From IV to SC: Multidisciplinary Strategies for Transforming ICI Delivery to Enhance Patient-Centered Care and Ensure Equitable Access

[00:01:50]

Introduction

Jerfiz Constanzo (CCO): Hello and welcome to this Practicing Clinicians Exchange presentation entitled from IV to Subcutaneous: Multidisciplinary Strategies for Transforming Immune Checkpoint Inhibitor Delivery to Enhance Patient-Centered Care and Ensure Equitable Access.

This activity is supported by an educational grant from Bristol-Myers Squibb.

[00:02:18]

Faculty

It is my pleasure to introduce the faculty for this program. Joining us today is Deborah Fischer, who is a Physician Assistant at the Mayo Clinic in Jacksonville, Florida; and Kathleen Madden, who is an Oncology Nurse Practitioner at NYU Langone Perlmutter Cancer Center in New York, New York.

[00:02:49]

Faculty Disclosures

Shown here are their disclosures.

[00:02:56]

Learning Objectives

These are our learning objectives for today.

[00:03:09]

Outcomes Analysis: What Did You Learn?

Please note that some of the questions in this activity will be presented twice, once at the beginning of the relevant content, then once again at the end of that section. Thank you in advance for helping us assess the impact of this educational activity.

[00:03:30]

A Quick Poll

First, a few quick polls.

[00:03:37]

Poll 1

For how many patients with cancer do you provide care for in a typical month? Is it:

1. One to 4;
2. 5 to 10;
3. 11 to 15;
4. 16 to 20;
5. More than 20; or
6. Not applicable.

Please vote.

[00:04:11]

Poll 2

Which best describes your practice setting? Is it:

1. Academic; or
2. Community.

Please vote.

[00:04:35]

Agenda

Thank you for answering all those polls. I will hand things over to Kathy, who will get us started with the role of APPs in comprehensive care of patients receiving immune checkpoint inhibitors.

[00:05:03]

The Role of APPs (NPs/PAs) in Comprehensive Care of Patients Receiving ICI

Kathleen Madden (NYU Langone Perlmutter Cancer Center): Thank you so much. Welcome everyone for joining us. The role of APPs, NPs and PAs in comprehensive care of patients receiving ICI, which stands for immune checkpoint inhibitors. You will be seeing that quite a bit through the program.

[00:05:41]

Pretest 1

Let us start off with a pretest question. Which of the following is a benefit reported for subcutaneous ICI, immune checkpoint inhibitor, vs IV formulation?

1. Improved efficacy and safety;
2. Demonstrated better efficacy only;
3. Lower cost compared to IV formulation; or
4. Convenience (reduce time in clinic).

Please make a selection.

[00:07:05]

Why Subcutaneous ICIs? Setting the Stage

Let us get started. Why subcutaneous ICIs? Let us set the stage. Immunotherapy has transformed the standard of care across solid tumors. Most ICIs are administered intravenously, requiring prolonged infusion time and clinical resources.

Subcutaneous formulations are emerging as equally effective, more convenient alternatives, and less time in clinic.

FDA approvals and pending decisions are expanding subcutaneous access across tumor types. APPs play a role in evaluating suitability, managing delivery and educating patients.

[00:07:52]

Role of APPs (NPs/PAs)

The role of the APPS, NPs and PAs were there to assess performance status/frailty in patients about to receive ICI therapy. Monitoring requirements for comorbid conditions.

Patient education remains the absolute key. Risk factors for post subcutaneous injections are still similar to IV and subcutaneous. Blood count monitoring for toxicities soon after subcutaneous injections do remain the same.

[00:08:29]

Evolving Indications for Immune Checkpoint Inhibitors

There are evolving indications for immune checkpoint inhibitors. Let us take a look at those.

[00:08:39]

Currently Approved Intravenous ICI Therapies

Since 2023, there has been a tremendous amount of approval across the landscape of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, as well as LAG-3 inhibitors.

Many of these medications have made advances across the spectrum of tumor types, such as:

• Non-small cell lung cancer;
• Small cell lung cancer;
• Renal cell carcinoma;
• Hepatocellular carcinoma; and
• Melanoma.

Several of these medications are already approved in the subcutaneous format. All of them are approved in the intravenous format, and pembrolizumab is pending approval for later this year.

[00:09:34]

FDA Approval Status of SC ICI Product

The FDA approval status of the subcutaneous ICI product. As we can see, the FDA-approved products are atezolizumab. The atezolizumab is administered through a hyaluronidase injection. Just of note, the hyaluronidase does help dissolve some of the hyaluronidase in the subcutaneous tissue, creating space for the additional volume, which the atezolizumab or the nivolumab will be injected into.

There are some proteins that break down. The half-life is about 24 hours. The proteins that break down stimulate the reproduction of hyaluronidase. It does have this reparative effect in itself, which thereby makes this a very effective delivery mechanism to introduce the medications into the subcutaneous tissue.

But when we look at the administration of the IV, first infusions over 60 minutes for the atezolizumab and the subcutaneous is over 7 minutes. It is definitely a very big cost saving time in terms of time frame where patients have chair time, staff can utilize that time to treat additional patients.

When we look at cost, the cost efficiency is pretty much right on the mark, and they are very much equal at this point in time.

It would take our attention to nivolumab. There are very similar types of comparators to the atezolizumab. There is a shorter injection time for the subcutaneous and that the cost is comparable. The treatment time frame is similar.

