Atezolizumab/Bevacizumab Combo Sets the Standard for New Doublets in Advanced HCC

Amit Singal, MD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) has become the frontline standard of care for most patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy, said Amit Singal, MD. He added that the combination’s approval comes with questions regarding optimal second-line therapy, a need to identify biomarkers of response, and the promise of other doublet regimens in the pipeline.

“The introduction of atezolizumab and bevacizumab has completely transformed the landscape of advanced HCC,” said Singal. “We’ve moved away from targeted therapies being the mainstay of therapy for patients with advanced HCC. [In turn], we’ve seen significant improvement in progression-free survival, and [atezolizumab plus bevacizumab] is incredibly well tolerated.”

Although the advanced HCC paradigm is rapidly evolving with ongoing research efforts, the roles of multidisciplinary care, early detection, and locoregional therapies remain key pillars in the overall care for patients with HCC, Singal explained.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on gastrointestinal cancers, Singal, medical director of the Liver Tumor Program and clinical chief of Hepatology, as well as the Dedman Family Scholar in Clinical Care and the David Bruton Jr. Professorship in Clinical Cancer Research, discussed the expanding landscape of advanced HCC, potential approaches to second-line therapy following the approval of atezolizumab and bevacizumab, and the importance of early detection, curative-intent therapies, and multidisciplinary care.

OncLive®: How have some of these positive data changed the HCC paradigm, which experienced a long period of little advancement since the approval of sorafenib (Nexavar)? What lessons were learned from the negative trials with targeted therapy?

Singal:After the SHARP trial, all of us [in the HCC field] expected to see multiple agents come to the market over the next couple of years. Unfortunately, we entered into a 10-year drought where all we had was negative trial after negative trial related to a combination of factors.

HCC is one of the few tumors we, unfortunately, do not biopsy. [HCC] is based on imaging diagnosis in the vast majority of cases. Our understanding of HCC, even from a basic target standpoint, is likely far behind where it could be from a research perspective if we were more aggressive with tissue collection.

Agent selection is a little bit like shooting in the dark. [The regimens] that have succeeded [in HCC incorporate] a combination of hitting enough targeted pathways to avoid escape mechanisms while not being too selective where it’s easy for the tumor to otherwise find another mechanism to continue growing. Those were the lessons that we learned from [the use of] targeted therapies over the past several years.

Of course, more recently, we’ve entered into the era of checkpoint inhibition, which started with CheckMate-040 with nivolumab [Opdivo]. We’ve learned from CheckMate-459, as well as the KEYNOTE trials that single-agent PD-1 inhibition does induce durable responses in approximately 15% to 20% of patients, but it’s likely not as effective as we would like [a monotherapy to be].

Now, with the IMbrave150 trial, as well as all the other [ongoing trials], we are seeing the potential for doublet therapies to move the field forward and improve the prognosis for patients with advanced HCC.

What about HCC makes immunotherapy a valuable treatment option? Are options beyond PD-1/PD-L1 inhibition on the horizon?

The basic rationale for immunotherapy is that tumors in general can induce an immune break. PD-L1 can bind PD-1 and [prevent] T-cell activation and activity. The checkpoint inhibitors [essentially] take the foot off the brakes; they get between PD-1/PD-L1 binding, which allows the T cells to remain active.

Of course, our early evaluation of checkpoint inhibition in HCC has largely focused on this PD-1/PD-L1 access, although [there are] many different targets.

The next target that is being evaluated is CTLA-4, which similarly allows increased T-cell recruitment. Over the next several years, we are going to move beyond PD-1, PD-L1, and CTLA-4 towards other targets in HCC, as well as in other cancer types.

How have the updated data from IMbrave150 solidified the role of atezolizumab/bevacizumab as the frontline standard of care for patients with HCC?

[The combination] has become the standard of care for most patients with advanced HCC, with the caveats [that patients have to have] good liver dysfunction and [a low] risk of bleeding as assessed by an upper endoscopy. For eligible patients, [the combination] is incredible and we can say it notably moved the field forward.

With the updated analysis [of IMbrave150] that was presented earlier in 2021, we see that [atezolizumab/bevacizumab] not only improves survival significantly, but we now have a point estimate for what we anticipate the median survival to be as [the combination] rolls out in clinical practice.

For patients with advanced HCC, we see a median survival right around 19 months, which is an incredible advance from where we were just a couple of years ago when the median survival was less than 1 year. [The updated data from IMbrave150] get rid of the skepticism and, in part, the difficulty of treating patients with advanced HCC.

[Atezolizumab/bevacizumab] really set the bar for where we hope and need to see other doublets coming through. We need to see a median survival of around 19 or 20 months.

