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Professor of Clinical Medicine
Division of Hematology-Oncology
Director, Signal Transduction and Therapeutics Program
Jonsson Comprehensive Cancer Center
David Geffen School of Medicine at UCLA
Los Angeles, California
Richard Finn, MD, has disclosed that he has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Lilly, Merck, Pfizer, and Roche/Genentech.
In the past 3 years, several targeted agents and immunotherapies have been approved for treating patients with advanced HCC, marking the first approvals since sorafenib in 2008. The combination of atezolizumab plus bevacizumab was most recently approved as first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC), including unresectable and metastatic disease. In this commentary, I review the data supporting this approval and discuss how I plan to use this new therapeutic option in my practice.
Where We’ve Been: Tyrosine Kinase Inhibitors
Sorafenib, a multitargeted tyrosine kinase inhibitor (TKI), was established as the standard of care for advanced HCC after the 2008 phase III SHARP study demonstrated an OS improvement with this agent vs placebo. At that time, no drug had been shown to improve survival in advanced HCC. It is important to briefly define those patients with advanced HCC who are appropriate candidates for systemic therapy: patients with Barcelona stage C disease (those with HCC that has metastasized outside the liver or remains within the liver but has invaded the liver vasculature) and patients with intermediate-stage or Barcelona B disease (those with HCC that remains confined to the liver [ie, no extrahepatic spread or no vascular invasion]) who have not responded to or progressed after TACE (chemoembolization) or other locoregional treatments.
During the decade following the approval of sorafenib, studies with numerous agents failed to demonstrate improved or noninferior outcomes vs sorafenib. In 2018, a study of lenvatinib (another TKI) in patients with advanced HCC showed that this agent was noninferior, but not superior, to sorafenib in terms of OS (although lenvatinib treatment was associated with improved secondary endpoints ORR and PFS).
Immunotherapy for Advanced HCC
The impact of immune checkpoint inhibitors on patient outcomes in numerous cancer types has been significant. Both nivolumab and pembrolizumab were assessed in nonrandomized phase II studies in patients with advanced HCC and subsequently received accelerated FDA approval for treating patients who previously received sorafenib. These studies showed that these immune checkpoint inhibitors were associated with response rates of 15% to 20%.
These findings generated excitement about immunotherapy in advanced HCC and led to several phase III studies. We now have results for 2 of these studies. Unfortunately, in CheckMate 459, there was no improvement in survival with nivolumab vs sorafenib for patients who had not received previous systemic therapy. Similarly, in the second-line setting, the KEYNOTE-240 study did not show a statistically significant OS improvement with pembrolizumab vs placebo after sorafenib.[
However, it was clear from these data sets that there is a subgroup of patients who obtain significant benefit from these drugs, although no biomarker has been identified that might indicate which patients these might be. As a result, investigators began combining immune checkpoint inhibitors with other drugs, as with atezolizumab and bevacizumab in IMbrave150 (described below). Numerous first-line phase III combination trials are ongoing, including LEAP-002 (lenvatinib + pembrolizumab vs lenvatinib), HIMALAYA (durvalumab ± tremelimumab vs sorafenib), COSMIC-312 (cabozantinib + atezolizumab vs sorafenib), and CheckMate 9DW nivolumab + ipilimumab vs sorafenib or lenvatinib).
Atezolizumab Plus Bevacizumab as First-line Therapy for Advanced HCC
Atezolizumab is an anti–PD-L1 antibody, and bevacizumab is a vascular endothelial growth factor inhibitor. The rationale behind the therapeutic combination of these agents was that combining an antiangiogenic therapy with immune checkpoint inhibition may promote immune responsiveness in the HCC microenvironment and reduce local immune suppression.
This combination was initially assessed in a phase Ib study in patients with advanced HCC who had received no previous systemic treatment (n = 104) and demonstrated an ORR of 36% with a provocative median PFS of 7.3 months. Compared with the first-line TKIs typically used in liver cancer (lenvatinib and sorafenib) or even to single-agent checkpoint inhibitors, this response rate was very high. No unexpected safety signals were seen with the combination, which was associated with typical bevacizumab-related toxicities, such as hypertension, pyrexia, and some increase in bleeding (although there were few major bleeding events). Expected adverse events of atezolizumab were also observed, including autoimmune-related rash and thyroid issues. Generally, the combination of atezolizumab and bevacizumab was felt to be well tolerated and safe.