Pembrolizumab, as I mentioned in previous slide that, this is pending due to potential approval towards the end of the year. This landscape and this spectrum is really advancing quite quickly. It really behooves us have these conversations at this time frame, because definitely it seems that there are measures moving in that direction very quickly.

[00:12:03]

Comparative Efficacy and Pharmacodynamics for SC and IV Immune Checkpoint Inhibitors

At this time, I would like to hand the program over to my colleague, Deborah, to take over the next portion.

Deborah Fischer (Mayo Clinic): Thank you, Kathleen. This section will look at comparative efficacy and pharmacodynamics for subcutaneous and IV immune checkpoint inhibitors.

[00:12:27]

Pretest 2

Let us look at pre-survey question number 2. Which of the following statements is true regarding efficacy and safety of subcutaneous first IV immune checkpoint inhibitors across different tumor types based on the data presented from the phase III MK-3475A-277 and phase Ib/III IMscin001 studies with patients with lung cancer and the phase III CheckMate 67T in patients with renal cell carcinoma?

1. Improved efficacy and safety;
2. Improved efficacy but worse safety;
3. Similar efficacy but improved safety; and
4. Similar efficacy and safety.

[00:13:28]

What Do the Trials Say? Evidence Comparing SC vs IV ICI

As APPs who are providers and prescribe these medications, I think it is important that we have a basic understanding of the important clinical trials that helped bring these agents through FDA approval.

But before diving into the individual trials, it is important to understand how this subcutaneous immune checkpoint inhibitor studies are typically designed.

Most are non-inferiority trials, meaning they are structured to demonstrate that subcutaneous formulations performed just as well as the established IV versions. Key endpoints typically include the trough concentration, which is the lowest level of drug in the bloodstream before the next dose. The area under the curve, which reflects overall drug exposure over time.

We look at both C-trough and AUC because they tell us different but equally important things. C-trough helps us make sure that the drug levels do not drop too low between doses, which is key for keeping treatments effective, especially for monoclonal antibodies and immunotherapies, where you need to have a steady immune activity or receptor coverage.

AUC, on the other hand, shows the total amount of drug that the body absorbs, which tells us if the 2 delivery methods, like IV and subcutaneous are giving patients the same overall exposure.

So C-trough and AUC are the key pharmacokinetic endpoints usually required by the FDA when evaluating new formulas like subcutaneous vs IV.

Other common key endpoints are the objective response rate, which measures how well the tumor responds to the treatment, and the treatment-related adverse events, which helps assess safety.

When you are reviewing these studies and other similar studies, focus on whether the subcutaneous formulations achieve equivalent systemic exposures and whether any new safety concerns emerge. These 2 elements, the pharmacokinetic equivalence and the consistent safety profiles, are cornerstones for validating subcutaneous formulations and administration as viable clinical options.

[00:15:50]

IMscin001 Part 1: SC Atezolizumab in Patients With Locally Advanced or Metastatic NSCLC

This slide introduces the IMscin001, which is a 2-part trial. But here we are looking at part 1. This is a phase Ib, open-label, dose-finding trial, evaluating subcutaneous atezolizumab in patients with advanced or metastatic non-small cell lung cancer. All participants were immunotherapy naive and had progressed after platinum-based chemotherapy.

The aim of the study was to determine a subcutaneous dosing strategy that would achieve similar serum drug levels as the standard IV formulation. Patients were enrolled in 1 of 3 cohorts with varying subcutaneous injection strategies differing in dose amounts, scheduling, and injection sites before transitioning to IV atezolizumab.

The primary objective was to identify a subcutaneous dose that achieved comparable trough concentrations to the IV. Secondary endpoints included peak serum concentration, total drug exposure over time, and safety events.

It is worth noting that the atezolizumab was the first immune checkpoint inhibitor to receive FDA approval for subcutaneous administration based in large part to this study, and that makes this a foundational to the shift towards a more flexible and patient-centered delivery for immune checkpoint inhibitors.

[00:17:19]

IMscin001 Part 1: Atezolizumab Serum Concentration Over Time and SC vs IV C_trough (Primary Endpoint)

Here we see the primary pharmacokinetic results from part 1 of the IMscin001 study. The goal was to determine whether subcutaneous administration of atezolizumab could achieve serum concentrations comparable to IV dosing. I would not go too deep into the data here, but I do think it is worthwhile to highlight how the pharmacokinetics support subcutaneous formulation, especially in consistency of exposure and the importance of injection site selection.

The graph on the left shows the mean atezolizumab concentration over the 3 cohorts. Cohort 1 received a single 1800 mg subcutaneous injection in the thigh and achieved the highest trough concentration at 121 mcg/mL. Cohorts 2 and 3 had lower C-trough values, particularly when the subcutaneous dose was given in the abdomen.

Bioavailability was also higher for thigh injections at 83% compared to abdomen at 71%, supporting the thigh as the preferred subcutaneous select.

PK parameters were up to 20% to 30% lower when injected into the abdomen, which reinforces the importance of the injection site when considering subcutaneous delivery. Importantly, the maximum concentration was reached consistently within 3 to 4 days across all cohorts, and the safety profile for subcutaneous atezolizumab was comparable to IV, with no new safety signals observed.

