At the beginning of 2017, patients with inoperable hepatocellular carcinoma (HCC), or liver cancer, were hungry for novel treatments: It had been a decade since the targeted drug Nexavar (sorafenib) was approved by the Food and Drug Administration (FDA). By the end of the year, the oncologists’ toolbox contained two more medications that could be used after Nexavar in case of disease progression — the targeted treatment Stivarga (regorafenib) and the immunotherapy Opdivo (nivolumab).
Now, additional targeted drugs and immunotherapies are moving through the pipeline, along with a virus designed to infect and kill liver cancer cells but spare surrounding healthy cells.
“This has been an incredible year and positive time regarding our therapies for (patients with) liver cancer,” says Ghassan K. Abou-Alfa, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. “We have been trying for the past 10 years to see how we can improve on the outcome of sorafenib by trying different things — going into combination therapies or even looking at second-line therapy. Many great efforts have been done, and, unfortunately, all of them have been negative. However, this year has been quite impressive.”
Nexavar was “the first systemic therapy with a survival benefit for HCC,” according to Amit G. Singal, M.D., associate professor of internal medicine and medical director of the Parkland Liver Tumor Program at University of Texas Southwestern Medical Center in Dallas. The drug is known as a tyrosine kinase inhibitor (TKI) because it works by targeting and disabling specific cancer- driving proteins, or kinases.
In April 2017, the FDA approved another TKI, Stivarga (regorafenib), because it was shown to improve survival compared with placebo after prior exposure to Nexavar, Abou-Alfa says. In a phase 3 trial, median overall survival was 10.6 months with Stivarga plus best supportive care compared with 7.8 months for placebo plus best supportive care. Stivarga, which disables proteins that help grow the blood vessels that feed tumors, is meant to be used after Nexavar if disease progression occurs.
In the trial that led to the approval, the most common serious or severe side effects associated with Stivarga were hypertension, hand-foot skin reaction, fatigue and diarrhea. Other common side effects included pain, decreased appetite, infection, dysphonia (a voice control problem), elevated bilirubin (which can indicate a liver problem), fever, mucositis (ulceration of the lining of the digestive tract), weight loss, rash and nausea.
A different class of drug was approved in September 2017. Opdivo is an immunotherapy known as a checkpoint inhibitor because it targets a protein that would normally keep the immune system in check; this frees up the immune system to fight harder against cancer.
In a phase 2 trial, 15 percent to 20 percent of patients with liver cancer responded to Opdivo, leading to its FDA approval in the second-line setting, meaning it should be used after initial treatment with a medication such as Nexavar, if needed. That second-line designation could change, however, when results of a large phase 3 trial, Checkmate-459, come in, Abou-Alfa says; the trial is considering whether Opdivo might be more effective than Nexavar in the firstline setting.
In the phase 2 trial, the most common side effects overall with Opdivo were itchiness, fatigue, rash and diarrhea. The most common serious or severe side effects were indicators of potential liver or pancreas damage.
POISED FOR APPROVAL
Another TKI seems likely to be approved for the initial treatment of liver cancer, according to Abou-Alfa. Lenvima (lenvatinib) was compared with Nexavar in a clinical trial, and no meaningful difference in survival outcomes was found, he says.
In June 2017, the results of a phase 3 trial showed that the median overall survival with Lenvima was 13.6 months compared with 12.3 months for Nexavar, numbers that are statistically considered to be on par with each other. Lenvima was more effective at prolonging progression-free survival, however, with a median 7.4 months versus 3.7 months with Nexavar.
Serious side effects were more common with Lenvima than with Nexavar (57 percent versus 49 percent, respectively). The most common serious or severe side effects with both drugs were hypertension, decreased weight, decreased platelet count, elevated aspartate aminotransferase indicating potential liver damage, decreased appetite, diarrhea and hand-foot skin reaction.
