Key Takeaways

• The current treatment landscape for the administration of immune checkpoint inhibitors for the treatment of cancer is rapidly evolving, with more data emerging in support of subcutaneous formulations.
• Clinical trials in lung cancer and kidney cancer have provided a robust dataset for equivalent pharmacodynamics, efficacy, and safety profiles of the subcutaneous and intravenous formulations of immune checkpoint inhibitors.
• Atezolizumab and nivolumab are now available as subcutaneous injections for most of the previously approved indications for intravenous infusions with almost seamless implementation in the clinic/inpatient setting.

In this commentary, experts in the treatment of non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), and melanoma, Patrick Forde, MD, PhD, Saby George, MD, FACP, and Evan J. Lipson, MD, respectively, discuss subcutaneous (SC) administration of immune checkpoint inhibitors (ICIs) including the rationales for SC vs intravenous (IV) formulation use, the most recent clinical data for SC ICIs in NSCLC and RCC, ongoing trials in melanoma, and practical considerations for successful integration of SC ICIs into everyday practice and low resource settings.

Rationale for the Use of SC vs IV ICIs in Cancer
Patrick Forde, MD, PhD:
There is an increasing burden of cancer in the United States and globally likely due to patients with cancer living longer because of improved survival with ICIs. This is putting pressure on our oncology care systems regarding the increasing number of patients coming through the infusion centers, longer wait times for receiving care, and overall time spent by patients getting through the system.

Emerging data for SC ICIs suggest that we could significantly reduce oncology visit time for patients (eg, the time in the infusion center) compared with IV ICI administration. I think this is a major benefit of the SC formulations. There are also other limitations to using the IV formulations, such as patients having difficulty identifying IV access.

Evan J. Lipson, MD:
We should also recognize patients for whom SC ICIs may not be optimal. These include patients with a very low body mass index where SC tissue might be limited. In other words, it might be challenging to administer even 5 or 10 mL of a SC ICI in such patients. In our clinic, we have heard from a few patients that they object to the bruising that can accompany some of the SC ICI injections. Thus, in patients whose preference is to get IV ICI we certainly consider that. Anecdotally, I have also heard some patients say infusion time means that they get to spend time with loved ones (ie, somebody is accompanying them to their infusion visit).

Saby George, MD, FACP:
I would also mention that if a patient is already on an IV ICI, they might be skeptical about transitioning to SC. They may ask if the SC drug is going to be as efficacious as the IV drug and if the data are similar or equivalent regarding adverse events (AEs). This is a great segue into our next discussion on the available data for SC ICIs.

Emerging Efficacy and Safety Data for SC ICI vs IV ICI Administration for Patients With Cancer
NSCLC
Patrick Forde, MD, PhD:
The 2-part, open-label, dose-finding phase Ib IMscin001 study (NCT03735121) was among the first studies evaluating SC ICIs. Part 1 of the study enrolled patients aged 18 years or older with locally advanced or metastatic NSCLC who had not received previous immunotherapy—although they could have had progression on prior chemotherapy—had a good performance status, and measurable disease. Patients were assigned to receive SC atezolizumab 1800 mg once in the thigh then IV 1200 mg every 3 weeks (Q3W) (cohort 1, n = 13); SC atezolizumab 1200 mg in the thigh every 2 weeks for 3 cycles, then IV 1200 mg Q3W (cohort 2, n = 15); or SC atezolizumab 1800 mg in the abdomen Q3W in cycle 1, then in thigh Q3W for 2 cycles, then IV 1200 mg Q3W (cohort 3, n = 39). Of note, all SC atezolizumab doses were administered with recombinant human hyaluronidase. The primary objective of IMscin001 part 1 was to determine the SC dose of atezolizumab yielding comparable serum trough (C_trough) with that of IV administration. Other secondary endpoints included pharmacokinetics and safety. Study investigators determined that SC atezolizumab at a dose of 1800 mg Q3W yields high probability of exposure equivalent to IV 1200 mg Q3W. Moreover, pharmacokinetic parameters C_trough, C_max, and area under the concentration curve days 0-21 (AUC_0-21) were 20%, 28%, and 27% lower, respectively, with the abdomen vs thigh SC administration, suggestive of better bioavailability with thigh injections. According to study investigators, the safety profile of SC atezolizumab was consistent with that of IV atezolizumab, which was comparable across cohorts.