[00:19:10]

IMscin001 Part 2: SC vs IV Atezolizumab in Previously Treated LA or Metastatic NSCLC

Now we will consider part 2 of the IMscin001 study, which was a phase III randomized, open-label study designed to confirm what was established in part 1 of the trial. While part 1 focused on identifying the right subcutaneous dose and injection site, part 2 was the pivotal trial that directly compared subcutaneous to IV atezolizumab directly in a larger patient population with previously treated advanced or metastatic non-small cell lung cancer.

Patients were randomized 2:1 to receive either 1875 mg subcutaneous or 1200 mg IV every 3 weeks. The primary endpoints were again key pharmacokinetic markers used to confirm drug exposure.

Secondary endpoints included safety, efficacy, steady state levels, and immunogenicity. The subcutaneous formulations again met noninferiority criteria, meaning it delivered drug levels similar to the IV with no new safety concerns.

For APPs, this means that we can confidently recommend subcutaneous immune checkpoint inhibitor to our patients, knowing that it provides comparable efficacy to IV formulations, especially for those patients who prefer shorter clinic visits and face challenges with IV access.

[00:20:45]

IMscin001 Part 2: Cycle 1 C_trough and AUC on Days 0-21 (Co-primary Endpoints)

This slide shows the pharmacokinetic and early efficacy results for part 2 of this trial. Cycle 1 trough levels were very similar at 89 mcg/mL for subcutaneous vs 85 mcg/mL for IV. The AUC from days zero to 21 was slightly lower in the subcutaneous group, but it remained within the FDA's noninferiority margin.

On the efficacy side, progression-free survival and objective response rates were nearly identical between the 2 groups. There was a slightly higher rate of anti-drug antibody formulation for subcutaneous dosing, but this did not impact efficacy.

Overall, these datas reinforced the case that subcutaneous dosing is clinically equivalent as an option to IV atezolizumab.

[00:21:50]

IMscin001 Part 2: Cycle 1 C_trough and AUC on Days 0-21 (Co-primary Endpoints)

The key takeaway is that subcutaneous atezolizumab delivers drug exposures comparable to the IV formulations, with nearly identical progression-free survival and objective response rates.

Injection site reactions were mild and manageable, and the overall safety profiles were consistent across IV and subcutaneous delivery methods. These findings are aligned with what we see in real-world clinical settings, where patients tolerate subcutaneous administration well. Workflows are more efficient, and outcomes remain consistent as with the IV-based care.

When you are presenting this option to your patients, it is important to emphasize that subcutaneous atezolizumab and the other ICIs are not experimental or less effective. They are FDA-approved, evidence-based alternatives that offer convenience without compromising efficacy or safety.

[00:22:47]

CheckMate 67T: SC Nivolumab (+ Hyaluronidase) vs IV Nivolumab in Advanced/Metastatic ccRCC

We have just seen how subcutaneous atezolizumab, which is the first subcutaneous ICI to gain FDA approval, demonstrated pharmacokinetic equivalence and strong clinical feasibility.

Next, we will take a look at the CheckMate 67T trial, which followed closely behind and became one of the earliest large scale randomized trials to evaluate subcutaneous ICI delivery, this time with nivolumab in advanced renal cell carcinoma.

This is a multicenter, phase III trial that evaluated subcutaneous nivolumab in patients with advanced or metastatic clear cell renal cell carcinoma. Patients were randomized to receive either subcutaneous nivolumab every 4 weeks or standard IV nivolumab every 2 weeks.

Co-primary endpoints were again looked at pharmacokinetics, and secondary endpoints included response rates, safety profiles, and anti-drug antibody development.

One practical highlight here is that the subcutaneous injections took less than 5 minutes to administer, making it a promising alternative from both a patient and a workflow standpoint.

[00:24:04]

CheckMate 67T: PK Noninferiority

Similar to the results that we saw with atezolizumab, the CheckMate 67T trial confirmed that subcutaneous nivolumab delivers consistent systemic exposure when compared to IV formulation.

This slide highlights the 2 key pharmacokinetic endpoints the average serum concentration over the first 28 days and the minimum concentration at steady state, and both were well within the FDA's noninferiority margins. Notably, levels were actually higher with the subcutaneous administration. This again reinforces that the subcutaneous route does not compromise drug exposure and that therapeutic levels are reliably maintained between injections, which is critical for both efficacy and patient safety.

[00:24:55]

CheckMate 67T: PFS by BICR

Progression-free survival was comparable between subcutaneous and IV nivolumab with a median of 7.2 months for subcutaneous and 5.7 months for IV. You can see here that the Kaplan-Meier curves were nearly overlapping, reinforcing that subcutaneous administration does not compromise efficacy.

[00:25:27]

CheckMate 67T: PFS by BICR

These findings supported the FDA approval for subcutaneous nivolumab across all existing adult solid tumor indications.

[00:25:41]

MK-3475A-D77: CT + IV or SC Pembrolizumab With Berahyaluronidase Alfa as 1L Treatment in NSCLC

Continuing with this trend, we saw with atezolizumab and nivolumab. This is a phase III trial that evaluated subcutaneous pembrolizumab in combination with platinum-based chemotherapy for first-line non-small cell lung cancer. Patients here were randomized 2:1 to receive either subcutaneous pembrolizumab at 790 mg every 6 weeks, or IV at 400 mg every 6 weeks.

This study stands out because it tested subcutaneous administration in a more complex combination setting. It was the first subcutaneous immune checkpoint inhibitor trial to test subcutaneous delivery alongside an active IV combination regimen from the start not just testing it as a monotherapy.

