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Division of Hematology and Oncology
University of California, San Francisco
San Francisco, California
R. Kate Kelley, MD, has disclosed that she has received funds for research support paid to her institution from Adaptimmune, Agios, AstraZeneca, Bayer, Bristol-Myers Squibb, EMD Serono, Exelixis, Lilly, Merck, Novartis, Partner Therapeutics, QED, and Taiho and consulting fees from Exact Sciences, Genentech/Roche, Gilead Sciences, and Ipsen.
Chief of Hepatology
Medical Director, Liver Tumor Program
Professor, Department of Internal Medicine
UT Southwestern Medical Center
Amit G. Singal, MD, MS, has disclosed that he has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Glycotest, GRAIL, Merck, Roche/Genentech, and Wako.
In this commentary, R. Kate Kelley, MD, and Amit G. Singal, MD, MS, answer questions on the real-world use of immunotherapy for advanced HCC that were posed during a live CCO Webinar in January 2021.
Atezolizumab plus bevacizumab has become the current first-line standard of care for many patients with advanced hepatocellular carcinoma (HCC), but with additional first-line systemic therapy options expected to be approved in the near future (including durvalumab plus tremelimumab, nivolumab plus ipilimumab, pembrolizumab plus lenvatinib, and atezolizumab plus cabozantinib), how might healthcare professionals select among these different options?
R. Kate Kelley, MD: This is a timely question, as 4 ongoing phase III trials of first-line immunotherapy combinations for advanced HCC have either completed or nearly completed enrollment. Two ongoing studies are evaluating PD-1/PD-L1 inhibitors plus CTLA-4 inhibitors, with the premise that dual checkpoint inhibition can enhance the immune response in the tumor microenvironment, improve response rates, and enhance response durability. The HIMALAYA trial is assessing the combination of durvalumab (a PD-L1 inhibitor) plus tremelimumab (a CTLA-4 inhibitor) vs sorafenib. The CheckMate 9DW trial is comparing nivolumab plus ipilimumab with either sorafenib or lenvatinib. The other 2 trials, which have completed enrollment, are assessing the combination of a PD-1 or PD-L1 inhibitor with a tyrosine kinase inhibitor (TKI). In LEAP‑002, the combination of lenvatinib plus pembrolizumab is being compared with lenvatinib alone, and in COSMIC‑312, the combination of cabozantinib plus atezolizumab is being compared with sorafenib.
I don’t think it is yet clear as to how these therapies will be optimally selected. My hope is that cross-trial subgroup analyses will identify patient subpopulations that might benefit more from combining CTLA-4 inhibitors with PD-1/PD-L1 antibodies or from combining TKIs with PD-1/PD-L1 antibodies. In real-world clinical practice, despite the challenge of selecting treatment, it is truly progress to have multiple choices.
In the extended period of time before long‑term pooled analysis data or additional biomarker data become available, I will likely make choices based on the comorbidity and toxicity profiles associated with these regimens. For example, patients with baseline diabetes and/or proteinuria may not be ideal candidates for a lenvatinib‑based regimen, as proteinuria is a particular concern with this agent.
Amit G. Singal, MD, MS: We all hold out hope that, at some point, there will be a biomarker‑driven strategy to allow us to better tailor therapies for individual patients with HCC and have some degree of precision medicine as we move forward. Current biomarkers that have been assessed have unfortunately not provided positive results. Biomarkers like tumor mutational burden and MSI status are unfortunately rare in patients with HCC, and other biomarkers such as PD-L1 status have not been significantly associated with response in patients with HCC.
Can limited ablation of a single lesion < 3 cm be combined with immune checkpoint inhibition to create an abscopal effect?
Amit G. Singal, MD, MS: In general, the term abscopal effect refers to the phenomenon in which localized radiation has been observed to induce tumor shrinkage not only at the site of irradiation, but also at site of other tumors; it is thought this effect may be related to immune responses. While this is exciting, with good preclinical rationale, we are still awaiting phase III data to demonstrate that the combination of locoregional therapy with immune checkpoint inhibitors can improve downstream outcomes such as progression-free or recurrence-free survival and, most notably, overall survival.
In our current clinical practice, we do not generally combine immune checkpoint inhibition with ablation outside of a clinical trial. Dr. Kelley, how do you approach this in your clinic?
R. Kate Kelley, MD: I agree that this should only be explored in a clinical trial. That said, I have the occasional patient with extensive metastatic disease but with progression in just one site. If the bulk of tumor shows ongoing response (eg, to PD-1 inhibitor monotherapy), I have used radiation to treat a single focus. However, I consider this investigational at this point.
If a patient with advanced HCC has active coronary artery disease, would you consider an alternative to atezolizumab plus bevacizumab for first-line therapy?
R. Kate Kelley, MD: This is an important question. In my opinion, it is incumbent upon all of us to track our clinical experience and perform additional retrospective studies and pooled analyses as we increasingly use the recently approved combination of atezolizumab plus bevacizumab in the clinic. This combination was approved as first-line systemic therapy for patients with unresectable/metastatic HCC based on the phase III IMbrave150 trial, which excluded patients with an active coronary syndrome event or active arteriovenous thrombosis within 6‑12 months before enrollment. In my current practice, I generally rely on the protocol employed in the trial. So, for example, if a patient has untreated active coronary disease or an active pulmonary embolism, I would not use bevacizumab—at times, I have questioned whether an antiangiogenic TKI would be an appropriate alternative agent in this situation. In patients who have active clot burden, I will consider nivolumab, based on the data from the phase III CheckMate 459 study, but I would only consider this approach if patients are truly not eligible for other antiangiogenic therapies.
Amit G. Singal, MD, MS: This is exactly how we approach patients with coronary artery disease in our clinical practice as well.
In your opinion, does survival differ in patients with advanced HCC who have been treated with atezolizumab plus bevacizumab based on whether they develop antidrug antibodies (ADAs) or not? Do you feel ADAs are clinically relevant?
R. Kate Kelley, MD: This is a current topic of interest. The FDA label for atezolizumab states that patients in IMbrave150 who developed treatment-emergent ADAs to atezolizumab (~ 30%) had higher rates of clearance of this agent and suggested that these patients may have a shorter median OS. A caveat is that many types of ADAs exist, not all of which are neutralizing. It is unclear what percentage of the ADAs seen in IMbrave150 were neutralizing, and more data are needed to identify which patients had them. There is currently no clinical test available to monitor for these antibodies, and they cannot be predicted in advance. Currently, this finding is of academic and mechanistic interest only and is not practice changing.Your Thoughts