiation	PFS (24 month): 68% vs 57%; HR 0.70; CI 0.55-0.89	Improvement in PFS with the addition of pembrolizumab to chemoradiation and as maintenance
Tisotumab Vedotin
innovaTV-204/GOG-3023/ENGOT-cx6	recurrent or metastatic, progression on or after chemotherapy	tisotumab vedotin	ORR 24%, 17% PR, 7% CR; CI 16-33	Tisotumab vedotin has durable antitumor activity in women with previously treated cervical cancer
			mDOR 8.3 months, CI 4.2-NR
ENGOT-cx12/GOG-3057/innovaTV-301	recurrent or metastatic, progression on or after chemotherapy	tisotumab vedotin	mOS: 11.5months vs 9.5 months; HR 0.70; CI 0.54-0.89	Improvement in OS, PFS, and ORR with tisotumab vedotin vs investigators choice chemotherapy
			PFS: HR 0.67; CI 0.54-0.82
			ORR: 17.8% vs. 5.2%; OR 4.0; CI 2.1-7.6
HER-2 Directed Therapy
DESTINY-PANTumor02	HER2 IHC +, locally advanced or metastatic, received ≥1 prior line of therapy or without alternative treatment	trastuzumab deruxtecan	ORR: 50.0%; CI 33.8-66.2	Meaningful ORR, promising OS with trastuzumab deruxtecan in HER2+ cervical cancer
			ORR (IHC3+): 75.0%; CI 34.9-96.8
			OS: 13.6 months

Figure 1 –

FDA approvals for cervical cancer therapeutics since 2014

5. Poly ADP-ribose polymerase Inhibitors

Poly (ADP-ribose) polymerases (PARPs) are a group of enzymes involved with several key cellular functions, including the repair of single stranded breaks in DNA which is of interest in the oncologic setting. Small molecule PARP inhibitors (PARPi) are an antineoplastic drug class with a mechanism of action aimed at blocking DNA repair in malignant cells [94]. PARPis have been studied in a variety of cancers, including in gynecologic malignancies [95]. In the context of gynecologic malignancies, PARPi use has the strongest biologic rationale and longest history of use in ovarian cancer; however, In cervical cancer, preclinical studies have demonstrated PARP is found in high levels in tumor cells[96] and that increased apoptosis and sensitization of these cells to treatment occur in response to cytotoxic treatment with the addition of PARPi [97–99]. Furthermore, studies have demonstrated PARPi induce immunogenic cell death and higher neoantigen loads, including PD-L1, which could increase the anti-tumor immune response to immunotherapy [100].

A phase 1 trial evaluated the addition of the PARPi, veliparib, in combination with paclitaxel and cisplatin in persistent or recurrent cervical cancer and demonstrated that the regimen was feasible and safe; investigators report ORR was achieved in 34% (95% CI, 20%-53%) of patients with measurable disease at the time of trial enrollment, mPFS of 6.2 months (95% CI, 2.9-10.1 months), and OS of 14.5 months (95%CI, 8.2-19.4 months) [101]. Another phase 1-2 trial evaluated the combination of veliparib with topotecan and bone marrow support with filgrastim or pegfilgrastim in 27 patients with persistent or recurrent cervical cancer [102]. This study demonstrated poor clinical activity of the regimen with only 2 (7%) PRs and 4 patients with progressive disease more than 6 months after the initiation of therapy. Furthermore, significant hematologic toxicities were observed with over 50% of patients experiencing severe, treatment related anemia. Of note, in a subset of women with low levels of PARP-1 expression demonstrated statistically significant higher PFS and OS which supports future study of PARP-1 as a biomarker that could help identify cervical cancer patients who may receive the most benefit from PARPi therapy.

To date, there is limited clinical data to suggest the efficacy of PARPi in cervical cancer. Several previous studies investigating the role of this therapy in combination with cytotoxic therapy, as maintenance therapy, and as a radiosensitizer have reported negative results or have been suspended. However, to our knowledge, there is no published data regarding the addition of PARPi to immunotherapy in cervical cancer.

6. Novel Therapies (Therapeutic Vaccines and Cell Based Therapies)

While there is only one cell-based therapy and no therapeutic vaccines with clinical approval for use in cervical cancer, as these therapies are further studied and refined, they hold great promise in treatment of this disease. Advancing research to understand the cervical cancer tumor microenvironment and relevant clinical biomarkers will help us to better distinguish which patients may derive the greatest benefit from these therapies and guide clinical treatment decisions in this regard. Although a comprehensive review of these therapies is out of the scope of this review, here we summarize the most notable and promising experimental immunotherapeutic approaches for the treatment of cervical cancer. For further information, see the following reviews: [103, 104].

