Targeted therapies
Targeted therapies represent the mainstay in the treatment of patients with advanced/metastatic HCC [
4]. To date, the multi-tyrosine kinase inhibitors sorafenib in the first-line and regorafenib in second-line have been approved for HCC [
4] and other targeted therapies—lenvatinib, cabozantinib, and ramucirumab—have demonstrated efficacy in phase III studies [
6‐
8]. Unlike cytotoxic chemotherapy, these agents generally lead to disease stabilization rather than tumor shrinkage [
26]. However, even though a rare event (≤1%), CR has been reported for some molecular targeted therapies tested in phase III studies (Table
2; [
6‐
8,
27‐
38]). Most data are available on sorafenib, as this drug was approved as the first systemic treatment for HCC over a decade ago, while other agents became available only recently [
4]. Several cases of complete response with sorafenib have been reported in the literature, of which almost all patients had advanced stage HCC characterized by macrovascular tumor invasion and/or extrahepatic disease [
39‐
58].
Table 2
Complete response with targeted therapies in randomized phase III trials of advanced hepatocellular carcinoma
| Sorafenib (299) | RECIST | N/R | 0 |
Placebo (303) | RECIST | N/R | 0 |
| Sorafenib (150) | RECIST | N/R | 0 |
Placebo (76) | RECIST | N/R | 0 |
| Sunitinib (530) | RECIST | 2 (<1) | N/R |
Sorafenib (544) | RECIST | 1 (<1) | N/R |
| Brivanib (263) | mRECIST | N/R | 0 |
Placebo (132) | mRECIST | N/R | 0 |
| Brivanib (577) | mRECIST | 2 (<1) | N/R |
Sorafenib (578) | mRECIST | 5 (1) | N/R |
| Everolimus (362) | RECIST | 0 | N/R |
Placebo (184) | RECIST | 0 | N/R |
| Linifanib (514) | RECIST 1.1 | N/R | N/R |
Sorafenib (521) | RECIST 1.1 | N/R | N/R |
| Sorafenib + Erlotinib (362) | RECIST | 2 (<1) | N/R |
Sorafenib (358) | RECIST | 1 (<1) | N/R |
| Ramucirumab (283) | RECIST 1.1 | 1 (<1) | N/R |
Placebo (282) | RECIST 1.1 | 0 | N/R |
| Regorafenib (379) | mRECIST/RECIST 1.1 | 2 (1%)/0 | N/R |
Placebo (194) | mRECIST/RECIST 1.1 | 0/0 | N/R |
| Lenvatinib (478) | mRECIST/RECIST 1.1 | 6 (1)/− | 10 (2)/2 (<1) |
Sorafenib (476) | mRECIST/RECIST 1.1 | 2 (<1)/− | 4 (1)/1 (<1) |
| Tivantinib (226) | RECIST 1.1 | N/R | 0 |
Placebo (114) | RECIST 1.1 | N/R | 0 |
| Tivanitinib (134) | RECIST 1.1 | N/R | N/R |
Placebo (61) | RECIST 1.1 | N/R | N/R |
| Cabozantinib (470) | RECIST 1.1 | 0 | N/R |
Placebo (237) | RECIST 1.1 | 0 | N/R |
| Ramucirumab | RECIST 1.1 | 0 | N/R |
Placebo | RECIST 1.1 | 0 | N/R |
In 7 of the phase III studies listed in Table
2, a total of 2926 patients received sorafenib monotherapy as test drug or comparator. Of these, only 9 (0.3%) patients achieved CR when assessed according to per protocol criteria. However, it must be noted that different response evaluation criteria were used (RECIST, RECIST 1.1, mRECIST) and radiological assessment was done locally in some trials and centrally in others.
In a nationwide Japanese case–control study, 18 of 3047 (0.6%) patients treated with sorafenib achieved a complete response according to mRECIST [
59]. Three patients had portal vein invasion and 8 patients presented with distant metastases. The median time to CR was 119 days (range, 35–447 days). Female sex, low body weight, early clinical stage, and a low initial dose of sorafenib were more frequently observed in patients with CR. Furthermore, hand–foot–skin reaction, arterial hypertension, diarrhea, alopecia, fatigue, anorexia, and nausea occurred more often in complete responders [
59]. Notably, the occurrence of early dermatological adverse events was independently associated with improved survival in a prospective study and may represent a surrogate marker for enhanced sorafenib efficacy [
60].