The multicenter, randomized, open-label, phase III Mscin001 part 2 study was a noninferiority trial comparing SC atezolizumab 1875 mg administered with recombinant human hyaluronidase Q3W as a ready-to-use, less than 10-minute injection in the anterior thigh vs IV atezolizumab1200 mg infusion Q3W (N = 371; NCT03735121). The coprimary endpoints were cycle 1 C_trough and model predicted AUC_0-21. The secondary endpoints were steady-state exposure, efficacy, safety, and immunogenicity. As we know now, the observed cycle 1 C_trough (89 μg/mL vs 85 μg/mL; geometric mean ratio [GMR]: 1.05) and AUC_0-21 (2907 μg/mL vs 3328 μg/mL; GMR: 0.87) values were similar for SC atezolizumab vs IV atezolizumab, respectively. Median progression-free survival (PFS): 2.8 vs 2.9 months; HR: 1.08; 90% CI: 0.82-1.41), overall response rates (ORRs) (12% vs 10%) and anti-atezolizumab antibody development (19.5% vs 13.9%) were similar between SC vs IV treatment arms. These data were reassuring for me.

Data from Mscin001 part 1 and part 2 led to FDA approval of SC atezolizumab 1875 mg plus hyaluronidase-tqjs injection for all the adult indications of the IV formulation, including NSCLC, small-cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma.

Results from a patient and healthcare professional treatment preference crossover trial (phase II IMscin002) in patients aged 18 years or older with resected stage II-IIIB (T3N2) or chemotherapy-naive metastatic NSCLC, and PD-L1 positive (N = 179; NCT03735121) identified 3 main reasons for patients preferring SC atezolizumab over IV. These were: it requires less time in the clinic (n = 56, 64%), it feels more comfortable (n = 40, 46%), and it is less emotionally stressful (n = 26, 30%). More patients in this study chose to continue an SC ICI (79.4%) compared with those choosing IV ICI (20.6%) for the continuation phase.

The randomized, open-label, noninferiority phase III MK-3475A-D77 study is evaluating 2 cycles of SC pembrolizumab 790 mg with berahyaluronidase alfa every 6 weeks (Q6W) plus chemotherapy (CT) Q3W vs IV pembrolizumab 400 mg Q6W plus CT Q3W followed by up to 16 cycles of SC pembrolizumab 790 mg with berahyaluronidase alfa Q6W plus pemetrexed maintenance (if nonsquamous) vs IV pembrolizumab 400 mg Q6W plus pemetrexed maintenance (if nonsquamous) disease. Patients enrolled in this study were aged 18 years or older with metastatic NSCLC and had no previous systemic therapy, no radiation therapy to the lungs in the last 6 months, and/or no prior radiotherapy 2 weeks from start of study or being treated for radiation-related toxicity with corticosteroids (N = 377; NCT05722015). The coprimary endpoints of the study are cycle 1 AUC_0-6wk and steady state of pembrolizumab on cycle 3 C_trough. Secondary endpoints included ORR, PFS, overall survival (OS). Results from this study were presented at the European Lung Cancer Congress 2025 and demonstrated equivalent efficacy (median PFS: 8.1 vs 7,8 months; median OS: not reached vs not reached; HR: 0.81; and ORR: 45.4% vs 42.1%) for SC pembrolizumab plus CT vs IV pembrolizumab plus CT. Moreover, efficacy outcomes across patient subgroups were similar between the 2 treatment formulations. With regard to safety, I think data looked very similar between the 2 formulations, in particular rates of grade 3/4 toxicities. Injection-site reaction was observed in patients receiving SC pembrolizumab with erythema, hemorrhage, induration, or other reaction seen in at least 1 patient (0.4%).

