Second-Line Or Later Apatinib May Boost Advanced HCC Overall Survival

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Results from the AHELP trial of Chinese patients with advanced hepatocellular carcinoma (HCC) suggest that second- or later-line treatment with the vascular endothelial growth factor receptor (VEGFR) inhibitor apatinib may improve overall survival (OS) compared with placebo. 

As reported in The Lancet Gastroenterology & Hepatology, the phase III trial investigators recruited 400 patients, attending 31 Chinese hospitals, who had previously received one or more lines of systemic chemotherapy or targeted treatment for advanced disease, and had a Child-Pugh score of 7 or less and a Barcelona Clinic Liver Cancer stage of B or C. 

The 261 patients who were randomly assigned to receive apatinib 750 mg/day in 28-day cycles had a history of hepatitis B (85%) or C (15%) virus infection; 77% had received one prior line of systemic chemotherapy and 23% two or more lines, while 41% had previously received sorafenib. 

The 132 patients who were instead given placebo had a similar profile to their apatinib-treated counterparts with regard to history of hepatitis B (89%) and C (11%) virus infection, and receipt of one or at least two lines of systemic chemotherapy (80 and 20%, respectively) and sorafenib (41%). 

After a median follow-up of 7.6 months, just 5% of patients were continuing with their study treatment, with the majority (66%) discontinuing because of radiographical disease progression, report Shukui Qin, from Nanjing Chinese Medicine University, and co-workers. 

Apatinib use was associated with a significant improvement in OS, with a median duration of 8.7 months versus 6.8 months with placebo and a hazard ratio (HR) of 0.79.  

This included higher rates of OS at the 6-month (70.0 vs 56.1%) and 12-month (36.8 vs 28.9%) checkpoints, although the 95% confidence intervals for the latter OS estimates overlapped between the two treatment arms, the team says. 

Subgroup analyses showed that patients were significantly more likely to derive an OS benefit from apatinib versus placebo if they were aged 65 years or younger (HR=0.78), had an alpha-fetoprotein level of 200 μg/L (HR=0.73), had not previously received sorafenib (HR=0.73) and had received just one line of systemic chemotherapy (HR=0.73). 

The researchers note that the survival curves of the two treatment groups crossed later in follow-up but restricted mean survival time analysis also “provided evidence of an improvement of overall survival” with apatinib.  

The late crossing of the survival curves may be the result of apatinib-treated patients being less likely than their placebo-treated counterparts to receive post-study drugs (37 vs 43%), including targeted treatments (16 vs 23%), the researchers hypothesise. 

There was also a significant progression-free survival advantage with apatinib versus placebo, with median durations of 4.5 and 1.9 months, respectively, and a HR of 0.47. And apatinib-treated patients were more likely than controls to achieve an objective response (11 vs 2%) or disease control (61 vs 29%). 

Safety analyses were conducted in 257 patients given apatinib for a median 3.6 months and 130 patients given placebo for a median 1.8 months. These showed that apatinib treatment was “well tolerated” and “consistent” with earlier reports for the agent, the investigators say. 

Grade 3–4 treatment-related adverse events occurred in 77% and 19% of the groups, respectively, with the most common incidents being hypertension (28 vs 2%), hand–foot syndrome (18 vs 0%) and reductions in platelet (13 vs 1%) and neutrophil counts (11 vs 0%). 

“Given that all patients in this study were from non-Japan Asia, in whom the baseline disease characteristics of advanced hepatocellular carcinoma are complex and aggressive, the findings of this study are encouraging”, conclude Shukui Qin and co-authors. 

“The results of the AHELP trial have led to the approval of apatinib as second-line treatment in patients with advanced hepatocellular carcinoma” in China, they add. 

Discussing the findings in a linked comment, David Pinato and co-workers, from Imperial College London in the UK, observe that the study design does not allow “meaningful conclusions as to whether apatinib might be effective in the post-sorafenib setting.” 

They also caution that the use of chemotherapy before afatinib is “reflective of Chinese clinical practice” but “certainly restricts the capacity to extrapolate the results of this study to the global context of contemporary sequencing strategies, in which sorafenib, lenvatinib, and now atezolizumab and bevacizumab are first-line systemic therapies of choice”. 

Nevertheless, the commentators say that the AHELP study “validates the therapeutic efficacy of VEGFR2 targeting” for hepatitis B virus-related disease and supports apatinib as “a novel treatment option in treatment-experienced patients” with advanced HCC. 

References 

Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol; Advance online publication 7 May 2021. DOI:10.1016/S2468-1253(21)00109-6

Pinato DJ, Valeri N, Muhammed A, Cortellini A. Therapeutic targeting of VEGFR2 in HBV-associated hepatocellular carcinoma. Lancet Gastroenterol Hepatol; Advance online publication 7 May 2021. DOI:10.1016/S2468-1253(21)00134-5