CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: February 01, 2023
Expiration: January 31, 2024
In this module, Stacy Stein, MD, presents recent clinical data on systemic therapies in advanced hepatocellular carcinoma (HCC).
She discusses frontline regimens for advanced HCC including dual immune checkpoint inhibitor (ICI) combinations, ICIs plus antiangiogenic agents, and newer data on ICIs in combination with tyrosine kinase inhibitors (TKIs). In addition, she gives insight into optimal sequencing of second-line therapy.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
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Before continuing with this educational activity, please take a moment to answer the following questions.
For liver cancer, the appropriate treatment algorithm cannot be planned without thinking about the underlying liver function. Patients with early-stage HCC and good liver function, good performance status, and early disease are potentially able to get curative intent therapy with ablation or surgical resection. Other patients may be eligible for a transplant based on strict criteria, and those patients also usually have a very good prognosis.
At the intermediate stage, patients who have potentially multinodular disease, but relatively good liver function and performance status are usually referred to interventional radiology or chemoembolization.
Medical oncology is focused on patients with advanced stage C disease based on the Barcelona Clinic Liver Cancer staging system. These patients may have portal invasion, lymph node metastases, or distant metastases but still maintain relatively good liver function and performance status. These are the patients we traditionally think of as receiving systemic therapy.
Finally, patients with poor liver function or performance status are directed to best supportive care, unfortunately with a much shorter prognosis.
We will start by looking at the current first-line options for the treatment of advanced HCC.
The phase Ib GO30140 study looked at the combination of atezolizumab (anti–PD-L1 antibody) plus bevacizumab (anti-VEGF antibody) against different solid tumors, including one treatment arm that included patients with previously untreated unresectable advanced or metastatic HCC (n = 104).1 The ORR for this arm was an impressive 36%.
Based on these data, the open-label phase III IMbrave150 trial was initiated to evaluate atezolizumab plus bevacizumab vs sorafenib (a small molecule TKI) in patients with locally advanced or metastatic and/or unresectable HCC with no previous systemic therapy.2 Patients on this study (N = 501) were randomized 2:1 to receive either atezolizumab plus bevacizumab or sorafenib, with the coprimary endpoints of OS and PFS. Key secondary endpoints included ORR and duration of response (DoR).
The updated efficacy data at a median follow-up of 15.6 months show that the atezolizumab plus bevacizumab combination had an impressive median OS of 19.2 months compared with 13.4 months for sorafenib (HR: 0.66; 95% CI: 0.52-0.85; P <.001). The median PFS with the combination therapy was 6.9 months vs 4.3 months for sorafenib (HR: 0.65; 95% CI: 0.53-0.81; P <.001), and as seen in the figures, there was visible separation of the curves for both OS and PFS at 6, 12, and 18 months.2 This was interesting, since in other studies, the sorafenib control arm always seems to do better over time, with many patients going on to subsequent lines of therapy.
The ORR was 30% with atezolizumab plus bevacizumab and 11% with sorafenib, with a median DoR of 18.1 months and 14.9 months, respectively.
Based on the efficacy shown in IMbrave150, the FDA approved atezolizumab in combination with bevacizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy.3,4
Adverse events (AEs) commonly seen with TKIs were higher in the sorafenib arm, including diarrhea, palmar–plantar erythrodysesthesia, and decreased appetite. Hypertension was seen in both treatment groups, which is from the VEGF inhibition. Some AEs (eg, proteinuria from bevacizumab, increased alanine aminotransferase) were increased in the combination arm.2,5
However, grade 3/4 AEs were relatively uncommon in both arms, with the most frequent being hypertension, which is usually well controlled with medication.
