December 11, 2020 - The European Medicine Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for pembrolizumab monotherapy for the frontline treatment of adult patients with metastatic microsatellite instability–high or mismatch repair deficient colorectal cancer.
The European (EU) Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for pembrolizumab (Keytruda) monotherapy for the frontline treatment of adult patients with metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).1
The decision is based on data from the pivotal phase 3 KEYNOTE-177 trial (NCT02563002), which showed that the PD-1 inhibitor induced a clinically meaningful and statistically significant improvement in progression-free survival (PFS) compared with chemotherapy in patients with MSI-H CRC.
The immunotherapy doubled the PFS compared with chemotherapy, at 16.5 months vs 8.2 months (HR, 0.60; 95% CI, 0.45-0.80; P = .0002). The PFS rates at 24 months were 48.3% with pembrolizumab vs 18.6% with chemotherapy.
“Patients in Europe with MSI-H/dMMR CRC have had only chemotherapy-containing regimens available to them in the first-line treatment setting and have historically faced poor outcomes,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “This positive EU CHMP opinion reinforces the potential of [pembrolizumab] as a new option for patients with MSI-H/dMMR CRC and illustrates our ongoing commitment to pursuing biomarker research to help address the needs of patients who have few effective options.”
The phase 3 KEYNOTE-177 trial enrolled a total of 307 patients with MSI-H stage IV CRC who were naïve to treatment, had an ECOG performance status of 0 or 1, and had measurable disease per RECIST v1.1 criteria.2 Patients were randomized 1:1 to receive either pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles or investigator’s choice of chemotherapy, which could include several options, such as: intravenous (IV) mFOLFOX6 every 2 weeks, mFOLFOX6 plus IV cetuximab every 2 weeks, IV FOLFIRI every 2 weeks, FOLFIRI plus IV bevacizumab (Avastin) every 2 weeks, or FOLFIRI plus IV cetuximab every 2 weeks.
Patients with centrally verified progressive disease via RECIST v1.1 central review, who were on the control arm, had the potential to crossover to pembrolizumab arm to receive 200 mg of the PD-1 inhibitor every 3 weeks for up to 35 cycles.
Participants received treatment until intolerable toxicity, progressive disease, or patient/physician decision to withdraw.
The co-primary end points of the trial included PFS per RECIST v1.1 criteria and blinded independent central review (BICR) and overall survival (OS). Secondary end points comprised objective response rate (ORR) per RECIST v1.1 criteria by BICR and safety. Tumor response was evaluated at week 9 of treatment and every 9 weeks thereafter in accordance with RECIST v1.1 criteria by BICR.
At the time of the presentation of the data delivered at the 2020 ASCO Virtual Scientific Program, 2 patients on the pembrolizumab (n = 153 assigned, 153 treated) were still receiving treatment and 57 had completed their course; 94 of these patients discontinued. On the chemotherapy arm (n = 154 assigned, 143 treated), 6 patients were still on treatment and 137 had discontinued.
The median age of participants across the arms was 62.3 years, 49.5% of patients were male, and 52% had an ECOG performance status of 0. Fifty-two percent of patients in the pembrolizumab arm had metachronous disease vs 48% in the chemotherapy arm. In the pembrolizumab cohort, 67% had a right-sided tumor, 30% had a left-sided tumor, and 3% had this information missing; in the chemotherapy arm, these rates were 70%, 27%, and 3%, respectively.
Twenty-two percent of patients in the pembrolizumab arm had received previous adjuvant treatment vs 24% in the chemotherapy arm; 3% vs 5%, respectively had prior neoadjuvant treatment, while 75% vs 71%, respectively, did not receive prior systemic treatment.
Additional results revealed that the ORR with pembrolizumab was 43.7% versus 33.1% with chemotherapy (P = .0275). In the pembrolizumab arm, these responses included an 11.1% complete response (CR) rate and a 32.7% partial response (PR) rate; 20.9% of patients achieved stable disease, with a disease control rate (DCR) of 64.7%. Forty-five patients experienced disease progression.
In the chemotherapy arm, ORR was comprised of a 3.9% CR rate and a 29.2% PR rate, with 42.2% of patients achieving stable disease; the DCR was 75.3% and 12.3% of patients experienced disease progression.
The median duration of response (DOR) had not yet been reached with pembrolizumab vs 10.6 months with chemotherapy. At 24 months, the DORs in the investigative and control arms were 83% vs 35%, respectively.
Pembrolizumab also showcased an improved toxicity profile over chemotherapy, with a lower incidence of grade 3 or higher treatment-related adverse effects (AEs), at 22% vs 66%, respectively. Grade 3 or higher AEs in the pembrolizumab arm included diarrhea (2%) and fatigue (2%); those reported in the chemotherapy arm included diarrhea (10%), fatigue (9%), nausea (2%), decreased appetite (2%), stomatitis (4%), vomiting (4%), decreased neutrophil count (17%), neutropenia (15%), and peripheral sensory neuropathy (2%).
With regard to immune-related AEs, 31% occurred in the pembrolizumab arm vs 13% in the chemotherapy arm; rates of grade 3 or higher AEs were 9% vs 2%, respectively. Grade 3 or higher effects reported in the experimental arm included colitis (3%), adrenal insufficiency (1%), hepatitis (3%), pancreatitis (1%), severe skin reactions (1%), and type 1 diabetes mellitus (1%). The only grade 3 or higher immune-related toxicities reported in the chemotherapy arm were infusion reactions (1%) and severe skin reactions (1%).
The CHMP recommendation will now be reviewed by the European Commission for marketing authorization in the EU. A final decision on the drug and indication is anticipated for the first quarter of 2021.
1. Merck receives positive EU CHMP opinion for Keytruda (pembrolizumab) as first-line treatment in adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. News release. Merck. December 11, 2020. Accessed December 11, 2020. https://bit.ly/3qKaiG6.
2. Andre T, Shiu K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(suppl 18):LBA4. doi:10.1200/JCO.2020.38.18_suppl.LBA4