Ahmed Omar Kaseb, MD, discusses the role of immunotherapy in the treatment landscape of HCC and the impact it could have in the presurgical setting.
Ahmed Omar Kaseb, MD
In a randomized phase II trial presented during the 2019 Gastrointestinal Cancers Symposium, patients with resectable hepatocellular carcinoma (HCC) were treated with either single-agent nivolumab (Opdivo) or nivolumab plus ipilimumab (Yervoy) prior to surgery. The goal of this phase II trial is to introduce immunotherapy into the presurgical setting and lower the risk of recurrence.
Patients with HCC have very limited treatment options. Those who are not candidates for surgery lack effective therapies, while patients who do undergo surgery have a high rate of recurrence with limited treatment options.
“The approach [in this trial] was designed to look into the value of presurgical treatment with immunotherapy,” said lead study author Ahmed Omar Kaseb, MD.
In an interview withTargeted Oncology,Kaseb, associate professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the role of immunotherapy in the treatment landscape of HCC and the impact it could have in the presurgical setting.
TARGETED ONCOLOGY:Can you give an overview of the current treatment landscape for HCC?
Kaseb: Currently, when it comes to HCC, all systemic therapy is considered palliative only. We don’t have any drugs approved in the neoadjuvant or adjuvant space, so therefore the majority of patients who are not surgical [candidates] really suffer from a lack of effective adjuvant therapies to downsize their tumors. Those that do make it to surgery suffer from lack of any effective drugs to lower the recurrence rates.
TARGETED ONCOLOGY:Can you discuss the rationale for this study evaluating nivolumab alone versus nivolumab plus ipilimumab?
Kaseb: In the majority of patients who have resectable disease, they still recur. About 50% to 60% of patients recur after resection. Our study was designed to address the need in this population to have more effective therapies to lower the rate of recurrence.
The study is designed in a randomized way, a 1:1 ratio. Arm A will only receive nivolumab before surgery with 3 doses every 2 weeks and surgery on week 6, then 4 weeks later, they start the adjuvant [treatment]. In the second arm, they will receive nivolumab plus ipilimumab, 1 dose of ipilimumab and 3 doses of nivolumab before surgery, followed by 4 doses of ipilimumab every 6 weeks, and nivolumab after surgery will follow as well.
TARGETED ONCOLOGY:What findings have you seen so far?
Kaseb: In terms of the immune profiling and the paired biopsy we have done thus far, I presented the interim analysis of the first 8 cases resected. We were very impressed with the fact that 3 out of the 8 patients who were analyzed and studied carefully with immune profiling were found to have pathologic complete response (CR).
We analyzed a very specific T cell population, the effector T cells and also the inhibitory T cells, the regulatory subpopulation. Our results confirm that this effect was mainly because of influx of specific populations of effector T cells and increase in the ratio between the effector cells to the inhibitory cells. Before treatment, we get a biopsy and then we get the surgical sample, and we have seen significant increase in the effector T cells and in the ratio between effector and inhibitory cells. We think that’s probably why we had this incidence of CR.
TARGETED ONCOLOGY:What are the next steps with this research?
Kaseb: It’s really exciting for our patients because in this case, there really is nothing approved, so the next step after we finish our study and do the final analysis would be to go for a larger study to validate the results. We are approaching intergroup studies, such as SWOG, to enroll a larger number of patients and validate these results.
TARGETED ONCOLOGY:How can these data impact the treatment landscape?
Kaseb: If the larger study validates the results that we are experiencing, this could really change the standard of care and introduce immunotherapy in the presurgical space, which could effectively transform the immunotherapy role in HCC from just being palliative in the advanced setting to being curative if it could really be translated into a lower recurrence rate and CR at time of surgery.
TARGETED ONCOLOGY:Is there other research you’re involved in that you would like to highlight?
Kaseb: We also have been doing similar work with paired biopsies in patients with advanced HCC who are not surgical [candidates], so combining checkpoint inhibitors with targeted therapy. One of them is pembrolizumab plus lenvatinib. Another study is combining pembrolizumab with a hepatis C drug in a hepatitis C patient population. We are trying to take this to the next level and trying to study subsets of patients with HCC because with T cell infiltration, tumor profiling is expected to be different based on the underlying risk factor on chronic liver disease. We’re excited about the hepatitis C study because it will combine the hepatitis C drug with a checkpoint inhibitor in a co-treatment of hepatitis C and HCC in the same patient population.
TARGETED ONCOLOGY:What are some of the challenges that still exist for this patient population?
Kaseb: One major challenge is the co-existing of the underlying of chronic liver disease. In HCC, we follow the breakdown of how we treat patients in clinic. Only 10% to 15% are surgical [candidates], and even if they do surgery, they recur. About 5% could be candidates for liver transplant, and the rest are non-surgical non-transplant candidates, so the majority of them would require systemic therapy at some point. When it comes to systemic therapy, it’s only palliative and doesn’t really downsize the tumors to enable surgery transplant, so that’s 1 major challenge.
The other major challenge is the underlying liver disease that poses more risk of higher incidence of side effects to the patients, so not only should the treatments be more effective, but they should be more tolerable as well. Immunotherapy carries the promise of being a double-edge sword. It carries the promise of being more effective and more tolerable as well as less toxic to the liver. That’s why we could actually start combining it with other targeted therapy agents. In patients with excellent liver condition, they could also get combination of chemotherapies or localized therapies. We are trying to take this to the next level to the community of GI medical oncologists to incorporate immunotherapy into different lines and combining it with targeted therapy, local therapy, or even chemotherapy.
TARGETED ONCOLOGY:Can you also discuss the role of molecular profiling in patients with HCC?
Kaseb: One of the other challenges when it comes to HCC is the fact that the field has been relying on imaging criteria to diagnose and treat HCC. Basically [we are] trying to avoid the biopsy in patients with underlying liver disease. However, our practice has been changing recently to allow us to obtain biopsies from patients who are not at risk for bleeding or clinical deterioration. Those with no coagulopathy and no thrombocytopenia to pose a risk of bleeding after biopsy. The field is really evolving towards necessitating a tumor biopsy to enable us to perform immune profiling and molecular profiling for our patients and understand the biology of the tumor.
The field has lagged behind other cancers when it comes to molecular profiling and immune profiling, but we see this changing now. As a community of GI medical oncologists who are trying to necessitate obtaining biopsies, not only for diagnosis but also for clinical trial entry. The importance of paired biopsies is also showing some impressive results, such as a study presented at the meeting and other studies as well. This is really going to help all of us help our patients in the end.