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I will get started just with a quick very high level refresher on the subcutaneous immune checkpoint inhibitors that are available and some of the specifics related to those drugs.

Our two subcutaneous immune checkpoint inhibitor products that are FDA approved to-date. Atezolizumab was approved in the late fall of 2024, and nivolumab, very late right after the holiday in 2024 as well.

You will see here also that pembrolizumab is also going to have a subcutaneous product soon to be FDA approved.

FDA approved products, we have our atezolizumab and nivolumab products with hyaluronidase.

You will see that the subcutaneous administration is relatively shorter compared to the IV administration, where atezolizumab is given over 60 minutes for that first infusion, and then the subsequent infusions are over 30 minutes after that.

The subcutaneous version of that is only given over about seven minutes total.

For nivolumab, again, you have that IV version that is given over 30 minutes, and that subcutaneous version again, that is given over a smaller amount of time three to 5 minutes.

Pembrolizumab still being studied and not approved yet, but that IV version is given over 30 minutes as well. And the subcutaneous version, The range that we are seeing in the studies is anywhere from one to 12 minutes, with the median being two minutes.

When you look at cost, you will see today manufacturers are making these drugs at parity, one is not less than or more than the other, but they are pricing out the drugs at parity.

You will also see that for the subcutaneous version, you will notice that some of the dosing is higher, right? You have to have more bioavailability of that drug to get into that subcutaneous tissue. Even though the dosing is slightly higher, that subcutaneous version is still priced at the same cost, and it is predicted that pembrolizumab will probably follow soon with its subcutaneous version when it comes out as well.

Hyaluronidase, it is an enzyme. What it is working to do is depolarize that hyaluronic acid in the tissue, so it decreases that tissue viscosity, increases permeability, and overall is really just working to increase drug absorption.

The effect is actually pretty transient, gone a little bit within about 24 hours after administration. It rapidly degrades or deactivates within the body. So it is gone pretty quickly after the administration; allows for a large volume subcutaneous administration.

For atezolizumab, this always blows my mind. When I think about a subcutaneous product in the sheer volume of a subcutaneous administration. It is 15 milliliters that is given in the thigh 15 milliliters, whereas nivolumab depending on the dose is anywhere between 5 and 15 milliliters that can be given in either the abdomen or the thigh.

Pembrolizumab in studies so far also abdomen or thigh as well. That subcutaneous volume also depends on the dosing. If it is every 3-week dosing, it is 2.4 milliliters. If it is every 6-week dosing, it is 4.8 milliliters.

Shawna Kraft (University of Michigan College of Pharmacy):

Thank you, Kelly.

To give you a little background, I do work mostly in solid tumors, breast, melanoma and GU a lot of renal cell.

I also work In breast where we have been using these large volumes.

We have been doing this for several years now. It is quite comfortable for patients. It is a shocking volume, especially when I am speaking to nurses in my other clinics as these agents are coming on the market, I am assuring them I am like, I promise patients, our breast patients with these other drugs are doing just fine with the large subcutaneous volumes, again, because that hyaluronidase that Kelly mentioned.

There is many cancers and disease states that these subcutaneous agents are studied in with data. We are going to start. We are just going to do a couple. We are going to do kind of a snippet today of some of the most robust data that is out there. We will start off with non-small cell lung cancer.

Atezolizumab, or atezo I sometimes call it for short.

We know we are using atezolizumab 1,200 milligrams IV every three weeks in these lung cancer folks. Is 1,200 enough subcutaneous? Do we need to do 1,800?

What we see here is the 1,200 milligram subcutaneous is probably not enough to get us to equivalent to IV in terms of our pharmacokinetics. So 1,800 is the dose that we need and also thigh had a better bioavailability. The bioavailability for thigh was 82.9% and it was 71.1% for abdomen. Hence atezolizumab needs to be done in the thigh. That is what this data was initially showing.

We see PK seems to not be significantly different, but do we need to worry about efficacy

Here we see similar efficacy with the subcutaneous that we see with the IV formulation.

This is now approved for all adult indications we have got for non-small cell lung cancer. They have extended it to some of their other approvals. So hepatocellular carcinoma, melanoma, and sarcoma as well.

Well, do patients and providers, what do they think?

They did a questionnaire to see like what was your preference. 70% of patients preferred sub-Q. We did have 7% patients who did not care, probably because of atezolizumab infusion. I mean, these immunotherapies, it is not like it is a 90-minute infusion going down to sub-Q, but still it is much quicker in the infusion center.

They did ask about feeling more comfortable. 46% of patients actually felt like it was more comfortable. 30% felt less emotionally stressful.

