A combination of the kinase inhibitor cabozantinib and the immunotherapy nivolumab may make curative surgery possible for some patients with liver cancer who would generally not be considered candidates for surgery, according to research published by Ho et al in Nature Cancer.
Rates of Resection
Among 15 people with hepatocellular carcinoma (HCC) in the study who could not be treated previously with surgery, treatment with the combination allowed 12 patients to undergo successful surgical removal of their cancer. Of these 12 patients, 5 had 10% or less of their tumor remaining after the drug treatment.
The combination therapy offers a much-needed treatment of HCC, which makes up more than 90% of all primary liver cancers and is the fourth-leading cause of cancer-related deaths worldwide. Fewer than 30% of HCC cases globally can be surgically resected at the time of diagnosis, either because the liver is too damaged or the cancer has spread into tissues that make surgery too difficult.
“The patients who are enrolled in this study are typically just thought of as incurable in the current conventional sense, so the fact that we saw these responses was really exciting, because this suggests this strategy could be adopted for very challenging incurable diseases,” said Won Jin Ho, MD, Assistant Professor of Oncology at the Johns Hopkins University School of Medicine and first author of the study.
HCC is unusual among solid tumors because there have been no systemic therapies used to treat the cancer to make it more amenable to surgery, said Mark Yarchoan, MD, Assistant Professor of Oncology at the Johns Hopkins University School of Medicine and senior author of the study. “We had a hunch there were patients who were currently incurable that we could get to surgery who would do well, and sure enough, there was a group of patients who participated in this study who are alive today without tumor who would not have been offered surgery before.”
Mark Yarchoan, MD
The findings also suggest that the drug combination may improve the rates of cancer recurrence after surgery. Even among patients who have successful surgeries, the rate of recurrence can be 50% or higher. In the current study, the researchers found that the five patients who underwent surgery and had their tumors shrink significantly have remained disease-free for more than 230 days so far. Four of the seven patients who did not have a significant tumor response developed disease progression between 56 and 155 days after the end of treatment.
Cabozantinib and nivolumab have been used separately and in combination to treat advanced liver cancer before. However, the researchers wanted to test their use specifically to see whether they could render more patients eligible for potentially curative surgery.
“We wanted to use a combination that reflected the standard of care,” said Dr. Yarchoan, “and this combination reflected where we feel the field is going in terms of using two drugs together to try to maximize the therapeutic effects.”
All of the patients were recruited from the Kimmel Cancer Center’s Liver and Biliary Cancer Multidisciplinary Clinic, where patients are evaluated by multiple experts in surgery, pathology, medical oncology, and other disciplines to come up with a comprehensive treatment plan. The multidisciplinary teamwork is good for patients but is also helpful in this type of study, Dr. Yarchoan added. “At other institutions where you might just see a surgeon, there isn’t an opportunity to discuss adding in medicines.”
The research team took a closer look at the immune response and tumor microenvironment in blood and tissue biopsies from patients enrolled in the study to learn more about exactly how HCC responded—or didn’t respond—to the combination treatment. Imaging mass cytometry allowed the clinicians to observe multiple types of cells at once “and really understand their relationships with one another,” said Dr. Ho.
For instance, the researchers noted that a distinct aggregation of immune B cells was indicative of a response to cabozantinib and nivolumab, supporting a strong antitumor response. The technique also helped the researchers see how the proximity of B cells and T cells to some macrophage immune cells with an immunosuppressive effect was characteristic of tumors that were resistant to the combination treatment.
Moving forward, this type of in-depth look at the tumor microenvironment may help clinicians to search for drugs that promote a B-cell response or reprogram immunosuppressive immune cells in the liver to make them more responsive to therapy, the researchers noted.
Disclosure: The work was supported by the Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, Emerson Collective Cancer Research Fund, the National Institutes of Health, Exelixis, and Bristol Myers Squibb. For full disclosures of the study authors, visit nature.com.
