Hepatocellular carcinoma (HCC) is a rapidly deteriorating malignancy with poor prognosis. Since the introduction of sorafenib (SHARP and the Asia Pacific studies) a decade ago, successes with novel agents have been scarce. This year’s American Society of Clinical Oncology (ASCO) annual meeting included two Phase III studies in the second-line treatment of the disease. Moreover, data with several immune-checkpoint inhibitors were presented, including the KEYNOTE-224 with pembrolizumab. Welcome to the summary of the ASCO 2018 HCC track.
NEW EVIDENCE FOR SECOND-LINE TARGETED THERAPIES IN ADVANCED HCC
In the randomised Phase III REACH-2 study (NCT02435433), ramucirumab significantly improved median overall survival (OS) (8.5 months) of patients with advanced HCC and elevated alpha-fetoprotein when compared to placebo (7.3 months) in the second-line treatment of HCC (P=0.0199).1 The VEGFR2-directed monoclonal antibody (MAb) also significantly improved median progression-free survival (PFS) (2.8 months vs 1.6 months for placebo); P<0.0001), as well as increased the objective response rate (ORR) (4.6% vs 1.1% for placebo; P=0.1156) and disease control rate (DCR) (59.9% vs 38.9% for placebo; P=0.0006).1
CELESTIAL (NCT01908426), another Phase III randomised trial in the second-line treatment of HCC, revealed that cabozantinib, a small molecule inhibitor of MET, the VEGF receptors, and AXL, significantly improved median OS (10.2 months vs 8.0 months for placebo; P=0.0049) and median PFS (5.2 months vs 1.9 months for placebo; P<0.0001) for previously treated patients with advanced HCC.2 Subgroup analysis showed improved efficacy of cabozantinib, in both patients younger than 65 years as well as patients 65 years and older.3 Hepatitis B virus (HBV) was associated with HCC in patients younger than 65 years. The distribution of hepatitis C virus (HCV) was evenly distributed over the two age groups. Another subgroup analysis looked at CELESTIAL patients who received sorafenib as the only prior systemic therapy; cabozantinib improved the OS and PFS, an effect irrespective of the duration of sorafenib treatment.4
ADVANCES IN IMMUNOTHERAPY
The ASCO 2018 HCC track contained two studies that independently showed anti-tumour activity of pembrolizumab in the second-line for advanced liver cancer. Preliminary data from the open-label, Phase II KEYNOTE-224 trial (NCT02702414) indicated an ORR of 16.3% to pembrolizumab, an immunotherapy medication.5 The trial also revealed that at 12 months, pembrolizumab had a PFS rate of 25.4% and OS rate of 53.6%.5 Notably, in the KEYNOTE-224, 21% were HBV carrier and 26% were HCV carrier. Another Phase II trial showed a median time to tumour progression of 3 months and median OS of 14 months.6
Japanese investigators of the SCRUM-Japan GI-SCREEN study (UMIN000016343) looked at tumour mutation burden (TMB) in advanced gastrointestinal (GI) malignant tissue samples (N=1,759) in the Cancer Genome Atlas (TCGA) to determine which patients may confer benefit from immunotherapy.7 Twenty-seven (1.5%) HCC samples were included of which 7% were found to be TMB-high.7
Do you like our ASCO 2018 HCC coverage? Subscribe to our non-intrusive newsletter today! We promise we won’t be spammy.
YOU MAY ALSO LIKE
Figure 1. Data of selected Phase II and III ASCO 2018 HCC studies
AFP=alpha-fetoprotein; BCLC=Barcelona Clinic Liver Cancer staging; DCR=disease control rate; ECOG PS=Eastern Collaborative Oncology Group performance status; EHS=extrahepatic spread; HCC=hepatocellular carcinoma; mo=months; NE=not evaluated; NR=not reported; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; TTP=time to progression; VI=vascular invasion.
TACE: UPDATES ON COMBINATION THERAPY AND REAL-WORLD USE
The Barcelona Clinic Liver Cancer (BCLC) criteria consider intermediate stage (B) HCC patients with multinodular disease and preserved liver function and good performance status (ECOG PS 0) candidates for TACE.8 BCLC intermediate stage (C) patients are those with extrahepatic spread (EHS) or vascular invasion (VI) and have a reduction in performance status of (ECOG PS 1 or 2); they are considered candidates for systemic treatment.8
The prospective, observational OPTIMIS trial (NCT01933945) included 1650 patients with unresectable HCC planned for TACE.9 The study found that 32% (N=529) had BCLC stage C disease at study entry. Moreover, 7% (N=118) had EHS and 7% (N=123) had VI.9 In total, 39% of patients receiving TACE at study entry were ineligible for the procedure by international and regional treatment guidelines.9 Additionally, the trial found that the rate of disease progression increased with multiple TACE procedures.9 The majority of the patients (91%) who became TACE ineligible during the course of the study (N=507) were either not prescribed sorafenib or received it late.9
Another study by Professor Kudo and colleagues investigated the combination of transarterial chemoembolisation (TACE) and sorafenib for patients with unresectable HCC in the randomised, open-label TACTICS trial (NCT01217034).10 In total 156 patients with Child-Pugh score ≤7, ECOG performance status ≤1, no VI, no EHS, a maximum lesion size ≤10 cm and with ≤10 nodules were randomised to sorafenib plus conventional TACE (cTACE) vs cTACE alone. ).10 Kudo et al. reported a significantly increased median PFS (25.2 months) when compared to cTACE alone (13.5 months) (p=0.006), the number of OS events had not been reached and the median time to unTACEable progression (TTUP) was 26.7 months (sorafenib plus cTACE) vs 20.6 (cTACE).10 There were no unexpected toxicities.10
Figure 2. Data of selected Phase I ASCO 2018 HCC studies
BCLC=Barcelona Clinic Liver Cancer staging; CR=complete response; DCR=disease control rate; ECOG PS=Eastern Collaborative Oncology Group performance status; HCC=hepatocellular carcinoma; mo=months; NE=not evaluated; ORR= objective response rate; PD-1=Programmed Death 1; pts=patients; TRAE=treatment-related adverse events.
