ESMO 2014: Second-Line Targeted Treatments in Patients with Advanced Hepatocellular Carcinoma

Studies with ramucirumab or axitinib plus best supportive care vs placebo plus best supportive care

The gastrointestinal researchers noticed that although a primary endpoint in two studies conducted in second-line treatment of patients with advanced hepatocellular carcinoma was not met, they observed some benefits from ramucirumab or axitinib if added to best supportive care. The findings were reported during the Proffered Paper session in Gastrointestinal Cancers at ESMO Congress 2014 in Madrid, Spain.

REACH: Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib

ESMO Congress 2014 LBA16 REACH OS

Overall survival in the study ITT population and in patients with baseline alpha‑fetoprotein ≥ 400 ng/mL. © Andrew Zhu

The results of the REACH randomised, phase III study were presented by Prof. Andrew Zhu of the Massachusetts General Hospital Cancer Center, Boston, USA.

Sorafenib is the only approved first-line treatment in hepatocellular carcinoma. No treatment has demonstrated a survival benefit in the second-line setting. Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signalling and angiogenesis likely contribute to pathogenesis of hepatocellular carcinoma.

Ramucirumab is a fully human IgG1 monoclonal antibody that binds to extracellular domain of VEGFR-2, preventing ligand binding and receptor activation. Preliminary evidence of ramucirumab anticancer activity in treatment-naive hepatocellular carcinoma was demonstrated in a single-arm phase II study.

The REACH study evaluated the safety and efficacy of ramucirumab in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib.

It was required that patients eligible for the study have advanced hepatocellular carcinoma (histological or radiographical imaging confirmation) in stage BCLC C or B, who are refractory or not amenable to loco-regional therapy, have Child-Pugh A, ECOG performance status 0 or 1, intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib, and adequate haematologic and biochemical parameters.

Patients were randomised 1:1 to receive ramucirumab i.v. plus best supportive care or placebo plus best supportive care every 2 weeks until disease progression, unacceptable toxicity, or death.

The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), time to progression, objective response rate (ORR), safety and patient reported outcomes.

The sample size of 544 patients was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75 and OS improvement from 8 to 10.67months in ramucirumab arm.

Between November 2010 and April 2013, 565 (intent to treat) patients were randomised: 283 in ramucirumab arm and 282 in placebo arm. Baseline patient characteristics were balanced between two arms.

In the intent to treat population, the OS HR was 0.866 (p = 0.1391); median OS was 9.2 months for the ramucirumab arm vs 7.6 months for the placebo arm. Forest plot of OS by subgroup favoured ramucirumab.

Median PFS in the intent to treat population with ramucirumab was 2.8 months and 2.1 months with placebo, respectively (HR 0.63, p <0.0001) with forest plot by subgroup in favour of ramucirumab.

Median time to progression was 3.48 months in ramucirumab arm vs vs 2.63 months in placebo arm (p<0.0001). The ORR was 7.1% in ramucirumab arm and 0.7% in placebo arm (p<0.0001).

The safety population comprised 553 patients (277 patients in the ramucirumab arm and 276 patients in the placebo arm). No new safety signals were observed. However, grade ≥3 adverse events occurring in >5% of treated ramucirumab patients included: hypertension (12.3% ramucirumab arm vs 3.6% placebo arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increase (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%).

In 250 patients with baseline alpha-fetoprotein (AFP) ≥400 ng/mL which was pre-specified, OS HR was 0.67 (p = 0.0059) with median OS of 7.8 months for ramucirumab vs 4.2 months for placebo.


The authors concluded that the study primary endpoint was not met, but in a selected population of patients with an elevated baseline AFP, a meaningful OS improvement in the ramucirumab arm was observed. An elevated baseline AFP may select a population likely to benefit from ramucirumab. The treatment was well tolerated and demonstrated an acceptable safety profile. Given the high unmet medical need for second-line treatment in hepatocellular carcinoma, further investigation of ramucirumab might be warranted.

Axitinib plus best supportive care in patients with advanced hepatocellular carcinoma following prior antiangiogenic therapy

ESMO Congress 2014 LBA17 OS

Overall survival in Asian vs non-Asian patients. © Yoon-Koo Kang

Prof. Yoon-Koo Kang of the Department of Oncology, Asan Medical Center, Seoul, Korea presented results of a study with axitinib plus best supportive care vs placebo plus best supportive care in patients with advanced hepatocellular carcinoma following prior antiangiogenic therapy.

