A large international phase 3 clinical trial has found that adding the immunotherapy drug pembrolizumab to standard chemoradiotherapy significantly improves overall survival in patients with high-risk, locally advanced cervical cancer. The randomized, double-blind, placebo-controlled ENGOT-cx11/GOG-3047/KEYNOTE-A18 study was conducted at 176 sites across 30 countries in Asia, Australia, Europe, North America, and South America. Funded by Merck Sharp & Dohme (a subsidiary of Merck & Co.), the study results were published in The Lancet on September 14, 2024.
The primary purpose of the study was to evaluate whether pembrolizumab, when administered concurrently with and after chemoradiotherapy, would improve outcomes compared to chemoradiotherapy alone in patients with newly diagnosed, high-risk, locally advanced cervical cancer. This population has historically had poor outcomes despite treatment with curative intent, with 5-year progression-free and overall survival rates ranging from 47% to 80%.
The study enrolled 1060 patients between June 9, 2020 and December 15, 2022. To be eligible, patients had to be 18 years or older with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients were required to have an Eastern Cooperative Oncology Group performance status score of 0 or 1, evaluable disease per RECIST v1.1 criteria, and adequate organ function. Key exclusion criteria included other cervical cancer subtypes, FIGO 2014 stage IVB disease, previous hysterectomy, and prior systemic therapy, immunotherapy, definitive surgery, or radiation.
The demographic and baseline characteristics were well-balanced between the two treatment arms. The median age was 49-50 years, with 11-15% of patients aged 65 or older. Approximately half of patients were White and around 30% were Asian. The majority (82-85%) had squamous cell histology. At screening, 57% of patients had FIGO 2014 stage III-IVA disease, and 83% had lymph node involvement. Over 90% of tumors were PD-L1 positive (combined positive score ≥1).
Patients were randomized 1:1 to receive either pembrolizumab or placebo in combination with standard chemoradiotherapy. The pembrolizumab/placebo regimen consisted of 5 cycles given every 3 weeks during chemoradiotherapy, followed by 15 cycles given every 6 weeks as maintenance therapy. Chemoradiotherapy included weekly cisplatin for 5-6 cycles plus external beam radiotherapy followed by brachytherapy. Importantly, radiotherapy quality was evaluated centrally before study initiation and for each patient's treatment plan throughout the study.
At the protocol-specified second interim analysis (data cutoff January 8, 2024), with a median follow-up of 29.9 months, the study met its primary endpoint of overall survival. The addition of pembrolizumab to chemoradiotherapy significantly reduced the risk of death by 33% compared to placebo plus chemoradiotherapy (hazard ratio 0.67, 95% CI 0.50-0.90, p=0.0040). While median overall survival was not reached in either group, the estimated 36-month overall survival rate was 82.6% in the pembrolizumab group versus 74.8% in the placebo group.
The overall survival benefit was generally consistent across most pre-specified subgroups, with hazard ratios favoring pembrolizumab. However, the benefit appeared less pronounced in patients aged 65 or older and those with PD-L1 negative tumors, though these subgroups had small sample sizes. As expected, patients with more advanced stage disease (FIGO III-IVA) derived greater benefit than those with earlier stage disease (IB2-IIB).
The progression-free survival results, which were positive at the first interim analysis, continued to show improvement with pembrolizumab at this later analysis. The risk of disease progression or death was reduced by 32% in the pembrolizumab group (HR 0.68, 95% CI 0.56-0.84). Objective response rates were high in both arms but modestly higher with pembrolizumab (87% vs 84%).
The safety profile was consistent with previous reports and the known toxicities of the individual therapies. Treatment-related adverse events of grade 3 or higher occurred in 69% of pembrolizumab-treated patients versus 61% of placebo-treated patients. The most common high-grade adverse events in both arms were hematologic toxicities. As expected with immunotherapy, immune-mediated adverse events were more frequent with pembrolizumab (39% vs 17%), though most were low grade. Importantly, the addition of pembrolizumab did not appear to compromise delivery of chemoradiotherapy.
The study authors concluded that pembrolizumab combined with chemoradiotherapy provides statistically significant and clinically meaningful improvements in overall survival compared to chemoradiotherapy alone in patients with newly diagnosed, high-risk, locally advanced cervical cancer. They stated that these findings, together with the previously reported progression-free survival benefit, support this regimen as a new standard of care for this patient population.
This trial has several notable strengths, including its large sample size, international scope, high-quality radiotherapy delivery, and rigorous design as a randomized, double-blind, placebo-controlled study. However, there are some limitations to consider. The use of FIGO 2014 staging (rather than the current 2018 system) may affect immediate identification of eligible patients in clinical practice. Additionally, subgroup analyses should be interpreted cautiously due to small sample sizes in some subgroups and the potential for multiple comparisons. Longer follow-up will be needed to determine the durability of benefit, particularly for earlier-stage patients.
The potential clinical impact of these results is substantial. This is the first phase 3 study to demonstrate a significant overall survival improvement by adding immunotherapy to modern, high-quality chemoradiotherapy in newly diagnosed, locally advanced cervical cancer. If widely adopted, this approach could meaningfully improve outcomes for many patients with this disease. However, implementation may face some practical challenges, including the additional cost of immunotherapy and the need for careful patient selection and monitoring for immune-related toxicities.
Several ongoing questions may influence the broader adoption of this regimen. Further research is needed to identify biomarkers beyond PD-L1 expression that may predict which patients are most likely to benefit. The optimal duration of pembrolizumab maintenance therapy also remains to be determined. Additionally, it will be important to assess how this regimen compares to or might be integrated with other emerging approaches, such as the use of induction chemotherapy prior to chemoradiation.
In conclusion, the ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial represents a significant advance in the treatment of locally advanced cervical cancer. By demonstrating a clear overall survival benefit with the addition of pembrolizumab to standard chemoradiotherapy, this study establishes a new benchmark for future research in this field. As with any practice-changing finding, careful consideration will be needed to determine how best to implement these results in diverse clinical settings and patient populations. Nonetheless, these results offer new hope for improving outcomes in a disease that has seen few major therapeutic advances in recent decades.
References
Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2024 Nov 2;404(10464):1730. doi: 10.1016/S0140-6736(24)02371-7]. Lancet. 2024;404(10460):1321-1332. doi:10.1016/S0140-6736(24)01808-7