All patients on this study had an upper endoscopy (or esophagogastroduodenoscopy) within 6 months of starting therapy, and varices had to be treated according to the local standard of care, which sometimes included banding or treatment with β-blockers. The upper gastrointestinal bleeding rate in the combination arm vs sorafenib was 7.0% and 4.5%, respectively, consistent with historical TKI data and considered low enough to warrant the use of the treatment.5
There was also an improvement in median time to deterioration of symptoms for the combination treatment vs sorafenib (11.2 vs 3.6 months, respectively).5
There are several common immune-related AEs (irAEs) with ICI treatments, including diarrhea/colitis and dermatologic, hepatic, pancreatic, and endocrine AEs. Less common are pneumonitis and neurologic, musculoskeletal, renal, ocular, and cardiovascular AEs.6
The general guidelines for management of grade 1 irAEs are to observe and give supportive care, but usually the immune therapy can be continued. For grade 2 with moderate symptoms, we consider holding ICI treatment and waiting for resolution to grade ≤1. Corticosteroids may be considered, depending on the specific irAE and its effect on the patient. Please note that dose reduction of ICI therapy is not recommended.3,7,8
For the more medically significant grade 3 irAEs, we do have to stop the immune therapy immediately, hospitalize the patient, and give high-dose steroids, which are then tapered slowly, often over more than 1 month. Of course, the life-threatening consequences of grade 4 irAEs require urgent intervention with hospitalization, potentially in the intensive care unit along with high-dose steroids, and those patients would not be given immune therapy again.
There are several factors that can prevent a patient from being a candidate for atezolizumab plus bevacizumab. For patients with a history of transplant, there is a great concern that immune therapy may cause rejection of the liver.9
Patients with active autoimmune disease are not candidates for atezolizumab plus bevacizumab, although there are some exceptions. Patients with type 1 diabetes, hypothyroidism, or skin autoimmune diseases who have limited skin involvement are expected to tolerate the combination. We would usually not offer this treatment to a patient with any condition that requires chronic systemic immunosuppression.
In patients with untreated esophageal varices, we would be concerned about bleeding, specifically due to bevacizumab. In patients with uncontrolled hypertension, we would be worried about the risk of stroke or other long-term sequelae. If the hypertension is controlled, then we can get them on treatment. Patients with chronic heart failure would also not be good candidates for this combination.
Finally, keep in mind that patients with hepatitis B should be receiving antiviral therapy when they are receiving systemic therapy.
For patients who are unfit for atezolizumab plus bevacizumab, the TKIs sorafenib or lenvatinib may be an option.
Sorafenib was the longtime standard of care for systemic HCC therapy based on the phase III SHARP trial, published in 2008.10 This was the first study to demonstrate a benefit of any systemic therapy against advanced HCC, which is why the study was randomized to placebo. Patients with advanced HCC (N = 602) with no previous systemic therapy received either sorafenib or placebo. Coprimary endpoints were OS and time to symptomatic progression (TTP), and secondary endpoints included time to radiologic progression and safety. Patients receiving sorafenib had a significantly improved median OS of 10.7 months vs 7.9 months for placebo (HR 0.69; 95% CI: 0.55-0.87; P <.001).
The very similar randomized phase III ASIA-PACIFIC study was carried out in Asia with more patients with hepatitis B.11 Patients with advanced HCC (N = 226) were treated with sorafenib or placebo, and sorafenib resulted in an improvement in median OS of 6.5 months vs 4.2 months (HR: 0.68; 95% CI: 0.50-0.93; P = .014).
More recently, the open-label, randomized phase III REFLECT study compared lenvatinib with sorafenib, and it was shown to be noninferior in patients with advanced HCC and no previous treatment for advanced disease (N = 954).12 The curves for the primary endpoint median OS were very similar for both drugs. However, the secondary endpoints of PFS (7.4 vs 3.7 months; HR: 0.66; 95% CI: 0.57-0.77; P <.0001), median time to progression (8.9 vs 3.7 months; HR: 0.63; 95% CI: 0.53-0.73; P <.0001), and ORR (24.1% vs 9.2%; odds ratio: 3.13; 95% CI: 2.15-4.56; P <.0001) each showed significant improvement for lenvatinib compared with sorafenib.
Due to the efficacy shown in REFLECT, the FDA approved lenvatinib for first-line treatment of patients with unresectable HCC.13
I would say that based on these data, many healthcare professionals have likely switched their preferred TKI from sorafenib to lenvatinib.
This table shows the distribution of treatment-emergent AEs between the 2 arms of the REFLECT study. A couple of differences were seen when comparing the AEs between the 2 drugs, including slightly more hypertension with lenvatinib.12
There were more hand–foot skin reactions seen with sorafenib, and in general, we try to treat this hyperkeratosis and skin inflammation. Creams and ointments that contain urea, ammonium lactate, or salicylic acid can be used, and topical corticosteroids are sometimes also used for grade ≥2 inflammation. It is recommended at first occurrence for grade 2 reactions to continue treatment and apply topical therapy and pause treatment if there is no improvement over several days. For grade 3 reactions, we usually hold the treatment until the toxicity resolves and then resume at a lower dose.14 Of course, these are the recommendations, but the healthcare professional must listen to the patients about what they think is tolerable.
