The addition of Keytruda to external beam radiotherapy and concurrent chemotherapy, followed by brachytherapy, resulted in statistically significant and clinically meaningful improvements in progression-free survival in patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer.
Patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer experienced improvements in progression-free survival (the amount of time a patient lives without a disease spreading or worsening) due to the addition of Keytruda (pembrolizumab) to external beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy, when compared with placebo plus EBRT/chemoradiotherapy/brachytherapy, according to data from the phase 3 KEYNOTE-A18 study.
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 an associate professor of obstetrics and gynecology at the Catholic University of Rome.
“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, the median PFS was not yet reached (NR) for the 528 patients in the Keytruda plus chemoradiotherapy arm or the 530 patients in the placebo plus chemoradiotherapy arm. The 24-month PFS rates were 67.8% and 57.3%, 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 (a patient is limited in their ability to engage in strenuous activity), aged 65 years or older and with stage 3 to 4A disease at screening experienced the most pronounced benefit.
An increase in overall survival (OS) was reported in the Keytruda arm, however, median OS was NR in either arm. The 24-month OS rates was 87.2% in the Keytruda arm vs 80.8% in the placebo arm.
Improvements were seen regarding overall response rate (ORR, patients whose disease responded to treatment) in the Keytruda arm vs placebo arm as the ORR was 79.3% in the Keytruda arm, including a complete response (CR; disappearance of all signs 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.
KEYNOTE-A18 enrolled patients with treatment-naïve, stage 1B2 to 2B node-positive disease or stage 3 to 4A node-positive or node-negative disease.
Cisplatin chemotherapy was given weekly for five cycles with EBRT 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.
At the Jan. 9, 2023, data cutoff, patients in the investigative vs control arm were continuing treatment (57.8% vs 54.9%), completed treatment (11% vs 10.6%) or had discontinued the trial (31.3% vs 34.5%), respectively.
In both arms, patients received a median of five cycles of cisplatin and 11 cycles of Keytruda or placebo. The median overall radiation therapy treatment time was 52 days in the Keytruda and placebo arms; the median total physical cervix dose was 76 Gy and the total cervix EQD2 dose was 87 Gy in the Keytruda arm compared with 76 Gy and 87 Gy in the placebo arm, respectively.
Baseline characteristics were well balanced between the arms and most patients had a PD-L1 combined positive score of greater than 1 (94.9% vs 93.8%), squamous cell carcinoma (81.9% vs 84.9%) and planned to receive EBRT in the form of IMRT or VMAT (88.7% vs 88.5%) in the Keytruda vs placebo arms, respectively. Additionally, patients had an ECOG performance score of 1 (28.2% vs 25.2%), stage 1B2-2B (44.4% vs 42.7%) or stage 3-4A (55.6% vs 57.3%) disease at screening and planned to receive a total radiotherapy dose of 70 Gy or greater (91.1% vs 91.3%) or less than 70 Gy (8.9% vs 8.7%).
Lymph node involvement was positive pelvic only (61.6% vs 61.0%), positive para-aortic only (2.6% vs 1.9%), positive pelvic and para-aortic (19.8% vs 19.6%) or no positive pelvic/para-aortic (15.9% vs 17.5%) in the Keytruda vs placebo arms, respectively.
In a discussion of the trial, Monk noted that a diverse population was enrolled. “Fifty-one percent of the patients in this study were non-White, (which is) perhaps one of the highest non-White enrollments ever,” he said.
In the Keytruda vs placebo arm patients were White (48% vs 49.7%), Asian (29.3% vs 27.9%), multiple races (14.7% vs 16.2%), American Indian or Alaska Native (4.5% vs 4.1%), Black (2.6% vs 1.5%) and Native Hawaiian or other Pacific Islander (0.4% vs 0.2%), respectively.
Regarding safety, grade 3 or higher treatment-related side effects occurred in 67% of patients in the investigative arm vs 60.6% of those in the control arm and serious side effects were reported in 17.2% vs 12.3% of patients, respectively. Two patients in each arm died from side effects and five patients in the Keytruda arm compared with six patients in the placebo arm died from all-cause side effects. Any grade immune-mediated side effects 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.
Any grade side effects 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% vs 28.3%), leukopenia (23.7% vs 17.4%), decreased platelet count (22% 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%).
Merck previously announced that the Food and Drug Administration (FDA) has 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 Jan. 20, 2024 and the regulatory decision was supported by data from KEYNOTE-A18.
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