Sorafenib, multi-targeted tyrosine kinase inhibitor is the current standard treatment for advanced hepatocellular carcinoma. It prolonged OS over placebo in patients with advanced disease. However, other molecular targeted agents failed to show survival benefit in first- or second-line hepatocellular carcinoma. Therefore, unmet need exists for treatment of patients who progressed on or are intolerant to sorafenib.

The efficacy and safety of axitinib, a potent and selective inhibitor of VEGF receptors 1-3, was evaluated in this global, randomised, double-blind phase II clinical trial in patients with locally-advanced or metastatic hepatocellular carcinoma.

Eligible patients who progressed on or were intolerant to one prior antiangiogenic therapy, Child-Pugh Class A or B (score 7 only) and ECOG performance status 0 or 1 were randomised 2:1 to receive axitinib plus best supportive care or placebo plus best supportive care. They were stratified by tumour invasion defined as a presence vs absence of extrahepatic spread and/or vascular invasion, and geographic region (Asia vs non-Asia).

The primary endpoint was OS and secondary endpoints included PFS, time to progression, ORR, duration of response, disease control rate, safety, health related quality of life and biomarkers.

The study had 80% power to detect an improvement in median OS from 5.0 to 8.3 months with axitinib plus best supportive care, corresponding to a HR 0.60 (1-sided α=0.025).

To achieve the targeted number of 150 events (deaths) for final analysis, 198 patients had to be enrolled. From December 2010 to July 2012, 202 subjects were randomised. An interim analysis was performed after approximately 50% of OS events occurred. The Independent Data Monitoring Committee recommended to proceed as per plan. As of the data cut-off for primary analysis ( 3 March 2014) 151 events were reported with 29 patients alive, 8 on treatment (axitinib 7 vs placebo 1).

Two hundred two patients were randomised (134 in axitinib arm and 68 in placebo arm). They were predominantly of Asian origin (63% vs 62%). Baseline patient characteristics and stratification factors were well balanced between the axitinib vs placebo arms. All patients had Child-Pugh A category and 76% of patients in both arms had tumour invasion.

ESMO Congress 2014 LBA17 PFS

Progression-free survival in Asian vs non-Asian patients. © Yoon-Koo Kang

Median OS with axitinib was 12.7 months vs 9.7 monhs with placebo, a difference that was not statistically significant (HR 0.870; p = 0.211). In Asian patients median OS was 13.5 months vs 6.3 months in non-Asian, but this difference was not statistically significant either.

Investigator-assessed median PFS in all randomised patients was 3.6 months with axitinib vs 1.9 months with placebo and was statistically significant (HR 0.618; p = 0.004). The difference between PFS in Asian patients vs non-Asian was statistically significant too, 3.6 vs 1.8 month (HR 0.527, p = 0.002).

The ORR was 9.7% with axitinib vs 2.9% with placebo (p = 0.083).

Overall disease control rate was 31.1% vs 11.8% in favour of axitinib treated patients (p = 0.002).

Safety profile with axitinib was consistent with earlier clinical trials and no new safety signal was detected. However, more patients discontinued treatment due to adverse events with axitinib vs placebo.

Most common all causality adverse events in axitinib vs placebo group were:

  • diarrhoea (54% vs 12%),
  • hypertension (54% vs 13%),
  • decreased appetite (47% vs 21%),
  • fatigue (35% vs 26%),
  • abdominal pain (34% vs 21%),
  • hand-foot syndrome (34% vs 6%),
  • weight decrease (27% vs 3%),
  • nausea (26% vs 10%),
  • dysphonia and hypothyroidism (25% vs 0% each).

Grade ≥ 3 adverse events were higher in the axitinib group: diarrhoea (20% vs 0%), hypertension (26% vs 1%), and hand and foot syndrome reaction (15% vs 0%).


The authors concluded that axitinib plus best supportive care did not demonstrate statistically significant improvement in median OS but improved median PFS when compared with placebo plus best supportive care in patients with advanced hepatocellular carcinoma who received prior antiangiogenic therapy. Regional differences in the efficacy were noticeable.

Dr Michel Ducreux, who discussed the results from the both studies, summarised by saying that there is something there but the researchers were unable to demonstrate it because hepatocellular carcinoma is an entity of different diseases with different biological pathways and different clinical features.

The REACH study was sponsored by Elli Lilly. The LBA17 study was sponsored by Pfizer Inc.