‘Imfinzi-Imjudo combo achieves unprecedented results in liver cancer long-term survival’

At the European Society for Medical Oncology Annual Congress (ESMO 2024), held Sept. 13-17 in Barcelona, Spain, five-year survival data from the phase 3 HIMALAYA study comparing the combination of Imfinzi (durvalumab) and Imjudo (tremelimumab) to sorafenib monotherapy in patients with unresectable hepatocellular carcinoma (uHCC) was presented.

The HIMALAYA study has provided the most extended follow-up of any phase 3 liver cancer study. It was recognized for its five-year overall survival (OS) rate of 19.6 percent in the Imfinzi and Imjudo combination arm and 9.4 percent in the sorafenib arm, which is unusual for stage 4 liver cancer.

On the day of the study's presentation, Korea Biomedical Review met with the presenters, Professor Lorenza Rimassa from Humanitas University in Italy and Professor Chon Hong-jae from the Department of Hematology-Oncology at CHA University Bundang Medical Center and asked them about the clinical value of the HIMALAYA five-year OS results and the implications for liver cancer treatment in Korea.

Korea Biomedical Review: What are the implications of the five-year long-term follow-up results of the HIMALAYA study presented at ESMO 2024 in liver cancer treatment?

Professor Lorenza Rimassa: The HIMALAYA study is a phase 3 trial that demonstrated significant overall survival (OS) improvement and safety of the STRIDE regimen (single tremelimumab regular interval durvalumab) compared to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). Through this study, the STRIDE regimen has become a new first-line standard of care for HCC.

The five-year long-term follow-up results presented this time are the longest follow-up data among phase 3 trials in patients with unresectable HCC. The analysis showed that the five-year survival rate was about 20 percent for the STRIDE group while it was around 9 percent for the sorafenib group. This means that one in five patients with advanced HCC who received STRIDE as first-line treatment can now expect to survive for five years. This is unprecedented data in the field of HCC treatment and is clinically very meaningful.

Additionally, the presented analysis confirmed that the survival benefit was more pronounced in patients whose tumors shrank on STRIDE treatment. However, we also found that even patients who achieved stable disease (without significant tumor shrinkage) showed improved survival, suggesting that conventional tumor response evaluation alone cannot fully predict the long-term survival benefit of STRIDE.

It’s also significant that despite 20 patients still receiving STRIDE treatment at the time of data analysis, there were no major differences in the safety profile over the five-year follow-up compared to the primary analysis. This data not only provides unprecedented long-term survival information for advanced HCC but also shows that STRIDE maintains a consistent safety profile. It’s also notable that patients with stable disease or slight tumor reduction can still experience long-term survival benefits.

Professor Chon Hong-jae: In liver cancer, OS has been previously confirmed for up to four years, but few OS data follow up to five years. This is because it is a difficult cancer to determine survival beyond five years, with only 3 percent of patients with stage 4 liver cancer having a five-year survival rate. Nevertheless, the 20 percent survival rate in the five-year OS data is highly significant.

KBR: The five-year OS in the sorafenib arm, the control group, was also 10 percent. Wasn’t it?

Chon: I suspect that the OS data in the sorafenib arm included a lot of follow-up treatment or other immuno-oncology therapies. The biggest expectation with immuno-oncology is that patients who respond to sorafenib alone will continue to respond for a long time. I expect that quite a few patients used sorafenib in the first line and then immuno-oncology in the second or third line, and those patients would have benefited (from long-term survival).

Assessing OS is quite challenging because there are often other factors involved, including follow-up care. In many cases, excellent progression-free survival (PFS) can be achieved without satisfactory OS, such as when immuno-oncology is added, but it's good to have these data.

Rather than focusing on the 10 percent five-year OS in the sorafenib arm per se, it is important to note that the more than twofold OS difference in sorafenib treatment, even with multiple subsequent immuno-oncology therapies, suggests that the first-line benefit of the STRIDE regimen was sustained over the long term.

KBR: Previous studies have mainly examined progression-free survival (PFS). However, the HIMALAYA study has OS as the primary endpoint. We are curious about the intention.

