TKIs Trump Immunotherapy Following Atezolizumab/Bevacizumab Treatment in HCC

Mar 22, 2021

The combination of atezolizumab and bevacizumab is the clear frontline standard of care for patients with advanced hepatocellular carcinoma without contraindications.

Arthur A. Winer, MD, member of Inova Medical Group

Arthur A. Winer, MD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is the clear frontline standard of care for patients with advanced hepatocellular carcinoma (HCC) without contraindications, said Arthur A. Winer, MD, who added that emerging retrospective evidence suggests that single-agent multikinase inhibitors can be considered for second-line therapy for patients with progressive disease.

“All patients, apart from those with uncontrolled autoimmune disease, precluding a PD-L1 inhibitor, a very high bleeding risk, or high Child-Pugh [score], should be considered for atezolizumab/bevacizumab in the frontline setting. This combination is the standard of care outside of a clinical trial setting,” said Winer.

The combination received regulatory approval in May 2020 for the frontline treatment of patients with unresectable or metastatic HCC. Findings from the phase 3 IMbrave150 trial, which served as the basis for the approval, have since been updated and presented at the 2021 Gastrointestinal Cancers Symposium. At a median follow-up of 15.6 months, the median overall survival (OS) was 19.2 months with the combination vs 13.4 months with sorafenib (Nexavar; HR, 0.66; 95% CI, 0.52-0.85; P = .0009).1 The median progression-free survival (PFS) was 6.9 months vs 4.3 months, respectively (HR, 0.65; 95% CI, 0.53-0.81; P = .0001).

Additional data presented at the meeting indicated that among patients who discontinued the combination, sorafenib and lenvatinib (Lenvima) monotherapy were the most frequently used second-line agents, leading to an overall median PFS of 3.4 months (95% CI, 1.8-4.9 months) and OS of 14.7 months (95% CI, 8.1-21.2).2

“We’re probably going to see more retrospective analyses at upcoming national and international meetings as larger numbers of patients are put on these drugs in the post–PD-L1/VEGF inhibitor era. Then, we can be more confident that this [approach] will work,” said Winer.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Winer, a member of Inova Medical Group, discussed the current treatment landscape of HCC and ongoing research that could shake the paradigm once more.

OncLive®: When did the treatment landscape shift toward the use of immunotherapy in HCC?

Winer: The treatment landscape has exploded in the past decade. Before 2008, we really only had best supportive care, then came sorafenib, the [multikinase] TKI that attacks the blood vessel supply to [HCC] tumors. [Sorafenib] showed a modest survival benefit of about 3 months vs placebo. However, that was all we had up until 2017 when we started to see second-line treatment options like regorafenib [Stivarga] in the post-sorafenib setting as well as other frontline treatments including lenvatinib, which was found to be noninferior to sorafenib. [We also saw] other agents that target the VEGF pathway such as ramucirumab [Cyramza] in the second-line setting, as well as immunotherapy, which has shown some success in this disease.

The immune system is active in cirrhotic livers, where there’s chronic inflammation, and the body’s trying to heal the liver, and we see that in the background of HCC. The immune system has the potential to attack these tumors and be unleashed to control them. Starting in 2017, we started seeing results with nivolumab [Opdivo] and pembrolizumab [Keytruda] in the CheckMate 040 study and the KEYNOTE-224 study, showing a decent overall response rate of about 15% to 20% in the second-line or later settings. Those studies set the groundwork for the IMbrave150 trial.

What is the significance of the primary and now updated findings from the IMbrave150 trial?

[The IMbrave150 trial has] thrown [the frontline treatment paradigm] on end a little bit because that was the first trial really to show that a regimen was superior to sorafenib. Before then, we only had the data with lenvatinib [showing that it was] noninferior [to sorafenib]. Therefore, we [only had the option of choosing] between lenvatinib and sorafenib.

In IMbrave150, patients were randomized to atezolizumab, a PD-L1 inhibitor and bevacizumab, a VEGF inhibitor vs sorafenib alone. The primary end points were OS and PFS. The trial did meet both of those end points. The publication came out in May of 2020 in the New England Journal of Medicine, which did show that the OS had not yet been reached in the combination arm vs about 13 months in the sorafenib arm. Updated data at the 2021 Gastrointestinal Cancers Symposium showed that the OS was about 19 months, [translating] to an improvement of about 6 months [with the combination]. We’re starting to see there’s the possibility of a tail on the curve, where some patients have a very prolonged response and their cancer is under control for much longer than that if the median was 19 months or well over 2 years for some of these patients, which had been unheard of in this disease.

Can these data be extrapolated to patients with Child-Pugh B or C disease?