ASCO 2018 HCC: IN THE PIPELINE
A single arm Phase II trial of icaritin, a highly selective oestrogen receptor a 36 (ERa36) modulator, in advanced HCC (N=70) found the drug to be safe (NCT01972672).11 No Grade 3 or higher drug-related adverse events were reported.11 Median OS was 254 days and disease control was achieved in 34.4% of patients.11 The study included subgroup analysis: the presence of high PD-L1 expression, interleukin (IL)-6 advantage, or a neutrophil-lymphocyte ratio (NLR)-advantage all showed better OS outcomes.11
A Phase Ib study of patients with unresectable or metastatic HCC who were naive to systemic treatment revealed that atezolizumab plus bevacizumab was well tolerated and had no new safety signals (NCT02715531).12 The combination therapy was associated with a 62% confirmed response rate in the selected study population.12
Another Phase I study investigated the combination of SHR-1210, a fully human IgG4 monoclonal antibody against PD-1, and VEGFR2 inhibitor apatinib in patients with several advanced GI cancers, including HCC refractory to standard therapy (NCT02942329).13 The investigators concluded the novel combination therapy had a manageable toxicity profile and showed early signs of clinical activity. Fourteen patients with HBV-related HCC were treated at different dosing levels and evaluable. The ORR and DCR were 50.0% and 85.7%, respectively.13
Finally, initial results from a Phase Ib trial combining the multikinase inhibitor lenvatinib with PD-1 MAb pembrolizumab in patients (N=13) with BCLC stage B (not amenable for TACE) or C, Child-Pugh class A, and ECOG PS ≤ 1 unresectable HCC (NCT03006926).14 The study revealed good safety profile and potential anti-tumour activity; with 6 partial responses and 6 stable diseases, the disease control rate (DCR) was 93%. The response assessment of 1 patient could not be evaluated.14
UNSUCCESSFUL CLINICAL DRUG CANDIDATES
Some ASCO 2018 HCC studies were not successful.
A Phase IB study showed that enzalutamide was not efficacious for patients with either androgen receptor (AR)-positive or AR-negative HCC.15 The trial also investigated the combination of enzalutamide plus sorafenib, but this combination was limited by drug-drug interactions (NCT02642913).15
A Phase II trial in the second-line setting for advanced HCC found that sorafenib plus doxorubicin after first-line failure on sorafenib did improve OS but was not well-tolerated.16 The investigators do not recommend further investigations of the combination therapy (NCT01840592).16
- Zhu AX et al. J Clin Oncol 2018;36(suppl):Abstr 4003
- Abou-Alfa GK et al. J Clin Oncol 2018;36(suppl):Abstr 4019
- Rimassa L et al. J Clin Oncol 2018;36(suppl):Abstr 4090
- Kelley RK et al. J Clin Oncol 2018;36(suppl):Abstr 4088
- Zhu AX et al. J Clin Oncol 2018;36(suppl):Abstr 4020
- Feun LG et al. J Clin Oncol 2018;36(suppl):Abstr 4086
- Nakamura Y et al. J Clin Oncol 2018;36(suppl):Abstr 12094
- Forner A et al. Lancet 2018;391(10127):1301–14
- Peck-Radosavljevic M et al. J Clin Oncol 2018;36(suppl):Abstr 4018
- Kudo M et al. J Clin Oncol 2018;36(suppl):Abstr 4017
- Sun Y et al. J Clin Oncol 2018;36(suppl):Abstr 4077
- Stein S et al. J Clin Oncol 2018;36(suppl):Abstr 4074
- Xu JM et al. J Clin Oncol 2018;36(suppl):Abstr 4075
- Ikeda M et al. J Clin Oncol 2018;36(suppl):Abstr 4076
- Harding JJ et al. J Clin Oncol 2018;36(suppl):Abstr 4083
- El Dika IH et al. J Clin Oncol 2018;36(suppl):Abstr 4080
This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).
© Copyright 2018 MediPaper Medical Communications Ltd. – ASCO 2018 HCC Track – #ASCO18 Hepatocellular Carcinoma – ASCO18 Liver Cancer