Transcript:Ghassan K. Abou-Alfa, MD: Systemic therapy is quite necessary and essential because, sadly, many patients will present with metastatic disease or many patients, as we just heard, will progress or recur. Sorafenib has been around us now, since its approval, for almost 10 years. Katie, tell us what happened in 2007 with sorafenib. Where are we today in that regard?

R. Kate Kelley, MD: So, 2007 was when the landmark SHARP trial, published in the New England Journal of Medicine the following year, was a huge step for liver cancer by becoming the first to have a systemic therapy that showed a meaningful survival benefit in a randomized phase III trial. And so, that’s a definite advance for the field. But we certainly have a lot of room to improve upon sorafenib. In a Child Pugh A, fit liver population, the median survival with sorafenib is 10.7 months compared to 7.9 months of placebo, which was highly statistically significant. We generally moved to sorafenib after liver-directed therapy or up front, depending on the extent of disease. So, patients with extensive metastatic disease would be somebody that we would initially treat with sorafenib or people after liver-directed therapy—they become untreatable due to too many tumors within the liver, signs of toxicity on liver-directed therapy or lack of response to liver-directed therapy for not seeing a benefit from arterial therapies or radiation. So, that’s generally the population where we look to sorafenib, and, again, it has been a meaningful improvement over the prior therapies, but we’re in great need for second-line treatments after progression.

Ghassan K. Abou-Alfa, MD: Sure. Sorafenib set the stage after many years where we’re really at least looking for a standard of care. I know sometimes you hear about doubts about it’s a value, but remember, this is really a work-in-progress. I think it’s a landmark of sorafenib as a standard of care in systemic therapy for HCC, which was very critical. Richard, within that context, we hear about it is not an easy drug to handle, the side effects, etc. So, please tell us a little bit more about that.

Richard S. Finn, MD: Sorafenib has been around for a decade, and it has held its place as the frontline treatment despite numerous efforts to unseat it. There have been numerous phase III studies, and clearly it has established itself as a benchmark in efficacy. Obviously, the survival benefit has to balance against toxicity. And while the drug has been developed—400 mg/twice a day being the full dose—all of us in clinical practice have realized that some patients can tolerate that and some can’t. That is probably unique to any other drug we use in clinical medicine, where we need to make appropriate dose adjustments based on how any given patient tolerates it. The toxicities are very predictable, the most common being hand-foot skin reaction and GI toxicities, specifically diarrhea being most concerning. And both of those can generally be easily managed; skin toxicity being managed with urea-based creams. There was a study in JCO that showed that helps alleviate that prophylactically and also educating patients to have Imodium. I think it’s very important that we see patients. It is an oral drug, but it’s not chemotherapy; it’s a biologic. So, we still need to see patients on a regular basis.

I know in my practice I will generally start a patient on 400 mg twice a day or 400 mg qDay (each day), with a plan to escalate quickly if they’re tolerating it. The distinction between those really is somewhat of an experience. If a patient is very robust, has good liver reserve, and no comorbidities, I really have no reservations about starting 400 mg BID (twice a day). However, if they have any of those negative criteria, comorbidities, less performance status, I might start a little slower and escalate. But regardless of the dose, I see them back within 10 to 14 days because I think early intervention to mitigate toxicities is key to keeping them on the drug. And to your point, I think any individual practitioner might have limited experience if they don’t see a large number of patients with HCC, unlike most of us on the panel. But in reality, I think it’s single-digit patients, numbers that are unable to tolerate some dose. And the dose reductions that have been studied as going from 400 mg BID to 400 mg qDay to even 400 mg QOD (every other day), where I have a number of patients who have been on for a very long time at that dose, it’s just what works for them and reacting to their toxicities.

Ghassan K. Abou-Alfa, MD: This is extremely important. We definitely hear sometimes that the patient did not tolerate therapy, and there’s a little bit of a quick move or a consideration for other therapies. And as we just heard from Dr. Finn, you clearly have to take the time to let the dose that really is appropriate for the patient settle in place. Remember, this is a biologic, so there is really a rather wide therapeutic range and you can definitely catch on it as you try to evolve patients through the therapy. With this said, another change we face, Katie, is some patients talking about how tumors are shrinking and it’s like the whole necrosis thing. Now you come and talk to them about sorafenib and say, “Well, it might not shrink,” and they look at you like, “What do you mean?”

R. Kate Kelley, MD: It’s true that only a minority of patients will have a measurable response on sorafenib, maybe 2% in the majority of clinical trials, but I think the great value of sorafenib is achieving disease stabilization and prevention of progression in a substantial number of people. And so, even though tumors aren’t shrinking, sometimes we’ll see some necrosis or lack of decrease in the blood flow to the tumor that can indicate less activity of the tumor. Sometimes that will correlate with decreased pain, so people will feel better, and those patients who are having some response in the tumor will often feel better and have an AFP decline or a decrease in their tumor marker. So, the benefits of sorafenib are not well captured by just response rate or the size of the tumor, and a lot of it is the combination of both their blood work, their tumor marker, the blood flow within the tumor on our follow-up scan, the so-called modified RECIST criteria, or the brightness of the tumor—which is a difficult measure to capture numerically—and how patients are feeling. And so, some of the patients, that I’m sure we’ve all had, that have done the best on sorafenib may not have had a dramatic shrinkage, but can have dramatic benefit in stabilization, sometimes for many months or even over a few years, without a measurable shrinkage.

Ghassan K. Abou-Alfa, MD: I totally agree. Actually, there’s an anecdote on that from the JCO paper that we published on the phase II trial for sorafenib. We have beautiful pictures of CT scans of the patient who was on the study with what appears to be, as we just heard from Dr. Kelley, a reduced blood flow and what appears to be a necrosis. What was conventional to that specific situation was a reduction of pain almost to without any need for narcotics; in addition to that, also a reduction in the alpha-fetoprotein, although we’re not necessarily implying here that it is a validated marker. It’s very important to look at the scans and talk to your radiologist, explain that you’re using a certain therapy to appreciate those other effects that sorafenib might impact.

Transcript Edited for Clarity