Recently, another immunotherapy-based regimen was approved for the first-line treatment of advanced HCC.
The open-label, randomized phase III HIMALAYA study looked at the combination of durvalumab (anti–PD-L1 antibody) plus tremelimumab (anti–CTLA-4 antibody) vs durvalumab monotherapy vs sorafenib in patients with advanced HCC and no previous systemic therapy (N = 1171).15-17 Patients receiving the durvalumab plus tremelimumab combination, also called the STRIDE regimen, received a single dose of tremelimumab 300 mg and durvalumab 1500 mg every 4 weeks. The primary endpoint was OS in the combination arm vs sorafenib, with a key secondary endpoint looking at OS noninferiority of the durvalumab single-agent arm vs sorafenib. Other secondary endpoints included PFS, ORR, DoR, and safety. The study design had a fourth arm (n = 153) in which patients received a different dosing regimen of durvalumab plus tremelimumab; this arm was closed after planned analysis of the phase II study.
There was a statistically significant improvement in median OS from 13.8 months with sorafenib to 16.4 months with durvalumab plus tremelimumab (HR: 0.78; 96.02% CI: 0.65-0.92; P = .0035) that was also clinically meaningful.16,17 There is clear separation of the curves that extends out to the 36-month endpoint, where you can see a significant increase in OS rate from 20% to approximately 30%.
Single-agent durvalumab met noninferiority criteria for OS vs sorafenib, with a greater 36-month OS (24.7% vs 20.2%) and an improved median OS (16.6 vs 13.8 months; HR: 0.86; 95.67% CI: 0.73-1.03).16,17
A comparison of the probability of PFS for all 3 arms revealed a significant overlap.
In terms of tumor response, looking at ORR, we saw rates of 5.1% with sorafenib, 17.0% with durvalumab alone, and 20.1% with the combination therapy.
Regarding safety, the concern is always that the addition of an anti–CTLA-4 antibody will lead to more irAEs. The frequency of all AEs was uniformly high across the treatment arms. Grade 3/4 treatment-related AEs including those leading to discontinuation were actually the most prevalent in the sorafenib arm.16,17 However, the percentage of AEs requiring treatment with high-dose steroids was higher in the combination arm with tremelimumab.
In the HIMALAYA trial, we saw an ORR of 20.1% and a median OS of 16.4 months with durvalumab plus tremelimumab therapy.16,17 In IMbrave150 study, the atezolizumab plus bevacizumab arm had a median OS of 19.2 months and an ORR of 30%.2 Cross trial comparisons have significant limitations, but I think the current question we face is, how does the durvalumab plus tremelimumab regimen fit into the treatment landscape?
I would still consider atezolizumab plus bevacizumab as the gold standard for first-line therapy for advanced HCC. I would think about durvalumab plus tremelimumab for patients who are candidates for immunotherapy but not for bevacizumab, ie, those with a history of bleeding or a high risk of bleeding.
There are several ongoing trials investigating novel strategies for the first-line management of advanced HCC.
In the open-label, dose-escalation/dose-expansion phase I/II CheckMate 040 trial, 262 patients received single-agent nivolumab (anti–PD-1 antibody), and previous sorafenib treatment was allowed.20 The ORR for patients in the escalation (n = 48) or expansion (n = 214) cohorts was 20% and 15%, respectively. Based on this study, the FDA granted accelerated approval to nivolumab for the treatment of HCC in patients who have been previously treated with sorafenib.7
Subsequently, nivolumab monotherapy was tested in the front line in the open-label phase III CheckMate 459 study.21 Patients with advanced HCC (N = 743) were randomized 1:1 to receive nivolumab or sorafenib. The patient population could have had previous local therapy, with good Child-Pugh Class A status, good performance status, and no previous systemic therapy. The primary endpoint was OS, and secondary endpoints included PFS, ORR, and association between PD-L1 expression and efficacy.
In the CheckMate 459 trial, there was not a large difference between the OS or PFS curves for nivolumab and sorafenib, and the predefined threshold for significance of median OS was not reached.21 However, at the tail of the OS curve, it is clear that some patients do derive benefit from nivolumab treatment. The ORR was 15% with nivolumab vs 7% with sorafenib, which is consistent with what we see clinically.
