FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for the Treatment of Patients with Hepatocellular Carcinoma (HCC) Who Have Been Previously Treated with Sorafenib
Approval Marks 14 th Indication for KEYTRUDA
Friday, November 9, 2018 4:21 pm EST
KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease,” said Dr. Andrew X. Zhu, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School. “Today’s approval of KEYTRUDA is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or 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.
“The approval of KEYTRUDA for advanced hepatocellular carcinoma marks the second FDA approval for hepatocellular carcinoma in Merck’s oncology portfolio this year, underscoring our commitment to help bring forward new treatment options for cancers that have historically been very challenging to treat,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “We look forward to continuing to advance research for hepatocellular carcinoma across our portfolio with the goal to help even more patients affected by this type of cancer.”
Data Supporting the Approval
The approval was based on data from KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating KEYTRUDA in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib. Additional eligibility included having measurable disease and Child-Pugh class A liver impairment. Patients with active and inactive hepatitis B virus (HBV) as well as patients with past or ongoing hepatitis C virus (HCV) infection were eligible for the trial. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial.
Patients received KEYTRUDA 200 mg every three weeks until unacceptable toxicity or confirmed disease progression. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every nine weeks. The major efficacy outcome measures were objective response rate (ORR) and duration of response according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, as assessed by blinded independent central review (BICR).
Among the 104 patients treated, the baseline characteristics were: median age 68 years (67% age 65 or older); 83 percent were male; 81 percent were White; 14 percent were Asian; ECOG PS of 0 (61%) or 1 (39%); Child Pugh class and score were A5 (72%), A6 (22%), B7 (5%), and B8 (1%); 21 percent were HBV seropositive and 25% HCV seropositive. Nine patients (9%) were seropositive for both HBV and HCV. Sixty-four percent of patients had extrahepatic disease, 17 percent had vascular invasion, and 9 percent had both, and 38 percent had alfa-fetoprotein (AFP) levels greater than 400 ug/mL. All patients received prior sorafenib; reasons for discontinuation were intolerance in 20 percent of patients.
In KEYNOTE-224, the ORR was 17 percent (95% CI, 11-26), with a complete response rate of 1 percent and a partial response rate of 16 percent. Among the responding patients (n=18), 89 percent experienced a DOR for six months or longer and 56 percent experienced a DOR for 12 months or longer.
Among the 104 patients in KEYNOTE-224, the median duration of exposure to KEYTRUDA was 4.2 months (range, 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or non-small cell lung cancer, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%). 作者: StephenW 时间: 2018-11-10 22:40