Pembrolizumab Plus Chemoradiotherapy in High-Risk Cervical Cancer: Phase 3 KEYNOTE-A18 Results

Abstract

The phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial examined the efficacy and safety of adding pembrolizumab to standard chemoradiotherapy in patients with newly diagnosed, high-risk, locally advanced cervical cancer. Pembrolizumab has demonstrated efficacy in persistent, recurrent, or metastatic cervical cancer, leading to interest in its potential benefit when combined with chemoradiotherapy. A total of 1,060 participants were randomly assigned to receive either pembrolizumab or placebo alongside chemoradiotherapy, followed by extended pembrolizumab or placebo treatment. The trial aimed to evaluate progression-free survival (PFS) and overall survival (OS) as primary endpoints. At a median follow-up of 17.9 months, progression-free survival at 24 months was notably higher in the pembrolizumab group compared to the placebo group (68% vs 57%). The hazard ratio (HR) for disease progression or death was 0.70, favoring the pembrolizumab group. Though overall survival rates at 24 months were also higher in the pembrolizumab arm (87% vs 81%), these findings did not yet reach statistical significance. The safety profile of pembrolizumab was consistent with previous studies, although higher rates of grade 3 or higher adverse events were observed in the pembrolizumab group (75% vs 69%). These findings suggest that pembrolizumab, when combined with chemoradiotherapy, may improve outcomes in patients with locally advanced cervical cancer.

Introduction

Cervical cancer remains a significant global health concern, especially in regions with limited access to screening and prevention programs. It is the fourth most common cancer among women worldwide, with approximately 600,000 new cases and over 300,000 deaths annually. Cervical cancer is often diagnosed at advanced stages, where treatment options become limited and outcomes are generally poor. While early-stage cervical cancer can often be effectively treated with surgery or radiotherapy, patients with high-risk, locally advanced cervical cancer face higher risks of recurrence and progression. The standard of care for these patients typically involves concurrent chemoradiotherapy, which combines the cytotoxic effects of chemotherapy with the localized treatment benefits of radiotherapy. However, even with this aggressive treatment, outcomes remain suboptimal, particularly in patients with high-risk disease features such as lymph node involvement or advanced tumor stage.

The advent of immunotherapy has revolutionized the treatment landscape for various cancers, including cervical cancer. Pembrolizumab, a monoclonal antibody targeting programmed death-1 (PD-1), has demonstrated significant efficacy in treating patients with advanced or metastatic cervical cancer, particularly in cases where the disease has become resistant to standard therapies. PD-1 inhibitors work by blocking immune checkpoint pathways, thereby reactivating the immune system's ability to recognize and destroy cancer cells. Based on the success of pembrolizumab in advanced cervical cancer, there is growing interest in exploring its potential benefit when combined with standard chemoradiotherapy in the treatment of locally advanced, high-risk cervical cancer.

The KEYNOTE-A18 trial (ENGOT-cx11/GOG-3047) was designed to investigate whether the addition of pembrolizumab to chemoradiotherapy could improve outcomes for patients with newly diagnosed, high-risk, locally advanced cervical cancer. This phase 3, randomized, double-blind trial aimed to evaluate the efficacy and safety of this combination, with progression-free survival and overall survival as the primary endpoints. This trial builds on the hypothesis that pembrolizumab's immunomodulatory effects could synergize with the tumor-killing capabilities of chemoradiotherapy, leading to enhanced treatment efficacy and longer-lasting remissions.

This study is particularly important in addressing the unmet clinical need for more effective therapies in high-risk cervical cancer, where the risk of recurrence remains a significant concern. By integrating immunotherapy into the standard treatment regimen for locally advanced cervical cancer, researchers aim to improve not only short-term responses but also long-term outcomes, including overall survival and quality of life.

Literature Review

Cervical Cancer Overview and Treatment Challenges

Cervical cancer has a well-documented association with human papillomavirus (HPV) infection, which is considered the primary etiological factor in the development of the disease. Despite widespread vaccination campaigns aimed at preventing HPV-related cancers, cervical cancer continues to pose a significant public health burden, particularly in low- and middle-income countries where vaccination and screening programs are less accessible. Early-stage cervical cancer is typically treated with surgery or radiotherapy, while chemoradiotherapy is the standard of care for locally advanced disease. However, despite aggressive treatment approaches, survival outcomes remain suboptimal, particularly for patients with high-risk disease features such as lymph node metastasis, advanced tumor stage, or large tumor size. Recurrence rates in high-risk cervical cancer are unacceptably high, with many patients eventually progressing to metastatic disease. For these reasons, there is an urgent need for novel therapeutic strategies that can enhance the efficacy of standard treatments and improve long-term outcomes.