Now, the ongoing randomized phase III CheckMate 9DW trial is looking at nivolumab plus ipilimumab (anti–CTLA-4 antibody) vs sorafenib or lenvatinib as first-line therapy (NCT04039607). Total planned enrollment is a little more than 1000 patients with advanced HCC, and the primary endpoint is OS with secondary endpoints of ORR, DoR, and time to symptom deterioration.
An alternative frontline approach pairs an ICI with a VEGF TKI.
Cabozantinib, which has shown OS and PFS benefits for the treatment of advanced HCC in the second-line setting,22 was also investigated in the first-line setting.
The randomized phase III COSMIC-312 trial looked at the efficacy of cabozantinib with or without atezolizumab vs sorafenib in patients with advanced HCC and no previous systemic treatment (N = 837).23 The primary endpoint was PFS for the combination vs sorafenib, and secondary endpoints were PFS, ORR, TTP, DoR, and safety of single-agent cabozantinib vs sorafenib. Although there were 3 arms, the statistical analysis compared 2 arms for each endpoint.
The figure on the left shows improved PFS of 6.8 months for cabozantinib plus atezolizumab vs 4.2 months for sorafenib (HR: 0.63 (99% CI: 0.44-0.91; P = .0012).23 However, the OS (figure on right) showed no obvious difference, and the ORR was 4% for sorafenib vs 11% for the combination. This is significantly less than what was seen with atezolizumab plus bevacizumab2 or with durvalumab plus tremelimumab.16,17 This result with a TKI inhibitor plus PD-L1 inhibitor is not considered practice changing.
The open-label phase Ib KEYNOTE-524 study looked at lenvatinib plus pembrolizumab (anti–PD-1 antibody) in patients with advanced HCC with no previous systemic therapy (N = 100).24 Primary endpoints included ORR, DoR, safety, and tolerability.
The ORR was 36% and the disease control rate was 88%. The median DoR for those who responded was 12.6 months, and the median OS was 22.0 months.
Based on KEYNOTE-524, the randomized phase III LEAP-002 study was designed to test first-line lenvatinib plus pembrolizumab vs lenvatinib plus placebo in patients with advanced HCC and no previous systemic therapy (N = 794).25 The primary endpoints were PFS and OS, and ORR was a key secondary endpoint.
At final analysis of the LEAP-002 trial, the median OS (21.2 vs 19.0 months; HR: 0.840; 95% CI: 0.708-0.997; P = .0227) and median PFS (8.2 vs 8.1 months; HR: 0.834; 95% CI: 0.712-0.978) of lenvatinib plus pembrolizumab vs lenvatinib plus placebo did not reach the prespecified efficacy parameters for statistical significance.26 However, the median OS with lenvatinib plus pembrolizumab (21.2 months) was the longest reported to date in first-line HCC phase III clinical studies.
The ORR in the immunotherapy arm vs lenvatinib plus placebo was 26.1% and 17.5%, respectively.
These results solidify lenvatinib’s position in first-line treatment regimens for advanced HCC.
Now that the first-line treatment has changed to include atezolizumab plus bevacizumab or durvalumab plus tremelimumab, an important question that often comes up is, how do we sequence beyond first line of therapy?
This slide is a flow chart of how we may think about next-line therapy. When patients receive atezolizumab plus bevacizumab in the first line, we often consider going back to the TKIs sorafenib or lenvatinib in what may be thought of as being like a first-line therapy, even though they have not been studied in the second line. This idea is not based on randomized studies, rather just the concept of returning to the first TKI with which we would usually treat.
There are data for regorafenib and cabozantinib as second-line TKIs after sorafenib and lenvatinib,22,27 so for patients with an autoimmune disorder, that would often be our best option. We know that ramucirumab has a potential benefit of a VEGF drug for patients with a α-fetoprotein level ≥400 ng/mL.28
Finally, there are second-line data for pembrolizumab29 and the combination of ipilimumab plus nivolumab,30 but we would not consider giving immunotherapy to someone with active autoimmune disease.
This slide shows some of the phase III studies on second-line VEGF-targeted therapies, with regorafenib on the left, cabozantinib in the center, and ramucirumab on the right.