Then when asked, in the continuation periods when they were given the choice, what did you want? Almost 80% of patients wanted the subcutaneous over IV.

But now talking about pembrolizumab, which again, is not approved yet. But as Kelly said, we suspect it will be approved.

This is a phase III non-inferiority. Here is the dose. Again, the doses that we are looking at are not equivalent. All of these subcutaneous drugs are not the exact milligram per milligram that we see for IV. They are done all as flat dosing as many of you who have been in practice a long time know with pembrolizumab and know with nivolumab, we started off with milligram per kilogram dosing, but we are starting off with a flat dosing here, which is helpful.

Two cycles here of the pembrolizumab 790 and its Q6 weeks. That is something to note. That is Q6 here, not Q3, but they were getting chemo Q3. They were getting pembrolizumab for 100 IV Q6 and then 3 and then up to 16 cycles.

Again, the reason for those of you practice in lung cancer, you know this. If we are doing pemetrexed maintenance, this is a non-squamous cell patient. Only if you are a squamous cell, you do not get much choice.

What do we see in terms of PK? We actually have a higher AUC with pembrolizumab.

You will see. In the fair amount of the PK data we are seeing across the board in general, like a higher AUC with the subcutaneous and sometimes a higher C_max than we see with the IV.

Good news is it is not less.

Then looking at efficacy of course. There is no difference here. Efficacy outcomes were comparable which is good.

Then safety. You can see it is pretty comparable. I mean, at minimum, well, it is less or similar to with the subcutaneous group.

We will see grades 3 to 5. Overall, 47% with subcutaneous and 47.6 with IV. So very, very similar.

Switching gears to renal cell carcinoma. The nivolumab SC was done weight based. So, that – I find this interesting because with the exception of when we are doing nivolumab with ipilimumab, we are not doing this weight-based nivolumab anymore. We are pretty much doing flat dose, but this was done. This was a worldwide study and I think that is possibly why.

This was 3 milligrams per kg Q2 weeks, which at least in our practice, we hardly ever do Q2, mostly during Q4. Then this was compared with 1200 Q4 with the subcutaneous [formulation].

Here is what they did when looking at. They had some just interesting definitions. They were looking at the average 28 days. We had a minimum serum concentration and then overall response rate was the key secondary endpoint.

One thing I really wanted to point out here, so one of the goals also is 67T when you read the papers that they were looking for real world. I do not know about your practice sites, but if you took majority of people who are less than 65 kilograms, that would not be a real world. At least in my practice site it would not be.

 They wanted it to apply to a whole bunch of different body types, are we going to see the same pharmacokinetics when we are having to do a subcutaneous injection with a higher BMI, or highest BMI?

They split their groups and they still had a fair number in the 65 to 90 kilos, which I would say are the majority of patients that I see. But there was still a good chunk also greater than 90 kilograms. I really liked the span, the weight categories here.

Normally, you would not think as much about that if we are doing IV.

Average administration time with nivolumab subcutaneous was less than 5 or equal to 5 minutes. Most of them got all their doses. One thing to point out here, which at first you can say, “Well, this doesn't make any sense.” Why did the mean number of doses, why was it half in the subcutaneous group than the IV? But remember, this IV study was every two weeks and this was every four. This makes sense that it was half because they were getting it less than the time.

Dose delays was much less. We have 38% of patients who had at least one dose delay in subcutaneous group versus 60%. No patients who had an interruption. Then you can see the meantime 4.7 and 30.9.

Looking at the pharmacokinetics. Again, this is where we are seeing that increase in the C_average and the C_min. We are seeing higher again because of the way it is distributing into the tissues but non-inferior, which is the hope.

Looking at the additional safety and efficacy data. One thing I want to point out here is looking for those anti-nivolumab antibodies. Our skin has a high antigen processing of efficiency. They have a lot of APCs especially dendritic cells in our skin. Most of these studies are looking at this ADA [antidrug antibody] positivity to say, “Okay, are we having a lot of that in the skin. Because then if you have a lot of antigen against what you are injecting, you could have less efficacy.”

Even though the ADA positivity in this study was higher, 22.8% versus 7%, it did not correlate to efficacy. We do not have worse safety outcomes. It is less. I think in grade 3, grade 4, 35.2% versus 40.8% and even less treatment related [adverse events].

The lines are overlapping, which is in this type of study, exactly what we want to see rates or have similar mean progression-free survival.

