DR BEKAII-SAAB: The presentation of Dr Demetri at ASCO was, I think, from the GI standpoint, one of the most positive studies in a GI cancer.
And essentially, as a premise to the Phase III study that was presented at ASCO, there was a Phase II study, a multicenter Phase II study — this is the publication in JCO — that looked at regorafenib in patients who actually failed at least 2 lines of therapy, imatinib and sunitinib, and showing, actually, a progression-free survival of 10 months in a third-plus-line setting and a disease control rate of 79% with survival not reached yet, showing an incredibly promising agent.
The regorafenib versus placebo study, the randomized Phase III trial that was presented at ASCO, which was running in parallel, was a 2-to-1 randomization in the favor of regorafenib with a crossover design, meaning patients who went on placebo were given the option of going on regorafenib once progressed.
The progression-free survival was quite positive, with a hazard ratio of .25, 4.8 versus .9 months, so close to a 4-month difference in PFS versus placebo. Of note, 100% of the patients had to fail imatinib or sunitinib, but many patients actually received multiple lines of therapy, including about 20% in both the placebo and the regorafenib arm receiving nilotinib.
The disease control rate was about 53%. Survival was not reached.
Toxicities were very much in line of what you expect with these types of tyrosine kinase inhibitors: hypertension, rash, hand-foot syndrome.
And what’s interesting, also, is that the patients who went from placebo and crossed over to regorafenib had a very similar benefit with progression-free survival than those who received regorafenib from the get-go.
So, overall, I think in an area of unmet need, following imatinib and sunitinib failure where we didn’t have an option, I think we can safely say with that JCO publication and, most importantly, with the Phase III randomized study, that patients now who progress on those 2 lines of therapy will have an option presented to them and an effective one with regorafenib.
DR LOVE: Any sense about the tolerability of regorafenib versus sunitinib?
DR GROTHEY: That is an interesting point. I mean, again, I’ve not treated patients sequentially yet from sunitinib to regorafenib. I do believe that patients who have kind of learned to tolerate one kinase inhibitor tend to manage toxicities better later.
But I think what’s concerning in the Phase II trial, which was published, 82% of patients on regorafenib had to have some form of dose reduction — 82%. They went from, let’s say, 160 milligrams 3 weeks on, 1 week off to some form of dose modification, either dose delays or dose reductions. And this is in the context of longer therapy than we see in colon cancer, which has a more rapid progression. So these cumulative toxicities might not necessarily play a role.
So I could see that in clinical practice, once the drug’s approved, we might actually find different ways of, let’s say, increasing doses over time, starting with, let’s say, one 20-mg dose per day, escalating the dose over time. Personally, I think it’s similar to what I do with sorafenib in HCC. I hardly ever start with full-dose sorafenib, but I ease patients in within a week and try to establish a full dose.