In the phase III RESORCE study patients with HCC and previous sorafenib therapy (N = 573) were randomized 2:1 to regorafenib or placebo.27 The primary endpoint was median OS, which showed an improvement of 10.6 months for regorafenib vs 7.8 months for placebo (HR: 0.63; 95% CI: 0.50-0.79; P <.0001).
In the phase III CELESTIAL study, patients with advanced HCC previously treated with sorafenib (N = 707) were randomized 2:1 to cabozantinib or placebo.22 The primary endpoint was OS, and secondary endpoints were PFS and ORR. Cabozantinib treatment showed significant improvement in median OS (10.2 vs 8.0 months; HR: 0.76; 95% CI: 0.63-0.92; P = .005) and median PFS (5.2 vs 1.9 months; HR: 0.44; 95% CI: 0.36-0.52; P <.001) compared with placebo. Based on these results, the FDA approved cabozantinib for patients with HCC who have been previously treated with sorafenib.31
In the phase III REACH-2 trial, patients with advanced HCC previously treated with sorafenib and α-fetoprotein concentrations of ≥400 ng/mL (N = 292) were randomized 2:1 to receive ramucirumab or placebo.28 The primary endpoint was OS, and secondary endpoints included PFS, ORR, time to radiographic progression, and safety, among others. At median follow-up of 7.6 months, ramucirumab significantly improved median OS (8.5 vs 7.3 months; HR: 0.71; 95% CI: 0.53-0.95; P = .0199) and PFS (2.8 vs 1.6 months; HR: 0.45; 95% CI: 0.34-0.60; P <.0001) compared with placebo. Based on this study, the FDA approved ramucirumab as a single agent for the treatment of HCC in patients who have an α-fetoprotein of ≥400 ng/mL and have been treated with sorafenib.32
As you can see, there were no large survival benefits in these studies, with an improvement in median OS of approximately 1-2 months vs placebo.
Looking at the AEs in these trials, it is not surprising to see TKI-related toxicity such as diarrhea, fatigue, and hypertension for regorafenib and cabozantinib. In the REACH-2 study with ramucirumab, we saw some fatigue, hypertension, and anorexia.22,27,28
Second-line immune therapy is an option for some patients with advanced HCC. In one part of the open-label phase I/II CheckMate 040 study, nivolumab was tested in combination with ipilimumab.30,33
Patients with advanced HCC and previous treatment with sorafenib (n = 148) were randomized 1:1:1 to 3 different dosing strategies that included 1 mg/kg or 3 mg/kg of nivolumab or ipilimumab in various combinations. In one arm, patients received nivolumab 1 mg (NIVO1)/ipilimumab 3 mg (IPI3) every 3 weeks (Q3W). In another they received nivolumab 3 mg (NIVO3)/ipilimumab 1 mg (IPI1) Q3W, and patients in the final arm received NIVO3 every 2 weeks (Q2W)/IPI1 every 6 weeks (Q6W). Coprimary endpoints included ORR, safety, and tolerability.
The ORR was similar in all 3 dosing regimens at 32% in the NIVO1/IPI3 Q3W arm, 31% in the NIVO3/ IPI Q3W arm, and 31% in the NIVO3 Q2W/IPI1 Q6W arm.
There was a slightly higher disease control rate in the NIVO1/IPI3 arm (54%) compared with the 2 NIVO3/IPI1 regimens (43% and 49%, respectively). The highest median DoR was in the NIVO3/IPI1 Q3W arm at 22.2 months vs 17.5 months in the NIVO1/IPI3 Q3W arm and 16.6 months in the NIVO3 Q2W/IPI1 Q6W arm. The NIVO1/IPI3 arm showed the highest median OS (22.2 months) compared with the 2 NIVO3/IPI1 arms (12.5 months in NIVO3/IPI1 Q3W and 12.7 months in NIVO3 Q2W/IPI1 Q6W).