Safety study, not any different than what we have been seeing with the other ones with any grade are similar treatment-related, so across the board. The one thing that I will call out, so select. So hypersensitivity and infusion-related reactions. I do not know about you guys but I tend to see a fair amount of these. It was less, so 0.4% for any grade. Then [subcutaneous] nivolumab had 2.9%.

Those that did have the injection site reactions from the [subcutaneous] nivolumab were low grade and transient. That mean duration three days and they resolved without treatment. Then in December 2024, nivolumab subcutaneous was approved. Very specific I want to call out here only for monotherapy. When we are doing ipilimumab-nivolumab, it is only approved right now that you are doing ipilimumab-nivolumab, you are doing IV-nivolumab with ipilimumab. Then when you are going to maintenance [nivolumab], you can switch to subcutaneous.

Thinking renal cell carcinoma. So if you are using your VEGF inhibitor, so nivolumab plus cabozantinib which we also use a fair amount, you can do subcutaneous nivolumab with ipilimumab-cabozantinib.

They did do a patient-reported outcomes, and again, high satisfaction preferring [subcutaneous nivolumab] over IV administration. Skin cancers: Immunotherapy has been the mainstay of therapy since 2011. Then 2014 when we got nivolumab and pembrolizumab. Looking at stage III, stage IV melanoma patient comparing nivolumab subcutaneous Q2 versus IV Q2. Then they switched to Q4 week cycles 5 plus.

Some of the preliminary safety data that we are seeing here. Again, similar, any grade side effects. So it seems to be similar what we have seen in lung cancer and renal cell.

Then also excitingly not FDA approved. Those of you who work in melanoma also see rela-nivo or relatlimab-nivolumab. So looking at a formulation of creating this as a subcutaneous product.

For IV relatlimab-nivolumab, it is in the same bag. It comes in the same vial and pharmacy.

They are administered simultaneously in this IV bag.

I would presume that we are going to see the same thing here as well because the subcutaneous are going to be in the same syringe.

Kelly Romo: 

Thanks, Shawna.

I think it is great to see that from the studies we are seeing similar efficacy and safety with the subcutaneous product. So that is really promising.

Now we are going to talk about some of those factors that will inform IV versus subcutaneous administration.

Some of the things we can think about when we are thinking about is the patient a candidate for either IV or subcutaneous in the rare occasion where they have a really bad infusion site reaction, some skin irritation. As Shawna was going over, these are usually transient, gone in three-ish days. They do not even need treatment. But if there was someone, there is always a niche patient who might have more reactions than others. You could always consider that IV, if there is any sort of bruising or platelet concerns.

Are they already getting other therapies as part of their overall regimen where they have a port? And maybe that patient preference is to continue with the IV. Then just making sure we are using chair time the best as we can is also an important consideration.

There may be overall patient satisfaction less in that IV population because it is more time consuming than getting it the other. But as Shawna and I have pointed out, it is not like you are saving 8, 4 hours for moving from an IV to a subcutaneous version.

I think manufacturers are working to create products that can be administered in a quicker time frame. They do not really have to come out with these products. They have an IV one that already works, so not necessary to come out with a subcutaneous but I appreciate that manufacturers are working towards that, working towards administration that could potentially happen in the home or just save chair and resources just because of sheer healthcare costs that are increasing over time.

On the subcutaneous side, these patients that are getting this immunotherapy are getting that long-term, right? They are getting repeated long-term treatment with these [IV immunotherapy] products. So really it is overall decreasing that treatment burden in terms of time for the patients.

Improving the efficacy over the overall healthcare system. So you no longer now need an IV bag, a transfer device, a potential filter, all these different things. You may just need a needle and a syringe. Working not towards just those resources of the nurses and the pharmacy team in terms of compounding and such, but also just the actual products needed for compounding and decreasing those healthcare costs.

But we could argue both of these products could potentially be used if payers are implementing site of care programs more often in the oncology space. So really you could have either an IV or a subcutaneous version in those professional type settings, which may be like a provider office, an ambulatory infusion clinic that is a standalone center or even in the home. Just having those additional options, I think, is always great for the patient.

Some of the current challenges. Again, I think I have talked about some of this a little bit is just that chair time. It is a modest improvement in chair time compared to other products that are available when moving from IV to sub-Q. But it is still some time, right? You know in the infusion center, we are always fighting for time and making sure that we can get patients in and get them treated as quickly as we can. That may also help to decrease that psychological burden that is on the patient, where they have to wait to get into the infusion area to get treated. That is a pro to that as well.

Then on the subcutaneous side, we really need to start thinking about this. Now that these products are more available, we always had them outside of this immune checkpoint inhibitor space. So that is being accepted. But now that we have subcutaneous version ICIs, think about all these different logistical aspects related to it.

