FDA approves Opdivo-Yervoy combination for previously treated hepatocellular carcinoma

The FDA granted accelerated approval to nivolumab plus ipilimumab for treatment of patients with hepatocellular carcinoma who previously received sorafenib.

The combination is the first dual immunotherapy approved in this setting, according to the agents’ manufacturer.

Nivolumab (Opdivo, Bristol-Myers Squibb) is an anti-PD-1 antibody. Ipilimumab (Yervoy, Bristol-Myers Squibb) is an anti-CTLA-4 antibody.

The FDA based the approval on results of the CheckMate-040 trial, a phase 1/phase 2 open-label study that included a cohort of patients with HCC who progressed on or were intolerant to sorafenib (Nexavar, Bayer).

Forty-nine patients received nivolumab dosed at 1 mg/kg via IV and ipilimumab dosed at 3 mg/kg via IV every 3 weeks for four doses, followed by nivolumab dosed at 240 mg every 2 weeks. Treatment continued until disease progression or unacceptable toxicity.

Overall response rate assessed by blinded independent review committee served as the major efficacy outcome.

After minimum follow-up of 28 months, researchers reported an ORR of 33% (95% CI, 20-48). This included four (8%) complete responses and 12 (24%) partial responses.

Duration of response ranged from 4.6 months to more than 30.5 months; 88% of responses lasted at least 6 months, 56% lasted at least 12 months and 31% lasted at least 24 months.

The most common adverse reactions included rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%) and weight loss (20%).

More than half (59%) of patients experienced serious adverse reactions, the most common of which were pyrexia, diarrhea, anemia, increased aspartate aminotransferase, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin and pneumonitis. Twenty-nine percent of patients discontinued treatment due to adverse events and 65% delayed treatment for the same reason.

“HCC is an aggressive disease in need of different treatment approaches,” trial investigator Anthony B. El-Khoueiry, MD, associate professor of clinical medicine and phase 1 program director at Keck School of Medicine of USC, said in a Bristol-Myers Squibb-issued press release. “The overall response rate observed in the Opdivo-plus-Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option.”

The FDA previously granted breakthrough therapy designation and priority review to nivolumab plus ipilimumab for this indication.

The combination also has been approved for treatment of patients with unresectable or metastatic melanoma; those with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma; and patients aged 12 years or older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer that progressed after treatment with a fluoropyrimidine, oxaliplatin and irinotecan.

Disclosure: El-Khoueiry reports a consultant role with Bristol-Myers Squibb.