The primary endpoints focused again on pharmacokinetics to demonstrate non-inferiority. Secondary endpoints included response rates, safety, and patient reported outcomes. The results echoed prior studies, subcutaneous form as well as IV with no new safety concerns supporting its use in multidrug regimens.

[00:27:01]

MK-3475A-D77: Efficacy Outcomes Summary

Again, the efficacy outcomes were comparable between subcutaneous and IV pembrolizumab. Progression-free survival, overall response rates and duration of response were nearly identical. There were no meaningful differences across treatment arms, confirming that subcutaneous delivery maintains clinical effectiveness in combination regimens.

Efficacy outcomes for subcutaneous pembrolizumab were comparable to IV across all endpoints, and these data support the pending biologic license application with FDA decision expected in September of 2025.

[00:27:58]

Review of Available Patient-Reported-Outcomes and Preference for SC vs IV ICI Formulation

Here, I will hand it back to you, Kathleen.

Kathleen Madden: Thanks, Deborah. Now I am going to take everyone through the review of available patient-reported outcomes and preference for subcutaneous vs IV ICI formulation.

[00:28:15]

IMscin002: Patient and HCP Preference for SC vs IV Atezolizumab for the Treatment of NSCLC

When we look at the IMscin002, the patient and healthcare provider preference for subcutaneous vs IV, the atezolizumab for the treatment of non-small cell lung carcinoma. This is a randomized phase II crossover trial.

The coprimary end points proportion were preferring subcutaneous vs IV. That was by patient preference questionnaire. The key secondary endpoints patient-reported satisfaction patient's choice of treatment, safety, including when switching formulations.

Beyond pharmacokinetics and efficacy, we also do need to understand how patients and providers feel about subcutaneous vs IV delivery.

In the IMscin, this did address this directly by comparing those preferences for subcutaneous vs IV atezolizumab. Patients received both formulations before choosing how to continue. This is a very interesting design, because patients did both receive the IV and the subcutaneous, and then they had the opportunity to choose which one they wanted to continue during that continuation period of time.

The study offers valuable insight into real-world acceptability, satisfaction and the potential impact on treatment adherence for patients.

[00:29:42]

IMscin002: Patient Preference for Atezolizumab SC vs IV and Choice of Formulation in the Continuation Period

In this patient preference, to continue the conversation, after patients experienced both the IV and the subcutaneous, more than 70% of patients preferred the subcutaneous formulation. Their top reasons for the subcutaneous required less time in clinic. They felt more comfortable, and it was less emotionally stressful for them.

Importantly, when patients are given the choice, nearly 80% chose to continue with the subcutaneous formulation, and every patient who had expressed a preference for the subcutaneous opted to remain on that given the choice.

These findings really do help reinforce that subcutaneous delivery aligns not only with clinical goals, but also with what matters to patients: comfort, convenience, and control.

[00:30:39]

Phase I/II CheckMate 8KX: Patient-Reported Outcomes

When we look at the phase I/II CheckMate 8KX, we are building upon the patient preference data that we saw with the atezolizumab. Similar findings emerged with the subcutaneous nivolumab in the CheckMate 8KX study. It is a separate trial focused on patient preference.

This was an early phase trial which captured patient reporting outcomes using a structured questionnaire after subcutaneous administration. Most patients reported high satisfaction with subcutaneous over IV, noting minimal discomfort and faster-than-expected injection times.

In most of the groups, the subcutaneous administration took under 5 minutes. Only patients receiving subcutaneous via a syringe pump had longer durations, averaging about 30 minutes. Overall, this reinforces the idea that subcutaneous delivery is not only clinically effective, but also really well tolerated and preferred by patients.

[00:31:49]

Posttest 1

Let us take a look at one of our questions, our post-test question number one. Which of the following is a benefit reported for subcutaneous ICI vs IV formulation?

1. Improved efficacy and safety;
2. Demonstrated better efficacy only;
3. Lower cost compared to IV formulation;
4. Convenience (reduced clinic in time).

Please make a selection.

[00:32:29]

Posttest 1: Rationale

Let us go ahead through the answer D, convenience (reduce time in clinic) is the correct answer. Option D is correct because the average injection time with subcutaneous anti-PD-1, such as nivolumab is less than 5 minutes, which is much shorter than the 30-minute duration of the IV infusion.

Option A is incorrect because based on data from the CheckMate 67T, rates of immune-mediated adverse events are comparable between subcutaneous and IV formulations. Option B is incorrect because data from CheckMate 67T also showed that the efficacy of subcutaneous and IV formulations against renal cell carcinoma is similar.

Option C is incorrect because in patients with subcutaneous and IV administration in the clinic, they do have a similar cost at this time.

[00:33:28]

Posttest 2

Let us take a look at post question number 2. Which of the following statements is true regarding the efficacy and safety of subcutaneous vs IV ICIs across different tumor types based on data presented from the phase III MK-3475A-D77 and the phase Ib/III IMscin001 studies in patients with lung cancer and the phase III CheckMate 67T in patients with renal cell carcinoma?

1. Improved efficacy and safety;
2. Improved efficacy, but worse safety;
3. Similar efficacy but improved safety;
4. Similar efficacy and safety.

Please choose.

