Novel Agents Prompt Need for New Sequencing Strategies in HCC

Anita T. Shaffer @Shaffer1
Published: Friday, Sep 14, 2018

Tim Meyer, MD, PhD
Tim Meyer, MD, PhD
The rapid development of novel therapies for patients with unresectable hepatocellular carcinoma (HCC) has dramatically expanded the options for systemic treatments over the past 2 years, creating the need for new sequencing strategies, according to a presentation at the 2018 International Liver Cancer Association (ILCA) Annual Conference.

The recent advancements are a welcome change after a decade in which sorafenib (Nexavar) was the only available therapy for this patient population, but treating patients has become more complex, according to Tim Meyer, MD, PhD, a professor and director of the University College of London Experimental Cancer Medicine Centre in the United Kingdom.

For frontline therapy, lenvatinib (Lenvima) appears to have some benefits over sorafenib, but there are no data on outcomes for second-line options for patients who progress, Meyer said.

For second-line therapy, he said, study findings have established benefits with regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza); subgroup analyses identify patient populations that help inform therapy selection. Meanwhile, the PD-1/PD-L1 checkpoint inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq) are demonstrating promising outcomes in phase II trials that could eventually change the paradigm.

Meyer mapped out several sequencing strategies based on median overall survival (OS) outcomes from pivotal studies.

At the same time, he noted that, from a clinician’s viewpoint, his top concerns are more immediate. “If you have a patient in front of you, then you have to decide what’s the best treatment to give that patient at that moment rather than decide, ‘If I give this treatment then I have the option to give him that subsequent treatment.’ We know that a lot of patients will never get on to a second-line treatment.”

Lenvatinib Versus Sorafenib

In August 2018, the FDA approved lenvatinib as a first-line therapy for patients with unresectable HCC based on data from the phase III REFLECT trial, which randomized 954 patients to lenvatinib (n = 478) or sorafenib (n = 476). The trial met its primary endpoint of OS noninferiority; the median OS by investigator review with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06).1

Notably, however, the secondary endpoint of objective response rate (ORR) shows “quite remarkably high response rates for lenvatinib,” Meyer said. The ORRs by modified RECIST (mRECIST) criteria were 40.6% for lenvatinib versus 12.4% for sorafenib (HR, 0.60; P <.0001). By RECIST 1.1 criteria, the ORRs were 18.8% versus 6.5%, respectively.

In terms of toxicities, the incidence rates of hypertension were higher for patients treated lenvatinib than with sorafenib (all grade, 42% vs 30%; grade ≥3, 23% vs 14%, respectively) as were the rates for weight loss (all grade, 31% vs 22%; grade ≥3, 8% vs 3%). Among patients who received sorafenib, the incidence of palmar-plantar erythrodysesthesia was greater compared with lenvatinib (all grade, 52% vs 27%; grade ≥3, 11% vs 3%) as were the rates for diarrhea (all grade, 45% vs 39%; grade ≥3, 4% each).

“When you’re looking at toxicities it’s important to find out what’s the implication for the patient,” Meyer said. “Patients generally don’t care about hypertension as long as it can be treated. They do care about diarrhea and hand–foot skin reaction.”

In analyzing patient subgroups, lenvatinib held an advantage over sorafenib for those with greater tumor burden, defined as macroscopic portal vein invasion, extrahepatic spread (EHS) or both. The median OS for these patients was 11.5 months with lenvatinib compared with 9.8 months with sorafenib (HR, 0.87; 95% CI, 0.73-1.04). Additionally, patients with hepatitis B virus (HBV) who received lenvatinib had a higher median OS of 13.4 months verses 10.2 months for those who took sorafenib (HR, 0.83; 95% CI, 0.68-1.02).

However, the REFLECT trial excluded patients with main portal vein invasion. As a result, the European Association for the Study of the Liver (EASL) did not recommend lenvatinib as a first-line option for these patients in its recently updated guidelines.2 Nevertheless, Meyer said, it is not clear from prior studies that sorafenib offers a greater benefit for these patients.

Otherwise, EASL recommended both lenvatinib and sorafenib as first-line options for patients who are classified as Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) C status or have earlier stage tumors that progress with or are unsuitable for locoregional therapies.

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