RAHWAY, NJ - Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemoradiotherapy (CRT) for the treatment of patients with FIGO (International Federation of Gynecology and Obstetrics) 2014 Stage III-IVA cervical cancer. The approval is based on data from the Phase 3 KEYNOTE-A18 trial, in which KEYTRUDA plus CRT demonstrated an improvement in progression-free survival (PFS), reducing the risk of disease progression or death by 41% (HR=0.59 [95% CI, 0.43-0.82]) compared to placebo plus CRT in patients with FIGO 2014 Stage III-IVA disease. Median PFS was not reached in either group. This approval marks the third indication for KEYTRUDA in cervical cancer and the 39th indication for KEYTRUDA in the U.S.
“Today’s approval of KEYTRUDA plus chemoradiotherapy is welcome news and gives patients with newly diagnosed FIGO 2014 Stage III-IVA cervical cancer, for the first time ever, the option of an anti-PD-1-based regimen to treat their cancer,” said Dr. Bradley Monk, oncologist and professor of obstetrics and gynecology at University of Arizona’s College of Medicine and Creighton University School of Medicine. “This KEYTRUDA-based regimen offers a new treatment option for these patients, so today’s approval has important implications for the way we treat them moving forward.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.
“Building on the established role of KEYTRUDA in advanced cervical cancer, KEYTRUDA plus chemoradiotherapy is now the first anti-PD-1-based regimen approved in the U.S. for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer regardless of PD-L1 expression,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “This approval provides newly diagnosed patients with an anti-PD-1-based treatment option that has the potential to reduce the risk of disease progression or death compared to chemoradiotherapy alone.”
In the U.S., KEYTRUDA has two additional approved indications in cervical cancer: in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA-approved test; and as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
Study design and additional data supporting the approval
KEYNOTE-A18, also known as ENGOT-cx11/GOG-3047, is a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT04221945) sponsored by Merck and conducted in collaboration with the European Network for Gynaecological Oncological Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) investigating KEYTRUDA in combination with CRT (cisplatin and external beam radiotherapy [EBRT] followed by brachytherapy [BT]). The trial enrolled 1,060 patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. There were 596 patients with FIGO 2014 Stage III-IVA cervical cancer (tumor involvement of the lower vagina with or without extension onto pelvic sidewall or hydronephrosis/non-functioning kidney or has spread to adjacent pelvic organs) with either node-positive or node-negative disease, and 462 patients with FIGO 2014 Stage IB2-IIB cervical cancer (tumor lesions >4 cm or clinically visible lesions that have spread beyond the uterus but have not extended onto the pelvic wall or to the lower third of vagina) with node-positive disease; two patients had FIGO 2014 Stage IVB disease. Patients were randomized (1:1) to receive either:
- KEYTRUDA (200 mg intravenously [IV]) every three weeks (Q3W) for five cycles concurrent with cisplatin (40 mg/m2 IV) weekly for five cycles (an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by KEYTRUDA (400 mg IV) every six weeks (Q6W) for 15 cycles;
- Placebo IV Q3W for five cycles concurrent with cisplatin (40 mg/m2 IV) weekly for five cycles (an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by placebo IV Q6W for 15 cycles.
Treatment continued until RECIST v.1.1-defined progression of disease as determined by investigator or unacceptable toxicity. Assessment of tumor status was performed every 12 weeks from completion of CRT for the first two years, followed by every 24 weeks in year three, and then annually. The major efficacy outcome measures were PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, or histopathologic confirmation, and overall survival (OS).
The trial demonstrated a statistically significant improvement in PFS in the overall population. In an exploratory subgroup analysis for the 462 patients (44%) with FIGO 2014 Stage IB2-IIB disease, the PFS HR estimate was 0.91 (95% CI, 0.63-1.31), indicating that the PFS improvement in the overall population was primarily attributed to the results seen in the subgroup of patients with FIGO 2014 Stage III-IVA disease. Overall survival data were not mature at the time of PFS analysis, with 10% deaths in the overall population.
In the exploratory subgroup analysis of 596 patients with FIGO 2014 Stage III-IVA disease, 61 patients (21%) in the KEYTRUDA plus CRT arm (n=293) experienced a PFS event versus 94 patients (31%) in the placebo plus CRT arm (n=303). Median PFS was not reached in either arm. The 12-month PFS rate was 81% (95% CI, 75-85) for KEYTRUDA plus CRT versus 70% (95% CI, 64-76) for placebo plus CRT.
The median duration of exposure to KEYTRUDA was 12.1 months (range, 1 day to 27 months). Fatal adverse reactions occurred in 1.4% of 292 patients receiving KEYTRUDA in combination with chemoradiotherapy, including one case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with CRT. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with CRT. Serious adverse reactions occurring in ≥1% of patients included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were anemia (8%), COVID-19 (6%), SARS-CoV-2 test positive (3.1%), decreased neutrophil count (2.7%), diarrhea (2.7%), urinary tract infection (2.7%), and increased alanine aminotransferase (2.4%). The most common adverse reactions (≥10%) among patients receiving KEYTRUDA were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria and rash (11% each), and pelvic pain (10%).