[00:34:32]

Posttest 2: Rationale

D, similar efficacy and safety is the correct answer. Based on recent data presented from the phase III MK-3475A-D77 study, subcutaneous vs IV formulation of pembrolizumab showed comparable PFS efficacy, overall survival and safety, except for increased infusion-related reactions.

Similar efficacy data were reported with the phase III IMscin001 evaluating subcutaneous vs IV atezolizumab regarding PFS, overall response rates. Then data from the phase III CheckMate 67T showed that nivolumab subcutaneous demonstrated non-inferiority of exposures and efficacy when compared with nivolumab IV with relatively similar efficacy, although patients in the nivolumab arm exhibited infusion reactions which were low grade, transient, and most of them did resolve without treatment.

[00:35:35]

Managing the Safety Profile of Immunotherapies: What’s New With Subcutaneous Administration?

Now we are going to transition into the next section, Managing the Safety Profile of Immunotherapies: What is New with Subcutaneous Administration? Deborah is going to start us off on this section.

Deborah Fischer: Thank you, Kathleen. We just saw that patient preference strongly supports subcutaneous administration. It is just as important that we maintain vigilance around safety.

[00:36:12]

Pretest 3

Let us take a look at pretest question number 3. Your patient will be receiving subcutaneous immune checkpoint inhibitor plus chemotherapy for stage IIIB non-small cell lung cancer. Which of the following should you tell them is an adverse event experienced by patients receiving an immune checkpoint inhibitor that should be reported to their APP?

1. Cytokine-release syndrome;
2. Blurred vision or cataracts;
3. Weight gain;
4. Injection site reaction.

[00:37:09]

MK-3475A-D77: Safety Summary

This slide summarizes safety findings for the subcutaneous vs IV pembrolizumab trial in first-line non-small cell lung cancer.

The overall safety profile was comparable between arms with similar rates of treatment-related adverse events, serious events and treatment discontinuation.

Grade 3, 4 and 5 events occurred just under half of patients in both groups, consistent with what we expect in combined regimens and with chemotherapy and immune checkpoint inhibitors.

Injection site reactions were reported at 13% of subcutaneous patients, but nearly all were low grade. No grade 3, 4, or 5 events were observed. These data reinforce that subcutaneous pembrolizumab has a safety profile that is in line with IV formulations, local reactions that are generally mild and manageable.

[00:38:20]

CheckMate 67T: Safety Summary

This slide gives us a high-level summary of the safety findings from CheckMate 67T. First and foremost, the safety profile of subcutaneous nivolumab was consistent with the IV formulation, and importantly, no new safety signals were identified, again providing us with reassurance that when thinking about using these subcutaneous formulations in practice.

The most common side effect seen with subcutaneous was injection site reactions, but these were low grade, short lived, and most resolved on their own without any intervention. That is obviously what we are looking for and what we want to see when we are using these subcutaneous formulations.

Also, what is reassuring is that there was no increase in hypersensitivity reactions or anaphylaxis, which is something we always need to be watchful for when we are changing formulations. The data on immunogenicity was also in line with expectations.

So far, there is no signal of any clinically meaningful impact from immunogenicity with the subcutaneous route.

Finally, something that is really important in our workflow. The average administration time was under 5 minutes, and that is a huge shift from the infusion appointments. It could really reduce chair time and streamline patient flow.

[00:40:02]

Spectrum of Immune-Related Toxicity

Now let us explore the spectrum of immune-related toxicities. Immune checkpoint inhibitors unleash the body's own defenses to fight cancer. This can also trigger a wide range of immune-related adverse events, potentially affecting nearly every organ system.

The most commonly affected systems include the skin, the gastrointestinal tract, and endocrine system, which present as rash, colitis, thyroiditis. But it is also important to remember that other systems like the lungs, liver, nervous system, or even the heart can also be affected. While less commonly so, those events can be more serious and require prompt recognition and treatment.

Even though we are shifting from IV to subcutaneous delivery, the clinical evaluation does not change. The workflow still mirrors what we do with IV infusions, as the potential for immune-related toxicities remain the same. We still need to be just as vigilant.

[00:41:15]

Recognizing Immunotherapy-Related AEs Early

Even as we make the shift to subcutaneous delivery, the risk of systemic toxicity does not significantly change. Monitoring needs to stay just as it is with IV formulations.

APPs really take the lead when it comes to early detection and management of these immune-related adverse events, and it necessitates having a structured approach from baseline evaluation through early symptom detection through management.

Let us walk through key strategies that can help us catch immune-related adverse events early so we can intervene quickly, manage them effectively, and avoid unnecessary treatment delays.

Step 1 is start with a strong baseline:

• Know what is normal for your patient in terms of their labs, their symptoms, their performance status and follow those with consistent check ins;
• Use screening tools and ask the right questions;
• Incorporate checklists or trackers and use open-ended questions when speaking to your patients to create space to allow them to share details that maybe they would not otherwise share or think were important. Sometimes it is a subtle symptom, the ones they do not think to mention. That can be the key to catching an adverse event early;
• Educate patients and caregivers. Make sure they know what symptoms to report and that they understand even mild changes could be meaningful;
• Provide visual quick references and picture cards when you are able to, to help them identify those concerning early symptoms;
• Consider building EMR alerts and empowering your nursing teams;
• Consider setting up the system to flag early signs, whether it is live changes, symptoms like new fatigue or mild diarrhea. Just as importantly, make sure the team knows what to look for and when to act on it;
• Have a low threshold for initiating a workup. Even mild symptoms deserve attention, so run labs, get imaging, bring in a specialist early because that is how we stay ahead of the progression of these adverse events and avoid hospitalizations;
• Once you do spot an immune-related adverse event, do not wait. Manage it promptly and decisively;
• Standardize your steroid protocols. When you taper steroid therapy, go slow and bring in subspecialty support as needed to guide you; and
• Also, importantly, stay vigilant for rebound symptoms, especially during taper or when you are considering treatment re-challenge.

