Insights From:John L. Marshall, MD, Georgetown University Hospital;Mohamed E. Salem, MD, Georgetown University Hospital;Monica Chacha, RN, BSN, OCN, Georgetown University Hospital
John L. Marshall, MD: In the last year, there were 40 new medicines approved for cancer. And I’m lucky, I’m a GI oncologist. I only really have to focus on a couple of new medicines. Whereas if you’re a general oncologist, I don’t know how you do it. I don’t know how you keep up with all of the different new medicines out there, particularly ones that you’re not going to use all that often; that you might only use once or twice a year. And how do you know the subtleties of how to give the medicine? Because if you follow the package insert for a lot of these medicines, it’s not really the optimum way to go.
So, for the newest medicine, TAS-102, or Lonsurf, think of this as oral chemotherapy. Yes, it’s a cousin of fluoropyrimidine. But remember, it’s not a hand-foot, diarrhea, mucositis drug; it’s a myelosuppression drug. It’s different than what you would think with capecitabine. And it has funky dosing, 35 mg/m2. You’ve got to do some math. It has two pills sizes. Decide whether you’re going to use the two pill sizes to be precise or just pick the closest single pill that you can get in multiples up to the dose that you’re giving. Twice daily, 5 days on, 2 days off, 5 days on, 2 days off, 2 weeks off. This is something that’s immediately a bit confusing to patients. Make sure you provide calendars. Make sure you bring that patient back for that day 15 and days 28, 29. Check CBC (complete blood count) because a lot of these patients will have low ANCs (absolute neutrophil counts). You need to delay doses or consider growth factors in these patients.
We talk about this medicine having not much in the way of side effects, but in my experience, about 20% or so will have some nausea, some GI upset; so, prepare them for that. But a vast majority will tolerate this medicine very well. It also is not a drug that causes a great deal of responses, and I realize that a lot of us get hung up on wanting responses. But let’s just remember that in second-line, you didn’t get many responses either in your patients using those standard IV chemotherapies. And so, what this drug is about is stabilization of cancer. And in about 1 in 5 of patients, they’ll have stabilization up to 6 months. In this refractory setting, that is a meaningful chunk of time, and you don’t want to leave it on the table. Find the right patient. So, patients with good performance status, smaller-volume disease, are great patients to put on this. If you’re resting them from other things, myelosuppression is the big side effect here. It rests them from some of the other side effects. And I think these are some key tricks, key inside baseball, if you will, of how to manage Lonsurf, or TAS-102.
Mohamed E. Salem, MD: On September 22, 2015, the FDA approved a new drug for refractory colon cancer. It’s called Lonsurf, or TAS-102 (trifluridine/tipiracil). The drug is approved for patients who have progressed on standard therapies, such as fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. And if they are RAS wild-type, they also have to have anti-EGFR. Lonsurf is actually two drugs: the trifluridine and tipiracil. Trifluridine is the active compound that integrates in the DNA and causes cell cycle arrest. However, the problem, when you ingest trifluridine, it gets metabolized or degraded very quickly by an enzyme called thymidine phosphorylase. Therefore, once you combine tipiracil to trifluridine, the tipiracil actually inhibits that degrading enzyme. Therefore, you end up with an active compound; trifluridine can go and affect the cancer cells.
John L. Marshall, MD: This is an important moment for our patients. We’ve been taking care of them for a couple of years. They know the parking lot attendant’s name. They know how to do everything. They’re cancer veterans, if you will. A lot of times people focus on the response rate of these two medicines, that there isn’t an actual response rate. But we have to remember that it controls cancer in about half the patients; about 20% will have 6-month stabilization. Those are very valuable chunks of time for patients in this refractory setting, so we don’t want to minimize or de-value that control. But what are some of the other important things, at this point, for our patients?
Monica Chacha, RN: I think conversations we’re having at this time are (1) quality of life: how do they want their life to look right now while they’re on these medications. And then (2) we’re having a lot of discussions about goals of care, like what is the plan going forward. What is their goal?
John L. Marshall, MD: And we often haven’t had that discussion since maybe day 1, where the focus is aggressive and on management. But now that patient is a better consumer. Quality of life is important. Mohamed?
Mohamed E. Salem, MD: I agree with both aspects. I also agree with the quality of life. Because, at this time, you really want to also highlight that maybe they should take vacation time, they should go with their family, go to their grandkid’s graduation. And I don’t say, “Okay, you have to come on this cycle and that date.” You allow them to do what they like to do.
John L. Marshall, MD: So, a great advantage of these oral therapies is they’re free—they don’t have to come every 2 weeks and get IVs. They can do these kinds of things, and it makes for a perfect time for us as healthcare providers to readdress those really important goals of care for our patients.
Mohamed E. Salem, MD: The drug was approved based on the RECOURSE study, which was a randomized international phase III study, that had patients with refractory metastatic colon cancer in a 2:1 design to receive either Lonsurf plus best supportive care or best supportive care alone. The study included about 800 patients, who were enrolled in about 18 months, which I think was a fast accrual. And the primary endpoint was overall survival. The secondary endpoints were progression-free survival, safety, and tolerability. The study was given at 35 mg/m2 on days 1 to 5 and 8 to 12, every 28-day cycles. The maximum dose was 80 mg BID (twice daily). The study was positive, and it met its primary endpoint with improvement in survival. For patients who received Lonsurf, median overall survival was about 7.1 months. OS for patients on the placebo arm was about 5.3 months, with improvement in overall survival being about 1.7 months. The results were updated in ASCO GI in 2016, and the benefit was about a total of 2 months.
Because of the improvement in survival and also the progression-free survival, the study was approved in the refractory setting. Because of that approval, now we have two agents in the refractory setting. We’ll have Lonsurf, and we’ll have regorafenib.