Rimassa: In HCC treatment, the most important goal is improving survival. For patients with advanced HCC, the majority will eventually succumb to the disease, and what they truly want is to live as long as possible. This is a clinically important point, not just a scientific one.

We’ve seen in other trials that PFS improvements don’t necessarily translate into OS improvements, especially in studies involving immunotherapies. Several studies, including this one, have shown that PFS is not a suitable endpoint for combinations of immune checkpoint inhibitors in HCC, and there is no correlation between PFS and OS. Specifically, the long-term follow-up of the HIMALAYA study confirmed that PFS does not correlate with long-term survival improvements. This is likely due to the long-term activation of the immune system seen with dual immunotherapy, where the effects may not be captured by PFS, but the long-term survival benefit becomes evident over time.

In the five-year update of the HIMALAYA study, OS continues to improve gradually. The survival curve of the STRIDE regimen shows increasing benefits over time, with approximately 20 percent of patients surviving at five years. Additionally, the survival gap between the STRIDE group and the sorafenib group continues to widen over time. This is a groundbreaking result in HCC treatment, something never before demonstrated, and is likely a unique characteristic of dual immunotherapy.

KBR: Why did you choose to use the STRIDE regimen with a single, high-dose initial dose of Imjudo rather than continuing the combination of the two drugs as in other combination regimens, and what are the benefits of doing so?

Rimassa: The anti-CTLA-4 mechanism of tremelimumab is a key component of the STRIDE regimen, differentiating it from durvalumab monotherapy. STRIDE involves a one-time high-dose administration of tremelimumab, which offers important advantages.

Firstly, it reduces the burden of continuous treatment while still effectively activating the immune system. A previous phase 1b/2 study (Study 22) tested the STRIDE regimen, durvalumab monotherapy, and a standard dual immunotherapy regimen with four doses of tremelimumab (similar to ipilimumab-nivolumab combination). The study found that the STRIDE regimen showed better activation of the immune system, particularly in T-cell population changes, which were not seen with the four-dose regimen. Additionally, biomarker analyses on day 15 in the STRIDE regimen showed a higher immune activation.

Based on this scientific evidence, the HIMALAYA study selected the STRIDE regimen with high-dose tremelimumab, which demonstrated superior OS compared to sorafenib.

Chon: This initial high dose to increase the response rate is known as the priming effect. First, we need to understand how the cancer-immunity cycle works, which is the most representative in the immuno-oncology setting. After dendritic cells engulf antigens secreted by cancer cells, they present the cancer antigens as peptides on their surface to recognize T cells, activating T cells to infiltrate and kill the cancer.

Imfinzi, a PD-L1 inhibitor, is only effective when T cells are already near the cancer, resulting in a 10-15 percent response rate. To increase this response rate, a priming effect is needed to further stimulate the dendritic cells to give the T cells the signal to attack, and this is where Imjudo can play a role in the STRIDE regimen. By increasing stimulation through the administration of Imjudo, more dendritic cells will signal the T cells to attack, resulting in higher efficacy through the administration of Imfinzi. This is why dual immuno-oncology with a single high dose of Imjudo is so important.

KBR: Recently, various treatment options have been added to the first-line treatment of liver cancer. What makes the STRIDE regimen different?

Rimassa: There is no head-to-head comparison study to definitively say which drug is superior in terms of efficacy. However, in real-world clinical practice, there are several factors to consider before choosing a treatment. For example, patients with esophageal varices or a high risk of gastrointestinal bleeding may not be suitable for bevacizumab-containing therapies.

One of the biggest challenges in HCC treatment is the lack of biomarkers to guide treatment selection. Previous analyses have not been helpful either. A few years ago, there was a debate about whether patients with non-viral HCC could benefit from immunotherapy, but the HIMALAYA study and other recent studies have shown that treatment does not need to be selected based on etiology. There is also an exploratory analysis from IMbrave150 suggesting that patients with ALBI grade 2 don’t benefit from atezolizumab+bevacizumab.

Efficacy is also a complex issue. While it’s tempting to choose a drug based on median overall survival (mOS) in trials, without long-term data, this may not be the best approach.