Now I will give it back to you, Kathleen.

[00:44:38]

Toxicity Management With Single-Agent Immunotherapy

Kathleen Madden: Thanks, Deborah. We will walk through the toxicity management with single agent immunotherapy and how do we grade these. How do we figure out how to manage them?

I always like to say grading guides the management. It is not just for clinical trials. I think that a lot more people are embracing the CTCAE guidelines to really help support and navigate, and that we are all speaking the same language when it comes to evaluating our patients. It is really essential when to hold treatment and when to consider corticosteroids.

Most IRAEs are grade 1 or 2. When I speak with my patients, I reassure them because a lot of information that comes to them all sounds very serious. Then how do we sort it out for them? I explain to them that grade 1, we monitor. Grade 2, we pause and maybe we will implement some supportive care treatments. Maybe we will implement some low dose steroids, prednisone 0.5 mg/kg and we monitor.

We might still be able to continue to treat through grades 1 and 2 depending on some factors of if they are recurrent issues, how persistent they are and how much difficulty that they are imposing on the patient's functionality.

Grades 3 and 4 clearly, these are more serious and they require a hold, as well as higher level of care. Sometimes we need intravenous supportive care for grades 3, most certainly usually for grade 4. Oftentimes, grade 4 requires some hospitalization level of care, depending on the patient's presentation and symptomatology.

Grade 5, clearly, we try to keep all of the grading down to the lower levels and avoid them from escalating. Many of the toxicities are very manageable, especially if they are reported early as Deborah said, that we can intervene and act on them, and so we can prevent them from escalating to the higher level of toxicities.

It is important to have the conversations with patients not to keep these things secret, not to hold these things back. That it is never a bother to us, but it is very important to include us in what is going on, and that if we do not hear from them, we are operating on the fact that things are operating okay on their end.

[00:47:24]

General Management of irAEs Associated With ICIs

When we talk about the general management, most of the toxicities are managed very similarly with steroids. Corticosteroids, oftentimes prednisone intravenously, may be dexamethasone or methylprednisolone.

But when we look at the grading and then we look at how much of the steroids we use, usually for grade 1, we are not using steroids. Grade 2, we might use it selectively, as I mentioned, with 0.5 mg/kg and a limited duration, maybe a methylprednisolone pack, a 6-day taper.

Again, grades 1 and 2, we can generally continue treatment. But if the IRAEs are evolving or not responding to our interventions, we will hold. If it persists, we might need to escalate that steroid dosing.

Grades 3 and 4 really do require a higher dosing of 1-2 mg/kg of prednisone or equivalent. Oftentimes a slow taper is recommended, usually over 4 weeks. That means the patients are being tapered, usually by 10 mg every 3 or 4, maybe 5 days, depending on what the situation is and how sick the patient is and how well they are responding to the taper.

Several courses of steroids may be necessary. We really do try to avoid that. We like to hit the mark the first time when we taper patients. However, if we taper too quickly, especially for a higher-level toxicity rebound, a flare is definitely a very high risk and that patients may end up back in the hospital or that they may end up back on the same steroid taper perhaps longer. There is a lot that goes along with that.

We need to monitor for secondary infections. Look at if these patients do need supportive antimicrobials, antiviral medications. There are a lot of factors and a lot of moving parts, in addition to adding in organ specialists.

When do we call them in? When do we start? I think a lot of us who have been doing this have gotten very good and very skilled at initiating what we need to do before getting patients to specialty providers.

Steroids are amazing and wonderful. We do try to avoid using them when we can. We don't jump to it immediately. That is why we use this grading guideline, because we do not want to dampen the immune response. This is why it is not a premedication for the subcutaneous or the intravenous.

We are treating the patient, and we are treating the toxicity. We are not treating a treatment schedule. We refrain from speeding up a taper to meet a treatment date. We need to reevaluate the patient, reassess the patient. While we like to keep on schedule, I always tell my patients the schedule is a guide, and we have to go on with what their body and their immune system are telling us. That if we need to extend a taper, we can talk about then reinitiating treatment when patients are back down to a grade 1 or back down to grade 0 where it is safe.

[00:51:00]

General AE Management Strategy

Our general AE management strategy. It starts off with education. It starts off with the healthcare providers, educating all of our team, as well as the patients and the people who are involved in that patient's care.

We really emphasize and it is not just a 1-time intervention. It is a continuous intervention of education. At any time point when we see patients not just at appointments, but maybe over the telephone, maybe a message through the EMR, the patient portal. We educate them to identify symptoms early and report things early.

Anything that is different when you tell them when the clock starts, when you start this new treatment. Then we should be your first call. Since we are leading with these very powerful medications that we should know what is going on first. If we need to integrate another provider, even someone who they have been very well established with, that allow us to be part of the conversation so we can help delineate, is this issue you are having related to the medication that we are giving you in the oncology arena, or is this related to something else?

Looking at collaborating. I mentioned, as did Deborah, integrating organ specialists and toxicity experts to help us when we need someone who is a little bit more niche in the area or to help us with long-term management.

