NOVEMBER 20, 2018
Keytruda Granted Accelerated Approval for Treatment of HCC
The FDA expanded the approved indications for pembrolizumab (Keytruda, Merck), granting the checkpoint inhibitor accelerated approval for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar, Bayer).
"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 Andrew X. Zhu, MD, PhD, the lead investigator of the KEYNOTE-224 trial, on which the approval was based. Dr. Zhu, the director of liver cancer research at Massachusetts General Hospital, in Boston, called the approval “important,” noting “it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib.”
During the single-arm, multicenter KEYNOTE-224 trial (ClinicalTrials.gov Identifier: NCT02702414), Dr. Zhu and his colleagues evaluated 104 patients with HCC who had disease progression on or after sorafenib or intolerance to sorafenib. The patients were a median age of 68 years (67% aged 65 years or older); 83% were men; 81% were white and 14% were Asian. All patients had measurable disease, ECOG Performance Status of 0 (61%) or 1 (39%), and Child-Pugh class A liver impairment: A5 (72%), A6 (22%), B7 (5%) and B8 (1%). Sixty-four percent of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both; 38% had alfa-fetoprotein levels greater than 400 mcg/mL. Twenty-one percent of the patients enrolled were hepatitis B virus (HBV)-seropositive, 25% were hepatitis C virus (HCV)-seropositive, and nine patients (9%) were seropositive for both HBV and HCV.
Exclusion criteria were active autoimmune disease, more than one etiology of hepatitis, medical conditions requiring immunosuppression, or evidence of ascites.
Patients were given 200 mg of pembrolizumab as an IV infusion every three weeks until disease progression or unacceptable toxicity, for up to 24 months. The median duration of exposure to pembrolizumab was 4.2 months (range, one day to 1.5 years).
The major efficacy outcome measures were objective response rate (ORR) and duration of response according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, 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 (ICR). The confirmed ICR-assessed ORR was 17% (95% CI, 11-26), with one complete response and 17 partial responses. Among the responding patients (n=18), response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of six months or longer, and 56% had response durations of 12 months or longer.
Adverse events (AEs) occurring in patients with HCC were similar to those described in the pembrolizumab product labeling; however, there were increased incidences of grade 3 or 4 ascites (8%) and immune-mediated hepatitis (2.9%). Grade 3 and 4 laboratory abnormalities that occurred at a higher incidence than in other pembrolizumab trials were elevated aspartate aminotransferase (20%), alanine aminotransferase (9%) and hyperbilirubinemia (10%).
The pembrolizumab prescribing information includes a warning related to immune-mediated AEs, which may be severe or fatal, that can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid-organ transplant rejection and complications of allogeneic hematopoietic cell transplantation. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate. Pembrolizumab also can cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.
View the full prescribing information for pembrolizumab.
—Clinical Oncology News Staff
Based on press releases from the FDA and Merck.作者: StephenW 时间: 2018-11-21 13:48