Tyrosine kinase inhibitors plus immune checkpoint inhibitors as neoadjuvant therapy for hepatocellular carcinoma: an emerging option?

KEYWORDS:

• Hepatocellular carcinoma
• liver cancer
• cabozantinib
• nivolumab
• neoadjuvant
• immunotherapy
• tyrosine kinase inhibitors

1. Introduction

Hepatocellular carcinoma (HCC) remains a common malignancy and represents an important cause of cancer-related death worldwide [1]. Despite several treatment modalities have been investigated in recent years (e.g. radiofrequency ablation, liver transplantation, novel tyrosine kinase inhibitors [TKIs], etc.), HCC patients with advanced disease have a poor prognosis [2]. Surgery and ablative modalities represent the first-line treatment for resectable HCC; however, local therapies result to be curative only for a small proportion of patients diagnosed with HCC, due to the high recurrence rate (Figure 1) [3]. In addition, most of HCC patients present with unresectable disease, due to low functional liver reserve, gross invasion of the portal or hepatic veins, or extrahepatic invasion, while only one-fifth of HCCs are deemed resectable at diagnosis [4]. Although neoadjuvant strategies have the potential to allow radical resection for locally advanced disease, to reduce tumor volume and micrometastatic disease, lastly resulting in improved clinical outcomes, no systemic treatment is approved as neoadjuvant approach for HCC due to the disappointing results observed in clinical trials investigating this therapeutic strategy [5].

Figure 1. Barcelona Clinic Liver Cancer (BCLC) Staging System. Abbreviations: CLT: cadaveric liver transplantation; LDLT: living donor liver transplantation; PEI: percutaneous ethanol injection; PS: performance status; PST: performance status test; RF: radiofrequency ablation; TACE: transarterial chemoembolization.

In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several hematological and solid malignancies, including unresectable HCC [6,7]. However, clinical trials on nivolumab and pembrolizumab monotherapy have shown controversial results in this setting. Firstly, single-agent nivolumab was investigated in sorafenib-naïve and sorafenib-experienced HCC patients with advanced disease in the CheckMate 040 phase I/II clinical trial; the most up-to-date analysis of CheckMate 040 has observed a median overall survival (OS) of 28.6 months (95% Confidence Intervals [CI], 16.6 – Not Reached [NR]) and 15.6 months (95% CI, 13.2–18.9) in treatment-naïve and pretreated patients, respectively [8]. Similarly, the KEYNOTE-224 tested the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab as monotherapy in previously treated HCC patients, reporting a median OS of 13.2 months (95% CI, 9.7–15.3) [9]. However, the phase III CheckMate 459 and KEYNOTE-240 trials assessing nivolumab and pembrolizumab monotherapy were negative, with non-statistically significant but clinically meaningful benefits which were observed for HCC patients treated with ICIs [10]. In order to enhance the antitumor activity of ICIs monotherapy, immune-based combinations have been investigated in the metastatic setting. Among these, the IMbrave150 phase III trial has highlighted a survival benefit in treatment-naïve HCC patients treated with the combination of atezolizumab-bevacizumab compared to single-agent sorafenib; the IMbrave150 represented a historical step forward in medical treatment for HCC, since over more than a decade no therapy had shown superiority over sorafenib in head-to-head comparisons [11]. In addition, the recently presented updated analysis of IMbrave150 has reported 8% of complete response rate for the experimental arm compared to 1% in the control group, with a confirmed overall response rate (ORR) of 35.4% for atezolizumab-bevacizumab and 13.9% in the sorafenib group according to HCC mRECIST [12]. Another combination, the one including the TKI lenvatinib plus pembrolizumab, has been evaluated in the KEYNOTE-524 phase Ib study; the immune-based combination reported an ORR of 46% according to modified RECIST, with complete response and partial response highlighted in 11% and 35% of included subjects, respectively [13]. Moreover, after a median follow-up of 11.7 months, median OS was 22 months (95% CI, 20.4 – NR) although more mature survival data are awaited, as well as the results of the LEAP-002 phase III trial comparing lenvatinib plus pembrolizumab versus single-agent lenvatinib in treatment-naïve patients with advanced hepatocellular carcinoma (NCT03713593).