In all of these trials, Child-Pugh A patients were part of the inclusion criteria. The [Child-Pugh] score looks at how healthy livers are. [Child-Pugh A] patients are the healthiest and [Child-Pugh C patients are] the least healthy. [Child-Pugh A] patients are in the healthy category of [cirrhotic disease], so it’s hard to apply these results outside of that setting, although we have a lot of patients with HCC with [Child-Pugh] B disease who have sort of intermediate-grade cirrhosis. A lot of oncologists do apply the results of all these clinical trials outside of the [population] they were studied in to give these patients an opportunity to receive treatment. Although you can do okay [with that approach], there is no formal trial data [in those patients], which is something to always take into account.

How does a patient’s bleeding risk affect their eligibility for the combination?

The other thing is that with any VEGF inhibitor, you’re attacking the blood vessels of a tumor, so bleeding is a complication we worry about, and cirrhosis does predispose you to bleeding. All of these patients had to be scoped endoscopically for swollen varices or enlarged blood vessels in the esophagus within 6 months of initiation on treatment to minimize their bleeding risk. Those are certainly things you need to take into consideration if you’re going to use this combination.

What work is being done to overcome resistance mechanisms to antiangiogenic agents?

The short answer is [that this research is] in its infancy. A lot of preclinical suggest that various alternative growth pathways are upregulated, such as c-MET in the tumors that are resistant to angiogenesis inhibitors, or AXL or other growth pathways, as well as other angiogenesis pathways. [There are other] pathways that cause blood vessel formation; vascular endothelial growth factor is just one of them. Platelet-derived growth factors are another. Transforming growth factor beta is another. All of these [pathways] have been shown in various tumor models and various mouse models to be upregulated if a tumor starts to become resistant.

The field is going to sample and explore those pathways [to determine] whether we can overcome mechanisms of resistance by targeting them and providing alternative inhibition of those pathways. Preclinically, it makes sense to use an agent such as cabozantinib [Cabometyx], which was also approved in the second-line setting, which targets c-MET and AXL, or lenvatinib or sorafenib, which probably have the most data as they touch on platelet-derived growth factor receptors.

Until formal data are seen, only expert opinions exist, which suggests that we should be using TKIs in the second-line setting after atezolizumab and bevacizumab. However, as a mentor once said to me, expert opinion is the worst evidence that we have, so we really need clinical data and clinical trials. I’m excited to see what comes forward as the years progress to help guide our therapy in the future.

How have multikinase inhibitors performed in patients who progress on the combination of atezolizumab and bevacizumab?

There are little data to suggest how these patients do because [the combination] was approved by the FDA [in 2020]. If the median PFS is measured in months, we’re just now starting to see patients progress on these agents in the past few months. Some early data out of an Asian research group in Taiwan and Korea [was presented at the] 2021 Gastrointestinal Cancers Symposium, which showed a response rate and a disease control rate of about 60% with lenvatinib or sorafenib in the post atezolizumab/bevacizumab setting. That study was small; a few dozen patients were included.

They also found a pretty good OS post atezolizumab/bevacizumab of 1 year or more with these agents, so they can still show activity. However, I do caution that those results are retrospective. [These patients] may have just [had] slow-growing [tumors that] initially responded [to the combination] and then slowly progressed.

Could the results of the LEAP-002 study lead to another paradigm shift in the near future? Where will immunotherapy make the greatest impact?

We’re going to see [more] combinations of TKIs plus immunotherapy, which is going to make things much more complicated because we won’t know which is better, be it atezolizumab/bevacizumab or lenvatinib/pembrolizumab, which is [being evaluated in the] LEAP-002 study. [The results of the LEAP-002 study are] probably going to come out in the next year or two. I would be surprised if that’s a negative trial. Then, we’ll really have to figure out how to sequence [these combinations]. It’s exciting to have that problem in this disease when we really had 1 therapy 15 years ago.

We’re also seeing the combination of checkpoint inhibitors working in this disease. The combination of ipilimumab [Yervoy] and nivolumab received accelerated approval from the FDA in 2018 based on another arm of CheckMate 040, which had a very impressive OS benefit of about 22 months.

However, that was not a randomized study; it was a single-arm study. [That regimen] hasn’t been compared with these other treatments we’re talking about, but we’re going to see that combination move forward in the frontline setting. Also: How do you use that after you already used a PD-L1 inhibitor? There is a lot of preclinical rationale, and there is some added benefit to doing that in other diseases such as melanoma where we know there’s a better benefit of the combination vs a single agent. In general, that’s going to be [a] data free [zone], so we’re going to have to use our expert opinion and our rationale to help our patients.


  1. Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(suppl 3):267. doi:10.1200/JCO.2021.39.3_suppl.267
  2. Yoo C, Km JH, Ryu MH, et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: a multinational, multicenter retrospective study. J Clin Oncol. 2021(suppl 3):272. doi:10.1200/JCO.2021.39.3_suppl.272.
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