Frontline Decision Factors for Metastatic Disease

Transcript:

Masatoshi Kudo, MD, PhD: The REFLECT trial is a global phase 3 noninferiority trial comparing the efficacy and safety of lenvatinib and sorafenib. Results were positive: Overall survival was at 95% confidence intervals; upper limit was 1.06, which was smaller than predefined noninferiority margin of 1.08. So the noninferiority was proven. But regarding the efficacy, such as response rate and the PFS [progression-free survival], the PFS is much longer in lenvatinib arm, which is 7.4 months, and the sorafenib arm was 3.7 months; the difference was, of course, significant.

An objective response rate in lenvatinib was 40.6%. In the sorafenib arm, objective response was 12.4 months. Response rate and the PFS are much better, and tumor effect was superior in lenvatinib. Regarding how to select an agent, we prefer lenvatinib for intermediate-stage HCC [hepatocellular carcinoma] with a high tumor burden because we can achieve the response, as I said, and follow TACE [transarterial chemoembolization]. We can achieve, at times, complete response.

For advanced-stage HCC, of course, there are several reports with systemic therapy. That report said the objective response in RECIST correlates with overall survival. That means the agent with the high objective response provides survival benefit for even more patients. We prefer to use the lenvatinib first. But in the REFLECT trial, there are different profiles of adverse events in the sorafenib arm: Hand-foot skin reaction, diarrhea, and alopecia are more frequently seen.

But in the lenvatinib arm, hypertension, hypothyroidism, or proteinuria are more frequent. Additionally, in the lenvatinib arm, fatigue is more frequent. In elderly patients or patients with uncontrollable hypertension or patients with liver and renal dysfunction, maybe we prefer to use sorafenib first. The younger populations will tolerate well, and we, therefore, might select lenvatinib.

Minsig Choi, MD: What are treatment options for first-line therapy? Sorafenib has been available for the last 13, 14 years, and that was the only option for patients with unresectable liver cancer. There were a lot of clinical trials conducted because sorafenib is a multikinase inhibitor, and we all thought that by using different multikinase inhibitors and VEGF inhibitors, we can improve the clinical outcome in patients with unresectable HCC. However, many of these prior phase 3 clinical trials have failed to demonstrate a clear-cut overall survival improvement, but actually they were inferior to sorafenib.

Recently there was a study conducted using lenvatinib versus sorafenib. This was the REFLECT clinical trial, a noninferiority, large phase 3 international study that enrolled 954 patients. The primary end point was overall survival because there were no other treatment options in this patient population. It had 2 kinds of end points. The first was overall survival. Because there were so many failures in the past, there was also an assessment to look at a noninferiority study. It means that the drug is as good as sorafenib.

The study has shown that lenvatinib had overall survival of 13.6 months, and sorafenib had 12.3 months. However, the hazard ratio here was 0.92 There was a numerical improvement in overall survival with lenvatinib, but the confidence interval crossed 1; therefore, lenvatinib was not superior to sorafenib, but lenvatinib is as good as sorafenib.

However, the secondary end point of the study includes progression-free survival as well as overall response rate was superior in the lenvatinib arm. The PFS was 7.3 months versus 3.7 months, and 41% response rate for lenvatinib was pretty impressive for a tyrosine kinase inhibitor, and 12% for sorafenib. In my clinic patient, I usually see a patient who has good performance status, who is relatively well. I would use lenvatinib in those patient populations. If I see a frail patient whose liver function is not very good or a Child-Pugh B, which is not the best-case scenario, I would think of using sorafenib in those patients because lenvatinib is not well studied in patients with poor liver function.

Transcript Edited for Clarity