Adding Keytruda (pembrolizumab) to external beam radiotherapy (EBRT) and simultaneous chemotherapy, followed by brachytherapy, lengthened the time to disease worsening or death (a statistic known as progression-free survival or PFS) in patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, according to findings from the phase 3 KEYNOTE-A18 clinical trial.
Findings from the first interim analysis of the trial, which were presented during the 2023 ESMO Congress, support adding Keytruda to chemoradiotherapy, which has been in place as standard of care (SOC) for this patient population since 1999,according to study principal investigator Dr. Domenica Lorusso.
“This is a celebration for patients because we’re challenging a treatment paradigm that has stood for more than two decades,” Dr. Bradley J. Monk, a professor in the Division of Gynecologic Oncology at the University of Arizona College of Medicine in Tucson and the medical director of the US Oncology Research Network–Gynecologic Program, noted in a discussion of Lorusso’s presentation at ESMO.
At a median follow-up 17.9 months (range, 0.9-31.0), the median PFS was not yet reached (NR) for patients in the Keytruda plus chemoradiotherapy arm (528 patients) or patients in the placebo plus chemoradiotherapy (530 patients) arm. This means that not enough patients experienced disease progression or death for the researchers to determine an average PFS. The 24-month PFS rates were 67.8% vs 57.3%, in the Keytruda-containing and placebo groups, respectively.
Data presented from protocol-specified subgroups suggested consistent benefit was observed with the addition of Keytruda to treatment; those with an ECOG performance status of 1 (indicating that they can perform all of their daily tasks with little or no assistance), aged 65 years or older and with stage 3 to4A disease at experienced the most pronounced benefit.
An increase in overall survival (OS; time from treatment until death from any cause) was reported in the Keytruda arm, however, median OS was not reported in either arm. The 24-month OS rates was 87.2% in the Keytruda arm vs 80.8% in the placebo arm.
“OS data are not yet mature referring to less than 43% of the information fraction,” Lorusso said. “But the (confidence interval) crossed the unit, and the data are not significant according to the prespecified threshold of alpha significance we defined in the protocol.”
A 95% confidence interval outlines the range by with researchers are 95% sure the true outcome lies. When the confidence intervals of two outcomes have overlapping numbers — as was seen in the OS data — researchers cannot say for certain that one outcome is truly superior than the other.
Improvements were seen regarding overall response rate (ORR; percentage of patients whose disease shrinks or disappears from treatment) in the Keytruda arm vs placebo arm as the ORR was 79.3% in the Keytruda arm, including a complete response (CR; complete disappearance of cancer) rate of 50.7% and a partial response (PR) rate of 28.6% vs 75.9% in the placebo arm, with a CR rate of 48.7% and a PR rate of 27.2%. The 12-month OS rates were 81.4% vs 77.3%, respectively.
Enrollment Criteria and Dosing
KEYNOTE-A18 enrolled patients with treatment-naïve, stage 1B2 to 2B disease that was present in the lymph nodes or stage 3 to 4A node-positive or node-negative disease according to International Federation of Gynecology and Obstetrics 2014 criteria; disease needed to be measurable per RECIST 1.1. Eligible patients were randomly assigned 1:1 to the investigative and control arms and stratified based on planned EBRT type, stage at screening and planned total radiotherapy dose.
Cisplatin was given at 40 mg/m2 once weekly for five cycles with ERBT followed by brachytherapy in both arms; for five weeks those in the investigative arm received concurrent Keytruda and those in the control arm received concurrent placebo. Keytruda or placebo was then administered every six weeks for 15 cycles.
Primary end points were PFS as well as OS and key secondary end points included 24-month PFS, ORR, patient-reported outcomes and safety. Lorusso, who is an associate professor of Obstetrics and Gynecology at the Catholic University of Rome in Italy, noted that two key protocol amendments occurred as well.
“In January 2021 we decided to change our primary end point from blinded independent central reviewed assessed PFS to investigator assessed PFS because cervical cancer is an asymptomatic tumor, and the evaluation of the clinician is always more informative than simply reviewing a CT scan,” Lorusso noted. Additionally, in November 2022 investigators changed the multiplicity strategy in the SAP.
At the Jan. 9, 2023, data cutoff, patients in the Keytruda vs control arm were continuing treatment (57.8% vs 54.9%), completed treatment (11.0% vs 10.6%) and had discontinued the trial (31.3% vs 34.5%), respectively.
In both arms, patients received a median of five cycles (range, 1-7) of cisplatin and 11 cycles (range, 1-20) of Keytruda or placebo. The median overall radiation therapy treatment time was 52 days in the Keytruda (range, 12-139) and placebo (range, 2-166) arms; the median total physical cervix dose was 76 Gy (range, 14-94) and the total cervix EQD2 dose was 87 Gy (range, 14-118) in the Keytruda arm compared with 76 Gy (range, 3-125) and 87 Gy (range, 3-207) in the placebo arm, respectively.
Manageable and Expected Safety Profile
Regarding safety, grade 3 or higher side effects occurred in 67.0% of patients in the investigative arm vs 60.6% of those in the control arm and serious treatment-related side effects were reported in 17.2% vs 12.3% of patients, respectively. Two patients in each arm died from a treatment-emergent side effects and five patients in the Keytruda arm compared with six patients in the placebo arm died from all-cause side effect. Any grade immune-mediated side effects (side effects that occur as a result of the immune system being activated) occurred in 32.6% vs 11.7% of patients and at grade 3 or higher in 4.2% vs 1.1% of patients, respectively. No immune-mediated side effects led to death in either arm
“We paid particular attention to diarrhea because there is a possible overlapping toxicity between immune colitis by pembrolizumab and the post radiotherapy enteritis, but no difference (was observed) with respect to diarrhea,” Lorusso said.
Any grade side effect in the Keytruda vs placebo arm included anemia (59.3% vs 55.1%), nausea (57.2% vs 59.4%), diarrhea (50.4% vs 51.1%), decreased white blood cell count (32.6% vs 34.2%), decreased neutrophil count (29.0% vs 27.9%), vomiting (25.0% vs 28.3%), leukopenia (23.7% vs 17.4%), decreased platelet count (22.0% vs 20.4%) and neutropenia (21.4% vs 17.4%), respectively. The most common immune-mediated side effects that occurred were hypothyroidism (19.3% vs 4.5%), hyperthyroidism (11.4% vs 2.1%), and colitis (2.7% vs 1.7%).
The EORTC Quality-of-Life Core 30 analysis revealed that there were no clinically meaningful between-group differences in changes in score from baseline to week 36 for global health status/quality of life or physical function scores.
PDUFA Date Upcoming for KEYNOTE-A18
On Sept. 20, 2023, Merck announced that the FDA accepted a supplemental Biologics License Application for priority review seeking approval of Keytruda in combination with EBRT plus concurrent chemotherapy, followed by brachytherapy for the treatment of patients with newly diagnosed high-risk locally advanced cervical cancer.
The Prescription Drug User Fee Act (PDUFA) date has been set for January 20, 2024, and the regulatory decision was supported by data from KEYNOTE-A18.
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