The HCC medical community has tried to translate the evidence observed in metastatic disease in the neoadjuvant setting, with ICI combinations including anti-VEGF agents such as TKIs appearing as a promising downstaging strategy in HCC patients. In fact, preclinical studies have highlighted the biological rationale behind the use of neoadjuvant ICI-TKI combinations, based on the synergistic effect of different drug classes [13]. Notably enough, TKI monotherapy has shown low response rates in HCC, as reported in pivotal clinical trials (e.g. SHARP, CELESTIAL), while interesting and sometimes long-lasting responses have been observed in studies investigating ICIs [3,4]. In this respect, tumor burden and response to ICIs appear to be associated in unresectable disease, since patients with high tumor burden usually experience lower clinical benefit by the use of immunotherapy; thus, early-stage disease could present the higher probability of response to ICIs. Moreover, a key point to consider in HCC is represented by clinical characteristics of patients eligible to surgery, that often present good performance status and inferior tumor burden; typically, several studies have highlighted the presence of less clonal heterogeneity and loss of heterozygosity in small size tumors, suggesting higher likelihood of immune responses and long-term clinical benefit [14]. In addition, neoadjuvant ICI-TKI combinations have the potential to ‘convert’ patients who are initially not eligible for curative-intent surgery into resection candidates; similarly, for patients awaiting liver transplantation ICI-TKI combinations could lead to downstaging of the tumor, despite the lack of clinical data regarding safety in this specific patient population and the presence of different indications for liver transplantation according to the geographic area [14].

Based on these premises, at the American Society of Clinical Oncology (ASCO) 2021 Gastrointestinal Cancers Symposium, Yarchoan and colleagues presented the results of a phase I study (NCT03299946) investigating neoadjuvant combination of oral cabozantinib 40 mg daily plus 240 mg of nivolumab (intravenously every two weeks) in 15 patients with borderline resectable or locally advanced HCC [15]. The neoadjuvant treatment has been administered for 8 weeks, according to the study design.

The combination met the primary safety and feasibility endpoint of this single-arm, open-label phase I trial, with 12 patients undergoing successful margin negative surgical resection (R0), 5 of which (41.7%) achieving major or complete pathologic responses after 8 weeks of treatment [15]. At a median follow-up of 12 months, 4 out of the 5 patients with pathologic responses did not have disease recurrence; conversely, 7 HCC patients experienced no pathological response or a minor pathological response following the investigational treatment [15].

In terms of safety, the 53.3% (8/15) of patients experienced grade 1–2 fatigue with other common low grade adverse events including nausea (33.3%), vomiting (20%), anorexia (13%), diarrhea (13.3%), and palmar-plantar erythrodysesthesia (13.3%). Only 2 HCC patients showed grade 3–4 adverse events – 1 patient with myasthenia gravis and 1 case of autoimmune hepatitis.

In addition, other clinical trials evaluating the role of ICI plus anti-VEGF combinations are ongoing and will shed further light on the role of this approach in HCC (NCT04425226, NCT04727307).

2. Expert opinion

The study conducted by Yarchoan has recently drawn the attention of the HCC medical community to cabozantinib plus nivolumab as neoadjuvant treatment option for patients with HCC who were initially ineligible for curative surgery [15]. Notably enough, the study has represented the first clinical trial investigating a TKI in combination with an ICI in this setting, providing also the first prospective evidence on the use of modern immune-based combinations aimed at downstaging HCC. However, the study included a small sample size (n = 15), and larger well-designed clinical trials of neoadjuvant approaches are warranted to confirm the findings by Yarchoan and colleagues [15]. At the same time, the authors should be acknowledged for bringing this interesting evidence to the field of investigational neoadjuvant treatments in HCC; in particular, in addition to clinical benefits, the trial has also evidenced that the tumor microenvironment of responders presented not only increased T cells but also high infiltration of B cells organized in tertiary lymphoid aggregates. More specifically, an enrichment of IFNγ+ effector memory, CD4+ and granzyme B+ effector, CD8 + T cells along with tertiary lymphoid aggregates has been observed in the pathologic responders [15].

Another element to consider when interpreting the results of this trial is the inclusion of a heterogeneous patient population. In fact, according to the study design, patients with locally advanced HCC were defined as borderline resectable in presence of a solitary tumor bigger than 5 cm, or unilobar multifocal disease with either three tumors or one tumor bigger than 3 cm, or bilobar disease, or if their tumor was bigger than 3 cm with macrovascular invasion [15]. Conversely, patients with bilateral left and right branch portal vein involvement were excluded from the trial. Since 40% (n = 6) of enrolled patients had multinodular disease, 4 (27%) presented portal vein invasion, 9 (60%) infiltrative disease, and 6 (40%) tumor diameter over 10 cm, the results observed in terms of pathologic responses and long-term benefit are of particular interest and deserve attention [15]. Moreover, more details and information regarding hepatic reserve change during the investigational treatment are awaited.

Further results of the safety and efficacy from early-phase clinical trials of neoadjuvant ICI-TKI combinations in HCC are eagerly awaited and could provide information on the possibility of translating the response rates observed in metastatic disease in this setting; similarly, well-designed and adequately powered randomized controlled studies are required to better define the effective benefit of this strategy and the appropriate timing for surgery in order to maximize treatment outcomes. In such a scenario, researchers are called to focus specific studies on the identification of prognostic factors as well as predictors of response to neoadjuvant ICI-TKI combinations with the hope of improving clinical outcomes of this frequent and aggressive liver malignancy with many unanswered questions.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.