14 November 2018 - - The US Food and Drug Administration has approved Keytruda, US-based pharmaceutical company Merck's (NYSE: MRK) anti-PD-1 therapy, for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib, the company said.

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.

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.

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 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 as well as patients with past or ongoing hepatitis C virus 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 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.

Among the 104 patients treated, the baseline characteristics were: median age 68 years (67% age 65 or older); 83% were male; 81% were White; 14% were Asian; ECOG PS of 0 or 1 ; Child Pugh class and score were A5, A6, B7, and B8 ; 21 % were HBV seropositive and 25% HCV seropositive.

Nine patients were seropositive for both HBV and HCV. Sixty-four percent of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both, and 38% had alfa-fetoprotein levels greater than 400 ug/mL.

All patients received prior sorafenib; reasons for discontinuation were intolerance in 20 % of patients.

In KEYNOTE-224, the ORR was 17% (95% CI, 11-26), with a complete response rate of 1% and a partial response rate of 16%.

Among the responding patients, 89 % experienced a DOR for six months or longer and 56% 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.

Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST, ALT, and hyperbilirubinemia.

Keytruda is an anti-PD-1 therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry's largest immuno-oncology clinical research program. There are currently more than 850 trials studying Keytruda across a wide variety of cancers and treatment settings.

The Keytruda clinical programme seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.