What role do TKIs, such as lenvatinib (Lenvima) and sorafenib, play amid the integration of atezolizumab/bevacizumab?

Although atezolizumab plus bevacizumab is the standard of care for most patients with advanced HCC, it unfortunately can’t be used in all patients. Some patient populations are not eligible to receive this combination. Most notably, a large proportion of patients have more advanced liver dysfunction, whether that is Child-Pugh B cirrhosis or more significant portal hypertension.

We don’t have data regarding the safety of atezolizumab and bevacizumab in those patient populations, whereas we do have some safety data for the multikinase inhibitors, including sorafenib and lenvatinib. Those therapies continue to be the preferred agents in patients with more advanced liver dysfunction.

Likewise, with the CheckMate 040 trial, we have some data for nivolumab monotherapy in well-selected patients with Child-Pugh B cirrhosis, so [nivolumab] could also be considered in some of those patients.

Even patients with Child-Pugh A cirrhosis and acceptable portal hypertension need an upper endoscopy to screen for varices and other high-risk bleeding situations [that could occur] with atezolizumab and bevacizumab. A portion of patients will have large varices, stigmata indicating a high risk of bleeding, and significant portal hypertensive gastropathy, that would set someone up to have a higher risk of bleeding. Once again, in those patient populations, we would want to consider alternate agents [to atezolizumab and bevacizumab], including sorafenib and lenvatinib.

Although we have this incredible new combination [of atezolizumab and bevacizumab], the TKIs continue to play a notable role in many, if not most patients with advanced HCC, even in the frontline setting.

What ongoing trials have the potential to further refine the frontline setting of advanced HCC?

Atezolizumab and bevacizumab was the entry point for doublets being the standard first-line therapy, but many more are in the pipeline. We have the [LEAP-002 (NCT03713593)] trial evaluating the combination of lenvatinib and pembrolizumab [Keytruda]. The phase 1b data [with lenvatinib and pembrolizumab] looked very promising. Once again, we hope that the efficacy and safety signals hold up in the phase 3 trial.

We also have the HIMALAYA trial [NCT03298451] that is evaluating the combination of durvalumab [Imfinzi] and tremelimumab. This will be one of our first PD-1 and CTLA-4 inhibitor combinations. Likewise, we have the combination of nivolumab and ipilimumab [Yervoy] that was evaluated in the second-line setting through CheckMate 040.

Finally, we have the COSMIC-312 trial [NCT03755791] that is evaluating cabozantinib [Cabometyx] in combination with [atezolizumab] in the frontline setting.

We are all optimistic that those other trials will continue [to demonstrate] high efficacy and high safety so that we will have multiple options in the frontline setting.

If all these regimens reach the frontline setting of advanced HCC, how do you anticipate you will approach treatment selection? Do you think biomarkers could be useful in navigating the paradigm?

The good thing is that if all of these agents come to fruition and these trials are positive, we will have several options in the frontline setting. How do we then choose between these different agents? I don’t know whether I have the optimal answer for this right now. [The regimens] will have some small differences in terms of eligibility criteria and adverse effects that may be considered when selecting between them. In the beginning, that is what we are going to be dependent on in terms of selecting therapy.

For example, we know that bevacizumab increases a patient’s risk of gastrointestinal bleeding, which may not be as true with the combination of PD-1 and CTLA-4 inhibitors. Some of these minor differences are really not so minor and may end up [determining] how we select between these options in the beginning, assuming that the regimens show similar efficacy and safety overall.

The hope is for us to eventually have biomarkers [to determine treatment selection] and move toward a field of precision medicine rather than [selecting therapy] based on clinical features alone. However, our initial search for these biomarkers has been somewhat frustrating and we have not come up with anything great.

[Biomarkers] such as PD-L1 status, tumor mutational burden, and microsatellite instability–high status are relatively uncommon for patients with HCC, so we don’t have the ability to use some of the biomarkers that can be used in other tumor types. However, much like we’ve moved beyond the 10-year drought in therapies for advanced HCC to, now, the golden age of multiple therapies coming to market, I continue to hold out hope that medicine will push forward, and we will [identify] biomarkers at some point.

How are you optimizing second-line therapy for patients who progress on atezolizumab/bevacizumab?

With atezolizumab and bevacizumab becoming the standard first-line therapy, one can take two different approaches when considering second-line therapy. We can take this “T-minus-1” approach, where we say atezolizumab and bevacizumab is the frontline therapy and sorafenib or lenvatinib would become second-line options. Then, the currently approved second-line therapies would move to the third-line setting. Many people are using this strategy.

