Targeted therapies
Sorafenib was the only approved agent for advanced HCC for a long time. For patients who have progressed or intolerant to sorafenib, there were no standard of care. Chemotherapy has been tried with unclear role in this setting and most of the patients go to hospice care directly. There was an urgent unmet need for almost a decade until recent breakthroughs. FDA recently approved regorafenib and nivolumab as second therapy after progression on sorafenib [
12,
15]. Cabozantinib has also showed overall survival benefit in a recent phase III study [
11]. Ramucirumab demonstrated survival benefit as well in patients with elevated alpha-fetoprotein (AFP) > 400 ng/ml at diagnosis [
14].
Regorafenib is the agent approved for second line HCC in April 2017, based on the results of phase III, randomized, double-blind, and placebo controlled trial (RESORCE) [
12]. Regorafenib is an orally active inhibitor of angiogenic VEGF1-3, oncogenic and stromal receptor tyrosine kinases. The study selected patients who tolerated sorafenib (≥ 400 mg daily for at least 20 of the 28 days before discontinuation) and had Child–Pugh A liver function. A total of 573 patients were randomized with regorafenib showing improved OS (10.6 months vs 7.8 months for placebo) with a hazard ratio of 0.63 (95% CI 0.50–0.79; one-sided p < 0.0001) [
12]. The most common grade 3 or 4 adverse events included hypertension, hand–foot skin reaction, fatigue, and diarrhea [
12]. Since this study only included patients who progressed while on sorafenib and required a minimum of 20 out of 28 days of at least 400 mg daily dose, overall survival benefit conclusions about the efficacy of regorafenib in patients who do not tolerate sorafenib cannot be drawn. This study also showed sequential use of multikinase inhibitors with appropriate management of adverse events led to extension in survival [
23].
Cabozantinib, an inhibitor of MET, VEGFR, and AXL, was studied in double-blind, randomized, global, phase 3 trial (CELESTIAL trial) compared to placebo in previously treated patients with advanced HCC [
11]. However, previous tolerance to sorafenib was not required. Primary outcome was overall survival. A total of 707 patients were randomized and the results showed median OS 10.2 months for Cabozantinib vs 8.0 months for placebo (HR 0.76, 95% CI 0.63–0.92; p = 0.0049). Median PFS was statistically improved as well from 5.2 months vs 1.9 months (HR 0.44, 95% CI 0.36–0.52; p < 0.0001) [
11]. Hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%) were reported in cabozantinib vs placebo group [
11]. Due to the significant improvement of OS and PFS, cabozantinib can potentially gain FDA approval in the second line setting of advanced HCC.
Ramucirumab is a monoclonal antibody binds to VEGFR-2 receptor and block its activation. Initial phase II trial of 42 patients showed ORR of 10% and median OS of 12 months indicating modest degree of activity in patients with no prior systemic treatment [
24]. A phase III trial of ramucirumab compared to placebo in patients with advanced HCC following first-line treatment with sorafenib (REACH) failed to show a significant survival advantage (median OS 9.2 vs 7.6 months) [
25]. However, unplanned subset analysis suggested survival benefit in patients with elevated AFP > 400 ng/ml at diagnosis [
25]. A follow up phase III trial (REACH-2) in 292 patients with baseline elevated AFP was conducted and confirmed significant survival benefit of ramucirumab treatment in patients who progressed or were intolerant to sorafenib [
14]. Ramucirumab has significantly improved OS: 8.5 months vs 7.3 months (p = 0.0199); PFS: 2.8 months vs 1.6 months (p < 0.0001); and disease control rate: 59.9% vs 38.9% (p = 0.0006) compared to placebo [
14]. Hypertension and hyponatremia were observed more in the study arm for serious toxicities [
14]. Patients with elevated AFP at baseline have worse prognosis in general. REACH-2 is the first positive study in this particular biomarker selected patient population.
Everolimus, mammalian target of rapamycin (mTOR) inhibitor, was studied in a large phase III trial of patients with progression or intolerance to sorafenib [
26]. mTOR is a key regulator of cell growth and angiogenesis and this pathway is activated in 40–50% of patients with HCC. This study showed no improvement in OS (7.6 vs 7.3 months with everolimus and placebo respectively) [
26].
Axitinib is a selective second generation TKI that targets the VEGFRs. It was studied in a phase II trial compared to best supportive care in 202 patients previously treated or intolerant to sorafenib with advanced HCC. The difference in median OS (12.7 vs 9.7 months) was not statistically significant [
27]. Its use cannot be recommended outside of clinical trial.
