How Subcutaneous Delivery of Checkpoint Inhibitors Enabled a Remote Oncology Trial at USC

You are running an oncology trial that will be conducted almost entirely remotely using SC administration. What is this trial and what is the current status?

The protocol is one that calls for largely home administration, with telemedicine visits for these large volume subcutaneous infusions of checkpoint inhibitors. Because checkpoint inhibition has become such a cornerstone to the care of oncology patients across many different tumor types, it was on us to find a way to to distribute these drugs to the people who need them in a way that is simplest, cost-effective and efficacious.

We have received an IND from the Food and Drug Administration and are waiting for final regulatory approval from the Ethics Committee at USC, so we’re very close to starting.

What do you hope to learn from this trial about SC delivery for cancer care?

I’d like to demonstrate feasibility, because we’re trying to figure out if this works. And from there, we can assess where the bugs are, the kinks, and how we can fix them. I don’t anticipate it to be perfect, but we are going to find out what the issues are. I would like us to make cancer care easier for people. And if we can do that, then we’ll have done something of value. 

"I don’t anticipate it to be perfect, but we are going to find out what the issues are. I would like us to make cancer care easier for people."

Was the decision to use a subcutaneous delivery route included in the design of this remote trial from the beginning?

The need for it originally came from the COVID pandemic, and the fact that some of our patients didn’t want to come into infusion centers. Now that the need is driven further by this Great Resignation phenomenon; healthcare is no exception to workers leaving their roles in the pandemic.

We have had trouble finding enough nurses to staff our infusion centers. Because of that, we have to find ways of being able to deliver these drugs more efficiently.

We could have done home IV administration with remote monitoring, and used all of our digital tools to do that, but subcutaneous delivery is another way of doing it, whether at home or in the office.

What specific considerations come along with SC delivery in the home setting?

First, the formulation has to change. In order to effectively do a large volume infusion, you need to formulate something that allows the antibodies to be well-absorbed, such as hyaluronidase, which is included in subcutaneous atezolizumab. There needs to be data that shows you achieve levels comparable to IV administration. Once you’ve done that, it should be something that ultimately can be self-administered. In this program, we’re not going all the way to self-administration, but I do think that self-administration is certainly something that could be done in the future, especially after someone was trained in self-administration. 

Was there trepidation around administering a monoclonal antibody at home?

These products are incredibly safe. I’ve been in oncology now for a number of years, and I’ve had a lot of products that give me headaches with infusion reactions in the clinic. There have been drugs like rituximab that I was used to getting panicked phone calls from the infusion center about patients having fever or chills.

We don’t get those phone calls very much with checkpoint inhibitors. They don’t cause very much in the way of acute infusion center reactions. And so once you think about antibody products that don’t cause a lot of reactions, you start asking, “Why can’t they be administered at home?”

"I’ve been in oncology now for a number of years, and I’ve had a lot of products that give me headaches with infusion reactions in the clinic. We don’t get those phone calls very much with checkpoint inhibitors."

Does a subcutaneous administration bypass adverse reactions or is it drug-specific?

It’s a little bit of both. Rituximab can be given by subcutaneous infusion and has approval to do that. 

There are fewer reactions when it’s given more slowly. With subcutaneous administration, although the drug goes into the patient faster, it gets absorbed into the body slower. Therefore, you do have some protection from certain categories of infusion reactions. In general, subcutaneous is very safe, both in the clinic and at home.

How will oncologists get compensated if they’re prescribing subcutaneous oncology products that then move to alternative settings like the home?

If you were to ask me 20 years ago, how this is going to work, I would say this is impossible, because oncologists all make a living on the profit margin of the drugs that they’re administering in their own offices. But that reimbursement model for oncologists doesn’t continue to hold a lot of water. 

We have many oncologists who practice in managed care settings, where a profit margin on the administered drug is not the main source of their reimbursement. With the 340B pricing structures that have been created, most oncologists have moved now to this employee model, working for large cancer centers. We’re not running our own businesses and making a profit margin off drugs that we purchased. We’re just employees providing a service.

The question is who makes the money in a subcutaneous delivery model? It then depends on who owns the pharmacy, and whether the pharmacy is owned by the insurance company or whether the pharmacy is owned by the hospital.

How is the bioavailability of a drug affected by changing from IV to SC?

If you formulate it right, minimally, and then if you dose it right, minimally. With our subcutaneous atezolizumab study, the amount of drug that goes into the patients is slightly higher than what would be given intravenously. You have to make that adjustment so that you achieve similar levels to what would be achieved intravenously. 

Fortunately, with the checkpoint inhibitors, they have this tremendously large therapeutic index and range. Prior studies compared two milligrams per kilogram to 10 milligrams per kilogram of nivolumab, and found no difference in outcomes. Another great thing about this class of drugs is we don’t have to achieve very tight dosing regimens. That’s why we can also use fixed dosing with these drugs.

We don’t have to use weight based dosing. That gives you a sense of just how much room we have, in terms of difference between dose needed and safety.

Does the dosing schedule remain consistent between the two routes of administration?

We’re doing it on a three-week schedule, which is the same that one would most commonly use with atezolizumab. There are four-week intravenous schedules that exist.

We haven’t tested the whole spectrum of potential dosing schedules that could be used. A lot of this is based on pharmacodynamics more so than pharmacokinetics.

Are there significant differences in the pharmacokinetics of a 30 ML dose given in 15 minutes versus an IV infused over an hour or two?

Not if you pick the right dose, because with monoclonal antibodies, they circulate for weeks once administered. Unlike small molecule drugs, where you look at peak and trough concentrations, and those metrics are very important; with monoclonal antibodies, it’s just less so.

"It’s usually these very small changes in volume that impact your ability to clear a backlog."

How have you seen patients respond to a subcutaneous dose that may be a larger volume than they are used to?

In studies where they’ve done randomized comparison of patient preferences for the drugs that are out there and are available such as trastuzumab for example, patients prefer the subcutaneous dosing. It’s faster and easier. If everybody was getting subcutaneous injections, everyone would think the IV was weird. It’s just about expectations. For people who are new to having cancer, they don’t have any expectations. 

What is the potential impact of switching to subcutaneous on your hospital?

Right now, if you’re a new cancer patient at the public hospital, and you want an infusion of chemotherapy, you might be waiting several weeks for the next available appointment. That is because we just don’t have enough infusion beds available. For a hospital like that, if we just decrease the volumes by 10%, we would get rid of the waits almost entirely. Because when you have a waiting list, you’re doing the same amount of work, you’re just doing it later. And it’s usually these very small changes in volume that impact your ability to clear a backlog.