Gong Gives Perspective on Sequencing Challenges Faced in Advanced HCC

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Jun Gong, MD, discusses the impact of the IMbrave150 trial on the advanced HCC treatment paradigm and challenges faced with sequencing.

Many of the FDA-approved second-line and beyond options for advanced hepatocellular carcinoma (HCC) are indicated for use following treatment with sorafenib (Nexavar), and now that atezolizumab (Tecentriq) plus bevacizumab (Avastin) has become the new frontline standard, sequencing challenges have become more pronounced, according to Jun Gong, MD.

Data from the phase 3 IMbrave150 trial (NCT03434379) showed that atezolizumab/bevacizumab resulted in a 42% reduction in the risk of death vs sorafenib (HR, 0.58; 95% CI, 0.42-0.79; P = .0006); the doublet also led to a 41% reduction in the risk of disease progression or death vs sorafenib (HR, 0.59; 95% CI, 0.47-0.76; P <.0001). Based on these results, the FDA approved the atezolizumab/bevacizumab in May 2020.

“The FDA approval of this immunotherapy-based combination in the first-line treatment of [patients with] advanced HCC [has led to] a new standard,” Gong said. “[The trial also] raised several questions about what appropriate treatment sequencing of available FDA-approved agents [looks like] in patients who progress on, or are intolerant to, atezolizumab plus bevacizumab.”

In an interview with OncLive® during a 2021 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignances, Gong, a medical oncologist at the Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, and Urologic Oncology Program in the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, discussed the impact of the IMbrave150 trial on the advanced HCC treatment paradigm and challenges faced with sequencing.

OncLive®: Could you speak to the significance of the IMbrave150 trial and how this shift in first-line standard of care may impact later-line decisions?

Gong: The IMbrave150 trial set a new first-line standard in the treatment of advanced HCC. The combination of the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab showed superior median OS over the oral TKI sorafenib, which was the first-line standard for advanced HCC for many years.

Several second-line agents are FDA approved in advanced HCC. For example, regorafenib [Stivarga] was given [the green light based on data] from the phase 3 RESORCE trial [NCT01774344], ramucirumab [Cyramza] based on findings from the phase 3 REACH-2 trial [NCT02435433], and cabozantinib [Cabometyx] based on data from the phase 3 CELESTIAL trial [NCT01908426]. All these agents were approved by the FDA [for use] following treatment with sorafenib. We need more studies to investigate second-line and beyond agents following atezolizumab/bevacizumab because the data are limited.

Many immunotherapy agents were approved in the second-line setting over the past few years; again, these options were all [indicated for use] following sorafenib. For example, nivolumab plus ipilimumab [Yervoy] was FDA approved based on [the results from] the phase 3 CheckMate-040 trial [NCT01658878]. Additionally, pembrolizumab [Keytruda] was approved in the second-line setting, [for use] following sorafenib in [patients with] advanced HCC.

The important thing to point out with these immunotherapy drugs is that they remain viable FDA-approved options for patients who were treated with first-line oral TKIs. However, with the advent of atezolizumab/bevacizumab in the first-line setting, second-line immunotherapy drugs will be used less and less often. We have not had good data to show that immunotherapy drugs work in the second-line setting if [a patient has] already progressed on a first-line immunotherapy combination.

Cabozantinib also represents a meaningful second-line option. The CELESTIAL trial permitted [patients who were receiving treatment in the] first, second, and third line; it was one of the few trials to have enrolled patients who had previously been treated with immunotherapy. This provided a little bit of context and rationale for using cabozantinib as a second-line option.

[In] the third-line setting and beyond, it really is dealer's choice. You must balance patient comorbidities, patient preferences, and provider preferences. We are left with cross-trial examinations, which are admittedly limited. A clinical trial is always [an option to] consider, particularly for patients with preserved performance status in the second- and third-line space.

Are there any subsets of patients for whom atezolizumab/bevacizumab may not be utilized?