6.1. Therapeutic Vaccines

As previously discussed, the development of prophylactic vaccination for HPV has significantly reduced the global impact and mortality from cervical cancer. Unlike these prophylactic vaccines which are designed to generate a protective antibody response prior to exposure to the virus, therapeutic vaccines are designed to generate cytotoxic cellular responses to established infections and resulting malignant cells. Currently, several therapeutic vaccine strategies are being developed for the treatment of cervical cancer with varying delivery platforms: DNA, RNA, antigen-presenting cells, peptides, proteins, and viral and microbial vectors. These varying strategic approaches are being widely studied in different stages of development and carry with them unique advantages and pitfalls. Many of these vaccines target E6 and E7, quintessential HPV proteins, though investigators are currently exploring additional target tumor antigens. One phase II trial investigating ADXS11-001, a Listeria-based bacterial vector vaccine encoding HPV16 E7, demonstrated promising results in patients with persistent, recurrent, or metastatic cervical cancer with a 12-month survival of 38.5% [105]. Unfortunately, as subsequent phase III trial comparing ADXS11-001 to placebo was terminated early and efficacy data were not collected (NCT02853604). Importantly, there are several clinical trials underway investigating the role of therapeutic vaccination to control pre-malignant, persistent HPV16 infections which could significantly reduce the incidence of cervical cancer. Ongoing and future studies aimed at discerning the most effective therapeutic vaccination strategies and possible synergies with other immunotherapeutic approaches or known, active therapies hold significant promise.

6.3. Adoptive T cell Therapies

Adoptive cell therapy (ACT) consists of three major categories: tumor infiltrating lymphocytes (TILs), engineered T-cell receptor T cells (TCRs), and chimeric antigen receptor (CAR) T cells. In general, this therapeutic strategy utilizes naturally occurring immune cells which are collected, genetically expanded or engineered, and re-administered to the patient to specifically eliminate tumor cells [106]. ACT, specifically CAR-T therapy, has proven to be incredibly successful in hematological malignancies though has historically demonstrated limited efficacy in solid tumors, like cervical cancer [107]. Despite this, there is significant hope for application of this technology and treatment in cervical cancer with HPV oncogenes as attractive tumor-specific antigen targets for ACT therapy. In fact, there are many ongoing trials and several notable historic trials in this area.

6.3a. Tumor Infiltrating Lymphocytes (TILs)

Of the ACTs, TILs have demonstrated the most efficacy in cervical cancer to date. A phase 2 clinical investigation reported a single infusion of HPV-TILs in HPV-positive, previously treated, metastatic cervical cancer led to objective tumor responses in 5 out of 18 (28%) of patients with two complete responses ongoing >5 years after treatment [108]. Investigators also report a correlation between the HPV reactivity of the infused T cells and observed clinical responses warranting continued investigation and promise for the use of TILs in cervical cancer. An ongoing phase 2 clinical trial evaluating LN-145 TIL therapy in advanced cervical cancer reported preliminary efficacy results with an ORR of 44%, including 1 complete response and 9 partial responses [109]. Based on these impressive results with a tolerable safety profile, the FDA approved LN-145 for use in recurrent, metastatic, or persistent cervical cancer with disease progression on or after chemotherapy [110]. Ongoing investigations are evaluating potential synergy between immune checkpoint inhibition and TIL therapy in cervical cancer.

6.3b. Engineered T-cell Receptor T cells (TCRs)

As opposed to TILs therapy, engineered TCR therapy utilizes host derived T cells modified to express a specific tumor-targeting T cell receptor instead of expanding tumor-specific T cells already present. A phase I/II trial demonstrated E6 engineered TCR T cells in HPV16+ cancers of any primary tumor cite induced regression of these cancers with two patients experiencing objective responses, one with no evidence of disease >3 years after treatment [111]. There are several ongoing clinical trials exploring HPV oncoprotein engineered TCT T cells for the treatment of cervical cancer.

6.3c. Chimeric Antigen Receptor (CAR) T cells.

CAR T therapy utilizes T cells engineered with chimeric antigen receptors, or synthetic recognition structures, attached to the host T cell. While CAR T therapy has had dramatic efficacy in hematologic malignancies, there are current, limited uses of this therapy in solid tumors. To our knowledge, there are no published data regarding CAR T therapy for the treatment of cervical cancer though there are several ongoing trials.

7. Conclusions

Cervical cancer is a largely preventable disease with significant morbidity and mortality worldwide. Even in regions with higher healthcare resources, patients with recurrent, progressive, and metastatic disease have an overall poor prognosis. After decades of limited progress in identifying new, effective therapies, we have entered a new era for cancer treatment with the rapid development of biologic, targeted, and immunotherapeutic drugs with applications in cervical cancer. Despite this, responses to these therapies in cervical cancer have overall been modest and a clear need for improved pharmacotherapies exists. Certainly, there are opportunities to progress the treatment of advanced and metastatic cervical cancer by combining treatment modalities, either novel or conventional, to maximize synergistic therapeutic effects. Future research should explore clinically useful cervical cancer biomarkers to enhance the individualization of treatment plans to improve outcomes. Ongoing support for enrollment of these patients in clinical trials will allow us to continue to investigate new, promising therapies to improve current and future outcomes.