Likewise, many people are using an alternative strategy and using atezolizumab and bevacizumab in the frontline setting, then all of [the other available] agents in the second-line setting. Essentially, that creates a big box that has sorafenib, lenvatinib, regorafenib [Stivarga], cabozantinib, ramucirumab [Cyramza] if that patient has elevated alpha fetoprotein [AFP], and nivolumab plus ipilimumab in the United States to then select from in the second-line setting for patients who progress on or are intolerant of atezolizumab plus bevacizumab.

Personally […] I don’t see much benefit to going to single-agent PD-1 inhibition. Therefore, I don’t see a lot of excitement for nivolumab or pembrolizumab monotherapy after failure of atezolizumab and bevacizumab. Likewise, I don’t know whether there will be as much activity with ramucirumab; we want to see data regarding how active ramucirumab would be after failure of atezolizumab and bevacizumab since the VEGF pathway was already acted upon. That being said, data from other cancer types have shown differences in terms of VEGF inhibitors and [their interaction with the] VEGF receptor, so [the efficacy of ramucirumab] needs to be evaluated [in this setting].

What do you anticipate that the future of checkpoint inhibitors will look like in HCC?

Checkpoint inhibitors have suddenly taken over and clearly transformed our approach to treating patients with advanced HCC. However, the trials that are moving these agents into earlier stages of disease are exciting.

We’re seeing combinations of checkpoint inhibitors with locoregional therapies, such as chemoembolization, radioembolization, and stereotactic body radiotherapy, for patients with intermediate-stage HCC. Checkpoint inhibitors are also being evaluated as neoadjuvant or adjuvant therapy with resection and ablation. A lot of excitement [has been generated with this approach] since strong preclinical [evidence showed] increased neoantigens in which the checkpoint inhibitors can take advantage of the abscopal effect. As we’ve seen, checkpoint inhibitors improve the prognosis for patients with advanced HCC. We’re hoping they can improve survival for patients with earlier stages of disease. It is really the beginning of the story, and we still have a lot of writing to do.

In your opinion, how important is multidisciplinary care in HCC?

Of course, as we start to see these different therapies being offered, particularly when we start talking about appropriate transitions between different therapies, such as locoregional to systemic therapy, decisions need to be made in the context of a multidisciplinary group. We need close and continual communication between all providers.

This gets to the point of HCC being a disease that almost exclusively occurs in the setting of chronic liver disease. We know that over 90% of HCC [cases] in the United States occur in the setting of cirrhosis, so [HCC treatment is] really treating a disease within a disease and another point of why multidisciplinary care is critical.

Many specialties need to be involved [in the treatment of patients with HCC], but at the bare minimum [specialists from] hepatology, surgery, interventional radiology, and medical oncology should be present. Other specialties, such as radiation oncology, palliative care, nursing support, social workers, and others [could also be included]. A lot of people need to be around the table to maximize the appropriate treatment for patients with HCC at any stage.

An important thing to remember is that multidisciplinary care is not just a feel-good concept for patients with HCC. Several studies have shown that [multidisciplinary care] improves appropriate guideline concordant care, time-to-treatment, and most notably, survival, and should be regarded as the standard of care for patients with HCC. It is a critical element for us to provide good care for these patients.

Why is early detection of HCC a critical component of a patient’s outcome?

We’ve seen notable [milestones] in the advanced-stage setting, but we also have to keep in mind that despite these improvements, one of the strongest prognostic factors continues to be finding patients at an early stage. Early detection continues to remain critical.

We have an identifiable patient population, so it is critical that we continue to promote and perform screening for HCC in adverse patients. The current recommendation is to perform a semi-annual ultrasound with or without AFP in at-risk patients, particularly those with cirrhosis or chronic hepatitis B. Several studies have shown that performing these relatively simple and cheap screening tests significantly improves early detection, our ability to offer curative treatments, and notably, overall survival.

If we find patients at an early stage, it is critical that we perform curative therapies if and when possible. Although a lot of excitement [surrounds] advances in locoregional therapy and systemic therapy, our best therapies continue to be surgical. When somebody [with HCC] is identified early and they are eligible to receive surgical resection, we should [pursue surgery]. If a patient [is identified] early and they are eligible for liver transplant, including patients who are downstaged into transplant [eligibility], it is critical that we refer them for liver transplant.

[Surgical options] continue to be our only therapies that offer 5-year survival rates that far exceed 60%. I can’t highlight it enough that despite improvements in the advanced-stage setting, early detection and curative therapies are critical for us to implement in clinical practice. I hope that we can start to use combination therapies so that it is not just surgical resection or liver transplant alone, because we can combine these therapies to maximize effectiveness and [prolong] survival in the future.