Immunotherapy in HCC—No rush despite the hype
Authors: Bruno Sangro, Josepmaria Argemí
Journal: Hepatology (2022)

SEE ARTICLE ON PAGE 1000 Clinical trials remain the gold standard to test new drug therapies against cancer in an attempt to mitigate bias from different sources through randomization, stratification, blinding, and other design tools. Restrictions to enrollment based on tumor and patient characteristics also help mitigate bias but result in only a fraction of the potential candidates being represented in the trial population. The size of this fraction depends on the adequacy of the inclusion and exclusion criteria. Typically, patients are excluded if they are better served by more effective treatments, have contraindications to the drugs that are tested, or have comorbidities that can reduce their likelihood to benefit from the experimental therapy. In the case of HCC, such comorbidities include the commonly underlying liver cirrhosis, which competes for the risk of adverse events and death. Once a therapy with proven benefit is approved and widely available, physicians may and usually do expand to some extent the indication and treat patients who do not fully meet the selection criteria in the corresponding trial. The analysis of this experience in real‐world studies (RWSs) certainly contribute to the general knowledge of a given therapy but carry a risk of being misleading or harmful. Based on the superior overall survival (OS) and progression‐free survival observed in the pivotal Imbrave 150 clinical trial,[1] regulatory agencies worldwide have approved the use of atezolizumab plus bevacizumab for the treatment of adult patients with unresectable HCC who have not received prior systemic therapy. Moreover, clinical practice guidelines have recommended this use.[2,3] The indication does not consider restrictions based on liver decompensation or dysfunction. In this issue of hepatology, D’Alessio et al.[4] report on a retrospective analysis of the outcome of 202 patients with HCC who were treated with atezolizumab plus bevacizumab at 11 centers in 7 countries from America, Europe, and Asia. There were important differences in the patients’ profile of this RWS compared with the profile of patients enrolled in the Imbrave 150 trial. As could be expected from their geographical origin, fewer patients had HBV infection (17% vs. 49%), and more were uninfected (47% vs. 30%). In terms of tumor burden, fewer patients had extrahepatic metastasis (38% vs. 63%). However, most notably, a significant number of patients had decompensated cirrhosis (31% had ascites and 12% hepatic encephalopathy), and 24% were in Child‐Pugh B (CPB) class. The analysis of this subgroup of patients with decompensated cirrhosis that would have been excluded from the clinical trial is indeed the main novelty of the study. RWSs are important because the performance of a given therapy among patients enrolled in a randomized trial could be worse in the daily clinical practice, due to lower compliance among less motivated patients, worse tolerability due to less intensive monitoring, inferior clinical conditions at the time of treatment, reduced experience in treating physicians, or increased competing risks of death. In this sense, this RWS provides some reassurance that the performance of atezolizumab plus bevacizumab is not greatly attenuated in the general population of patients with HCC with Child‐Pugh A and an indication of systemic therapy. The response rate was the expected one and was not influenced by tumor stage or disease etiology (viral vs. nonviral). OS was worse than in the Imbrave 150 trial (median 14.9 vs. 19.2 months), but this can be largely explained by the inclusion of CPB patients given the 16.8‐month (95% CI, 14.1–23.9) median OS observed in Child‐Pugh A patients. From a safety perspective, patients in the RWS experienced fewer treatment‐related adverse events of grade 3–4 (27% vs. 43%) or leading to treatment discontinuation (5% vs. 22%). Much of these differences can be explained by the shorter follow‐up and treatment duration (median 9 vs. 15.6 months and 3.5 vs. 8.4 months, respectively) and the less stringent monitoring of toxicities in RWS compared with clinical trials. Altogether, the data support the good tolerability of the combination immunotherapy, which has been shown across tumor types. Yet, bleeding and thrombotic events induced by bevacizumab are a matter of concern in patients with HCC. Patients with cirrhosis carry an increased risk of gastrointestinal bleeding events from ruptured gastro‐esophageal varices or hypertensive gastropathy. This risk is further increased in the presence of portal vein invasion,[5] and the risk of severe bleeding is increased in CPB patients.