The Role of Immunotherapy in Cancer Treatment

Immunotherapy has emerged as one of the most promising developments in cancer treatment over the past decade. Unlike traditional cancer therapies that directly target the tumor, immunotherapy harnesses the power of the immune system to recognize and eliminate cancer cells. Among the various immunotherapeutic approaches, immune checkpoint inhibitors have gained significant attention for their ability to block inhibitory signaling pathways that prevent the immune system from attacking tumors. Pembrolizumab, a PD-1 inhibitor, is one such checkpoint inhibitor that has demonstrated efficacy in a wide range of cancers, including melanoma, lung cancer, and cervical cancer.

In the context of cervical cancer, pembrolizumab has been studied in both recurrent and metastatic settings. The KEYNOTE-158 trial was a landmark study that led to the approval of pembrolizumab for the treatment of PD-L1-positive recurrent or metastatic cervical cancer. This trial demonstrated that pembrolizumab could induce durable responses in a subset of patients, highlighting the potential for immunotherapy to play a role in the management of cervical cancer. However, the success of pembrolizumab in advanced cervical cancer has raised questions about its potential benefit in earlier stages of the disease, particularly when used in combination with standard treatments such as chemoradiotherapy.

Combining Immunotherapy with Chemoradiotherapy

The combination of immunotherapy and chemoradiotherapy is an area of active investigation across various cancer types, including cervical cancer. Chemoradiotherapy has been the cornerstone of treatment for locally advanced cervical cancer for many years, with cisplatin-based chemotherapy serving as a radiosensitizing agent that enhances the efficacy of radiotherapy. While chemoradiotherapy has been effective in controlling local disease, it has limited ability to prevent distant metastases and recurrence. This has prompted researchers to explore whether the addition of immunotherapy could provide a more comprehensive approach to treatment by stimulating systemic immune responses that target both local and distant tumor sites.

Preclinical studies have shown that radiation therapy can modulate the tumor microenvironment in ways that make it more susceptible to immune-mediated destruction. For example, radiation can induce the release of tumor antigens, increase the expression of immune checkpoints, and promote the infiltration of immune cells into the tumor. These effects suggest that combining radiation with immunotherapy could create a more favorable environment for immune activation and enhance the overall efficacy of treatment. Similarly, chemotherapy can induce immunogenic cell death, leading to the release of tumor-associated antigens that further stimulate immune responses. By combining these modalities with immunotherapy, the goal is to maximize the therapeutic potential of each approach and improve both local control and systemic disease management.

Several clinical trials have explored the combination of checkpoint inhibitors with chemoradiotherapy in various cancers, with promising results. In head and neck cancer, for example, the combination of pembrolizumab with chemoradiotherapy has shown improved outcomes compared to chemoradiotherapy alone. These findings have provided a strong rationale for investigating similar combinations in cervical cancer, where the need for more effective treatments is particularly pressing.

The KEYNOTE-A18 Trial: Rationale and Design

The KEYNOTE-A18 trial (ENGOT-cx11/GOG-3047) was designed to evaluate the potential benefit of adding pembrolizumab to chemoradiotherapy in patients with newly diagnosed, high-risk, locally advanced cervical cancer. The trial was based on the hypothesis that pembrolizumab, by inhibiting the PD-1/PD-L1 pathway, could enhance the immune response against cervical cancer cells and improve the overall efficacy of chemoradiotherapy. The primary endpoints of the trial were progression-free survival (PFS) and overall survival (OS), with secondary endpoints including safety, tolerability, and quality of life.

Patients enrolled in the trial were randomly assigned to receive either pembrolizumab or placebo in combination with standard chemoradiotherapy, followed by maintenance pembrolizumab or placebo for up to 15 cycles. The inclusion of a maintenance phase was designed to assess whether prolonged immunotherapy could provide sustained control of the disease and reduce the risk of recurrence. The trial also included stratification by factors such as cervical cancer stage, radiotherapy modality, and planned radiation dose, allowing for a more nuanced analysis of outcomes based on these important clinical variables.

The KEYNOTE-A18 trial represents a significant step forward in the exploration of immunotherapy for locally advanced cervical cancer, building on the success of pembrolizumab in metastatic disease. By integrating pembrolizumab into the standard treatment regimen for high-risk cervical cancer, this trial aims to address the unmet need for more effective therapies that can improve long-term survival and quality of life for patients with this challenging disease.