8. Expert Opinion

Systemic therapy remains the cornerstone of improving outcomes in both locally advanced as well as recurrent, metastatic and persistent cervical cancer. Clinical trials during the last 15 years have profoundly impacted not only the contemporary management of cervical cancer but more importantly have resulted in improved patient outcomes as well. Consequently, the impact of these management changes based on trial results necessitates not only modification in current therapy but also new avenues for future focus. At present, PD-L1 helps determine treatment recommendations for those with a first recurrence, persistence of disease following chemoradiation or de novo metastatic disease. For the majority of patients with PD-L1 positive tumors, immunotherapy in combination with chemotherapy and bevacizumab has been demonstrated to result in the best clinical outcomes, including an improvement in overall survival. For those without PD-L1 tumor expression, chemotherapy with bevacizumab remains the preferred therapy, although with less robust outcomes predicted as compared to when immunotherapy can be utilized. The role of alternative immunotherapy treatment either as a single agent, or perhaps more likely as immunotherapy combinations for PD-L1 negative tumors is warranted.

Most impactful, not only in terms of improved patient outcomes but also future management approaches and strategies, are the results from the A18 as well as KEYNOTE-826 and BEATcc clinical trials. As all these trials have reported positive outcomes, immunotherapy is likely to increase for both those with Stage III-IV LACC as well as those that present with primary metastasis or recurrence following prior therapies. Importantly, as all three of these landmark trials were performed in patients without exposure to immunotherapy including checkpoint inhibition, new therapies will need to be considered as it seems less likely that they will benefit from retreatment with checkpoint inhibition. Alternatively clinical trials which specifically evaluate the utility for immunotherapy following immunotherapy may be pursued. Despite these encouraging clinical trial data, continued focus on both financial as well as the feasibility of prolonged maintenance periods are warranted.

Following immunotherapy use, either in combination with chemoradiation or with chemotherapy alone, tisotumab vedotin would generally be considered and favored based on clinical trial data as the preferred second-line therapy. Ongoing clinical trial evaluations (NCT 03786081) with various agents in combination with tisotumab vedotin may identify either novel options for use in the recurrent setting, or perhaps identify options for investigation in earlier lines. Unfortunately, traditional chemotherapies other than those used with immunotherapy seem to offer patients little benefit for recurrent cervical cancer. Accordingly, while early results with trastuzumab deruxtecan are encouraging, the lack of widespread overexpression of HER2 will limit its applicability in managing cervical cancer patients. Identification of other antigenic targets for which active therapies exist may allow other therapeutic options for patients.

In conclusion, while increased and predicted widespread use of immunotherapy, either in combination with chemoradiation for those with LACC or in combination with chemotherapy for recurrent or metastatic disease, will likely improve outcomes, recurrence following these therapies will still occur. As clinical trials with immunotherapy were performed in an era where patients had not been exposed to various immunotherapeutics, understanding resistance mechanisms as well as determining if novel strategies for effective retreatment are warranted. Additional ongoing investigations outlined above may identify other options for patients when currently approved therapies have been unsuccessful. Importantly, as cervical cancer is most common in under resourced individuals a continued focus on prevention is paramount, although following cancer development easing access to these therapies remains critical.

Article highlights.

1. Immunotherapy in combination with chemotherapy, with or without bevacizumab, improves outcomes including overall survival for patients with recurrent, persistent or metastatic cervical cancer based on two randomized controlled trials.

2. Pembrolizumab combined with chemoradiation for those with locally advanced cervical cancer has improved progression-free survival compared to chemoradiation alone.

3. While tisotumab vedotin and trastuzumab deruxtecan are active therapies, only a small proportion of patients receive a clinical benefit.

4. Development of new therapies following recurrence or progression of immunotherapy are desperately needed.

5. Novel combinations including agents discussed is an opportunity to improve outcomes further.

Abbreviations:

CPS

Combined positive score

CR

Complete response

CRT

Chemoradiation

HPV

Human papillomavirus

ICI

Immune checkpoint inhibitors

irAEs

Immune-related adverse events

LACC

Locally advanced cervical cancer

mDOR

Median duration of response

mOS

Median overall survival

mPFS

Median progression free survival

ORR

Overall response rate

OS

Overall survival

PD-L1

Programmed death-ligand 1

PFS

Progression free survival

PR

Partial response

SD

Stable disease