First-line treatment of advanced unresectable HCC with an oral multikinase inhibitor
History and presentation
A 52-year-old man with a history of hepatitis B virus (HBV) infection presented with pruritis in October 2018. CT scan revealed a large tumour in the right lobe of the liver, which was inoperable. The patient had Child-Pugh class A liver function, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 1, and serum alpha-fetoprotein (AFP) level of 3,773 ng/mL at the time of diagnosis.
Treatment and response
Transarterial chemoembolization (TACE) was initiated to treat the low-grade hepatocellular carcinoma (HCC). This led to a decrease in AFP level to 1,056 ng/mL at 2 weeks and to 594 ng/mL at 4 weeks post-treatment. (Figure) The patient, however, subsequently developed transient TACE-related transaminitis.
During the follow-up visit in November 2018, the patient expressed a preference for starting a more aggressive therapy immediately, instead of waiting another month for CT assessment of tumour response to TACE. He was then initiated on lenvatinib 8 mg/day. One week later, the lenvatinib dose was increased to 12 mg/day in view of improved liver function with recovery from TACE-related transaminitis. In December 2018, his AFP level dropped to 47 ng/mL and CT showed significant tumour shrinkage. The patient was referred for resection of the tumour. Preoperative tracer PET-CT scan showed necrotic metastatic lesions in the manubrium, indicating both a systemic effect of lenvatinib as well as a locoregional treatment effect on the primary tumour. (Figure) This patient underwent surgery uneventfully in February 2019, with pathology showing complete pathological necrosis.
History and presentation
An 83-year-old man, in otherwise good health condition, was found to have unresectable HCC in segment 8 of the liver, a previously resected site, and left adrenal metastases during a routine follow-up visit in January 2014. He had an ECOG PS of 0 and AFP level of 54 ng/mL. He was a known HBV carrier, who was first diagnosed with HCC in 2003 and underwent subsequent segment 4/8 wedge resection of the liver in the same year. In 2011, he had sectionectomy of a metachronous primary tumour in segment 5. In June 2012, he underwent another operation for a recurrent tumour in segment 6, followed by postoperative TACE from July to October 2012.
Treatment and response
The patient was enrolled into the REFLECT 304 study (Hong Kong site) in 2014 and was randomized to receive lenvatinib 8 mg/day. He responded well to treatment, with the latest radiological assessment showing stable disease, while his blood pressure was well controlled at 140/80 mm Hg. He did not experience hand-foot syndrome (HFS) or significant side effects from lenvatinib treatment. However, after 5 years of lenvatinib treatment, he developed lymphoproliferative disease, a low-grade lymphoid malignancy that was considered to be another malignancy unrelated to the treatment and was not HCC disease progression. As a result, he had to drop out of the trial.
Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor-alpha,
RET, and KIT. Sorafenib has been the standard of care and the only approved first-line systemic treatment for advanced unresectable HCC over the past decade. Based on the favourable findings of the REFLECT study and real-world clinical experience, the 2018 European Association for the Study of the Liver (EASL) Clinical Practice Guidelines on HCC management recommended lenvatinib as a first-line treatment option, and the 2018 American Association for the Study of Liver Diseases (AASLD) Guidelines have also recommended lenvatinib as a first-line treatment option for intermediate-stage (progression after TACE) and advanced-stage HCC.1-3
The global, randomized, open-label, phase III REFLECT study established the noninferiority of lenvatinib vs sorafenib with respect to the primary endpoint of overall survival (OS) (13.6 months vs 12.3 months; hazard ratio [HR], 0.92; 95 percent confidence interval [CI], 0.79 to 1.06), as the upper limit of CI was below the predetermined noninferiority margin of 1.08. Lenvatinib also showed statistically significant improvements vs sorafenib for secondary efficacy endpoints, including progression-free survival (PFS) (7.4 months vs 3.7 months; HR, 0.66; 95 percent CI, 0.57 to 0.77; p<0.0001), time to progression (TTP) (8.9 months vs 3.7 months; HR, 0.63; 95 percent CI, 0.53 to 0.73; p<0.0001), and objective response rate (ORR) by masked independent review based on modified Response Evaluation Criteria in Solid Tumours (mRECIST) (40.6 percent vs 12.4 percent; odds ratio, 5.01; 95 percent CI, 3.59 to 7.01; p<0.0001).1
A subgroup analysis of Chinese patients from mainland China, Taiwan and Hong Kong (lenvatinib, n=144; sorafenib, n= 144) further demonstrated the relevance of the REFLECT trial results to our local patient cohort, as reflected in the favourable treatment results of our two cases above.4
Despite the higher median baseline AFP level (poorer prognosis) of patients in the lenvatinib arm of the Chinese subgroup vs the overall population (267.1 ng/mL vs 133.1 ng/mL), lenvatinib still prolonged OS vs sorafenib among these patients (15 months vs 10.2 months; HR, 0.73; 95 percent CI, 0.55 to 0.96; p=0.0262). Other efficacy results were consistent with or better than those in the overall study population. In the Chinese subgroup, lenvatinib’s benefits vs sorafenib with respect to TTP (11.0 months vs 3.7 months; HR, 0.53; 95 percent CI, 0.40 to 0.71; p=0.00001) and PFS (9.2 months vs 3.6 months; HR, 0.55; 95 percent CI, 0.42 to 0.72; p=0.00001) were greater than in the overall study population. ORR with lenvatinib was consistent with the overall population (21.5 percent and 24.1 percent by investigator review per mRECIST, respectively), while lenvatinib produced a slightly higher disease control rate (DCR; defined as complete response, partial response and stable disease) in the Chinese subgroup vs the overall study population (77.8 percent vs 75.5 percent).4
The most common treatment-emergent adverse events observed with lenvatinib were hypertension, diarrhoea and decreased body weight, which were manageable. A significantly lower incidence of palmar-plantar erythrodysesthesia in patients treated with lenvatinib vs sorafenib has contributed to better compliance with lenvatinib, and possibly to greater efficacy.1,4
Lenvatinib’s high tumour response rate, which is predictive of PFS and OS benefits, and manageable safety profile are reflected in tumour downstaging achieved in case 1 and the long-term effect (ie, stable disease) and tolerability in our elderly patient in case 2. For patients who require surgical intervention, such as the patient in case 1, it is recommended to withhold lenvatinib for 1 week before surgery and resume 1 week after or until adequate wound healing.5,6