Another retrospective multicenter study from Korea [
61] reported that 7 of 523 patients (1.3%) treated with sorafenib achieved CR according to mRECIST after a median time of 3 months. All patients had advanced stage HCC, 6 due to vascular invasion and 1 because of bone metastasis. Recurrence was observed in 3 patients 3, 10, and 12 months after achieving CR; 2 patients discontinued sorafenib before or after experiencing CR and one patient continued sorafenib treatment. Median disease-free survival was only 9 months [
61].
In a retrospective Spanish multicenter study [
14], 12 of 1119 patients (1.07%) treated with sorafenib were classified as complete responders according to RECIST 1.1 plus SHARP trial criteria amendments (define additional nodules in cirrhosis, avoid registration of ascites and pleural effusion as progression; [
62]). Ten patients had advanced HCC, 8 because of macrovascular invasion and 2 subjects due to extrahepatic spread (peritoneal and lung). Notably, two patients had very large tumors with a diameter of 7.5 and 11.0 cm, respectively. The median time to CR was 13.3 months (range, 0.9–33.3 months). The outcome was excellent with a median overall survival of 85.8 months (95%CI, 67.8–103.8 months). Four patients were still on sorafenib at the end of follow-up and did not show recurrence. Of 7 patients who discontinued sorafenib after experiencing complete response, 5 subjects had tumor recurrence and the other 2 remained in complete remission. Median time to recurrence after sorafenib discontinuation was 16.9 months (range, 8.5–73 months). All except of one patient—the only patient who initiated sorafenib at half dose—developed early dermatological side effects. The authors proposed that CR may result from sorafenib-mediated immune modulation [
14].
Immune checkpoint blockers
Checkpoint inhibitors have become a mainstay in the treatment of certain malignancies, including melanoma and lung cancer, and achieved excellent response rates in these tumor types [
63,
64]. Until now, several phase I and II studies have investigated checkpoint blockers in advanced stage HCC, but despite promising overall response rates (up to around 25%), CR was a rare event [
65‐
72] (Table
3). Interpretation of these data is limited by a small sample size in most studies and the lack of a control group.
Table 3
Complete response with immune checkpoint inhibitors in selected trials of advanced hepatocellular carcinoma
Monotherapy
|
| Tremelimumab (21) | RECIST | 0 | N/R |
| Nivolumab (262) | RECIST 1.1 | 7 (2.7) | 4 (1.5) |
| Durvalumab (40) | RECIST 1.1 | 0 | N/R |
| Pembrolizumab (104) | RECIST 1.1 | N/R | 1 (1) |
Combination with checkpoint inhibitors
|
| Durvalumab + tremelimumab (40) | RECIST 1.1 | 0 | N/R |
Combination with ablation
|
| Tremelimumab + subtotal ablation (32) | RECIST 1.1 | 0 | N/R |
Combination with targeted therapies
|
| Lenvatinib + pembrolizumab (26) | mRECIST | 1 (3.8) | N/R |
| Atezolizumab + bevacizumab (23) | RECIST 1.1 | 0 | 1 (4.3) |
The largest study published to date investigated nivolumab in a phase I/II dose-escalation/dose expansion study in sorafenib-naive (
n = 80) and sorafenib-experienced (
n = 182) patients [
9,
65]. Of 262 patients in total, 7 (2.7%) had CR according to RECIST 1.1 by investigator assessment and 4 (1.5%) when evaluated by blinded central review [
65]. In subgroup analysis, sorafenib-experienced patients with complete or partial response (
n = 22) had an excellent outcome with survival rates at 18 months and 45 months of 100 and ∼90%, respectively [
73]. Recently presented preliminary data from a single-arm phase II study testing pembrolizumab in sorafenib-experienced patients (
n = 104) reported 1 CR (1%; [
66]). Taken together, even though checkpoint blockers can induce durable responses in advanced HCC [
9,
66], CR was reported only occasionally in phase I/II studies. Large phase III trials testing checkpoint inhibitors in advanced HCC are underway (e.g., nivolumab [NCT02576509], pembrolizumab [NCT02702401, NCT03062358], durvalumab/tremelimumab [NCT03298451], atezolizumab [NCT03434379]) and their results are eagerly awaited.