Second-Line Therapeutic Options
Following the sorafenib approval, clinical studies of several other agents did not meet their primary endpoint and failed to show improvement in clinical outcomes compared to sorafenib. However, over the past years the treatment landscape for advanced HCC has been changed with the approval of several agents in the second line. The overall response rate (ORR) has become the new theme for management of advanced disease. With multiple therapeutic options available, optimal sequencing now plays a critical role, especially for transitioning from locoregional to systemic therapy. Five drugs are now indicated for second-line treatment of patients who progressed on or were intolerant to sorafenib: regorafenib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab.
Regorafenib
Regorafenib was evaluated in the advanced HCC setting in a single-arm, phase 2 trial involving 36 patients with Child–Pugh class A liver disease who had progressed on prior sorafenib.18 Patients received regorafenib 160 mg orally once daily for 3 weeks on/1 week off cycles. Disease control was achieved in 72% of patients, with stable disease in 25 patients (69%). Based on these results, regorafenib was further evaluated in the multicenter, phase 3, 2:1 randomized, double-blind, placebo-controlled RESORCE study, which enrolled 573 patients.19 Due to the overlapping safety profiles of sorafenib and regorafenib, the inclusion criteria required patients to have tolerated a sorafenib dose of at least 400 mg daily for 20 of the past 28 days of treatment prior to enrollment. The primary endpoint of the study, OS, was met (median OS of 10.6 months in regorafenib arm versus 7.8 months in placebo arm; hazard ratio [HR], 0.63; P < 0.0001). Serious adverse events occurred in 44% of the patients who received regorafenib; the most common were hypertension (15%), hand-foot-skin reaction (HFSR, 13%), fatigue (9%), bleeding events (6%), and diarrhea (3%). Seven (2%) deaths in the regorafenib group were attributable to this drug. HFSR due to regorafenib was found to be associated with better survival outcomes.20 In the selected subpopulation for the study, treatment with the sequence of sorafenib followed by regorafenib resulted in a median OS of 26 months.21
Cabozantinib
CELESTIAL was a phase 3, double-blind study that assessed the efficacy of cabozantinib versus placebo in patients with advanced HCC who had received prior sorafenib.22 In this study, 707 patients with Child–Pugh class A liver disease who progressed on at least 1 prior systemic therapy were randomized in a 2:1 ratio to treatment with cabozantinib at 60 mg daily or placebo. Patients treated with cabozantinib had a longer OS (10.2 months vs 8.0 months), resulting in a 24% reduction in the risk of death (HR, 0.76), and a longer median PFS (5.2 months versus 1.9 months). The disease control rate was higher with cabozantinib (64% vs 33%) as well. The incidence of high‐grade adverse events in the cabozantinib group was twice that of the placebo group. Common adverse events reported with cabozantinib included HFSR (17%), hypertension (16%), increased aspartate aminotransferase (12%), fatigue (10%), and diarrhea (10%).
Ramucirumab
REACH was a phase 3 study exploring the efficacy of ramucirumab that did not meet its primary endpoint; however, the subgroup analysis in AFP-high patients showed an OS improvement with ramucirumab.23 This led to the phase 3 REACH-2 trial, a multicenter, randomized, double-blind biomarker study in patients with advanced HCC who either progressed on or were intolerant to sorafenib and had an AFP level ≥ 400 ng/mL.24 Patients were randomized to ramucirumab 8 mg/kg every 2 weeks or placebo. The study met its primary endpoint, showing improved OS (8.5 months vs 7.3 months; P = 0.0059). The most common treatment-related adverse events in the ramucirumab group were ascites (5%), hypertension (12%), asthenia (5%), malignant neoplasm progression (6%), increased aspartate aminotransferase concentration (5%), and thrombocytopenia.
Immunotherapy
HCC is considered an inflammation-induced cancer, which renders immunotherapeutic strategies more appealing. The PD-L1/PD-1 pathway is the critical immune checkpoint mechanism and is an important target for treatment. HCC uses a complex, overlapping set of mechanisms to evade cancer-specific immunity and to suppress the immune system. Initial efforts to develop immunotherapies for HCC focused on anti-PD-1 and anti-PD-L1 antibodies. CheckMate 040 evaluated nivolumab in 262 sorafenib-naïve and -treated patients with advanced HCC (98% with Child–Pugh scores of 5 or 6), with a median follow-up of 12.9 months.25 In sorafenib-naïve patients (n = 80), the ORR was 23%, and the disease control rate was 63%. In sorafenib-treated patients (n = 182), the ORR was 18%. Response was not associated with PD-L1 expression. Durable objective responses, a manageable safety profile, and promising efficacy led the FDA to grant accelerated approval of nivolumab for the treatment of patients with HCC who have been previously treated with sorafenib. Based on this, the phase 3 randomized CheckMate-459 trial evaluated the efficacy of nivolumab versus sorafenib in the first-line. Median OS and ORR were better with nivolumab (16.4 months vs 14.7 months; HR 0.85; P = 0.752; and 15% [with 5 complete responses] vs 7%), as was the safety profile (22% vs 49% reporting grade 3 and 4 adverse events). 26
The KEYNOTE-224 study27 evaluated pembrolizumab in 104 patients with previously treated advanced HCC. This study showed an ORR of 17%, with 1 complete response and 17 partial responses. One-third of the patients had progressive disease, while 46 had stable disease. Among those who responded, 56% maintained a durable response for more than 1 year. Subsequently, in KEYNOTE 240, pembrolizumab showed an improvement in OS (13.9 months vs 10.6 months; HR, 0.78; P = 0.0238) and PFS (3.0 months versus 2.8 months; HR, 0.78; P = 0.0186) compared with placebo.28 The ORR for pembrolizumab was 16.9% (95% confidence interval [CI], 12.7%-21.8%) versus 2.2% (95% CI, 0.5%-6.4%; P = 0.00001) for placebo. Mean duration of response was 13.8 months.
In the IMbrave150 trial, atezolizumab/bevacizumab combination, compared to sorafenib, had better OS (not estimable vs 13.2 months; P = 0.0006), PFS (6.8 months vs 4.5 months, P < 0.0001), and ORR (33% vs 13%, P < 0.0001), but grade 3-4 events were similar.29 This combination has potential for first-line approval. The COSMIC–312 study is comparing the combination of cabozantinib and atezolizumab to sorafenib monotherapy and cabozantinib monotherapy in advanced HCC.
Resistance to immunotherapy can be extrinsic, associated with activation mechanisms of T-cells, or intrinsic, related to immune recognition, gene expression, and cell-signaling pathways.30 Tumor-immune heterogeneity and antigen presentation contribute to complex resistance mechanisms.31,32 Although clinical outcomes have improved with immune checkpoint inhibitors, the response rate is low and responses are inconsistent, likely due to an immunosuppressive tumor microenvironment.33 Therefore, several novel combinations of checkpoint inhibitors and targeted drugs are being evaluated to bypass some of the resistance mechanisms (Table 3).