Brivanib is a selective dual inhibitor of fibroblast growth factor (FGF) and VEGF receptor tyrosine kinases. FGF proteins are involved in tumor growth and angiogenesis in HCC. Phase III BRISK-PS trial evaluated the efficacy and safety of brivanib in patients with advanced HCC who had disease progression on or intolerance to sorafenib. There was no significant improvement in the median OS compared to placebo (9.4 vs 8.2 months, HR = 0.89; 95.8% CI 0.69–1.15; p = 0.3307) [
28]. Table
2 lists the various studies done in the second setting line setting.
Table 2
Selected clinical trial for advanced HCC in the second line
Regorafenib vs placebo (RESORCE) | III | Multi-targeted TKI | OS | 10.6 vs 7.8 months (p < 0.0001) | 3.1 vs 1.5 months (p < 0.0001) | 11 vs 4 (p = 0.0047) |
Cabozantinib vs placebo (CELESTIAL) | III | Multi-targeted TKI | OS | 10.2 vs 8.0 months (p = 0.0049) | 5.2 vs 1.9 months (p < 0.001) | 4 vs 0.4 (p = 0.0086) |
Nivolumab | I/II | PD-1 immune checkpoint inhibitor | ORR | 15 months | – | 20 (95% CI = 15–26) |
Pembrolizumab | II | PD-1 immune checkpoint inhibitor | ORR | – | 4.8 months | 16.3 |
Ramucirumab vs placebo | III | Anti-VEGF | OS | 9.2 vs 7.6 months (p = 0.14) | 2.8 vs 2.1 months (p < 0.0001) | 7 vs < 1 (p < 0.0001) |
Axitinib + BSC vs placebo + BSC | II | Anti-VEGF | Tumor control | 12. 7 vs 9.7 months (p = 0.287) | 3.6 vs 1.9 months (p = 0.004) | 9.7 vs 2.9 (p = 0.091) |
Brivanib vs placebo | III | FGFR inhibitor | OS | 9.4 vs 8.2 months (p = 0.3307) | 4.2 vs 2.7 months (p < 0.001) | 10 vs 2 |
Everolimus vs placebo | III | mTOR inhibitor | OS | 7.6 vs 7.3 months (p = 0.68) | 3 vs 2.6 months | 8 vs 3 |
Immunotherapy
Immunotherapy is changing the landscape of oncology care in the last few years. Several immunotherapies, such as tumor antigen therapy, immune checkpoint inhibitors, and adoptive cell transfer (ACT) immunotherapy are currently being studied in HCC [
29]. Multiple checkpoint inhibitors have gained FDA approval for many different types of malignancies [
30,
31]. It has also been studied in several gastrointestinal malignancies with meaningful clinical activity [
32]. Several exciting clinical trials for advanced HCC patients are currently ongoing.
Nivolumab, an immune checkpoint inhibitor, was studied in a phase I/II multi-cohort trial (checkmate 040). It included a total of 262 eligible patients with HCC and Child–Pugh A cirrhosis who are either sorafenib naïve or had progression on sorafenib [
31]. Dose escalation phase established the safety profile of 3 mg/kg dose. Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase and showed objective response rate of 15–20% irrespective of line of therapy [
15]. Responses occurred within 3 months in 69% of responders. This study also showed 18 month-OS rates of 57% in sorafenib naïve and 44% in sorafenib experienced patients. Responses occurred regardless of HCC etiology or tumor cell programmed death-ligand 1 (PD-L1) expression [
33]. The common adverse reactions were similar to the previously reports for nivolumab with a higher incidence of elevations in transaminases and bilirubin levels. Immune-mediated hepatitis requiring systemic corticosteroids occurred in 8 (5%) patients [
34]. Nivolumab was granted accelerated approval based on durable response rates. Previous tolerance to sorafenib and rapidity of progression of disease might be taken into consideration of choosing regorafenib vs nivolumab in this setting. Nivolumab is currently being evaluated in Check Mate 459 phase 3 trial (NCT02576509) in comparison to sorafenib as a first- line treatment in patients with advanced HCC.
Pembrolizumab is another checkpoint inhibitor. It was studied in a single arm, open-label phase II KEYNOTE-224 study. 105 patients were enrolled with objective response rate of 16.3% (95% CI 9.8–24.9%), with 1 complete response. Median PFS was 4.8 months and median OS was not reached. The 6 month PFS and OS rates were 43.1% and 77.9%, respectively [
35]. The phase III KEYNOTE-240 is currently underway assessing the efficacy of pembrolizumab for pre-treated patients with HCC (NCT02702401).
