Cabometyx, Opdivo, Yervoy Triple Combo Shows Potential Benefits in Advanced HCC, Trial Data Show

Cabometyx, Opdivo, Yervoy Triple Combo Shows Potential Benefits in Advanced HCC, Trial Data Show

A combination of Opdivo (nivolumab) and Cabometyx (cabozantinib), with or without Yervoy (ipilimumab), induces clinically meaningful responses in people with advanced hepatocellular carcinoma (HCC) — the most common type of liver cancer — results from a Phase 1/2 trial show.

The CheckMate-040 trial (NCT01658878) assessed combinations of the immune checkpoint inhibitor Opdivo in patients with and without chronic viral hepatitis, regardless of prior treatment with standard Nexavar (sorafenib).

The findings from the Cabometyx groups were presented at the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium, held Jan. 23-25 in San Francisco. The oral presentation was titled “Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.”

HCC is the most common type of liver cancer in adults and is one of the leading causes of cancer-related deaths worldwide. Only a minority of HCCs are operable, and alternative treatment approaches often provide little survival benefit. Thus, only about 18% of patients live five years or more after their diagnosis.

The open-label, multicenter CheckMate-040 trial was sponsored by Bristol-Myers Squibb and Exelixis. It was designed to assess the safety and effectiveness of Bristol-Myers’ Opdivo in people with advanced HCC who had either never received Nexavar, were intolerant to the treatment, or had progressed while on that therapy.

Promising results from CheckMate-040 in 2017 led the U.S. Food and Drug Administration (FDA) to approve Opdivo for HCC patients who had not responded to Nexavar. Those results had shown that 14.3% of patients responded to Opdivo, and that responses were sustained for six months or longer in 91% of patients.

An additional part of the Phase 1/2 trial was designed to assess combinations of Opdivo plus Exelixis’ Cabometyx. That therapy was approved by the FDA in 2019 for people with HCC who had received prior treatment with Nexavar.

Participants in this group — a total of 71 — were assigned randomly to receive a combination of Opdivo plus Cabometyx or a triple combination of Opdivo, Cabometyx, and Yervoy. Both groups featured patients who had either been treated previously with Nexafar or who had not received that therapy.

Cabometyx is a small molecule designed to inhibit the activity of enzymes called tyrosine kinases, which are required for cell growth.

Opdivo and Yervoy — both sold by Bristol-Myers Squibb — are two immunotherapies falling under the umbrella of immune checkpoint inhibitors. They are both antibodies, each of which target different proteins involved in the processes used by cancer cells to escape the immune system. Opdivo targets the PD-L1 protein on cancer cells, and Yervoy targets the CTLA-4 protein on T-cells — immune cells with the ability to fight tumors.

The results presented at ASCO GI showed that the double combination significantly shrank tumors in 19% of patients, and that an additional 56% achieved disease stabilization, amounting to a disease control rate of 75%. These individuals lived without signs of disease worsening for a median of 5.4 months and their median overall survival was 21.5 months.

Even better results were found with the triple combo, with 29% of patients responding to treatment, and 83% achieving at least stable disease. The median time to progression or death was 6.8 months, and median overall survival had not been reached — meaning that at the time of the analysis, more than half of patients in this group were alive.

“As we just marked one year since Cabometyx was approved for the treatment of patients with advanced hepatocellular cancer who have previously received sorafenib, it’s exciting to be sharing new data featuring cabozantinib as part of a combination with immunotherapies,” Gisela Schwab, MD, president of product development and medical affairs and chief medical officer at Exelixis, said in a press release.

“The promising clinical activity observed for these cohorts in CheckMate 040 suggests combination therapy with cabozantinib and immunotherapy may potentially benefit patients with this aggressive disease,” Schwab said.

The researchers noted that patients treated with all three therapies had a higher rate of severe-to-life-threatening adverse reactions (71%) compared with those in the double-combo group (47%). These reactions included high blood pressure, diarrhea, high levels of enzymes related to protein, and fat synthesis. Adverse events led 11% and 20% of patients in each group to stop treatment.

Nevertheless, the results of the study warrant further investigations.

“Patients with advanced liver cancer need new and effective treatment options,” said Thomas Yau, MD, a professor at the University of Hong Kong and the study’s lead author.

“Cabozantinib in combination with immunotherapy offers a potentially powerful and attractive new treatment approach that warrants further study in advanced liver cancer populations,” he said.