The HIMALAYA study has provided 5-year survival data, showing that the survival rate for patients with advanced HCC, which was previously less than 5%, can now reach 20%. Specifically, 28.7% of patients with disease control (stable disease + objective responses) in the STRIDE arm were still alive at 5 years vs 12.7% in the sorafenib arm.

Ultimately, treatment decisions should be made based on the individual patient’s condition. This involves clinical judgment rather than purely scientific factors, considering comorbidities, concurrent medications, and the safety profiles of each treatment. Since each combination has a different safety profile, it’s important to factor that into the treatment decision.

Chon: There are many factors to consider when choosing a treatment option, but in liver cancer, unlike other cancers, it is important to choose an agent that can maintain liver function. In other cancers, such as breast, stomach, and colorectal cancers, we need to use highly effective drugs, including cytotoxic antitumor drugs, which are first-generation anticancer drugs, to kill the cancer. Targeted therapies and immunotherapies have recently been used, but cytotoxic antitumor drugs are still the most commonly used. However, the reason these drugs cannot be used in liver cancer is that even if the size of the cancer is reduced, the liver function is also reduced. The patient's condition will eventually deteriorate.

In a recent study of the atezolizumab-bevacizumab combination that we published with researchers from Europe and elsewhere, we found that patients whose liver function declined during treatment died sooner than patients whose cancer progressed during treatment. Liver function is important because if the cancer progresses during treatment, the risk of death increases ninefold, and if liver function declines, the risk increases twentyfold.

It is very difficult to combine stopping cancer progression with preserving liver function, but immuno-oncology is a treatment option that fits the bill. The STRIDE regimen combines two anticancer drugs, but because it is a single, high-dose dose of the CTLA-4 inhibitor Imjudo, it is not as toxic. When evaluating long-term data, there is little decline in liver function. Clinicians should take note of this point.

Even if the STRIDE and sorafenib arms of the HIMALAYA trial showed similar PFS, the options for patients with decompensated liver function will depend on whether or not they have decompensated liver function. Patients with decompensated liver function are less than 10 percent likely to receive follow-up treatment, which increases their risk of death. If the cancer is advanced, there are different options at different stages, so different follow-up treatments can be tried, but once liver function is compromised, that opportunity is lost. In this sense, STRIDE therapy has shown to be a gentler and safer treatment that can be used with very little reduction in patient liver function.

KBR: I understand that Italy reimburses STIRDE therapy.

Rimassa: Reimbursement is a common issue across many countries, including Asia area. In Italy, options such as the STRIDE regimen, atezolizumab-bevacizumab, lenvatinib, and sorafenib are available for first-line treatment of patients with HCC. However, access to subsequent treatment options is still limited.

In Korea, as I understand, STRIDE is not reimbursed, which could impose significant limitations on patient care. As I mentioned earlier, the STRIDE regimen is a highly effective treatment option, and HIMALAYA is the only phase 3 trial in unresectable HCC with five-year OS data. It’s unfortunate that despite this data, patients cannot access STRIDE therapy. If reimbursement for STRIDE were available in Korea, it would provide more treatment options for patients with HCC, improving survival rates and access to care.

Chon: The most important thing is reimbursement. Unlike surgery, which is a one-time procedure, chemotherapy needs to be continued every three to four weeks and even longer if the treatment is effective. If the salary is not paid, it is difficult for patients who cannot afford it to continue treatment.

In liver cancer, factors like the burden of the tumor itself and liver function, including the Child-pugh index, are vital considerations. In particular, patients with poor liver function are usually at risk of esophageal varices, which is a side effect of VEGF inhibitors, including bevacizumab, which increases the risk of bleeding in patients already at high risk of bleeding due to poor liver function. It is unavoidable if there is no other option, but when a new treatment option becomes available, it should be actively considered.

In this regard, the STRIDE regimen is likely to be evaluated on a similar level of significance to the atezolizumab-bevacizumab combination. Given that immuno-oncology therapies are already reimbursed, adding another treatment option should not be a problem for the government unless the financial burden is significant.