Based on that fairly large phase Ib study, the decision was made to initiate a randomized phase III study comparing the combination of atezolizumab and bevacizumab with sorafenib as first-line systemic therapy for patients with advanced liver cancer; this study was named IMbrave150. Of importance, like every phase III study in advanced liver cancer, IMbrave150 included patients with Child-Pugh A cirrhosis, thereby minimizing the risk of death from underlying liver disease or cirrhosis. Patients were required to have had an upper endoscopy within 6 months of starting treatment because varices are common in patients with cirrhosis and bleeding can occur in patients treated with bevacizumab.
The IMbrave150 results were published in May 2020, showing a 12-month OS of 67.2% with atezolizumab plus bevacizumab vs 54.6% with sorafenib, for an HR of 0.58 (P < .001). This 42% reduction in the risk of death was so significant, the study was stopped after its first interim analysis. In considering survival in a similar population of patients in the SHARP study, the OS benefit with sorafenib vs placebo yielded an HR of 0.69. IMbrave150 demonstrated an even lower HR of 0.58 with atezolizumab plus bevacizumab vs sorafenib. This is a very significant survival improvement and the median OS has not yet been reached with atezolizumab plus bevacizumab, although the median follow-up in the study is still relatively short at 8.6 months. Median PFS was 6.8 months with combination therapy vs 4.3 months for sorafenib with an HR of 0.59, which is very consistent with the OS benefit.
Similar to results from the preceding phase Ib study, the ORR for atezolizumab plus bevacizumab was quite remarkable (per RECIST: 27% vs 11.9% with sorafenib). Of note, the 11.9% response rate with sorafenib was the highest reported in an HCC study. Likewise, the disease control rate was 73.6% with atezolizumab plus bevacizumab vs 55.3% with sorafenib, and the median duration of response has not been reached with atezolizumab plus bevacizumab. These are very exciting efficacy data that are unprecedented in the liver cancer setting. Even in the absence of a biomarker for a response, the combination clearly improved both survival and responses compared with sorafenib.
Rates of AEs were very similar in both arms, with approximately 98% of all patients experiencing events of any grade. Rates of grade 3/4 events were also very similar in both arms, at 56.5% with atezolizumab plus bevacizumab vs 55.1% with sorafenib. Rates of grade 5 events were actually higher with sorafenib, at 5.8% vs 4.6% with atezolizumab plus bevacizumab, but rates of serious adverse events were slightly higher with the combination at 38.0% vs 30.8% with sorafenib. Overall, there was a favorable safety profile with atezolizumab plus bevacizumab, especially regarding common adverse events of atezolizumab and bevacizumab (eg, hypertension, fatigue), which were slightly higher than with sorafenib alone. Although there were more bleeding events with the combination, they were generally low grade. Of importance, hand–foot syndrome—an inherent concern with sorafenib—was seen in only 3 patients receiving atezolizumab plus bevacizumab vs 75 patients (48%) receiving sorafenib. Also, diarrhea of all grades was significantly more common with sorafenib at 49.4% vs 18.8% with atezolizumab plus bevacizumab. The time to deterioration in quality of life was markedly attenuated with atezolizumab plus bevacizumab compared with sorafenib (median: 11.2 vs 3.6 months; HR: 0.63). This is supported by other patient-reported outcome measures that all favor the combination over sorafenib.
Based on findings from IMbrave150, atezolizumab plus bevacizumab was approved by the FDA as a first-line systemic treatment for patients with unresectable or metastatic HCC.
How I Plan to Use Atezolizumab Plus Bevacizumab in My Practice
The IMbrave150 study results are exciting for patients with advanced HCC. Atezolizumab plus bevacizumab can offer improved OS, ORR, and PFS plus a very favorable adverse event profile and an improvement in quality of life vs sorafenib. Certainly, clinical trials are always appropriate and I strongly encourage patients to consider participation in research studies, but in clinical practice, atezolizumab plus bevacizumab should be considered our frontline regimen.
Patients who are being considered for this combination (administered IV once every 3 weeks) should have well-compensated liver function and no comorbidities that would preclude atezolizumab or bevacizumab. Patients should be closely followed for any toxicities, either autoimmune toxicities or adverse events from bevacizumab, such as hypertension and bleeding events. Clinicians should try to mitigate bleeding events by conducting endoscopies as needed prior to initiating treatment. If patients develop adverse events, intervening early is ideal; it may be preferable to see patients between cycles as well as at their every-3-week treatment appointment, at least until they appear stable on treatment.
Do you plan to adopt atezolizumab plus bevacizumab as first-line therapy for most of your patients with advanced HCC? Leave your comments below to join in the conversation.
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