Then acting efficiently and acting quickly and conducting the necessary assessments, but not to wait until things get bad or I cannot take it anymore. I could not tolerate it. Then I finally said something. We try to educate patients that it is never a bother, and there is always access to the providers. It is bidirectional and it is a collaboration, and it is a collaboration where we have to establish trust very, very quickly.

When we track the evolution of issues with the patients, we adjust the treatment accordingly. There are no real dose reductions in these therapeutics with the ICIs. There is usually a treatment hold and then we reassess. Then our main goal is safety. Our secondary goal is efficacy.

We will monitor the patients. Always just trying to encourage them that our plan is to continue on therapy as long as that is efficient and working for them.

[00:53:37]

Posttest 3

Let us take a look at post-test question number 3. Your patient will be receiving subcutaneous ICI plus chemotherapy for stage IIIB non-small cell lung carcinoma. Which of the following should you tell them is an AE experienced by patients receiving an ICI that should be reported to their APP?

1. Cytokine-release syndrome;
2. Blurred vision/cataracts;
3. Weight gain;
4. Injection site reaction.

[00:54:40]

Posttest 3: Rationale

The correct answer is D, injection site reaction. Although most reaction events are similar between the subcutaneous and IV formulations, and we have comparative studies to demonstrate that, injection site reactions are reported with subcutaneous ICI administration. Moreover, injection site reactions with subcutaneous nivolumab seen in the phase III CheckMate 67T were mostly low grade, transient. They lasted about 3 days and most resolved without any interventions or treatments.

[00:55:20]

Integrating SC ICI Into Everyday Practice

Now I am going to hand over the conclusion of the program back to Deborah.

Deborah Fischer: Thank you, Kathleen. You made some really great points in that last section. So far, we have explored the efficacy, safety, and patient preference data that supports subcutaneous ICI use across tumor types. But how do we actually make this work in practice?

In this next section, we will shift gears to focus on integrating subcutaneous ICI into everyday workflows, what APPs need to know about delivery models, site logistics, and multidisciplinary coordination to make this transition smooth and sustainable.

[00:56:06]

Poll 3

Let us now take a look at poll question 3. How confident are you in implementing effective multidisciplinary team processes to optimize the integration of subcutaneous immune checkpoint inhibitor therapies into clinical practice?

1. Not confident;
2. Low confidence;
3. Moderate confidence;
4. Confident;
5. Very confident.

Please choose.

[00:56:56]

Key Considerations for SC ICI Integration

As we transition to use of subcutaneous ICIs into our practice, there are 5 core considerations that can really help ensure smooth and effective rollout.

• First is patient selection. Evaluate who is clinically appropriate for subcutaneous ICI administration. This may include patients with poor IV access or those who have had difficulty tolerating infusions;
• Secondly, counseling and use of protocols. Fixed dosing of subcutaneous ICI definitely streamlines the process, but consistency in counseling and education still matters. So standardizing counseling scripts and clear protocols when you are able to, for both patient education and also for the administration team like your infusion nurses is extremely important. This helps to ensure that every patient gets the same high-quality information and care no matter who is delivering it;
• Institutional efficiency. Subcutaneous delivery often requires less chair time, fewer staff resources, and it can open up flexibility and scheduling, especially helpful in high volume practices;
• Delivery models. Think beyond the infusion chair, options like dedicated injection spaces or flexible treatment rooms. Even using mobile units can help expand access, reduce bottlenecks in the system, and streamline workflows. Meet people and patients where they are;
• Team coordination. Successful treatment of cancer patients with any therapeutic intervention hinges on strong team collaboration, and that means aligning workflows across APPs, nurses, pharmacists and schedules.

These 5 pillars can support a safer, more efficient, and scalable approach to subcutaneous ICI integration into everyday practice.

[00:59:34]

Assessing Performance Status/Frailty in Patients About to Receive IV ICI vs SC ICI

When deciding between use of IV vs subcutaneous ICIs, APPs can really be at the center of the evaluation process, balancing both clinical and logistical factors. For example, a patient who has stable labs but significant transportation barriers and finding it difficult to get to clinic appointments or leaning on family members who need to take time away from work might be ideal candidates for subcutaneous immune checkpoint inhibitor therapy.

Conversely, someone with thrombocytopenia, a higher body mass index, or history of injection site reactions may be better served continuing with IVI formulations. Consider that patients with limited subcutaneous tissue may have less predictable subcutaneous absorption and could experience more discomfort with subcutaneous injections.

Subcutaneous administration also brings meaningful advantages, which we have touched on throughout this program, with shorter infusion times, reduced chair time. The option to shift care to more flexible treatment settings like injection clinics. This opens the door for smoother experience for both patients and staff. This is exactly where APPs add value to the practice by applying their clinical insights to make thoughtful and individualized care decisions.

[01:01:13]

Patient Counseling Guides, Dosing Calculations, and Administration Protocols

When it comes to subcutaneous ICI administration, 1 of the biggest advantages is its simplicity. Fixed dosing takes the guesswork out. There are no weight-based calculations. There are fewer prep steps and less room for error. Most are packaged as prefilled syringes or kits, which further streamlines the workflows.

To support a smooth experience for patients, again, counseling is key. Many patients are used to IV infusions, so the switch to a very quick subcutaneous injection can feel surprisingly different to patients and a little unnerving. Setting clear expectations, for example, that there may be mild stinging at the injection site or redness, and that is normal and typically brief.

