John Marshall, MD: Allyson, let’s shift gears beyond first-line therapy through lines of therapy. I do think we, as academic doctors, tend to see a younger and fitter population. Where are we with options, as we go down lines of therapy?

Allyson Ocean, MD: In a patient who has had already 5-FU [5-fluorouracil]—based therapy first line, we sequence usually to GEM [gemcitabine]-based therapy, whether it can hopefully be GEM–nab-paclitaxel, GEM alone, or sometimes GEM–CAPE [capecitabine], although not usually GEM-Tarceva [erlotinib]. We don’t use that anymore. In the patients who do get GEM–nab-paclitaxel first line, we have liposomal irinotecan in combination with 5-FU as a standard option. The uniqueness of the drug is in the way it’s engineered. It really does deliver higher potency of SN-38 to the cell because of the shell, so the liposomal carboxymaltose formulation of this molecule gets in there. It gets in there, and it’s supposed to be less toxic. However, it can be toxic. I’ve had a lot of patients, unfortunately, who have had higher rates of bone marrow suppression and diarrhea, but it is an effective regimen second line. A lot of these patients may already have neuropathy first line, so it’s a non-neuropathy–causing, active second-line option for them.

John Marshall, MD: There are some response rates being recorded. You’ve got to watch the toxicity. I think it’s a PK [pharmacokinetic] thing, as well, with the exposure here.

Allyson Ocean, MD: Right, and they have to check. You have to check counts weekly on it. You can’t just say, as you would with FOLFIRI [leucovorin calcium, 5-fluorouracil, irinotecan], “Come back in 2 weeks.”

John Marshall, MD: That’s where I was getting to with my deconstruction question before. If you’ve done GEM—nab-paclitaxel, can you begin to deconstruct in lines of therapy, or is there something magical about the triplet therapy? You think this becomes a logical second- or third-line choice?

Shubham Pant, MD: Yes, I think it does become logical. The big thing is, when the original trial was done, you had the 5-FU and the liposomal irinotecan, the liposomal irinotecan single agent, and then the 5-FU. The single agent did not win out. I think if you were to administer it, it has to be 5-FU and liposomal irinotecan. The big thing about giving this drug is that you just need to talk to the patient about the toxicities and follow them very closely.

I think we’ve had success with that, but you really have to sit down and talk about supportive care with the patient, including what toxicities they can expect, and try to head off those toxicities, like diarrhea. That’s very important. And once the patients are educated, they know what to do or, if they get into trouble, to call about what to do, so I think they tend to do better. Then you can try to adjust the dose, depending on the toxicity. I think that’s very important—education, education, education about the toxicities, so that the patients can know what to expect and then they can probably stay on it and get more clinical benefit from it.

Edward Kim, MD: It’s important that this is the only high-level, randomized data that we have in this setting, so I think this is the evidence that you can deconstruct. After GEM-based therapy, doing 5-FU—nanoliposomal irinotecan should be the standard of care. That should be what people are thinking of. It’s not a head-to-head comparison versus regular nonliposomal irinotecan. In terms of safety, compared with historical controls, it looks similar in terms of rates of diarrhea and neutropenia, which we know are classically what we think about for irinotecan as well. There have been other attempts to look at 5-FU and irinotecan, or 5-FU and oxaliplatin, and this is the highest-level evidence we have.

John Marshall, MD: Some of the 5-FU—oxaliplatin studies have been negative in this space.

Edward Kim, MD: It’s confusing.

John Marshall, MD: Yes, and I’m always fascinated, having lived through the naked taxane trials with GEM, and then when we liposomally encapsulate taxane, all of a sudden, we get some activity there. I confess that you get some activity with regular irinotecan, but this is a different drug and maybe something that penetrates tumors better, as Allyson said, and targets the tumor.

Edward Kim, MD: There’s obviously the PK, so you have a greater average concentration that’s delivered. That seems to correlate with efficacy. The maximum concentration of the SN-38 that results seems to correlate with safety, but I think there is clearly evidence. In terms of dose, this is a lower dose than we traditionally give with regular irinotecan. There is evidence that this is a different drug, because it’s altering the PK.

John Marshall, MD: Yes, and you Californians are much cooler and smoother about end-of-life stuff, right? We East Coasters and Texans are panicked.

Transcript Edited for Clarity