Another check point inhibitor anti cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody tremelimumab is studied in Advanced HCC. It was tested in a pilot clinical trial (NCT01008358) in patients with HCC and HCV infection. Disease control rate was 76.4% and time to tumor progression was 6.5 months [
36]. Even though immunotherapy has achieved impressive results, a considerable proportion of patients do not respond. It has become important to identify patients who might respond to immunotherapy, thus paving a path for precision immunotherapy. It likely depends on number of factors such as tumor mutation burden, microsatellite instability status, neoantigen intratumoral heterogeneity, and immunohistochemistry biomarker assay for PDL-1 expression [
31,
37,
38]. Table
3 lists the selected ongoing clinical trials with immunotherapy.
Table 3
Selected clinical trial with immunotherapy for advanced HCC
NCT02702401 | Pembrolizumab vs best supportive care | PD-1 | PFS, OS | Phase III |
NCT02576509 | Nivolumab vs sorafenib | PD-1 | OS | Phase III |
NCT02519348 | Durvalumab + tremelimumab vs durvalumab monotherapy | PD-L1/CTLA-4 | Adverse events | Phase II |
NCT03298451 | Durvalumab vs durvalumab + tremelimumab vs sorafenib HIMALAYA | PD-L1/CTLA-4 | OS | Phase III |
NCT01658878 | Nivolumab vs nivolumab + ipilimumab vs sorafenib | PD-L1/CTLA-4 | ORR | Phase I/II |
Atezolizumab, anti-PD-L1 agent was studied in combination with bevacizumab in a phase Ib study in previously untreated patients with unresectable or metastatic HCC [
39]. Patients received atezolizumab 1200 mg + bevacizumab 15 mg/kg every 3 weeks until progression or unacceptable toxicity. Primary end point was the safety and tolerability of the combination. At a median follow-up of 10.3 months, ORR was 65% among 23 evaluable patients. Most common treatment related grade 3–4 adverse event was hypertension. FDA granted a breakthrough therapy designation for the combination as a first-line treatment for patients with advanced or metastatic HCC. The ongoing phase III IMbrave150 study (NCT03434379) is comparing atezolizumab/bevacizumab with sorafenib in the frontline setting for patients with locally advanced or metastatic HCC.
Chimeric antigenic receptor T cell (CAR-T) is a form of ACT Immunotherapy. It has been a huge success in treating refractory hematological malignancies, most notably B-cell acute lymphoblastic leukemia [
40]. Tumor cells express many aberrant proteins/antigens on surface which can be used as markers to target them with genetically engineered T cells [
41]. Expanding CAR-T therapy to solid tumors is very attractive but has many challenges. Identifying the precise target antigen and designing CARs that are highly selective are critical for clinical application of such therapies. Many studies are ongoing to explore the possibility of CAR-T immunotherapy in HCC and other solid tumors [
42,
43]. AFP is one such antigen which can be used as a specific target for CAR-T therapy in HCC [
42]. AFP is a secreted glycoprotein that is commonly overexpressed in tumors of endodermal origin including pediatric hepatoblastoma and HCC. AFP has been reported to promote cell proliferation and suppress apoptosis suggesting its role in tumor progression [
44,
45]. Other potential tumor associated antigens (TAA) in HCC are CEA, MUC1, MAGE-A1, NY-ESO-1, epithelial cell adhesion molecule (EPCAM) and Heat Shock Protein 70 (HSP70). Although CAR-T therapy appears very promising, it comes with many obstacles. Insufficient localization/penetration of CAR-T cells into tumor sites [
46] and immunosuppressive tumor microenvironment have been implicated in the low efficacy [
47,
48]. Lack of tumor specific antigens has proved to be a serious risk factor for toxicity associated with off-target or on-target/off-tumor effects [
49]. Potential serious cytokine release syndrome (CRS) is another major toxicity associated with CAR-T therapy. Many of these obstacles can be controlled or removed by further progress. Specificity of CAR-T cells can be enhanced by tandem CAR, a novel bispecific CAR [
50]. Poor localization and infiltration of CAR-T cells into solid tumors can be enhanced by expressing functional chemokine receptors like chemokine receptor type 2 (CCR2) [
51]. Utilization of glucocorticoids and monoclonal antibody like tocilizumab which targets IL-6 receptors can help with treatment of CRS [
52].