Methodology

This randomized, double-blind, placebo-controlled phase 3 clinical trial (ENGOT-cx11/GOG-3047/KEYNOTE-A18) was conducted across 176 medical centers in 30 countries. The trial enrolled adults (age ≥18 years) with newly diagnosed, high-risk, locally advanced cervical cancer. Patients were randomized in a 1:1 ratio to receive either pembrolizumab or a placebo in combination with chemoradiotherapy.

Randomization Process

The allocation of participants was conducted using an interactive voice-response system with an integrated web-response component. The randomization process was stratified based on three key factors:

1. Type of External Beam Radiotherapy (EBRT): Participants were stratified into two groups based on whether they would receive intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT), compared to those receiving non-intensity-modulated or non-volumetric-modulated arc therapy.

2. Stage of Cervical Cancer at Screening: Using the 2014 International Federation of Gynecology and Obstetrics (FIGO) staging system, participants were classified based on the extent of the disease. Those with stage IB2-IIB node-positive cancer were separated from those with stage III-IVA cancer.

3. Planned Total Radiotherapy Dose: Stratification was also determined based on the planned total radiotherapy dose, categorized as either less than 70 Gy or equal to or greater than 70 Gy.

Treatment Regimens

Patients assigned to the experimental group received pembrolizumab in addition to chemoradiotherapy, while the control group received a placebo with chemoradiotherapy. The treatment protocol consisted of:

• 5 cycles of pembrolizumab (200 mg) or placebo administered intravenously every 3 weeks during concurrent chemoradiotherapy.

• Following chemoradiotherapy, participants in the experimental group received 15 cycles of pembrolizumab (400 mg), administered intravenously every 6 weeks, while the control group continued receiving the placebo.

Chemoradiotherapy Details

Chemoradiotherapy involved concurrent cisplatin-based chemotherapy with external beam radiation therapy followed by brachytherapy (internal radiation). The type of radiotherapy was individualized based on the stratification discussed earlier.

Endpoints

The primary endpoints were:

• Progression-Free Survival (PFS): Defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, assessed by the investigator. Disease progression could also be confirmed through histopathological evaluation.

• Overall Survival (OS): Defined as the time from randomization to death from any cause.

Secondary endpoints included safety assessments, which evaluated the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and quality of life.

Statistical Analysis

The trial utilized intention-to-treat (ITT) analysis, which included all randomized participants for efficacy evaluations. Safety analysis was conducted on the as-treated population, including patients who received at least one dose of study treatment. Hazard ratios (HRs) for progression-free survival and overall survival were calculated with 95% confidence intervals (CIs), using Kaplan-Meier estimates to illustrate survival curves.

Results

The trial enrolled a total of 1060 participants between June 9, 2020, and December 15, 2022. At the time of data cutoff on January 9, 2023, the median follow-up duration was 17.9 months. The experimental group (pembrolizumab + chemoradiotherapy) included 529 participants, while 531 were allocated to the control group (placebo + chemoradiotherapy).

Progression-Free Survival

• The median progression-free survival was not reached in either group at the time of data cutoff. However, the 24-month PFS rate was 68% in the pembrolizumab group compared to 57% in the placebo group.

• The hazard ratio for disease progression or death was 0.70 (95% CI 0.55-0.89, p=0.0020), indicating a statistically significant benefit in favor of pembrolizumab.

Overall Survival

• At the 24-month mark, overall survival rates were 87% in the pembrolizumab group versus 81% in the placebo group. However, the overall survival hazard ratio for death was 0.73 (95% CI 0.49-1.07), which did not cross the boundary of statistical significance at the time of this interim analysis.

Safety and Adverse Events

• The rates of grade 3 or higher adverse events were slightly higher in the pembrolizumab group (75%) compared to the placebo group (69%). The most common treatment-related adverse events included fatigue, anemia, and neutropenia. Immune-related adverse events such as hypothyroidism and pneumonitis were more prevalent in the pembrolizumab group but were manageable.

• Discontinuation of treatment due to adverse events occurred in 15% of participants in the pembrolizumab group and 9% in the placebo group.

Exploratory Analyses

Subgroup analyses suggested consistent efficacy across various baseline characteristics, including age, FIGO stage, and radiotherapy dose. The benefit of pembrolizumab was observed regardless of these factors, reinforcing the robustness of the primary findings.

