FDA Approves Opdivo + Yervoy

This approval is based on the results from the global Phase III randomized, open-label CheckMate-9DW trial evaluating the combination of Opdivo plus Yervoy compared to investigator’s choice of tyrosine kinase inhibitor monotherapy (lenvatinib or sorafenib) in patients with unresectable or metastatic HCC who have not received prior systemic therapy. In the trial, Opdivo plus Yervoy demonstrated statistically significant overall survival (OS) and overall response rate (ORR) vs the comparator arm. It is the only trial supporting an FDA approval to show superior results against this comparator arm.

“The CheckMate-9DW approval is an important advancement for patients, considering the incidence of liver cancer has tripled in the last four decades, yet prognosis for HCC patients remains poor,” said Aiwu Ruth He, MD, PhD, a CheckMate-9DW study investigator while at MedStar Georgetown University Hospital. “The availability of a new first-line treatment option that demonstrated a deep response can offer adults with this form of liver cancer long-term overall survival and may help address an unmet need. Given the strength of evidence from the trial, especially considering the selection and performance of a strong comparator arm, I believe that Opdivo plus Yervoy has the potential to become a standard of care for the first-line treatment of patients with unresectable or metastatic HCC.”

In the CheckMate-9DW trial, in which 85% of patients in the comparator arm were treated with lenvatinib and 15% were treated with sorafenib, mOS with Opdivo plus Yervoy (n=335) was 23.7 months (95% CI: 18.8-29.4) vs. 20.6 months (95% CI: 17.5-22.5) with lenvatinib or sorafenib (n=333; HR=0.79; 95% CI: 0.65-0.96 P=0.0180), reducing the risk of death by 21%. Opdivo plus Yervoy showed an OS rate of 38% at three years vs. 24% with lenvatinib or sorafenib monotherapy. The trial also showed a deeper response with Opdivo plus Yervoy, demonstrating an ORR of 36.1% (95% CI: 31-41.5) compared to 13.2% (95% CI: 9.8-17.3; P<0.0001) of patients treated with lenvatinib or sorafenib (complete response 6.9% vs 1.8%; partial response 29.3% vs 11.4%). Longer responses were seen with Opdivo plus Yervoy with a median duration of response (mDOR) of 30.4 months (95% CI: 21.2-NR) and 12.9 months (95% CI: 10.2-31.2) with lenvatinib or sorafenib. DOR is not included in the statistical hierarchical testing and therefore is not a powered endpoint. The safety profile with Opdivo plus Yervoy is well-established and there were no new safety signals identified.

“Bringing Opdivo plus Yervoy to patients with HCC in the first-line setting is a testament to our ongoing commitment to research and delivering important progress for people living with cancer,” said Wendy Short Bartie, senior vice president of Oncology Commercialization at Bristol Myers Squibb. “Today’s approval builds on the legacy of our dual immunotherapy and the value it has brought to patients for years. We are thrilled to add this indication for this important therapy – our second approval for Opdivo plus Yervoy in the gastrointestinal space this week alone – and look forward to providing a new first-line treatment option to patients in need.”

The combination of Opdivo plus Yervoy was previously granted accelerated approval by the U.S. FDA in 2020 based on results from the Phase I/II CheckMate-040 trial and has been an established second-line treatment for patients with advanced HCC who were previously treated with sorafenib. Today’s FDA decision converts this existing indication to full approval and expands the indication into the first-line setting based on the results from the CheckMate-9DW trial.

About CheckMate-9DW
CheckMate-9DW is a Phase III randomized, open-label trial evaluating the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) compared to investigator’s choice of lenvatinib or sorafenib monotherapy in patients with unresectable or advanced hepatocellular carcinoma (HCC) who have not received prior systemic therapy. In the trial, 668 patients were randomized to receive Opdivo plus Yervoy IV infusion (Opdivo 1mg/kg with Yervoy 3mg/kg every three weeks for up to four doses, followed by Opdivo monotherapy 480mg every four weeks until disease progression, unacceptable toxicity or for a maximum duration of two years), or single agent lenvatinib (8mg orally daily, if body weight <60kg, or 12mg orally daily, if body weight ≥60kg) or sorafenib (400mg orally twice daily) in the control arm. The primary endpoint of the trial is overall survival and key secondary endpoints include objective response rate and time to symptom deterioration. The study was not designed to independently compare Opdivo plus Yervoy vs. lenvatinib or Opdivo plus Yervoy vs. sorafenib.

Select Safety Profile from CheckMate-9DW
The safety analysis in CheckMate-9DW included 657 patients, of whom 332 received Opdivo plus Yervoy. Serious adverse reactions occurred in 53% of patients treated with Opdivo plus Yervoy. The most frequent non liver-related serious adverse reactions reported in ≥2% of patients who received Opdivo with Yervoy were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%). Liver-related serious adverse reactions occurred in 17% of patients treated with Opdivo in combination with Yervoy, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in ≥1% of patients who received Opdivo in combination with Yervoy were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%). The most common adverse reactions reported in >20% of patients treated with Opdivo plus Yervoy were rash, pruritus, fatigue, and diarrhea. Fatal adverse reactions occurred in 12 (3.6%) patients who received Opdivo plus Yervoy; these included 4 (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure. Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated with Opdivo in combination with Yervoy. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), and hepatic failure (1.2%).