The kinase inhibitor Cabometyx (cabozantinib), an inhibitor of the protein c-MET, looks promising for secondline treatment. In the past, the experimental drug tivantinib, which also inhibits c-MET, did not prove effective when compared with placebo in c-MET-positive patients with liver cancer. But when Cabometyx was studied versus placebo in a broader group of previously treated patients — those whose liver cancers expressed mutated c-MET and those whose disease was negative for the protein — the trial brought hopeful results, Abou-Alfa says.
Those data were reported during January’s annual Gastrointestinal Cancers Symposium hosted by the American Society of Clinical Oncology. Researchers cited a median overall survival of 10.2 months with Cabometyx versus 8 months for placebo, and a median progressionfree survival of 5.2 months with Cabometyx versus 1.9 months with placebo. The overall response rate among participants was 4 percent with Cabometyx and 0.4 percent with placebo.
The most common serious or severe side effects that occurred more frequently in the Cabometyx group included hand-foot skin reaction, hypertension, signs of liver damage, fatigue and diarrhea.
FIRST LINE VERSUS SECOND LINE
If all or many of these drugs get approved, scientists and doctors will be left grappling with the question of which should be used as initial treatments and which in the second line. Abou-Alfa describes this sequencing issue as one of his biggest challenges. The answers will depend on data from ongoing clinical trials on Cabometyx, Opdivo and other drugs, he says.
If the phase 3 CheckMate-459 trial proves that Opdivo is more effective than Nexavar as a first-line treatment, and other studies also favor initial immunotherapy, patients will expect doctors to use checkpoint inhibitors as an initial treatment, pushing TKIs into the second-line setting, Abou-Alfa says, adding that there aren’t yet enough data to guess which TKIs will be used before others..
ON THE HORIZON
Other potential treatments are farther out on the horizon.
As a firstline treatment, researchers are testing a combination of the checkpoint inhibitors Imfinzi (durvalumab) and tremelimumab in the HIMALAYA study.
In the second-line setting, Keytruda (pembrolizumab), another checkpoint inhibitor, is being tested. Results released at the Gastrointestinal Cancers Symposium showed that the medication sparked a response in 16.1 percent of patients with advanced liver cancer, previously treated with Nexavar, who participated in a trial.
Six months out, of those initial responders, 43.1 percent continued to derive benefit from the drug and 77.9 percent had not experienced disease progression.
Side effects occurred in 73.1 percent of patients, with fatigue and signs of liver damage seen in more than 10 percent, and serious side effects, including one death, seen in 25 percent.
It’s not yet certain whether using immunotherapies and TKIs together will improve outcomes, but the idea is on the table, Abou-Alfa says. He is also quite hopeful about approaches to treatment that are local, rather than systemic. “I am very happy to see, and very proud that I am involved in, the effort with Pexa-Vec, which is being looked at as an intratumoral injection on top of sorafenib,” Abou-Alfa says of the oncolytic virus, designed to specifically target and kill liver cancer cells. “We’ll see that phase 3 trial soon. It is ongoing, and we will see where it’s going to take us.
“It is an impressive effort,” he continues, “but the other thing that will have a lot of potential, though we haven’t seen any data yet, will be CAR (chimeric antigen receptor)-T cell therapy.” This involves removing immune cells from patients, engineering them to recognize and kill cancer cells associated with specific proteins, and reinfusing the powerful T cells. Currently, it is thought that CAR T-cell therapies aimed at liver cancer might be most effective if they target alpha-fetoprotein, but questions remain, Abou-Alfa says.
A year from now, with more data in, Abou-Alfa expects that the scientific community will have more answers about whether Opdivo will best Nexavar in firstline treatment, as well as whether Imfinzi and tremelimumab, used together, will bring meaningful benefit. “More importantly,” he says, “we will see some efforts regarding answers about the sequencing, and I would like to see more activity from the novel components I mentioned, such as the Pexa-Vec virus or CAR T-cell therapy.”