Roxanne Nelson, BSN, RN

June 15, 2017

CHICAGO — A new first-line treatment for advanced hepatocellular carcinoma (HCC) appears to be on the horizon. The current standard is sorafenib (Nexavar, Bayer), but a new study has found that lenvatinib (Lenvima, Eisai) was noninferior in this setting.

The results come from the phase 3 REFLECT study and were presented here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.

Lenvatinib showed noninferiority in overall survival (OS) compared with sorafenib in patients with unresectable HCC. "Lenvatinib also demonstrated statistically significant and clinically meaningful improvements in secondary endpoints, including progression-free survival, time to progression, and objective response rates," said lead study author, Ann-Lii Cheng, MD, PhD, from the National Taiwan University Hospital. So are these results  practice changing?

"Well, not yet, as lenvatinib is not approved yet for liver cancer," commented Tanios Bekaii-Saab, MD, a medical oncologist at the Mayo Clinic in Phoenix, Arizona. "But it's clear that lenvatinib may become another first-line option for patients with advanced HCC," he added.

Lenvatinib is currently approved for use in thyroid cancer and renal cell carcinoma. The manufacturer has said that it plans to apply for approval of lenvatinib for first-line use in unresectable HCC on the basis of the findings from the REFLECT study.

Speaking at a "Highlight of the Day" session, Dr. Bekaii-Saab emphasized that this study was powered for noninferiority and not superiority, "so the only thing we can conclude is that lenvatinib is not worse than sorafenib, and we cannot make any conclusions about it being better."

The study met its primary endpoint and was not inferior, and there were suggestions that in progression-free survival and overall response rate — which were secondary endpoints — they were superior with lenvatinib, he noted. "But again, with a cautious note, these were secondary endpoints and cannot be considered other than exploratory."

"However, it certainly goes along with the fact that lenvatinib is as good as sorafenib," Dr. Bekaii-Saab added.

Promising Results

HCC remains a large unmet need, commented Dr Cheng. It is the second leading cause of cancer death worldwide, and sorafenib is currently the only approved systemic therapy proven to extend OS in the first-line setting.

"Over the past 10 years, four global phase 3 trials have failed to meet the primary endpoints of noninferiority or  superiority to sorafenib in overall survival," he said. " Lenvatinib showed promise in a previous phase 2 trial in patients with advanced HCC, and now this is the first positive study in 10 years' time."

The REFLECT trial randomly assigned 954 treatment-naive patients with unresectable HCC to lenvatinib at either 8 mg or 12 mg once per day (n = 478) or sorafenib at 400 mg twice daily (n = 476). Two thirds of patients had macrovascular invasion (MVI) and extrahepatic spread (EHS).

The median time to progression was 8.9 months with lenvatinib compared with 3.7 months with sorafenib (hazard ratio [HR], 0.63; P < .00001).

"This was a highly significant difference," said Dr Cheng.

In addition, lenvatinib demonstrated a significantly higher overall response rate compared with sorafenib (24% [n = 115] vs 9% [n = 44]; odds ratio, 3.13; P < .00001). 

in the lenvatinib group, there were 6 complete responses (CRs) and 109 partial responses (PRs), while 246 patients achieved stable disease and 71 had progressive disease (46 patients had unknown status).

For sorafenib, there were 2 CRs, 42 PRs, and 244 patients with stable disease, while 147 had disease progression (status for 41 was unknown).

OS was similar in the two groups: Median OS was 13.6 months with lenvatinib compared with 12.3 months with sorafenib (HR, 0.92).

Dr Cheng pointed out that the forest plot of OS favored lenvatinib in subanalyses except in the western population and among those with MVI and EHS. The forest plot favored all subgroups for progression-free survival.

As for adverse events, Dr. Cheng noted that the "safety profiles of lenvatinib and sorafenib in this study appear consistent with those previously reported in patients with HCC."

Grade 3 and higher events were more common with lenvatinib than with sorafenib (57% vs 49%), with hypertension (23% vs 14%), decreased weight (8% vs 3%), decreased platelet count (6% vs 3%), elevated aspartate aminotransferase (5% vs 8%), decreased appetite (5% vs 1%), diarrhea (4% vs 4%), and palmar-plantar erythrodysesthesia (3% vs 11%) being the most common.

Quality of life was similar in both groups, and after treatment, scores declined in both study groups.

"Role functioning, pain, and diarrhea scores worsened earlier and nutrition and body image deterioration was observed earlier in patients treated with sorafenib," he said.

On the Horizon

Dr Bekaii-Saab explained that ongoing studies are looking at other options in HCC.

"We are excited to see studies that are looking at immunotherapy in the first- and second-line setting," he said, "And we hope to include immunotherapy, as more treatment options are needed.

"There is currently an ongoing phase 3 study of nivolumab [Opdivo, Bristol-Myers Squibb] vs sorafenib in the first-line setting, so this may add a PD1 [programmed cell death 1] inhibitor into the mix," he said. "In second line there is an ongoing phase 3 study with another immunotherapy agent pembrolizumab [Keytruda, Merck] vs supportive care."

He added that if all of the agents currently being studied are eventually approved, there may even be options for patients in the third-line setting. "Which is exciting, since this is HCC and a few years ago we didn't even think we had a first line and now we are talking about perhaps a third line and even more. So these are exciting times for HCC — if all of these options pan out the way we hope they do."

Dr Cheng reports relationships with Bayer Schering Pharma, Bristol-Myers Squibb, Merck Serono, Novartis, ONXEO, and Sanofi. Several coauthors also report relationships with industry. Dr Bekaii-Saab reports relationships with Amgen,  ARMO BioSciences, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Exelixis, Genentech/Roche, Glenmark, Helsinn Therapeutics, Lilly, Merrimack, Nationa Comprehensive Cancer Network, National Cancer Institute, Oncolytics, Regeneron, Research to Practice, and Taiho Pharmaceuticals.

American Society of Clinical Oncology (ASCO) 2017. Annual Meeting.  Abstract 4001. Presented June 4, 2017.

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