Drug development for liver cancer has been slow, compared to those of other major types of cancer, such as lung cancer and breast cancer.

In liver cancer, treatment options for the second-line or higher-stage therapies have continued to expand. For the first-line treatment, however, there has been no drug that has confirmed survival improvement since the first targeted therapy sorafenib, which won approval more than 10 years ago.

However, the combination therapy using Tecentriq and Avastin obtained approval as the first-line treatment for hepatocellular carcinoma (HCC) for the first time in Korea on July 31. The licensing was based on the combo therapy's clinical results that confirmed the effect of prolonging survival and improving response rate statistically and clinically meaningfully compared to sorafenib.

Korea Biomedical Review has met with Chon Hong-jae, a professor at the Department of Hemato-Oncology at CHA University Bundang Medical Center, to learn the clinical implication of the Tecentriq plus Avastin treatment and changes in local HCC treatment strategies.

Question: Immunotherapy has entered the market as the first-line treatment for HCC. What are the limitations of the standard conventional therapy that was used before Tecentriq?

Answer: Sorafenib has been used as the first-line standard treatment for HCC for more than 10 years. The drug extended survival of HCC patients by two to three months. However, sorafenib causes a distinct side effect, called limb syndrome, and patients were afraid of it. Unfortunately, the first-line treatment of HCC has not made any progress for a long period since the sorafenib. Recently, another treatment option lenvatinib came out. It improved the response rate and reduced side effects.

However, this drug only showed non-inferiority rather than superiority. The arrival of the Tecentriq plus Avastin combo was significant because its benefits far exceeded those of existing treatments in HCC, where no drug had been available except for sorafenib for more than a decade.

Q: Can you explain the results of the IMbrave150 study that proved Tecentriq’s superiority to sorafenib?

A: The IMbrave150 study successfully achieved all pre-planned clinical goals from the beginning, although a long-term follow-up is needed. The study has yet to release long-term follow-up data for survival. Still, Tecentriq and Avastin's combo reduced the risk of death by 42 percent and the risk of disease progression and death by 41 percent, compared to the control group. The combo group’s objective response rate (ORR) was also improved to 27.3 percent, higher than that of the control group. In particular, complete remission (CR) occurred in 5.5 percent of the group treated with Tecentriq plus Avastin.

Q: So far, other immunotherapies have failed to prove their effectiveness on HCC. Why do you think the IMbrave 150 study on Tecentriq was successful?

A: Physicians could not change the standard care for HCC for 10 years because they had to consider the liver function, unlike other types of cancer. When treating gastric cancer or colon cancer, doctors do not have to consider the stomach or the colon's function. Even if drugs cause some side effects, the drugs can be regarded as successful if they treat cancer well.

However, 80-90 percent of HCC patients often progress from hepatitis B and C to liver cirrhosis, and cancer. So, an HCC treatment must satisfy two things -- suppressing cancer and maintaining the liver function simultaneously. In other words, the toxicity should be weak so that the quality of life can be maintained, and the anticancer effect should be strong. When the first immunotherapy came out, it drew high expectations. As immunotherapies caused few side effects and offered strong efficacy in other cancers, we thought they would be effective against HCC.

To measure the anticancer effect, researchers see the median value, in general. The great advantage of immunotherapies is that patients who respond to the treatment can survive for a long time. They also significantly helped patients with HCC who responded to them. If the proportion of patients with such long-term survival is large, this effect is reflected in the median value. However, in HCC, the response rate to single immunotherapy was very low at 15-20 percent. The pronounced effect in some patients was not expressed in the median. For this reason, many clinical trials of immunotherapies have had limited success.

In a trial on nivolumab in HCC patients, the response rate of nivolumab remained below 20 percent, and 40 percent of the patients had a disease progression in the first response evaluation. The most regrettable aspect of immunotherapies is that some patients benefit from the efficacy while others do not.

However, Tecentriq and Avastin's combination therapy increased the response rate to nearly 30 percent and reduced the disease progression to as low as 20 percent in the first response evaluation. Also, the clinical benefit of the treatment could be reflected in the median value. This means that all patients evenly received the therapeutic effect of the Tecentriq-Avastin combo.

