REFLECT Trial: Frontline Lenvatinib's Value in HCC

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Josep Llovet, MD: The trial comparing lenvatinib to sorafenib was meant to first demonstrate noninferiority, meaning to demonstrate that the drug’s effects were similar to those achieved by sorafenib. In the secondary endpoints, they also tried to demonstrate that the drug was superior to sorafenib. The first analysis was positive. Therefore, they demonstrated that the patients treated with lenvatinib had a similar survival rate to sorafenib. I think in the trial, the results were around 13.5 months for lenvatinib and 12.5 months for sorafenib.

This showed that the toxicity with lenvatinib is relevant but manageable. There were not a remarkable number of treatments going to death reported in the study. I would say the important additional information for this trial is that the treatment achieved objective response in 25% of patients, which is quite remarkable in frontline treatment, whereas for sorafenib, it is less than 10%. I think that this difference is appealing, particularly because when you are treating a patient, it’s always good to show objective responses. This means that the tumor is shrinking.

Riccardo Lencioni, MD: Here at ASCO GI, we presented the results of the central independent blind study that read the whole of imaging data collected for the REFLECT study. These included an independent blind assessment performed according to standard RECIST 1.1 and mRECIST [modified RECIST] criteria. The bottom line is that PFS and TTP are almost the same between standard and modified RECIST and almost the same as what was reported for the local assessments done at the sites.

This is not surprising, because the main difference between standard RECIST and modified RECIST is in the measurement of the target lesions. Therefore, this will mostly impact objective response rather than TTP or PFS. Now for objective response, the central blinded studies have confirmed that with the use of mRECIST, you can capture 2 times more responders in either treatment arm, both in sorafenib and lenvatinib. It also confirmed that lenvatinib had a significantly higher response rate than sorafenib.

Now the key question is whether response by mRECIST is a truly reliable surrogate for overall survival; in other words, whether responders truly had improved survival and clinical outcomes over nonresponders, as suggested by prior investigations. This is very important information that hopefully will be available in the near future. This new information could potentially be very helpful in the clinical decision-making process for clinical practice.

Josep Llovet, MD: The recent report in this ASCO GI meeting is addressing how in the general trial, they were reporting the response rate based on the investigator. In this study, they are reporting the objective response assessed by blinded independent central review. That generally is more precise. The data are quite shocking in a sense that the objective response by modified RECIST reaches 40%. This is unheard of for a TKI in HCC, and it is giving us an idea of how potent this drug is in terms of achieving an antitumor effect. This has also been reported in other tumors with the same drug, lenvatinib, in renal or the thyroid cancer.

Transcript Edited for Clarity