More news has emerged from this week’s meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC). The group voted 8 to 0 in favor of continuing the accelerated approval for pembrolizumab in sorafenib-pretreated patients with hepatocellular carcinoma; 6 to 2 against maintaining accelerated approval of pembrolizumab for the treatment of pretreated patients with PD-L1–positive recurrent or advanced gastric or gastroesophageal junction adenocarcinoma; and 5 to 4 against continuing the indication of nivolumab as a single agent for patients with hepatocellular carcinoma who have been previously treated with sorafenib.
Pembrolizumab for Sorafenib-Pretreated Patients With Hepatocellular Carcinoma
Pembrolizumab was first granted accelerated approval in this setting in November 2018, based on results of the KEYNOTE-224 trial, a single-arm, multicenter trial enrolling 104 patients with hepatocellular carcinoma. Patients were required to have disease progression on or after sorafenib or were intolerant to sorafenib, have measurable disease, and Child-Pugh Class A liver impairment.
Twenty-one percent of the patients enrolled were hepatitis B virus (HBV)-seropositive, 25% were hepatitis C virus (HCV)-seropositive, and 9 patients (9%) were seropositive for both HBV and HCV. Patients with active autoimmune disease, more than one etiology of hepatitis, medical conditions requiring immunosuppression, or clinical evidence of ascites by physical exam were ineligible. Patients received pembrolizumab at 200 mg as an intravenous infusion every 3 week until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
The major efficacy outcome measure was confirmed overall response rate. The confirmed overall response rate was 17%, with one complete response and 17 partial responses. Response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of 6 months or longer and 56% had response durations of 12 months or longer.
KEYNOTE-240 was the confirmatory trial for the treatment in this setting, and did not meet statistical significance for increased survival; another ongoing trial in the same setting, KEYNOTE-394, should deliver results soon.
Pembrolizumab for Pretreated PD-L1-Positive Gastric Cancer
According to a report from pharmaphorum, pembrolizumab failed to show a statistically significant improvement over third-line chemotherapy in either of two confirmatory trials— KEYNOTE-061 and KEYNOTE-062—in pretreated patients with PD-L1–positive recurrent or advanced gastric or gastroesophageal junction adenocarcinoma. As noted in the report, the CheckMate-649 trial, which led to the approval of nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma earlier this month, was a key consideration in the vote.
Nivolumab for Sorafenib-Pretreated Patients With Hepatocellular Carcinoma
According to a release from Bristol Myers Squibb, approval for this indication was originally granted by the FDA in 2017 under the accelerated approval program based on tumor responses from the phase I/II CheckMate-040 trial. CheckMate-459, the original confirmatory randomized study of nivolumab vs sorafenib in the first-line setting, did not achieve statistical significance for its primary endpoint of overall survival per the prespecified analysis.
“Immunotherapy is an important next treatment option for patients who have [had disease progression] on sorafenib or were unable to tolerate it. We are disappointed with today’s outcome for patients, and we will work closely with the FDA as it completes its review,” said Ian M. Waxman, MD, Development Lead, Gastrointestinal Cancers, Bristol Myers Squibb.
Patients should consult with their health-care provider on all aspects of their care, including which treatment options may or may not be appropriate for them.