Q: Recently, combined immunotherapies such as Tecentriq plus Avastin are drawing much attention. What’s your opinion on this?

A: The reason cancer cells can survive even though they are different from normal cells is that immune cells do not attack cancer cells. If there is a marker telling us that cancer cells are different from normal cells, immunotherapies can be sufficiently effective. If not, however, we need a drug that identifies cancer cells. Avastin, administered in combination with Tecentriq, also plays a role in “removing the transparent cloak.” Researchers initially thought that Avastin's function was to inhibit cancer vessels' formation, preventing cancer cells from absorbing the nutrients.

However, in the era of immunotherapies, researchers have recognized Avastin as an immunity booster. That is why the IMbrave150 study was so successful. In the same vein, anticancer viral drugs and CTLA-4 inhibitors such as ipilimumab are also expected to help the action of immune checkpoint inhibitors, like Avastin. This combination strategy is not limited to liver cancer but is tried in various cancers.

Q: In other immunotherapy studies, the survival graph of the treatment group and the control group “crosses over” in the first three months. Did that happen in the IMbrave150 research, too?

A: In the IMbrave150 trial, the survival graph of Tecentriq-Avastin combination therapy started to outpace that of sorafenib in the early stage. When observed for the last time, the combo treatment maintained the gap. Although we have to wait for long-term data, the study could be regarded as a successful one because it satisfied all the pre-planned goals.

Despite this, we want to see how the combo treatment affects patients' survival in real clinical settings. So, we need to check the combo’s effects on patients' long-term survival and what kind of side effects it can cause.

Q: Other first-line treatment options are all oral drugs, but both Tecentriq and Avastin are injections. Patients have to visit a hospital regularly and require a specialist’s observation during the treatment. Don’t you think the combo treatment offers low user convenience?

A: No, I think it’s the opposite. The Tecentriq-Avastin treatment needs a hospital visit only once every three weeks for an injection. It can be difficult for patients to have to take the medication on time every day. Existing targeted therapies require oral medications once or twice a day. Tecentriq and Avastin treatment’s administration time is a little longer at three to four hours at first, but it takes 30 minutes each from the third cycle. If a patient can spend an hour every three weeks, they don’t have to worry about the treatment in their daily lives.

Also, the combo of Tecentriq and Avastin causes far fewer side effects than conventional therapies. So, the treatment can reduce negative impacts on the quality of life. In general, chemotherapy hurts the quality of life. In the IMbrave150 study, the sorafenib-treated group started to experience the fall in the quality of life from 3.6 months, whereas the Tecentriq-Avastin group had the experience from 11.2 months. This means that the combo helped patients maintain the quality of life for nearly a year.

Q: CHA University Bundang Medical Center has gained experience in offering Tecentriq-Avastin therapy through the Expanded Access Program (EAP). Do you think domestic HCC patients show consistent results with the randomized, controlled trial (RCT) outcomes?

A: Twenty HCC patients have registered for the EAP. After approval, we prescribed additional Tecentriq-Avastin treatment for 20 patients and the results are consistent with those of the clinical trial. First of all, their response to treatment is nearly 30 percent. As I mentioned earlier, the single immunotherapy was disappointing because four to five patients out of 10 had a disease progression in the first evaluation of drug response. In the Tecentriq-Avastin group, only one or two out of 10 patients did.

Q: Despite the advantage of the combo therapy, the main issue in the first-line treatment of HCC is that there is no established second-line treatment except for sorafenib. Is there any other option as the second-line after the Tecentriq-Avastin combo?

A: It isn't easy to give you a conclusive answer, and we have to check it in real-world data. Tyrosine kinase inhibitors (TKIs) such as sorafenib can act differently even if they are angiogenesis inhibitors similar to Avastin. So, I think that their benefits are sufficient as the second-line treatment. Avastin targets vascular endothelial growth factor (VEGF), whereas conventional TKIs are multi-targeting treatments even though their main target is VEGF. This is why regorafenib works after the use of sorafenib.

The government tries to check phase-3 trial data mandatorily for secondary treatment options of HCC, but it is not desirable to limit treatment options for HCC patients. We need to create a basic “treatment sequence” for HCC patients.