Key opinion leaders break down the pharmacokinetic properties of subcutaneous formulations.
Adam M. Brufsky, MD, PhD: Are there pharmacokinetic and efficacy differences between IV [intravenous] and subcutaneous formulations? That’s a question people always ask.
Tim Peterson, PharmD, BCOP: Largely when we look at, for instance, the initial staging for getting FDA approval for trastuzumab subcutaneously, HannaH was the first study that’s really looking at that flat dose of 600 mg. They found similarly noninferior trough concentrations, and they actually looked at pathologic CR [complete response] for those too.
Adam M. Brufsky, MD, PhD: And it was neoadjuvant therapy, right?
Tim Peterson, PharmD, BCOP: Exactly. And they found no difference in the trough concentration, and actually in some cases at least…
Adam M. Brufsky, MD, PhD: A grade higher.
Tim Peterson, PharmD, BCOP: It was actually, yes, similar with rituximab study as well.
Adam M. Brufsky, MD, PhD: Right.
Tim Peterson, PharmD, BCOP: So there’s really no difference per se in the PK [pharmacokinetics] for trastuzumab subcutaneous.
Matthew J. Matasar, MD: Are there bounds for trastuzumab beyond which we don’t have the well-described PK curve, in terms of very low or very high BMIs [body mass indexes] or other problems?
Tim Peterson, PharmD, BCOP: The way it was phrased in HannaH and the follow-up studies is that there was really no difference regardless of subgroups.
Adam M. Brufsky, MD, PhD: They looked at the BMI. They did the upper quartile of BMI and the lower, and they found there was no difference.
Tim Peterson, PharmD, BCOP: Yes. And I don’t believe even on the extremes there was a difference.
Adam M. Brufsky, MD, PhD: Right, they did that on purpose.
Tim Peterson, PharmD, BCOP: Yes.
Adam M. Brufsky, MD, PhD: I saw that stuff in HannaH. And something about HannaH is—actually, I don’t know if they did this with lymphoma—they recently published data in a follow-up to it, showing, as we know in breast cancer, that if the PCR [pathologic complete response] rate is roughly the same in neoadjuvant therapy, the disease-free survival at 3 and 5 years should be the same. It was tracked. And so they show that in the HannaH. You said that they don’t really have the data for lymphoma yet.
Matthew J. Matasar, MD: We haven’t seen published longer-term outcomes. We have the early outcomes for which there was no statistically significant difference.
Adam M. Brufsky, MD, PhD: The question is, the FDA requires what? What exactly does the FDA require before they allow us to come to market?
Tim Peterson, PharmD, BCOP: Initially, the first step is looking at noninferiority for pharmacokinetic exposure. That’s the very first step.
Adam M. Brufsky, MD, PhD: It sounds like a biosimilar in a way.
Tim Peterson, PharmD, BCOP: Exactly. Second, they’re looking at safety and efficacy. That’s where we’re comparing these end points. We’re looking at our CR rates, we’re looking at our PFS [progression-free survival] for our rituximab patients. We’re looking at safety end points to see, is there a difference in any adverse event? When we think about trastuzumab, cardiomyopathy and things like that come into play, right? Similar rates were found for that too, right?
Adam M. Brufsky, MD, PhD: Because one would expect that you could argue, “Oh, it’s a higher flat dose. You get more cardiomyopathy.” No, I get it. It really wasn’t the case; it was the same.
Tim Peterson, PharmD, BCOP: Exactly, and to that point too, the recommendations for cardiomyopathy for trastuzumab subcutaneous are largely the same. Your baseline echocardiogram every 3 months during therapy, that kind of thing remains the same based on those data.
Adam M. Brufsky, MD, PhD: Are there any contraindications to subcutaneous dosing at all that you know of?
Matthew J. Matasar, MD: When we refer patients, the question is really, “Is there intact integument?” If people have chronic skin disease, that certainly can be a problem for patients who have some forms of B-cell lymphoma, for which you may just feel uncomfortable, frankly, in treating through the skin. But regarding the number of situations that have arisen clinically where I’ve said, “You know, I’m not comfortable giving you subcutaneous treatment on the basis of comorbidity or physiology,” I almost can’t think of such a case.
Adam M. Brufsky, MD, PhD: The one I would expect from my nurses is low platelets. If someone walks in the door with a platelet count of 25, I’m sure my nurses will say, “Dr Brufsky, you can’t do this. You never have.” This is really important to put online. I’d like people to know this, that it is not an issue.
Tim Peterson, PharmD, BCOP: That inquiry has definitely come up. I know that’s come up, and I’m sure that’s come to you from the treatment team, but that’s definitely not something that is a problem.
Adam M. Brufsky, MD, PhD: It’s reassuring to know you can do this with low platelets.
Matthew J. Matasar, MD: In my opinion there is no platelet count below which it is not safe to give subcutaneous rituximab.
Adam M. Brufsky, MD, PhD: And with lymphoma, there have been some pretty low platelets.
Matthew J. Matasar, MD: We see them low.
Adam M. Brufsky, MD, PhD: Right, exactly. OK, good, I got it.