Pishvaian Highlights Potential Role for Immunotherapy in Frontline HCC Treatment


Michael J. Pishvaian, MD, PhD, discusses the potential for atezolizumab and bevacizumab in the frontline setting of HCC, as well the overall impact of immunotherapy in the treatment landscape of HCC.

Michael J. Pishvaian, MD, PhD

Michael J. Pishvaian, MD, PhD

In the goal of establishing new therapeutic options for patients with advanced hepatocellular carcinoma (HCC), immunotherapy has established itself as a promising option in the frontline setting, according to Michael J. Pishvaian, MD, PhD.

For example, in data presented at the 2018 ESMO Congress, the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) and the VEGF inhibitor bevacizumab (Avastin) showed durable response rates as a frontline regimen for this population. The confirmed investigator-assessed objective response rate (ORR) in the study was 32% per RECIST v1.1 criteria. More than half of responders maintained their response for at least 6 months, and about one-quarter maintained response for at least 12 months.

The atezolizumab combination was granted an FDA breakthrough therapy designation in July 2018. Additionally, nivolumab (Opdivo) and pembrolizumab (Keytruda) are being investigated in the frontline setting as well. Both PD-1 inhibitors are currently approved as single agents for the second-line treatment of patients with HCC following progression on sorafenib (Nexavar).

In an interview withTargeted Oncology, Pishvaian, a gastrointestinal oncologist and head of the Phase I Program at the Georgetown Lombardi Comprehensive Cancer Center, discussed the potential for atezolizumab and bevacizumab in the frontline setting, as well the overall impact of immunotherapy in the treatment landscape of HCC.

TARGETED ONCOLOGY:Could you provide some background on the study?

Pishvaian: We know that for metastatic and advanced HCC, there is a high unmet need and additional therapies are needed. What is looking very promising are the immunotherapies. There have been several single-agent trials that have demonstrated some promise in this disease. Based on those single-agent responses, we wanted to do a trial with atezolizumab. However, there are preclinical data to suggest that bevacizumab will enhance the immune response with atezolizumab. This trial was designed to assess the contribution of bevacizumab to atezolizumab in advanced HCC.

TARGETED ONCOLOGY:What data have been reported thus far with this combination?

Pishvaian:I do not think we were expecting to see such promising results. For the first approximately 23 patients that were presented on a poster at the 2018 ASCO Annual Meeting, the response rate was above 60%. What was more exciting was the durability of responses. The data were gathered, and additional patients were enrolled.

The data presented [at the 2018 ESMO Congress] were for 73 response-evaluable patients. While the response rate was lower, which often happens as more patients are collected, the durability of the responses has been maintained. For example, the ORR was 32%, but there were patients who had complete responses. Of the 23 patients who responded, 19 remained in response at the time of data cut-off. It [seems to be] very promising, durable responses.

TARGETED ONCOLOGY:Are there any next steps planned?

Pishvaian:The next steps are definitely in motion. For the phase Ib trial, which is actually already a multi-arm study, arm F was added, [which is] atezolizumab monotherapy to assess the contribution of atezolizumab alone. In parallel, there is an ongoing phase III study comparing atezolizumab and bevacizumab to sorafenib as first-line therapy for patients with advanced or metastatic HCC.

TARGETED ONCOLOGY:Could you elaborate on the unmet needs in HCC that immunotherapy could address?

Pishvaian:Unfortunately, HCC is one of the most common diseases worldwide, and more than 80% of patients present with advanced disease from the get-go. While we know that surgery and transplant can be curative, the reality is, many patients aren’t eligible for curative therapy. There is the need for additional therapies.

Ten years ago, we had no drugs. Then we got sorafenib, which was great—we had an improvement in survival for the first time ever in this disease. Now, we are seeing a slew of agents that are helping to extend that survival further and further. What we really need to see in advanced HCC are durable, long-term responses, where we are taking patients from the roughly 1-year survival time, all the way up to the multi-year survival time. In a lot of the immune checkpoint inhibitor trials that are ongoing, the overall survival data are not reached, which is truly exciting because it means that these patients are living longer and longer.

TARGETED ONCOLOGY:What are some of these other immunotherapy trials?

Pishvaian:There are many ongoing studies. Essentially all the agents that have been developed are being explored in HCC. There was a phase I/II study with nivolumab that led to the approval of the agent in the second-line setting. However, even in the frontline setting, there was a nice response rate. Nivolumab is being studied with other agents, including bevacizumab and other immunotherapeutics in metastatic HCC. Pembrolizumab is showing some promising data alone, and it is likely to be approved in the second-line setting. In addition, there is an ongoing pembrolizumab plus lenvatinib (Lenvima) study. Durvalumab (Imfinzi) combined with tremelimumab is being studied in advanced HCC; that is an exciting study as well.


Pishvaian MJ, Less MS, Ryoo B-Y, et al. Updated safety and clinical activity results from a phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC).Ann Oncol.2018;29(8). doi: 10.1093/annonc/mdy424.028.

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