Atezolizumab/bevacizumab is going to be [used by the] majority [of patients] in the first-line setting. Outside of a clinical trial, the populations that would not use the combination is probably limited, but they do exist. For example, if you have patients with significant autoimmune conditions that prohibit the use of an immunotherapy combination, then this is a small but relevant population where atezolizumab/bevacizumab would not be preferred. Another population [for which this combination might not be used] is those with esophageal or gastric varices, who are at high risk of bleeding; this is because bevacizumab can cause significant bleeding, as was detected in the IMbrave150 trial, although at a very small percentage. [However], it is still recommended that prior to starting atezolizumab plus bevacizumab, patients undergo a routine endoscopy to rule out and manage varices to minimize the risk of bleeding.

Sorafenib has served as the control for several of these phase 3 trials. Because atezolizumab/bevacizumab is the new standard, do you foresee it serving as the new control in future trials? Is that needed to address some remaining questions?

Given that atezolizumab/bevacizumab is the new first-line standard, an evolving and adaptive strategy for clinical trials should reflect the current standard of care. In short, yes, given that this [combination] is the new standard, it should be the control arm going forward. However, we should note that several ongoing phase 3 trials are still using sorafenib [and other agents] as the control arm. [For example, the phase 3] LEAP-002 trial [NCT03713593] is investigating lenvatinib [Lenvima] plus pembrolizumab vs lenvatinib as the control arm, and the COSMIC-312 trial [NCT03755791] is examining cabozantinib and atezolizumab vs sorafenib. Then, you have the HIMALAYA trial [NCT03298451], which is evaluating durvalumab [Imfinzi] and tremelimumab vs sorafenib in the first-line setting. We are going to have to see the readouts of those results, but in the future, it may be important to take into consideration that there may be a new updated control arm that should be reflected in these trials.

How are you approaching sequencing for the second-line and beyond? What is your rationale for using one approach over another?

This is a very highly controversial topic, and it is likely to be an ongoing topic of discussion with oncologists. We are left with cross-trial comparisons because a head-to-head trial does not exist. However, if you put together all the evidence that we have, the FDA labels technically support cabozantinib and regorafenib in a post-sorafenib setting. Ramucirumab is a VEGFR2 inhibitor, so its use after a VEGF inhibitor like bevacizumab is unclear in advanced HCC. Although there is precedent [for its use] in colorectal cancer, we are unsure of whether this efficacy is going to hold in the HCC setting.

RESORCE, which studied regorafenib, required patients to tolerate sorafenib for at least 20 days out of a 28-day cycle. Therefore, you have this area of uncertainty if you follow atezolizumab/bevacizumab with regorafenib in this instance, [because] this was based on tolerability to sorafenib.

That really leaves CELESTIAL, which was a more permissive trial in allowing first-, second-, and third-line treated patients with HCC. It was one of the few studies that allowed a small population of patients previously treated with immunotherapy to be enrolled. Based on that context, it makes sense that cabozantinib remains a favored approach, even if it just has a slight edge.

Many will argue that sorafenib or lenvatinib still represent first-line options [for certain] populations. If you do end up using atezolizumab/bevacizumab [in the first line], sorafenib or lenvatinib may be considered as a second-line option, with an edge toward lenvatinib based on the superior PFS benefit [observed with the agent] vs sorafenib.

Where are research efforts being focused?

With the advent of VEGF TKI/immunotherapy combinations, patients with advanced HCC are experiencing improved outcomes. Beyond those combinations, another arena that we look forward to is [the work that is being done with] CAR T-cell therapies. Although still early in development, phase 1 trials have shown some promising safety and efficacy data [with this modality], which is targeting tumor phenotypes specific to HCC while recruiting T cells. This could represent another novel immunotherapy approach to treating [patients with] advanced HCC.


  1. FDA approves Genentech’s Tecentriq in combination with Avastin for people with the most common form of liver cancer. News release. Genenech. May 29, 2020. Accessed May 5, 2021. https://bit.ly/2Aneztc