Pembrolizumab Combo Shows Promising Results in High-Risk Cervical Cancer
Domenica Lorusso, MD, PhD, discussed the KEYNOTE-A18 trial, its findings, and implications for oncologists.
Domenica Lorusso, MD, PhD
Updated findings from the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study (NCT04221945) show the survival advantages of combining pembrolizumab (Keytruda) with chemoradiotherapy or administering pembrolizumab as monotherapy in patients with newly diagnosed, high-risk, locally advanced cervical cancer.
The phase 3 ENGOT-cx11 study, a randomized, double-blind, placebo-controlled trial, enrolled patients aged 18 years or older diagnosed with locally advanced cervical cancer characterized by specific high-risk histological features, including squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
To participate in the study, patients were required to have a confirmed diagnosis of locally advanced disease, assessed by FIGO 2014 staging from IB2 to IIB with node-positive involvement or stage III to IVA regardless of nodal status. Patients were also required to have an ECOG performance status of 0 or 1, measurable disease by RECIST 1.1 criteria, adequate organ function, and sufficient tissue availability for sampling.
At a median follow-up of 29.9 months (range, 12.8-43.0), significant differences in overall survival (OS) were observed between the pembrolizumab plus chemoradiotherapy group and the chemoradiotherapy-only group. The 36-month OS rate for patients receiving pembrolizumab in combination with chemoradiotherapy was 82.6% (95% CI, 78.4%-86.1%), compared with 74.8% (95% CI, 70.1%-78.8%) for those receiving chemoradiotherapy alone.
The study also noted that the median OS was not reached (NR) in either treatment arm, which was further supported by the hazard ratio (HR) of 0.67 (95% CI, 0.50-0.90), with a 1-sided P value of 0.0040, showing a statistically significant survival benefit in favor of the pembrolizumab arm. Notably, the HR for death remained below 1 across almost all prespecified subgroups.
Overall, the trial demonstrated that these regimens provided statistically significant and clinically meaningful improvements in survival when compared to chemoradiotherapy alone. These findings have important implications for managing high-risk cervical cancer, particularly in patients with treatment-naive, advanced, local disease.
In an interview with Targeted OncologyTM, Domenica Lorusso, MD, PhD, director of the Gynaecological Oncology Unit at Humanitas Hospital San Pio X, Milan, and full professor of Obstetrics and Gynaecology, Humanitas University, Rozzano, discussed the KEYNOTE-A18 trial, its findings, and implications for oncologists.
Concept of gynecologic cancer: © tom - stock.adobe.com
Targeted Oncology: Could you discuss the rationale behind the study?
Lorusso: For more than 25 years, the treatment of locally advanced cervical cancer has been represented by concurrent chemoradiation plus brachytherapy. But there were several preclinical and clinical data suggesting that when we combine immunotherapy [with] radiation treatment, radiation treatment may work as a primer and enhance the efficacy of immunotherapy. Immunotherapy does work in cervical cancer because cervical cancer is a [human papillomavirus (HPV)]-related disease. So, immunotherapy works in cervical cancer. Radiotherapy may work better in combination with immunotherapy, and that is the reason why we moved in the treatment of [patients with] locally advanced cervical cancer.
Who is the patient population in this study, and how does that reflect the broad demographic of those with this condition?
We chose the setting of locally advanced disease, and we chose to enroll patients with the locally advanced disease. We chose a 2014 classification FIGO and, in order to be enrolled in the trial, patients had to have FIGO stage IB to IIB and node positive [disease], or FIGO stage IIIA and IVA, regardless of nodal status. The incidence of locally advanced disease varies across the world and reflects the implementation of primary or secondary preventive strategies. In Europe, up to 35 patients are diagnosed with locally advanced disease, but in [areas] like Asia or Africa where there is no screening, this diagnosis involves up to 100% of patients.
What can you discuss about the methods and design of the study?
The trial was a randomized phase 3 trial. Patients were randomized 1:1 to receive concurrent chemoradiotherapy plus brachytherapy, or concurrent chemoradiotherapy radiation plus brachytherapy in combination with pembrolizumab 200 mg every 3 weeks, followed by pembrolizumab 400 mg every 6 weeks for 15 cycles, so about 2 years of maintenance treatment. The trial had 2 primary end points, progression-free and overall survival, which were analyzed in a hierarchical way.
Can you summarize the main findings from the study?
The trial met both primary end points at the first interim analysis with the 18 months median follow-up. A statistically significant and clinically meaningful increase in progression-free survival was reported, suggesting 30% reduction in the risk of progression, which has been confirmed this year with 1 year more of follow-up with a HR of 0.68. The drug confirmed the sustained benefit in PFS. But even more important, at the second interim analysis with about 30 months median follow-up, overall survival met the statistically significant criteria, with a hazard ratio of 0.67, translating to a 33% reduction in the risk of death. Seventy-five percent of patients were alive at 3 years in the placebo arm vs 83.5% of patients in the pembrolizumab arm, with the median overall survival not reached. We are happy for the overall survival advantage.
Were there any notable safety concerns associated with treatment?
We were surprised how manageable pembrolizumab is in combination with chemoradiation. There were no new safety signals. The most frequently reported toxicities were nausea, anemia, and diarrhea, but the incidence of type and severity of toxicities were similar between the 2 treatment arms. Most were grade 1 and 2, and it paints a good picture of the toxicity profile. Up to 40% of the patients treated with pembrolizumab experience immune-related adverse events. The most frequent were thyroid dysfunction. About 22% of patients experience hypothyroidism, but most of that was grade 1 or 2 and managed with hormone replacement therapy.
How does the treatment approach compare with current standards of care in the space?
The current standard of care is concurrent chemoradiation with modern chemoradiation, which is image-guided chemoradiation. That by itself, is curative in 75% of patients. We demonstrate that pembrolizumab is able to further decrease the risk of death by 33%, so we are confident in saying that this is the new standard of care.
What future trials do you think are necessary to further explore the findings from this study?
I think that we do not need further trials to explore the findings of this trial. Still, there are trials that are exploring different approaches to immunotherapy in the neoadjuvant setting or bispecific antibodies in the adjuvant setting. These are the 2 ongoing trials that will be further explored.
What are the key takeaways from the study for a community oncologist?
For the first time, we can cure a larger number of patients. We have pembrolizumab in the metastatic setting, which is good and has been reported to increase the median overall survival of about 12 months. But to live longer with cancer is not exactly to be cured by cancer, and the locally advanced setting is the only setting in which we can cure and save a larger number of patients. Pembrolizumab in this setting can cure more patients. I have no doubt that if I have to choose when to use the drug, it should be used in a curative setting.
