FDA Approves Pembrolizumab Plus Chemoradiation for FIGO 2014 Stage III to IVA Cervical Cancer

FDA

The FDA has approved pembrolizumab (Keytruda) plus chemoradiation for patients with FIGO 2014 stage III to IVA cervical cancer.^1,2

The safety and efficacy of the approach was evaluated in the phase 3 KEYNOTE-A18 trial (NCT04221945). Data indicated that pembrolizumab paired with chemoradiation significantly improved progression-free survival (PFS) vs placebo in the overall patient population.

Data from an exploratory subgroup analysis revealed a hazard ratio (HR) of 0.59 (95% CI, 0.43-0.82) for PFS in a subset of patients with FIGO 2014 stage III to IVA disease (n = 596). Twenty-one percent of patients on the immunotherapy arm vs 31% of those on the placebo arm experienced a PFS event. The median PFS was not reached (NR) in the pembrolizumab (95% CI, NR-NR) or placebo (95% CI, 18.8-NR) arm. The 12-month PFS rates were 81% (95% CI, 75%-85%) and 70% (95% CI, 64%-76%), respectively.

In those with FIGO 2014 stage IB2 to IIB disease (n = 462), the estimated HR for PFS was 0.91 (95% CI, 0.63-1.31). According to the FDA, this indicated that the PFS improvement observed in the overall population was primarily attributable to the subset of patients with stage III to IV disease.

At the time of the PFS analysis, overall survival (OS) data were not yet mature.

About KEYNOTE-A18

The multicenter, randomized, double-blind, placebo-controlled trial enrolled patients with cervical cancer who had not previously undergone definitive surgery or received prior radiation or systemic treatment.

Participants (n = 1060) were randomly assigned 1:1 to receive 200 mg of pembrolizumab intravenously or placebo every 3 weeks for 5 cycles plus chemoradiation, followed by 400 mg of pembrolizumab or placebo every 6 weeks for a total of 15 cycles. Chemoradiation was comprised of 40 mg/m² of cisplatin weekly for 5 cycles with an optional sixth cycle plus external beam radiation therapy (EBRT) and subsequent brachytherapy.

Treatment continued until disease progression by RECIST v1.1 criteria definition and investigator assessment or intolerable toxicity.

Randomization was stratified by type of planned EBRT (intensity-modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT] vs non-IMRT and non-VMAT), disease stage (stage IB2 to IIB vs stage III to IVA), and planned total radiation dose (EBRT plus brachytherapy dose of <70 Gy vs ≥70 Gy as per equivalent dose).

The trial's major efficacy outcomes included investigator-assessed PFS by RECIST v1.1 criteria, modified to follow up to 10 target lesions and up to 5 target lesions per organ, or histopathologic confirmation, and OS.

In the subset of patients with FIGO 2014 stage III to IVA disease, the median age was 52 years (range, 22-87), with 17% of patients aged 65 years or older. Moreover, 36% of patients were White, 34% were Asian, and 1% were Black. Thirty-eight percent of patients were Hispanic or Latino.

In terms of ECOG performance status, 68% had a status of 0 and the remainder had a status of 1. The majority of patients (93%) had a PD-L1 combined positive score of 1 or higher. More than half of patients had positive pelvic and/or positive para-aortic lymph nodes and the remainder had neither. Most patients (83%) had squamous cell carcinoma histology and the remainder had nonsquamous disease. In terms of radiation, 85% had IMRT or VMAT EBRT and the median EQD2 dose was 87 Gy (range, 7-114).

Safety Data

The median duration of exposure to the immunotherapy was 12.1 months (range, 1 day to 27 months).

Serious toxicities were experienced by 30% of patients. Adverse effects (AEs) resulted in interruption or discontinuation for 43% of patients. Seven percent of patients experienced AEs that led to discontinuation. The most common AE that led to discontinuation was diarrhea. The following AEs proved to be fatal for 1.4% of patients: large intestinal perforation (n = 1), urosepsis (n = 1), sepsis (n = 1), and vaginal hemorrhage (n = 1).

In the pembrolizumab plus chemoradiation arm, the most common AEs experienced by at least 10% of patients included nausea (all grade, 56%; grade 3/4, 0%), diarrhea (50%; 3.8%), vomiting (33%; 1%), constipation (18%; 0%), abdominal pain (12%; 0.7%), urinary tract infection (32%; 4.1%), fatigue (26%; 1%), pyrexia (12%; 0.3%), hypothyroidism (20%; 0.7%), hyperthyroidism (11%; 0.3%), reduced appetite (17%; 0.7%), weight loss (17%; 1.4%), dysuria (11%; 0.3%), rash (11%; 0.7%), and pelvic pain (10%; 1%).

The most common laboratory abnormalities that worsened from baseline and occurred in at least 20% of patients in the pembrolizumab arm included lymphopenia (all grade, 99%; grade 3/4, 96%), leukopenia (96%; 46%), anemia (88%; 31%), neutropenia (75%; 32%), thrombocytopenia (65%; 8%), hypomagnesemia (59%; 4.2%), hyponatremia (54%; 3.8%), increased aspartate aminotransferase (45%; 1%), increased alanine aminotransferase (44%; 2.1%), hypocalcemia (43%; 4.8%), hypokalemia (42%; 14%), increased creatinine (41%; 6%), hypoalbuminemia (37%; 0.7%), and increased alkaline phosphatase (34%; 0.3%).

References

1. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed January 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer
2. Pembrolizumab (Keytruda). Prescribing information. Merck Sharp & Dohme LLC. Updated January 2024. Accessed January 12, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125514s147lbl.pdf