Atezolizumab/Bevacizumab Lays the Groundwork for Optimal Sequencing in HCC

Milind Javle, MD

The approval of the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is a great gain for patients with advanced hepatocellular carcinoma (HCC) and one that has ushered in a wave of frontline and second-line immunotherapy trials that have the potential to modernize optimal sequencing strategies, explained Milind Javle, MD.

“The combination of durvalumab [Imfinzi] and tremelimumab is being evaluated in the first-line setting in the HIMALAYA study. That is an important trial to watch for. Other trials are evaluating other checkpoint inhibitor combinations, with PD-1/PD-L1 and CTLA-4 [agents] in the West, as well as in China,” said Javle. 

The emergence of more immunotherapy-based combinations in the frontline setting is expected to have downstream effects on second-line studies, such that future treatment options for patients with immunotherapy-refractory disease will be grounded in data in this population, rather than in sorafenib (Nexavar)-refractory populations, added Javle. 

“Second-line studies are now being conducted in patients who received first-line immunotherapy agents, where they are being combined with multitargeted TKIs or immune enhancing drugs,” said Javle. “This field is undergoing a change, and we hope that within the next 5 years, we will have more information regarding treatment for refractory disease in the second-line setting, as well as for patient selection for checkpoint inhibitors.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Javle, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, provided insight into the current treatment paradigm of advanced HCC and the potential influence ongoing research regarding biomarkers of response and novel combinations could have on the field. 

OncLive^®: To what degree have the advances that have been made with immunotherapy been successful in overcoming the unmet needs of patients with HCC? 

Javle: There have been some great developments recently in the management of HCC, both in the first-line setting of advanced disease and the second-line setting of refractory disease. However, most patients with HCC are dealing with 2 diseases. One is underlying liver disease from cirrhosis. A lot of these patients have compromised hepatic function and are not candidates for systemic therapy. The other aspect is that patients present often present with advanced disease, and they’re often not surgically resectable. These patients are candidates for systemic therapy, which has made great strides in the last 5 years, particularly with immune-oncology [IO]. 

However, it still benefits a minority of patients for a limited amount of time. There is still great unmet need in patients who have HCC and patients who have a compromised liver. There’s also great unmet need in the refractory setting in patients who received the more active IO agents [up front]. 

Could you expand on the challenges that the management of underlying liver disease and HCC presents? 

Among patients who have a compromised liver function and limited volume of disease, a small minority fit in the current transplant criteria. The Milan criteria, the University of California, San Francisco criteria, a small number of those patients can be considered for transplant. Most patients who have advanced liver disease or liver cirrhosis often present with HCC that is out of bounds for liver transplant. Most patients with Child-Pugh C and advanced HCC just get supportive care. 

These patients are not candidates for any systemic therapy but are rather managed in the palliative setting. Patients who have Child-Pugh A and have disease that is resectable or nonresectable have therapeutic options. That’s been the focus of clinical research at this time in HCC, but by doing so, we have not been able to help a large segment of the HCC population.

How have the approvals of novel agents affected the treatment paradigm? 

Sorafenib has been approved for several decades now and it has basically been the standard of care. Lenvatinib [Lenvima] has changed the situation, not necessarily for its improvement in survival, but for patients who have better tolerance and progression-free survival [PFS] with this agent. That has been the standard for the last 3 years. 

What has been remarkable has been the advent of IO in the management of HCC. In the first-line setting, the combination of atezolizumab and bevacizumab was approved earlier this year for patients with HCC with Child-Pugh A. These patients who receive this combination have an improvement in PFS, response rate, and overall survival compared with sorafenib. That has changed the treatment paradigm in the first-line setting.

On the other hand, single-agent nivolumab [Opdivo] was compared with sorafenib in the first-line setting, but did not meet the primary end point of the study. One of the reasons being that some patients in the sorafenib arm ended up getting nivolumab in the refractory setting.

In the second-line setting, we have several agents approved, such as ramucirumab [Cyramza] for patients with AFP [alpha-fetoprotein] more than 400 [ng/mL], cabozantinib [Cabometyx], and regorafenib [Stivarga]. What role they play in patients who have received prior immunotherapy is quite unclear, because these agents were approved in the sorafenib-refractory setting, not the atezolizumab/bevacizumab-refractory setting.

How do you approach sequencing in your practice?

In the first-line setting, if the patient has a clear contraindication, for instance, if they have a likelihood of gastrointestinal bleeding from esophageal varices, or there’s a risk of perforation, these patients would not receive bevacizumab. These patients would still be candidates for single-agent immunotherapy in the first-line setting. Lenvatinib is still a good option in the first-setting for patients who are not candidates for immunotherapy, such as those who have autoimmune disease or contraindications for bevacizumab.

In the second-line setting, people are using agents such as lenvatinib, which is currently approved in the first-line setting. The agent is an active, multitargeted TKI and it is fairly well tolerated, but there are other options as well, which include regorafenib, cabozantinib, and ramucirumab for those with high AFP. All [3 of] these agents could all be considered in second or subsequent lines of therapy. For those with experience in managing HCC, these agents are used sequentially and with therapeutic gain.

Does chemotherapy still have a role in HCC? 

Chemotherapy has been used for HCC, particularly in Asia. We don’t use it in our practice, and I don’t see a role for systemic chemotherapy for HCC at this time. Though, there may be a role for chemotherapy in composite tumors for patients who have combined HCC and cholangiocarcinoma.

What is the current state of biomarkers in HCC?

This is an area that is still untapped. There is a need for universal biomarker testing. It’s complicated because not all patients with HCC receive a biopsy. The diagnosis is made on clinical grounds. The study that compared nivolumab vs sorafenib in the first-line setting looked at PD-L1 expression in patients with HCC and found that in a minority of patients, there may be a role for PD-L1 as a prognostic and predictive factor. 

However, none of the current phase 2 or phase 3 trials have been sufficiently powered to make that conclusion. Additional pooled data have looked at the role of next-generation sequencing in the tumor as well as circulating DNA for predictors of response and nonresponse in HCC, but clearly this needs to be done in a more coordinated fashion so that we have better tools for patient inclusion in IO trials.

Do you believe the advances that are being made in HCC will continue to trend upward and expand the armamentarium?

The management of HCC is has evolved remarkably. There is a new first-line therapy option with atezolizumab and bevacizumab. We have 4 approved options in the second-line setting for HCC. We have upcoming trials of IO combinations in the first-line setting and subsequent-line settings. When I did my fellowship, there was a lot of nihilism about HCC and its management. This has changed remarkably, where patients now have many options available.

In surgically resectable disease, there are adjuvant trials with IO agents, combinations with liver-directed therapy, such as radioembolization, and TACE [transarterial chemoembolization], which are likely to be transformative in the management of this disease.