Although the combination of atezolizumab and bevacizumab has become the standard frontline treatment for patients with advanced hepatocellular carcinoma, whether immunotherapy could play a role in earlier lines of treatment remains the subject of ongoing research.
Although the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) has become the standard frontline treatment for patients with advanced hepatocellular carcinoma (HCC), whether immunotherapy could play a role in earlier lines of treatment remains the subject of ongoing research, said David J. Pinato, MD, PhD, who added that immune-based therapy could improve cure rates in early-stage HCC and overcome the survival plateau associated with transarterial chemoembolization (TACE) in intermediate-stage HCC.1
“It often happens in drug development that you take the knowledge that you have consolidated in advanced disease and move it earlier to other, less advanced stages of disease. However, doing so is accompanied by new treatment goals and new challenges,” said Pinato, clinical senior lecturer in medical oncology, clinician scientist, and consultant medical oncologist in the Department of Surgery and Cancer at Imperial College London, in a virtual presentation during the 2021 HCC-TAG Conference.
In early-stage HCC, patients have an estimated median overall survival (OS) of over 60 months, and standard of care therapies include resection, local ablation, and transplant, Pinato said. Notably, cure remains the main treatment goal in this setting.
In intermediate-stage disease, patients have an estimated median OS of approximately 24 months. Prolonged survival with TACE, which remains the standard of care, is the main treatment intervention.
However, in both settings, factors such as the severity of cirrhosis, anti-viral control, microvascular invasion, serum alpha-fetoprotein, focality, and tumor size contribute to a heterogenous tumor environment that can be difficult to treat. Moreover, up to 70% of patients relapse within 2 years.
In the past few years, many studies evaluating systemic therapy for non-advanced HCC have yielded negative results.
For example, the phase 3 STORM trial failed to demonstrate an improvement in recurrence-free survival (RFS) with adjuvant sorafenib (Nexavar) vs placebo after resection or ablation in patients with HCC.2
However, another phase 3 trial (NCT00699816) demonstrated increased RFS and OS with adjuvant autologous cytokine-induced killer cells vs no adjuvant therapy in patients who underwent curative treatment for HCC.3
“Immunotherapy is perhaps the only adjuvant therapy that is deemed and proven to be active in phase 3 studies,” said Pinato. “The problem is that the type of immunotherapy that is active in the adjuvant setting is cellular immunotherapy…Although there is evidence of improvement in RFS in [the] absence of any high-grade adverse events [AEs], this treatment is certainly not one that can be [universally] adopted.”
Multiple phase 3 trials, including Checkmate 9DX (NCT03383458), EMERALD-2 (NCT03847428), IMbrave050 (NCT04102098), and KEYNOTE-937 (NCT03867084), are ongoing and are evaluating adjuvant immunotherapy alone or in combination regimens in HCC.4-7 The results, which are expected to read out between 2022 and 2025, will “inform the basis of treatment decisions,” said Pinato.
The role of neoadjuvant checkpoint inhibition is also the subject of ongoing research and is being evaluated in multiple phase 1 or 2 trials such as CA209-956 (NCT03222076), AURORA (NCT03337841), PRIME-HCC (NCT03682276), and others.8-10
In weighing the advantages and disadvantages of both approaches, Pinato explained that neoadjuvant therapy could offer improved surgical outcomes, early treatment of micrometastases, the ability for in vivo sensitivity testing, and paired assessment of biomarkers before and after therapy. However, neoadjuvant immunotherapy requires histological confirmation, would defer primary therapy, and could elicit a high drop-out risk because of toxicity or progression.1
Conversely, adjuvant therapy doesn’t delay primary therapy and patient selection is based on histopathological risk-stratification. However, adjuvant therapy does not yield measurable responses because the patient underwent curative-intent therapy. It also defers treatment of micrometastases and doesn’t provide insight into the mechanism of action of the therapy.
“It will be a long time before we are actually going to be able to tell whether adjuvant or neoadjuvant [therapy] is better,” Pinato added.
Similar to early-stage disease, intermediate-stage HCC comprises a largely heterogenous patient population. Operation-dependent techniques, including conventional TACE and drug-eluting bead–TACE, are selected based on treatment factors, such as prior therapy and treatment schedule, patient factors, such as performance status, comorbidities, and age, tumor burden, and hepatic reserve.
Although TACE remains the standard of care, combination regimens with TACE and sorafenib have not shown a meaningful survival improvement vs TACE alone in clinical trials such as SOCRATES, TACTICS, SPACE, and TACE-2.11-14
“We know that these combinations are safe and potentially effective but [do not confer] significant improvement [in survival compared with TACE-based approaches alone],” said Pinato.
As such, utilizing TACE in the frontline setting as a locoregional inducer of immunogenic cell death is a potential strategy that could abate the survival plateau observed with TACE in patients with intermediate-stage HCC who will likely experience disease progression.
The ongoing phase 1b PETAL trial (NCT03397654)15 demonstrated a tolerable safety profile with no evidence of synergistic toxicity with the combination of TACE and pembrolizumab (Keytruda) in patients with intermediate-stage HCC.16 Limited and expected treatment-related AEs, including cough, dyspnea, hypoadrenalism, nausea, diarrhea, maculopapular rash, and infusion-related reactions, were observed. Additionally, the initial findings showed enrichment of pro-inflamed tumors on pre-treatment biopsies in patients who had prolonged responses to the combination.
Efficacy data of the PETAL trial are pending and are likely to be presented during the 2021 Digital Liver Cancer Summit, said Pinato.
“It is becoming quite difficult to choose [treatment] across many different approaches. It is fair to say that in early- and intermediate-stage [HCC], the use of TKIs in combination with either surgery or TACE is now a fully resolved question with evidence of efficacy. Whether immune checkpoint inhibitor combinations or monotherapies are going to be able to help us here, will be the subject of strong debate over the next few years,” concluded Pinato.