Now if you have a drug that has both a subcutaneous and an IV, you have to modify your system to allow to amend treatment times of when you are going to give it, any sort of like offsetting those times of administration in your EHR system and how does that work. Making sure that, basically the patient education on what to look out for, what the subcutaneous version versus an IV if you are discussing it with the patient and giving them the option.

In terms of insurance reimbursement, today we are seeing them at parity. Hopefully that will continue in terms of prior authorization, but if there was ever a preference for one over the other based on a payer, if pricing ends up changing at some point, that is also something to consider in the future.

They have got a picture of the wallet cards here. I know some places still use these to give to patients. When they present an emergency department says, “Hey, I'm on this,” to alert them.

For patients who are allergic to bees. In bee venom, which you may or may not know, is hyaluronidase.

There is actually data you do not need to be worried. Short answer is for those patients who have been allergies, they have done skin testing and actually, the allergen that is in bee venom that is causing the allergic reactions is not hyaluronidase..

Personally, I would still feel comfortable trying subcutaneous unless you had a patient who had a really horrible wasp allergy, then you might want to have a discussion.

[Just some takeaways about the subcutaneous versus IV administration. Again thinking about with subcutaneous, we are saving patient time. You are probably saving about 25-ish minutes for the products that are available today, utilizing less healthcare resources on the subcutaneous side, it opens up chair time for those patients. So you can actually treat more patients in your infusion center. You do not need that IV access or that port in order to treat. But it all depends on that regimen of that patient is getting. So you always need to be mindful of that.

Then it just offers more flexibility. Here is where I was talking about site of care. It does offer more flexibility. Maybe you can just give it in the clinic, but also potentially site of care requirements will exist for a lot of payers as we continue to move forward with these products, given that the cost of that parity.

Then there is some models that can be considered. When I think about like having a central team, I think this is kind of our old school. While we are standardly used to of having the drug compounded or drawn up and then administered in the infusion site by a nurse. There is a double check that occurs. Everything gets bar coded and scanned. You have a ton of staff there to help oversee that management of that patient. It is like the central team that can step in if needed.

I think as more subcutaneous products become available, we might need to start thinking about how could we free up even more time in that infusion center space and potentially move it to the clinic.

But is there some potential where you could have some sort of team that is drawing up or compounding these doses and then delivering them to wherever it is needed to be administered, making sure that those appointment times are all in sync and there is enough time for everything to occur.

You would have to still have that barcoding, that risk scanning, as well as a double check in order for safety measures to occur. I think there is a lot of things to think about if it could be done in the clinic, but it is a potential option

Takeaways from the reimbursement perspective. Again, they are all at parity today. Hopefully, this would not change and manufacturers will keep that parity. There is a little bit more of an emphasis on allowing that provider and that patient to make the decision based on what is appropriate for them and where it is being given and what that patient prefers.

There should also be some sort of group purchasing. Organizations should have some sort of favorable pricing discount with their contract. I would hope so. Then again, this could impact revenue, right? Because you are ultimately with subcutaneous products. You would have left in the infusion center, allowing for more chair time for other patients be able to bring in more patients for infusions. And so could bring in higher revenue in your infusion center to offset some of those costs.

Then again, we just need to keep thinking about being creative since our environment is changing and we used to always just have these like IV products, and now we are starting to always see subcutaneous.

Shawna Kraft:

Because the subcutaneous formulation results in reduced chair time, does this affect reimbursement to health systems and does this factor into cost besides possible drug?

We have not seen a difference in reimbursement of whether we are doing IV or subcutaneous in terms of actual amounts of things. At this point, we have not. But Kelly, I do not know from your perspective, but that is coming from the managed care side.

Kelly Romo:

Yeah. I would not think that this would be just because of the timing of the products, not a huge reimbursement perspective from this.

If it was something like daratumumab, where you are going from 8 to 4 hours, yes, that would be different because you get paid based on your every hour of administration.

For these products, not as big of a deal, but maybe something. There is some other products that have longer administrations and decreases when you go from IV to sub-Q. Again, is it that big that it really makes a huge difference? I do not think so, because then you are bringing in more patients also to fill in that time to get reimbursed for those patients. So I would say no to this as well.

Shawna Kraft:

Most of my patients [who] get immunotherapy, do not have a port. So they would prefer to not have that IV line going and just get it subcutaneous quicker. But if you have a little thin. We have had thin patients get these and do fine. But if I was a little thin patient or they bruise easy.