Aiwu (Ruth) He, PhD

GI Oncology Now

Aiwu (Ruth) He, PhD, MedStar Georgetown University Hospital, shares her insights on the evolving role of single-agent versus combination immunotherapy in the neoadjuvant setting for advanced hepatocellular carcinoma (HCC).She discusses the potential to downstage disease, key response data for FDA-approved regimens, and the challenges of balancing toxicity, recurrence risk, and emerging research directions.&mdash;How do you view the current role of single-agent versus combination immunotherapy in the neoadjuvant setting for patients with advanced HCC?Dr. He: Currently, there are three FDA-approved combination therapies for advanced-stage HCC. When treating patients with advanced disease, we sometimes observe significant tumor shrinkage, allowing them to undergo a potentially curative procedure such as resection. Naturally, we hope to extend that benefit to patients who have more disease than what is typically considered resectable. This raises the question of whether we should offer immunotherapy as pure neoadjuvant treatment for patients who are candidates for resection. For patients with unresectable HCC, our goal is to downstage the tumor to make resection possible. For those with resectable disease, we aim to reduce the risk of post-surgical recurrence through preoperative therapy. Currently, patients who undergo resection for HCC face a very high risk of recurrence.What does the available data tell us about the efficacy of ipilimumab/nivolumab, durvalumab/tremelimumab, and atezolizumab/bevacizumab, especially with regard to when to administer a specific combination to the patient in front of youDr. He: While we are not supposed to make cross-trial comparisons, it is difficult not to do so when reviewing the data. If the goal is neoadjuvant therapy to significantly shrink tumors in initially unresectable patients, then we want to select a regimen with a high response rate to increase the chances of converting to resectability. That said, we have observed meaningful tumor shrinkage even with regimens that did not demonstrate the highest response rates in clinical trials. In practice, significant responses have been seen with all of the approved combinations.Is it fair to say the response rates are relatively comparable between these combination options?Dr. He: The response rate for nivolumab plus ipilimumab is 36%, and for atezolizumab plus bevacizumab it is 30%, based on reported trial data. The response rate for tremelimumab and durvalumab is slightly lower. However, we have still observed significant tumor shrinkage with all of these regimens.How do you weigh the higher toxicity profile of CTLA-4&ndash;based combinations when considering the patient in front of you?Dr. He: When reviewing the trials, I focus on treatment-related adverse events, particularly serious or grade 3 and 4 events. Some combinations are associated with a slightly higher percentage of these events compared to others. However, these are not new safety signals; we have observed similar adverse events with the same regimens in other cancers. There have been no HCC-specific safety concerns with these combinations.Given our growing experience managing immune-mediated adverse events, we generally feel comfortable administering these treatments. That said, I am more cautious with elderly patients, particularly if they have comorbidities or may not communicate symptoms effectively. In those cases, I may select a regimen with a more favorable toxicity profile.For patients undergoing potentially curative treatment, how compelling is the idea of adjuvant immunotherapy or TKI in preventing recurrence? Do we have enough evidence to support either adjuvant approach yet?Dr. He: Current recurrence data are based on earlier studies of patients who underwent resection without receiving any neoadjuvant immunotherapy. According to surgical databases and published literature, the risk of recurrence can be as high as 60% to 80%, depending on the source. This is a very high risk.Over the years, we have conducted trials of adjuvant therapy to reduce this risk, including the STORM trial, which tested sorafenib and yielded negative results. More recently, the IMbrave050 trial evaluated one year of atezolizumab plus bevacizumab in this setting. While the initial results were promising, with longer follow-up the study became negative. Therefore, we still have work to do. With more available options now, we need to continue exploring this space. There remains a significant unmet need to reduce recurrence and prolong survival in these patients.Looking ahead, what most excites you from a research perspective in HCC: compelling adjuvant data, biomarker-focused trials, or something else?Dr. He: That is a challenging question. There is a great deal of ongoing research across all stages of HCC. In early-stage disease, several adjuvant trials are testing single-agent and combination therapies, including bispecific antibodies. These trials have completed enrollment, and we are awaiting the results to determine whether they meet their endpoints.In intermediate-stage disease, we are evaluating combinations of immunotherapy with locoregional treatments. Recently, two studies reported on the combination of TACE plus immunotherapy, and additional trials are investigating immunotherapy with Y-90 radioembolization. We are hopeful these will produce meaningful results.In advanced disease, we are testing multiple immune checkpoint inhibitors in the first-line setting. We are also exploring other approaches such as antibody-drug conjugates, CAR-T cells, vaccines, and precision oncology agents, primarily in second-line treatment.It is difficult to predict which strategy will ultimately prove effective. Considerable effort is also being dedicated to biomarker discovery. To date, no biomarker reliably predicts benefit from immunotherapy, except for alpha-fetoprotein in guiding the use of ramucirumab. For combination immunotherapy, we do not yet have a predictive biomarker. We are hopeful that advancements in AI will lead to meaningful discoveries in this area, but at present, it remains uncertain.

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Dr. He shares her insights on the evolving role of single-agent vs combination IO in the neoadjuvant setting for aHCC.