During a webcast, experts discussed the current and future treatment landscape of hepatocellular carcinoma and the need to explore combinations with chemotherapy.
Though approvals of anti-PD-1 inhibitors and tyrosine kinase inhibitors (TKIs) have helped shape the hepatocellular carcinoma (HCC) space, unmet needs persist as combinations with chemotherapy have not been explored.
In the first-line setting, sorafenib (Nexavar) and lenvatinib (Lenvima) have been approved for patients with HCC, and in the second-line, FDA-approved therapies include regorafenib (Stivarga), nivolumab (Opdivo), cabozantinib (Cabometyx), and ramucirumab (Cyramza).1 Treatments such as durvalumab (Imfinzi) with tremelimumab (Imjudo), pembrolizumab (Keytruda) with lenvatinib, camrelizumab (SHR-1210) and apatinib (Aitan), and more.
According to the National Comprehensive Cancer Network (NCCN) guidelines 2023, the preferred regimen is atezolizumab (Tecentriq) with bevacizumab (Avastin) for patients with HCC with Child-Pugh Class A disease, and tremelimumab with durvalumab. If disease progression, the subsequent line of systemic therapy options include regorafenib, cabozantinib, lenvatinib, and sorafenib.
Current systemic therapy in advanced HCC uses multikinase inhibitors or combines VEGF inhibition with PD-L1 checkpoint inhibition, or 2 different checkpoint inhibitors. However, experts believe that chemotherapy could provide further benefit to patients.
According to Jeff Evans, MD, treatment with fostroxacitabine bralpamide (fostrox; MIV-818) adds a third unique mechanism that can potentially synergize with current standard-of-care (SOC).
“We have had a fast evolution of treatments for this disease over the last 5 years, both primarily with immune checkpoint inhibitors and tyrosine kinase inhibitors alone or in combination,” said Evans, Beatson West of Scotland Cancer Center, during a webcast presented by Medivir AB.
Currently, traditional intravenous chemotherapy is not used for patients with HCC. Evans explained that chemotherapy has not been explored since a clear negative benefit-risk balance was observed with traditional intravenous chemotherapy in this space. Previously, chemotherapy has led to unacceptable toxicity that is often caused by high doses, which patients with HCC are extra sensitive to, and detoxifying mechanisms in hepatocyte-derived cancer cells cause inactivation of many local cytotoxic compounds.
However, new liver-directed chemotherapy, like fostrox, can provide options for combinations with the SOC, current treatments, and new ones.
“There are emerging changes in the treatment algorithms looking at systemic therapy beyond advanced and resectable disease, to these early disease settings,” added Evans.
As a monotherapy or in combination with other agents, systemic therapy has potential across stages of HCC. For example, the IMbrave 050 adjuvant study (NCT04102098) of high-risk patients with HCC who underwent curative resection or ablation received adjuvant atezolizumab plus bevacizumab or active surveillance.2 This was systemic therapy post-operatively to reduce risk of recurrence, delay recurrence, and improve overall survival (OS) in the adjuvant setting.
According to recent findings from the IMbrave 050 study,atezolizumab with bevacizumab given as adjuvant treatment following surgery showed improvement in recurrence-free survival compared with active surveillance in patients with early-stage HCC. Statistically significant and clinically meaningful improvements in OS were also noted with the combination vs sorafenib (HR, 0.58 [95% CI, 0.42-0.79]; P <.001), as well as progression-free survival (PFS; HR, 0.59 [95% CI, 0.47-0.76]; P <.001).3
Among the 501 patients followed for a median of 15.6 months, the median OS was 19.2 months with the combination of atezolizumab and bevacizumab vs 13.4 months with sorafenib. The median PFS was 6.8 months with atezolizumab plus bevacizumab vs 4.3 months with sorafenib.
“We demonstrated for the first time that systemic therapy can influence the risk of recurrence following resection or ablation. We look forward to the mature data to become available with long-term follow-up,” said Evans.1
Fostrox is liver-directed and must be combined with a more systemic therapy. In the clinical trial setting, investigators have been assessing fostrox with PD-1 inhibitors and TKIs. In combination with PD-1, fostrox induces DNA damage and tumor cell death which can lead to increased tumor antigen presentation and increased immune response. With TKIs, phosphoglycerate kinase 1 is increased and higher levels of fostrox activate metabolites.
Currently, investigators are assessing fostrox with lenvatinib in a phase 1b/2a dose-escalation and dose-expansion combination study (NCT03781934) compared with fostrox plus pembrolizumab. The first trial with fostrox evaluated it as a monotherapy to determine the recommended dose, and now, fostrox being combined with lenvatinib.4
The study is fully recruited and is evaluating the primary end points of safety and tolerability and the secondary end points of overall response rate, disease control rate, and PFS. The dose of 30 mg was selected to enable duration of treatment with optimal benefit-risk balance.
Those included in the study are those with advanced and intolerable HCC who have progressed on prior treatment. The median age of the first 6 patients in the study is 63 years, 83% of patients are male, 3 patients each have an ECOG performance status of 0 and 1, and the majority of patients have a background of viral hepatitis (83%). Extra hepatic disease was present in 50% of cases, 67% of patients were from Asia with the rest from Europe, 83% received prior treatment with atezolizumab and bevacizumab in the first-line, and half of the patients had prior local therapy with TACE.
Half of the patients started on 20 mg of fostrox while the other half started on 30 mg which was administered orally and daily for 5 days, repeated every 3 weeks.
Findings showed that 50% of patients had grade 3 or greater adverse events (AEs) including neutropenia (33%), hypertension (33%), and asthenia (17%). Fifty percent of patients had a dose reduction of lenvatinib and 17% required a dose reduction of fostrox. Five patients had stable disease, and 3 patients responded with 1 complete response.
Another unmet need in clinical practice is second-line treatment options for patients with HCC. All the trials in the first-line setting have used sorafenib as the control arm. However, this is no longer the SOC. Because of this, investigators face the challenge of having numerous options in terms of immunotherapy combinations with TKIs, but no data to support the use of the combinations in the second-line.
“We have first-line treatments, [but] at what point does the patient have to go to second-line treatment? The key questions are what is the alternative and what is the evidence to deciding discontinuation? We do not have the evidence supporting this,” added Maria Reig, MD, liver cancer unit, Hospital Clínic BCLC group, during the webcast.
With alternative options, treatment can be switched right at the time of treatment failure or when patients achieve substantial response. The key question that remains is, what is the best option after first-line treatment?
Reig notes that these questions are open to discussion and expresses the importance of clinical trials to help provide the needed answers.
“All of these questions are open, and we do not have the answers at this stage. That is why we encourage patients to consider the clinical trials, as we do not have the evidence to support that,” said Reig.