[6] In the Imbrave 150 trial, patients had an upper endoscopy performed during screening to secure that appropriate prophylaxis of variceal bleeding was provided. Surprisingly, only 53% of patients in the RWS had evidence of an upper endoscopy before treatment. Compared with the Imbrave 150 trial, a higher proportion of patients had variceal bleeding (4.4% vs. 0.9%), but none of them were fatal, and this is reassuring. Moreover, 26 patients (41% of those with varices) underwent band ligation with or without beta‐blockers, likely those at largest risk of bleeding. Bevacizumab impairs wound healing and may increase the chances of bleeding while varices eradication through ligation is completed. A detailed reporting on the management (e.g., delayed bevacizumab starting) and outcome of this subgroup of patients would have been very welcomed. Bleeding events of any nature were not associated with the presence of impaired liver function, portal hypertension or portal vein thrombosis, but the association was not investigated specifically for variceal bleeding events according to Child‐Pugh class and size of varices. RWSs are valuable to describe the outcome of patients who were not well represented or even excluded from pivotal trials. CPB patients are a nice example. However, it should be noticed that the lack of randomization makes the estimation of the treatment‐associated benefit inaccurate. Is the evidence provided by this RWS solid enough to support the treatment of every CPB patient with atezolizumab plus bevacizumab? The opinion of these editorialists is that we need more robust evidence to answer this question positively. The prognosis of CPB patients with HCC depends on the local and systemic complications of cirrhosis as much as on tumor growth. Only if the latter has a relevant contribution to the impaired liver function or increased portal pressure shall antitumor therapy provide clinical benefit. In other words, HCC is sometimes a by‐stander who silently witnesses the final stage of cirrhosis. The median OS at 6.7 months (95% CI, 4.3–15.6) observed in the CPB subgroup of the RWS is comparable to the 9.8 months (95% CI 3.7–14.3) reported for systemic therapy‐naïve patients receiving nivolumab in a prospective cohort in the Checkmate 040 trial.[7] These low numbers tell us that a benefit is at the most provided to only a fraction of the patients—likely those who achieve an objective remission. Indeed, median OS was not reached (95% CI, 10.4–not reached) among patients (12%) in the nivolumab cohort who experienced an objective tumor remission. This RWS strongly suggests that atezolizumab plus bevacizumab can be safely used in CPB patients, but we need stronger efficacy data, as well as more robust data on the risk of bleeding events related to portal hypertension, before we embrace this combination or any other one as the standard of care in this frail population. The study by D’Alessio et al. underlines the great opportunity and unmet need of investigating whether specific groups of patients not enrolled in clinical trials may benefit from immunotherapy combinations with undisputable antitumor efficacy, including atezolizumab plus bevacizumab and tremelimumab plus durvalumab.[8] The list is long and includes patients with recently and mildly decompensated cirrhosis, those with viral co‐infections (HBV and HDV) or infected with the HIV, and others (Figure 1). Studies should be prospectively conducted, have meaningful endpoints and sample size, and be designed with narrow rather than wide selection criteria.FIGURE 1: Supporting evidence for the use of atezolizumab plus bevacizumab within the Food and Drug Administration label. Histological subtypes include sarcomatoid, mixed hepatocellular‐cholangiocellular carcinoma, and othersRegarding the population of patients with a history of decompensated cirrhosis, those more likely to benefit from immunotherapy in this setting could be chosen through enrollment criteria based on clinical, imaging, or laboratory features assessed with a time perspective. Recent onset of ascites in the presence of a large tumor invading or compressing the hepatic veins should be interpreted differently than long‐term use of diuretics or than ascites occurring several years ago in a patient with a cause of cirrhosis that has been eliminated, such as HCV infection or alcohol abuse. The same reasoning may apply to a recent episode of encephalopathy in a patient with main portal vein invasion versus a long‐standing subclinical encephalopathy. Recent changes in the albumin‐bilirubin grade may also be considered relevant. Immunotherapy is changing rapidly the way we treat most patients with HCC in need of systemic therapies. Its unequivocal ability to induce in a few patients deep, sometimes complete, responses that may last even for several years has brought a lot of hype around. Compared with single agents, doublets increase the depth of response and the number of responding patients. Atezolizumab plus bevacizumab is already available in many countries, and tremelimumab plus durvalumab will soon join our armamentarium. While we welcome the news, rushing into expanding the indications to patients with unknown benefit may result in unnecessary health risks for patients and financial costs for health care providers. Rigorous research via prospective, ambitious, and well‐designed RWSs and clinical trials will eventually identify whether and how the indications can be broadened meaningfully. CONFLICT OF INTEREST B.S. consults for Adaptimmune, Astra Zeneca, Bayer, BMS, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Incyte, Ipsen, Novartis, Merck, Roche, Sirtex Medical and Terumo, is on the speakers’ board for Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Incyte, Ipsen, Novartis, Merck, Roche, Sirtex Medical and Terumo, and received research grants from BMS and Sirtex Medical.