In 2007, sorafenib became the first approved systemic therapy for hepatocellular cancers and the first agent to improve overall survival in these patients.1 In a similar multikinase inhibitor strategy, lenvatinib was found to be noninferior to sorafenib in overall survival in the same patient population.2 Thus, multikinase inhibitors have been the front-line therapy in patients with hepatocellular cancer for more than a decade.
The IMbrave150 study, as reported in The New England Journal of Medicine by Finn et al—and reviewed in this issue of The ASCO Post—now represents a nonmultikinase approach and a probable new standard of care for the treatment of patients with unresectable hepatocellular cancer.3 The IMbrave150 study also represents the successful clinical manifestation of a rational combination strategy for treating these difficult cancers and should signal the routine incorporation of patient-reported outcomes into future pivotal oncology clinical trials.
A. Craig Lockhart, MD, MHS
VEGF Inhibition Plus Immunotherapy: ‘A Natural Combination Strategy’
Globally, hepatocellular cancer has a considerable public health impact. Worldwide, it ranks as the sixth most common malignancy and fourth most common cause of cancer-related death.4 Therefore, novel therapeutic approaches in hepatocellular cancer have the potential for impacting a very large population of patients (more than 800,000 new worldwide cases annually).
With the clinical success of sorafenib and lenvatinib, which both inhibit the vascular endothelial growth factor receptor (VEGFR) as part of their kinase inhibition profile, it is clear that VEGF inhibitors are a validated treatment approach to these cancers. Beyond tumor angiogenesis, VEGF has well-described roles in modulating the tumoral immune milieu. In part, VEGF promotes the tumoral infiltration of inhibitory immune cells such as regulatory T cells and myeloid-derived suppressor cells. Additionally, VEGF suppresses dendritic cell maturation, decreases the T-cell immune response, and alters lymphocyte development and trafficking.5 It is therefore a natural combination strategy to combine VEGF inhibition with immunotherapy.
In hepatocellular cancer, and a number of other malignancies, immunotherapy and anti-VEGF therapy have demonstrated single-agent efficacy. In patients with hepatocellular cancer who had disease progression or unacceptable adverse effects with sorafenib, treatment with the PD-1 inhibitor nivolumab led to a median survival of 15.6 months and an overall response rate of 14.3% in a phase II trial.6 Of note, these therapies were shown to be safe in patients with hepatitis B (HBV) or C (HCV), which account for the development of a considerable percentage of hepatocellular cancer cases. The clinical data prompted U.S. Food and Drug Administration approval for nivolumab under the accelerated program. In two combination clinical trials adding immune checkpoint inhibitors to standard VEGF-targeted therapies to treat hepatocellular cancer, encouraging antitumor outcomes and adverse event profiles were observed, providing the impetus for the IMbrave150 study.7,8
Closer Look at IMbrave150
In the IMbrave150 study, a global, open-label, phase III trial, patients with unresectable hepatocellular cancer who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or standard sorafenib. The study co-primary endpoints were overall survival and progression-free survival.
As reported, for the patients in the atezolizumab-bevacizumab group (n = 336), the hazard ratio (HR) for death as compared with sorafenib (n = 165) was 0.58 (95% confidence interval [CI] = 0.42–0.79, P < .001). Overall survival at 12 months was 67.2% (95% CI = 61.3%–73.1%) with atezolizumab/bevacizumab and 54.6% (95% CI = 45.2%–64.0%) with sorafenib. Median progression-free survival was 6.8 months (95% CI = 5.7–8.3 months) vs 4.3 months (95% CI = 4.0–5.6 months; HR = 0.59, 95% CI = 0.47–0.76, P < .001). Therefore, the IMbrave150 study met its co-primary endpoints, confirming the success of this rational combination approach.3 Of note, no new toxicity signals were identified in the study group, and due to the risk of variceal bleeding in patients with cirrhosis, all study participants were evaluated and treated for esophageal varices as indicated.
In any hepatocellular cancer study such as IMbrave150, the population-specific outcomes can help to define the patients most likely to benefit when the therapy is applied to a general community population. The forest plot (in the supplemental materials) showed the therapy was beneficial in patients with HBV- or HCV-related hepatocellular cancer and in both Asian and non-Asian populations. The majority of patients had relatively well-preserved liver function, with more than 70% being Child-Pugh A5, so studies of the efficacy and toxicity in patients with more compromised liver function will be informative. An anticipated result is whether PD-L1 status will be predictive of study treatment success. In previous studies in hepatocellular cancer, PD-L1 status was not predictive of efficacy when patients were treated with PD-L1 or PD-1 inhibitors.9 We expect these results from the IMbrave150 study to be presented at a later date.
Benefits of Patient-Reported Outcomes
Patient-reported outcomes data captured from IMbrave150 showed that the atezolizumab/bevacizumab combination resulted in a longer time to deterioration of patient-reported quality of life and functioning than sorafenib. Considering the anticipated expense of the atezolizumab/bevacizumab combination, the favorable patient-reported outcomes are important. The incorporation of patient-reported outcome assessments into cancer clinical trials would potentially provide more comprehensive outcomes assessment of treatment effects, including the effectiveness of symptom management interventions; improve attribution of treatment-related toxicities; and assist with assessing the health-related economic value of an intervention.10 The encouraging patient-reported outcomes in favor of atezolizumab/bevacizumab provide some additional justification in support of the study combination.
The IMbrave150 study appears to be the culmination of preclinical and clinical studies supporting combining immunotherapy and VEGF inhibitors. The success of the combination strategy in hepatocellular cancer suggests that both atezolizumab and bevacizumab contribute to the overall treatment benefit. The favorable outcomes across essentially all study subgroups joined with the manageable and expected toxicity profile support the adoption of atezolizumab/bevacizumab as the standard-of-care first-line therapy for patients with hepatocellular cancer meeting the study inclusion criteria. The clear patient-reported outcomes in favor of the combination as well as the successful incorporation of patient-reported outcomes assessments into this study should encourage the future deployment of patient-reported outcomes into pivotal oncology studies. Future directions in this clinical setting should include using atezolizumab/bevacizumab as a therapeutic backbone for hepatocellular cancer studies, determining biomarkers that might predict therapeutic benefit, and focused evaluations of this combination in patients with less well-preserved liver function.
Dr. Lockhart is Associate Director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System.
DISCLOSURE: Dr. Lockhart has received research funding from Bristol-Myers Squibb, Merck, Astellas Pharma, and Sarah Cannon Research Institute.
REFERENCES
1. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008.
2. Kudo M, Finn RS, Qin S, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma. Lancet 391:1163-1173, 2018.
3. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.
4. Bray F, Ferlay J, Soerjomataram I, et al: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394-424, 2018.
5. Ohm JE, Carbone DP: VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res 23:263-272, 2001.
6. El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040). Lancet 389:2492-2502, 2017.
7. Ikeda M, Sung MW, Kudo M, et al: A phase 1b trial of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. 2018 ASCO Annual Meeting. Abstract 4076. Presented June 3, 2018.
8. Lee MS, Ryoo B, Hsu C, et al: Randomised efficacy and safety results for atezolizumab + bevacizumab in patients with previously untreated, unresectable hepatocellular carcinoma. ESMO 2019 Congress. Abstract 3502. Presented September 27, 2019.
9. Zhu AX, Finn RS, Edeline J, et al: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol 19:940-952, 2018.
10. Di Maio M, Basch E, Bryce J, et al: Patient-reported outcomes in the evaluation of toxicity of anticancer treatments. Nat Rev Clin Oncol 13:319-325, 2016.
