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The European Commission has granted an approval to pembrolizumab for the treatment of patients with select microsatellite instability–high or deficient mismatch repair solid tumors.
The European Commission has granted an approval to pembrolizumab (Keytruda) for the treatment of patients with select microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) solid tumors, representing the second approval for pembrolizumab in Europe based on MSI-H/dMMR status.1
The approval is indicated in adults with:
The approval is based on findings from the phase 2 KEYNOTE-164 (NCT02460198) and KEYNOTE-158 (NCT02628067) trials, which evaluated pembrolizumab in patients with advanced MSI-H or dMMR solid tumors.
“Our company has a strong track record of applying precision medicine, through biomarkers like MSI-H and dMMR, to help identify patients most likely to respond to [pembrolizumab] based on the genetic makeup of their individual cancer,” Scot Ebbinghaus, MD, vice president of global clinical development at Merck Research Laboratories, stated in a press release. “For patients with MSI-H/dMMR colorectal cancer, [pembrolizumab] monotherapy was approved in Europe as a first-line option in January 2021. Building on that approval, we are pleased that Keytruda is now approved for the treatment of additional MSI-H/dMMR tumors, in certain second- or later-line patients with colorectal, endometrial, gastric, small intestine or biliary cancer.”
The KEYNOTE-164 trial enrolled 124 patients with unresectable or metastatic MSI-H or dMMR CRC that progressed after prior fluoropyrimidine-based therapy plus irinotecan and/or oxaliplatin.
The KEYNOTE-158 trial enrolled 355 patients with unresectable or metastatic MSI-H or dMMR solid tumors, including endometrial, gastric, small intestine or biliary cancer. MSI or MMR tumor status was determined prospectively with polymerase chain reaction or immunohistochemistry, respectively.
In both trials, patients received 200 mg of intravenous pembrolizumab every 3 weeks until unacceptable toxicity or disease progression. Clinically stable patients with evidence of disease progression were allowed to continue treatment until confirmation of disease progression. Patients without disease progression were treated for up to 24 months.
The primary efficacy end point for the trials was objective response rate (ORR) as assessed by blinded independent central review per RECIST v1.1 criteria. Secondary efficacy end points included duration of response (DOR), progression-free survival, and overall survival.
Efficacy results from KEYNOTE-164 reflected an ORR of 34% (95% CI, 25.6%-42.9%) among patients with CRC (n = 124), including a complete response (CR) rate of 10% and a partial response (PR) rate of 24%, at a median follow-up of 37.3 months (range, 0.1-65.2). The median DOR was not reached (NR; range, 4.4-58.5+), and of responders, 92% had responses lasting at least 3 years.
In KEYNOTE-158, among patients with endometrial cancer (n = 83), the ORR was 51% (95% CI, 39.4%-61.8%), including a CR rate of 16% and a PR rate of 35%, at a median follow-up of 21.9 months (range, 1.5-64.0). The median DOR was NR (range, 2.9-60.4+). Of responders, 85% had responses lasting at least 1 year, and 60% had responses lasting at least 3 years.
Patients with gastric cancer (n = 51) experienced an ORR of 37% (95% CI, 24.1%-51.9%), including a CR rate of 14% and a PR rate of 24%, at a median follow-up of 13.9 months (range, 1.1-66.9). The median DOR was NR (range, 6.2-63.0+). Of responders, 90% had responses lasting at least 1 year, and 81% had responses lasting at least 3 years.
Patients with small intestine cancer (n = 27) achieved an ORR of 56% (95% CI, 35.3%-74.5%), including a CR rate of 15% and a PR rate of 41%, at a median follow-up of 29.1 months (range, 4.2-67.7). The median DOR was NR (range, 3.7+ - 57.3+). Of responders, 93% had responses lasting at least 1 year, and 73% had responses lasting at least 3 years.
Finally, patients with biliary cancer (n = 22) derived an ORR of 41% (95% CI, 20.7%-63.6%), including a CR rate of 14% and a PR rate of 27%, at a median follow-up of 19.4 months (range, 1.1-60.8). The median DOR was 30.6 months (range, 6.2-46.0+). Of responders, 89% had responses lasting at least 1 year, and 42% had responses lasting at least 3 years.
The safety of pembrolizumab was evaluated in 7,148 patients with advanced melanoma, resected stage III melanoma, non–small cell lung cancer, classical Hodgkin lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, colorectal cancer, endometrial, gastric, small intestine, biliary, pancreatic cancer, and renal cell carcinoma across 4 doses:
In this population, the most common adverse effects (AEs) with pembrolizumab were fatigue (31%), diarrhea (22%), and nausea (21%). Most AEs were grade 1 or 2 events. The most serious AEs were immune-related adverse reactions and severe infusion-related reactions. The incidences of all-grade and grade 3 to 5, immune-related adverse reactions in the adjuvant setting (n = 1,480) were 36.1% and 8.9%, respectively. In the metastatic setting (n = 5,375), these rates were 24.2% and 6.4%, respectively. No new immune-related adverse reactions were identified in the adjuvant setting.
“In the two studies supporting this approval, [pembrolizumab] monotherapy showed strong objective response rates and durability of response in patients with five different types of MSI-H/dMMR cancers,” Aurélien Marabelle, MD, PhD, immuno-oncologist at Gustave Roussy Cancer Center and professor of clinical immunology at the University of Paris Saclay, stated in a press release. “The EU approval of [pembrolizumab] is an important milestone for patients living with these MSI-H/dMMR cancers who have had few treatment options and face worse outcomes when diagnosed at an advanced stage.”