N Engl J Med 2020 May 14
Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
Abstract
Background
The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
Methods
In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
Results
The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.
Conclusion
In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, <a href="http://clinicaltrials.gov/show/NCT03434379" title="See in ClinicalTrials.gov">NCT03434379</a>.).
Related Questions
How long would you continue atezolizumab/bevacizumab in a patient with HCC who is having a prolonged response with stable disease?
Similar to how this was done in the phase 3 trial of atezolizumab/bevacizumab (vs sorafenib), I continue until progression or intolerance. Finn et al., PMID 32402160
What factors would make you choose IPI3/NIVO1 frontline for advanced unresectable and metastatic HCC based on CheckMate 9DW?
Great question! CheckMate 9DW with the combination IPI3/NIVO1 compared to sorafenib/lenvatinib (85% were lenvatinib in the control arm) significantly improved OS (23.7 months vs 20.6 months, HR 0.79, P-value 0.018), response 36% vs 13% (P-value <0.0001). Based on these data, it received FDA approval...
What non-variceal EGD findings, if any, deter you from using atezo/bev in patients with advanced HCC?
I would discuss the severity and risk of bleeding with the endoscopy team and start beta blockers as indicated before starting anti-angiogenesis therapy.
What clinical factors influence your first line treatment selection in advanced HCC?
With now many options of therapy for the treatment of advanced HCC, this is good news. It is also a challenge of how to pick and choose, and what factors may influence the choice of first line treatment.The possible choices would be either the combination of checkpoint inhibitor plus an add-on thera...
How does data from the HIMALAYA trial impact your first line treatment selection for advanced HCC?
The results from the HIMALAYA trial with the combination tremelimumab (CTLA-4 inhibitor) and durvalumab (PD-L1 inhibitor) reported an OS of 16.4 months compared to 13.8 months for sorafenib which was statistically significant (HR 0.78, p-value of 0.0035). With the limited data presented at ASCO GI 2...
Would you prioritize TACE or systemic therapy in BCLC B multifocal HCC with tumor bulk higher than "up to 7?"
This is a challenging area where we need more definitive studies. With the info available, I do favor systemic therapy for such patients. Liver directed therapy is unlikely to lead to adequate control for such multifocal disease and the patient is likely to require multiple treatments to different a...
For patients with EGFR mutation positive NSCLC who progress on first line TKI without actionable resistance mechanisms, would you consider chemotherapy + targeted therapy as a second line option, or chemotherapy +/- immunotherapy?
This is certainly not an easy question. Assuming that the patient doesn't have an actionable targetable mutation, two important things that may be helpful to know in such cases are disease behavior and the status of disease in the brain. If the disease is behaving aggressively, we SHOULD ALWAYS rule...
Would you use bevacizumab in a patient with advanced HCC and multiple large esophageal varices that have not been endosopically intervened upon?
Large varices should be treated endoscopically. I would avoid using Atezo/bev in a patient who has not had adequate treatment of their varices as there is a real risk of bleeding with bev in this setting.
What is your platelet cutoff for atezolizumab + bevacizumab in HCC in the absence of bleeding (variceal or otherwise)?
The platelet eligibility for IMBrave150 was 75K, I believe. Eligibility in the original SHARP trial was 60K, so I often consider somewhere around 60K. Although if truly no varices on EGD and no history of bleeding, I might consider down to 50K. Lower than that, I would probably think single agent ch...
Is anticoagulation a relative contraindication to atezolizumab/bevacizumab for advanced HCC?
Anticoagulation is considered safe with bevacizumab unless the patient has an increased of bleeding; as such, any varices should have been adequately treated before treatment with atezolizumab/bevacizumab; I would also avoid anticoagulation and atezo/bev concurrently in patients with platelet count ...
For patients with HCC receiving atezo/bev, would you advise any other clinical investigations scheduled during treatment other than basic lab monitoring?
In the IMBrave 150 study, the most common serious toxicity in the AB arm was GI bleeding. And everyone was required to have their varices both evaluated and treated. It’s not convenient, but get the EGD before starting treatment!
When would you continue atezolizumab/bevacizumab beyond progression in advanced HCC?
The key parameters I use when considering treatment beyond progression for a patient on atezolizumab bevacizumab are clinical symptoms as compared to baseline, performance status as compared to baseline, and underlying hepatic function as compared to baseline. If there is worsening in any of these a...
Are there any biomarkers that might indicate who might be responders to atezolizumab/bevacizumab for HCC?
Not at this time. Some preliminary studies are being done as ad hoc at this point and was not pre specified before the IMbrave study launching
How do you manage patients on atezolizumab/bevacizumab with advanced HCC who develop arterial thrombosis?
Arterial thrombosis such as coronary artery events or CVAs is an indication to discontinue bevacizumab. Patients with arterial thrombotic events within the past 6 months should not be treated with bevacizumab; events older than 6 months do not represent a contraindication, especially if the patient ...
For patients with HCC that have stable disease on immunotherapy alone, would you consider adding bevacizumab at the time of disease progression and continue immunotherapy?
Given we now have multiple options for treatment of HCC in the second line setting, at present, I would favor transition to a TKI or ramucirumab. If the patient had prolonged stable disease on single-agent immunotherapy and could potentially tolerate ipilimumab/ nivolumab, I would consider this regi...
How do you decide between systemic vs. arterially directed therapies in the first line setting for unresectable HCC?
In IMbrave150, 63% of patients treated with atezolizumab/bevacizumab had extrahepatic spread of disease, and my recommendation for patients with extrahepatic involvement is for first line systemic therapy. For patients with unresectable disease without extrahepatic spread, we take a multi-disciplina...
Would you use upfront atezo/bev in a patient with HCC and untreated hepatitis?
In the case of a patient with untreated chronic hepatitis C, I would offer upfront atezo/bev, as long as hepatic function is appropriate. At our center, hepatitis C treatment is generally not offered to patients with advanced HCC. Interestingly, only 21% of patients treated with atezolizumab/bevaciz...
Do you refer all of your patients for EGD prior to initiation of atezolizumab/bevacizumab for advanced HCC?
Per the trial, this was required within 6 months of starting the study. However, in practice, I don't know that this strict rule would be necessary. For example, what if an EGD was done 10 months ago without varices? I don't think I would feel strongly about this. Similarly, if we could get one shor...
Would you consider using bevacizumab/atezolizumab in HCC patients who received TKI in the first line?
This is a great question. After failure of a front-line single agent TKI, I would still favor the current FDA-approved agents: regorafenib; cabozantinib; ramucirumab in AFP-high; OR immunotherapy (nivolumab, pembrolizumab, OR nivolumab plus ipilimumab). It is important to note that the second-line ...
What is your preferred second line treatment for advanced hepatocellular carcinoma after progression on atezolizumab and bevacizumab?
Atezolizumab plus bevacizumab and other potential combination therapies will become what I have been calling line minus 1. This will help provide the proven value of sorafenib followed by regorafenib; lenvatinib as first line; ramicirumab as second line if AFP is >400mg/mL; and cabozantinib as secon...