Remind them that we rotate the injection sites to avoid irritation if they do have injection site reactions or irritation. For early doses, follow your institution's protocols around monitoring typically 15 to 30 minutes post injection observation periods.

Consider building standard scripts into your team's practice and reinforce key talking points like injection technique and site rotation during team huddles.

Finally, make sure that your staff is confident in their subcutaneous delivery skills. And your patients know exactly what to expect. A little reassurance for your patients can go a long way when you are introducing something new and different.

[01:02:56]

Institutional Efficiency Opportunities With SC vs IV ICI

One of the biggest institutional advantages of subcutaneous administration is improved operational efficiencies. Chair time significantly decreases with subcutaneous from 30 to 60 minutes for an IV infusion to just 5 or 10 minutes with subcutaneous, freeing up capacity infusion centers for other treatments and helping reduce patient backlogs.

Staffing efficiency improves as well, with shorter appointment times. Fewer nursing hours are needed per patient. Additionally, subcutaneous ICI can often be administered in injection clinics or outpatient areas rather than tying up space in the infusion suites. There is also less strain on pharmacy and facility resources, with fewer IV setups and less time needed for medication preparations.

Importantly, subcutaneous administration offers more flexibility and scheduling. Faster administration makes it easy to accommodate last minute changes or adjusting schedules during peak clinic hours, which can reduce cancellations and support higher patient throughput.

[01:04:08]

Key Enablers for SC ICI Implementation

To bring subcutaneous immune checkpoint inhibitors into routine practice successfully, we need to align 3 key components:

• Delivery models;
• Site logistics; and
• Multidisciplinary team coordination.

Starting with the delivery models. Some centers are creating dedicated injection blocks or repurposing existing outpatient areas. Others are piloting mobile units or using satellite clinics to reach patients who live farther away and have difficulty traveling to clinics. Then there is the logistics. While subcutaneous ICIs are fixed dose and often come in prefilled syringes, execution still depends on thoughtful planning, and that means having clear storage protocols, ordering and inventory workflows, and designated spaces for administration.

Integrating all of this into the EMR, including dosing, adverse event tracking and documentation. This all helps to standardize care and improve safety.

Lastly, but most importantly, team coordination. A smooth rollout depends on everyone being aligned and on the same page: pharmacy, nursing, APPs and schedulers. Even something as simple as a weekly huddle or clear onboarding protocols can go a long way in reinforcing expectations and catching issues early on.

Ultimately, the goal is to make subcutaneous delivery feel seamless, not just efficient, but centered on a better experience for the patient, but also for the clinical teams.

[01:05:50]

SC ICI Administration: Potential for Unlocking New Care Delivery Models

As we look to the future of oncology care, 1 of the most promising aspects of subcutaneous immune checkpoint inhibitor administration is how it opens the door to new delivery models that prioritize flexibility and access. Because subcutaneous ICIs do not require infusion pumps or long chair times, they can be administered in a variety of lower acuity settings, like outpatient clinics and urgent care pods, or even mobile units, as I said earlier.

These reduce strains on the infusion suites, and they expand our ability to reach patients in more convenient locations. In some select scenarios, nurse or APP-led home administration may also be feasible, especially when paired with remote monitoring or brief in-clinic checkups.

Of course, this requires careful patient selection and institutional protocols to ensure safety.

[01:06:50]

Key Takeaways for SC vs IV ICI Therapy

To wrap up, here are the 5 takeaways from today's module:

• subcutaneous immune checkpoint inhibitors have demonstrated comparable efficacy and safety to IV formulations in multiple clinical trials;
• patients overwhelmingly prefer subcutaneous administration for its convenience, shorter clinic time, and reduced emotional burden;
• APPs are central to implementation education and adverse event management, especially as delivery shifts from infusion suites and centers to outpatient or potentially alternate site-based settings;
• clinical trial data support expanding subcutaneous delivery across tumor types and treatment settings;
• education and workflow planning at the institutional level will determine how quickly and successfully subcutaneous ICI delivery becomes standard practice.

Thank you, Kathleen, for your attention today and for the work everyone does every day to improve oncology care for our patients.

[01:08:05]

Poll 4

Let us complete the final 2 practice change polls. Poll number 4. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No;
3. Uncertain.

Please make a selection.

[01:08:47]

Poll 5

Poll 5. Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

[01:09:08]

Go Online for More PCE Education on Immunotherapy!

Jerfiz Constanzo: Thanks again to our great faculty for a wonderful overview of subcutaneous immune checkpoint inhibitor options in patients with cancer. Thanks to you for participating in this activity. Please remember to go to the Practicing Clinicians Exchange website or the Clinical Care Options website for more content related to this discussion.

That is a wrap. Alrighty. Well, I would not keep you long, but thank you again for helping with this project. This is going to be an easy cleanup, as I said earlier. Those little redos will help guide some of those things and you should turn out pretty nice. Thank you again, Deborah and Kathy, for all your hard work to get to this point, but we made it. Please enjoy the rest of your weekend and we will be in touch soon.

Kathleen Madden: A big thank you to all of you, and especially Deborah. Thank you.

Deborah Fischer: Thank you both. Appreciate it, the opportunity. Thank you.

Kathleen Madden: Great.

Jerfiz Constanzo: Take care. Bye.

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