Insights From: R. Kate Kelley, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Josep Llovet, MD, PhD, Icahn School of Medicine at Mount Sinai; Masatoshi Kudo, MD, PhD, Kindai University; Arndt Vogel, MD, PhD, Hannover Medical School
Josep Llovet, MD, PhD: Now let’s focus on frontline options and second-line options. Based on subgroup analysis or analyzing the studies and your experience, how you will strategize the treatments in frontline and second line? Can I give my opinion later on?
R. Kate Kelley, MD: Yes. This is the question of the day. Of course, at an academic institution, we are always hoping to advance the field further and have a variety of clinical trials that are our priority. But, in patients not on clinical trials, right now we now have in the United States approved sorafenib, as well as lenvatinib. And, although the overall survival outcome for lenvatinib was noninferior, there are some distinctions between the drugs in the secondary efficacy endpoints, like lenvatinib having a higher response rate; on investigator and central review by mRECIST, as well as RECIST; and longer time to event, with my caveat always in an open-label study. So, those are a little harder to interpret than the shorter trials. But, conversely, there are also tolerability and toxicity differences between the drugs to balance in this decision in our inherent organ dysfunction population.
With those thoughts in mind, when I have a first-line patient and am considering sorafenib or lenvatinib as a standard first-line therapy, one thought that comes to mind right now…as my top deciding factor is, what is their liver function? Because we do have a substantial—at least from not only my own practice experience to date—experience of sorafenib; we have more data in hepatic dysfunction and organ dysfunction populations from the CALGB 60301 trial and from the original phase II trial, which included almost a third of patients with Child-Pugh B. We have more experience dosing in the drug in Child-Pugh B or worse hepatic dysfunction—I should say, in Child-Pugh B hepatic dysfunction, not worse—but in patients with more compromised liver function. And so if I’m not certain about their liver function, I will generally prefer sorafenib right now, because we can monitor very closely and know how to adjust the dose; potentially, empirically starting with a lower dose if needed and escalating is my current practice, actually.
Conversely, the lenvatinib response rate does incline one to think about a patient with a more bulky or large tumor that would benefit from shrinkage, either from the prospective of relieving pain or other impending obstruction or other complications from a bulky tumor. A higher shrinkage rate potentially might guide one toward lenvatinib. And then, I think within those considerations, there are also the differences in toxicity where for a patient with preexisting diarrhea, for example, one may be more inclined to use sorafenib, or for a patient who gets early hand-foot syndrome on sorafenib, one might want to switch to lenvatinib, because it has a lower rate of hand-foot. But those are the things I think about.
Josep Llovet, MD, PhD: Also, I think the data we have after thorough analysis of sorafenib throughout the years are that it works very well in hepatitis C–related HCC. Certainly, the hazard ratio is close to 0.5, so they are very strong data. They come from multivariate analysis of meta-analysis of the 2 main trials. And I think that this is quite strong to suggest that certainly for hepatitis C–related HCC, probably sorafenib may be the choice. The subgroup analysis of lenvatinib certainly shows us that with hepatitis B virus, lenvatinib works pretty well. So, eventually, this also may be another point to take into account in the decision making.
Arndt Vogel, MD, PhD: For systemic therapies, we had for a long time just 1 option, which was sorafenib, and we used it for many years as the standard of care in first-line therapy. And there were a couple of trials that investigated whether we can use other TKIs [tyrosine kinase inhibitors] or combination of drugs to improve the outcome for patients in first-line therapy. But all of these trials failed. And only recently, the REFLECT trial was reported, which basically evaluated the efficacy of lenvatinib compared with sorafenib in first-line therapy. This was a noninferiority study that was positive, and with this we have perfect evidence to use a second drug, lenvatinib, in first-line HCC.
The question of which drug would be the preferred drug I think is still open, and we have to see how we can really use lenvatinib in real-life practice. Based on the data we have seen in the clinical trial, there’s no benefit, or significant benefit, in overall survival. However, when we look at the secondary endpoints like PFS [progression-free survival], TTP [thrombotic thrombocytopenic purpura] response rate, we have good evidence that lenvatinib is a drug that might be more effective against the tumor compared with sorafenib. But, nevertheless, this did not really translate…directly into a longer overall survival. Therefore, I think we have 2 options and 2 drugs, and…in the future in relapsed setting, we will get the feeling which drug might be the best drug for which patient.
Masatoshi Kudo, MD, PhD: Currently, we have for frontline systemic therapy 2 options. One is sorafenib and the other is lenvatinib. Actually, lenvatinib was approved last year worldwide, and the REFLECT study showed no inferiority, but the antitumor effect is superior in lenvatinib as compared with sorafenib. So response rate is better, and PFS is better. So in Japan, 90% of frontline therapy is lenvatinib now. So all over the world, maybe lenvatinib is gradually become first choice of therapy. Of course, sorafenib is still a possible frontline agent.