Discussion

The ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial demonstrated that pembrolizumab, when added to standard chemoradiotherapy, significantly improves progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. The combination treatment achieved a 30% reduction in the risk of disease progression or death compared to chemoradiotherapy alone.

Mechanism of Action

Pembrolizumab, an anti-PD-1 monoclonal antibody, exerts its effects by blocking the interaction between PD-1 and its ligands (PD-L1 and PD-L2). This enhances T-cell-mediated immune responses against tumor cells. When combined with chemoradiotherapy, which can increase tumor immunogenicity, pembrolizumab further amplifies the immune system's ability to recognize and destroy cancer cells.

Comparison with Previous Studies

The results of this trial align with previous findings in persistent, recurrent, or metastatic cervical cancer, where pembrolizumab demonstrated efficacy in combination with chemotherapy. However, the current study extends these findings to earlier stages of locally advanced cervical cancer, indicating that immune checkpoint inhibition can provide benefits in high-risk, non-metastatic disease.

Tolerability and Safety

Although the addition of pembrolizumab increased the incidence of grade 3 or higher adverse events, the overall safety profile remained manageable. The increased immune-related adverse events are consistent with pembrolizumab's known mechanism of action, and the trial's safety data emphasize the importance of close monitoring and prompt management of these events.

Unmet Medical Need

Cervical cancer, particularly in its advanced stages, continues to be a significant cause of morbidity and mortality worldwide, especially in low- and middle-income countries where access to screening and early detection is limited. While chemoradiotherapy remains the standard treatment for locally advanced cervical cancer, approximately 40% of patients experience disease recurrence or progression within 3 years. The introduction of pembrolizumab offers a promising advancement in reducing recurrence rates and improving long-term outcomes in this high-risk population.

Conclusion

The addition of pembrolizumab to standard chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. While the overall survival data did not reach statistical significance at the time of the interim analysis, there is a strong trend toward improved survival outcomes, suggesting that longer follow-up may yield further benefits.

Clinical Implications

The findings of this trial support the integration of pembrolizumab into the treatment paradigm for high-risk, locally advanced cervical cancer. This combination represents a new standard of care, offering enhanced efficacy without compromising the safety profile of traditional chemoradiotherapy. The improvement in progression-free survival is particularly important, as it translates to prolonged disease control and potentially better quality of life for patients.

Future Prospects

The success of pembrolizumab in this trial opens several avenues for future research and clinical application.

Long-Term Survival and Quality of Life

Ongoing follow-up of the participants will be crucial in determining the long-term survival benefits of pembrolizumab. Additionally, future studies should assess the impact of this treatment on quality of life, particularly in reducing the psychological and physical burden of disease progression.

Biomarker-Driven Treatment Strategies

The identification of predictive biomarkers, such as PD-L1 expression or tumor mutational burden, could help optimize patient selection for pembrolizumab treatment. Future trials should focus on stratifying patients based on these biomarkers to identify subgroups that derive the most benefit from immune checkpoint inhibition.

Combination Therapies

Exploration of additional combination strategies, such as the use of pembrolizumab with other novel agents like anti-VEGF therapies or PARP inhibitors, may further enhance treatment outcomes. Preclinical data suggest potential synergistic effects between immunotherapy and these agents, and clinical trials investigating these combinations are warranted.

Global Accessibility and Implementation

Ensuring global access to pembrolizumab, particularly in low-resource settings, will be essential to maximizing its impact. Collaborative efforts between healthcare organizations, pharmaceutical companies, and governments will be necessary to address the cost and availability of this life-saving therapy in regions where cervical cancer prevalence is highest.

Research on Radiotherapy Enhancement

Given the positive interaction between pembrolizumab and radiotherapy, future research could explore optimized radiotherapy regimens, including dose escalation or novel radiation techniques, to further enhance treatment efficacy. Investigation into the immunomodulatory effects of different radiotherapy approaches may provide insights into maximizing the benefits of pembrolizumab.

Conclusion

The pembrolizumab plus chemoradiotherapy regimen marks a major advancement in the treatment of high-risk, locally advanced cervical cancer, significantly improving progression-free survival. As more data become available on overall survival and long-term outcomes, pembrolizumab may establish itself as a cornerstone of cervical cancer management. Future research should continue to explore combination therapies, biomarker-driven approaches, and efforts to ensure global access to this promising treatment.

In summary, this study's findings provide a foundation for pembrolizumab's integration into clinical practice, offering hope for improved outcomes in a disease that remains a major public health challenge worldwide.

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