Based on these results, the FDA granted accelerated approval to the combination of nivolumab and ipilimumab for patients with HCC who have been previously treated with sorafenib.7,34
This table shows safety data for the CheckMate 040 study, including some common irAEs such as skin toxicity (pruritus and rash), diarrhea, increased lipase and alanine aminotransferase, fatigue, and thyroid changes.30,33
Looking at another immune therapy option, the earlier single-arm phase II KEYNOTE-224 study showed potential efficacy (ORR: 17%) for pembrolizumab in 104 patients with advanced HCC who were either intolerant or had progressed on sorafenib, with good liver function.35 Based on these results, the FDA granted accelerated approval to pembrolizumab for patients with HCC who have been previously treated with sorafenib.8
This was followed by the randomized, open-label phase III KEYNOTE-240 study, which evaluated pembrolizumab vs placebo in patients with advanced HCC previously treated with sorafenib (N = 413).29 This study had coprimary endpoints of PFS and OS, with secondary endpoints of ORR, DoR, disease control rate, TTP, and safety.
KEYNOTE-240 did not reach prespecified cutoffs for significance in the primary analysis, either for median OS or median PFS for pembrolizumab vs placebo.29 In an updated analysis with a median follow-up of 40 months, the median OS for pembrolizumab vs placebo was 13.9 months vs 10.6 months (HR: 0.77; 95% CI: 0.62-0.96; P = .0112) and median PFS was 3.2 months vs 2.8 months (HR: 0.70; 95% CI: 0.56-0.88); P = .0011).36 The ORR was 18.3% for pembrolizumab vs 4.4% for placebo. Long-term follow-up remains, and there is some difference in these curves that does extend out to the tails, so there are some patients who do respond to single-agent immune therapy.
The very similar phase III KEYNOTE-394 study looked at pembrolizumab vs placebo in Asian patients with previously treated advanced HCC (N = 453).37 The difference in median OS (14.6 vs 13.0 months) was not statistically significant, much like KEYNOTE-240.
Finally, the ongoing randomized phase III Imbrave251 study is testing atezolizumab plus lenvatinib or sorafenib in patients with advanced HCC after previous treatment with atezolizumab plus bevacizumab (N = 554) (NCT04770896). The primary endpoint is OS, and the key secondary endpoints are PFS, ORR, TTP, and DoR. We look forward to the results of this trial as they will help us understand how to sequence therapy after atezolizumab plus bevacizumab.
There is much debate over the optimal sequencing of subsequent therapies. Questions often arise about whether to give additional immunotherapy after atezolizumab and bevacizumab vs sequencing TKIs. One criterion that could be considered in trying additional immunotherapy may be having had an initial response to atezolizumab plus bevacizumab and having tolerated it. But at this point, we do not have the data to give the optimal sequence.
Systemic therapy is often focused on advanced stage C patients. However, as more drugs are developed that have survival benefits for this patient population, there is great interest in moving systemic therapy earlier in the course of the disease to try to improve survival in a more meaningful way.
We know that recurrence rates can be high post resection,38 and we currently have no neoadjuvant or adjuvant therapies for HCC. This represents a large unmet need in HCC.
In the phase III STORM trial, patients with HCC who underwent hepatic resection (n = 900) or ablation (n = 214) with curative intent were randomized 1:1 to receive either sorafenib or placebo as adjuvant therapy. Median recurrence-free survival was the primary endpoint, and there was found to be no difference for sorafenib compared with placebo (33.3 vs 33.7 months; HR: 0.94; 95% CI: 0.78-1.134; P = .26).39 Unfortunately, the therapy was poorly tolerated and failed to produce significant benefit for OS or time to recurrence.
There are several key ongoing clinical trials looking at adjuvant or neoadjuvant therapies for advanced HCC.
Since immune therapies are known to be active in many patients in the more advanced setting, there is great interest in finding how they may perform in the adjuvant therapy setting for HCC. There are multiple ongoing studies that are looking at immune therapies (alone or in combination) vs placebo or active surveillance, and those data are eagerly awaited. Although adjuvant studies do take a while to read out, hopefully, one or more will be practice changing and improve outcomes for our patients.
There are also multiple ongoing studies looking at immunotherapy combinations in the neoadjuvant setting.
In this rapidly evolving field, we now have the atezolizumab plus bevacizumab combination that is often the first-line therapy for most patients with good liver function. Given the other options, it is up for debate what the subsequent lines of therapy should be. We will have to see where other immune therapy combinations fit and ask important questions such as: How do we incorporate the HIMALYA data in the landscape?
Of course, it is also important to look at moving immunotherapy earlier in the treatment of HCC, thinking about how to give neoadjuvant or adjuvant therapy. It is our hope that we will see positive results from some of the ongoing neoadjuvant and adjuvant therapy trials that can greatly improve treatment outcomes for our patients.
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