Of note, we may also use single-agent pembrolizumab as first-line treatment of NSCLC with no previous systemic anticancer therapy that are considered PD-L1 high (with a tumor proportion score [TPS] ≥50%). The ongoing phase III MK-3475A-F84 trial is evaluating SC pembrolizumab plus berahyaluronidase alfa Q3W vs IV pembrolizumab Q3W in patients 18 years of age or older with histologically or cytologically confirmed NSCLC, measurable disease, no previous systemic anticancer therapy, and PD-L1 TPS ≥50% (N = 160; NCT06698042). The primary endpoints of the study are AUC of pembrolizumab after the first dose (up to 14 months), C_trough of pembrolizumab at steady state, and at all designated time points (up to 18 months).

Taken together, the emerging data for SC ICI in NSCLC indicate comparable bioavailability, efficacy, and safety profile in favor of the SC ICI formulation.

RCC
Saby George, MD, FACP:
The multicenter, randomized, open-label, noninferiority, phase III CheckMate 67T evaluated the use of SC nivolumab 1200 mg plus recombinant human hyaluronidase Q4W vs IV nivolumab 3 mg/kg Q2W in patients with advanced or metastatic clear cell RCC that had progressed on 1 to 2 previous systemic therapies (N = 495; NCT04810078). The coprimary endpoints of the study were time-averaged serum concentration over the first 28 days (C_avgd28) and minimum serum concentration at steady state (C_minss). Other endpoints included pharmacokinetic exposures, safety, and efficacy. Of note, approximately 30% of patients were enrolled from the United States and Europe with the remainder being enrolled from South America, Mexico, and the rest of the world. We saw that the CheckMate 67T study met both coprimary endpoints with C_avgd28 (77.37 vs 36.87 µg/mL; GMR: 2.098) and C_minss (122.23 vs 68,90 µg/mL; GMR: 1.774) value improvements in favor of the SC nivolumab plus hyaluronidase arm vs IV nivolumab arm. Similarly, we saw improvement in ORR (24.2% vs 18.2%) and in median PFS (7.23 vs 5.65 mo).

The average administration time for SC nivolumab plus hyaluronidase was approximately 5 minutes vs an average of 30 minutes for IV nivolumab. The most common reason for dose delays was AEs. However, the safety profiles were similar between SC nivolumab plus hyaluronidase and IV nivolumab with treatment-related AEs (59.1% vs 64.5%) and AEs leading to therapy discontinuation (10.1% vs 11.8%) being similar for the SC nivolumab plus hyaluronidase arm vs IV nivolumab arm. Injection-site reactions in the SC nivolumab arm were low grade, transient, and had a mean duration of approximately 3.0 days—all resolving without treatment. Moreover, although the percentage of patients testing positive for antidrug antibodies against nivolumab were higher in the SC nivolumab plus hyaluronidase arm vs the IV nivolumab arm (22.8% vs 7.0%), data from further immunogenicity assessments did not identify apparent clinically meaningful impact of development of anti-nivolumab antibodies on pharmacokinetics, efficacy, or safety.

When looking at these data collectively we can say that SC nivolumab plus hyaluronidase was not inferior to IV nivolumab. As a result, in December 2024, the FDA approved SC nivolumab plus hyaluronidase across all approved adult solid tumor indications of IV nivolumab monotherapy and/or as maintenance following completion of nivolumab and ipilimumab combination therapy, or in combination with chemotherapy or cabozantinib.

Another important study, the phase I/II CheckMate-8KX (NCT03656718), looked at patient reported outcomes with SC nivolumab vs IV nivolumab and indicated that most patients reported high satisfaction with SC nivolumab administration vs IV nivolumab administration, which suggest similar findings to that of the lung cancer trials discussed earlier.

Skin Cancers
Evan J. Lipson, MD:
Data for skin cancers are still emerging with key ongoing trials including the phase III/IV CheckMate-6GE study exploring the role of SC nivolumab plus recombinant human hyaluronidase vs IV nivolumab in patients with stage IIIA-D or IV melanoma after complete resection in the previous 12 weeks before randomization or treatment assignment (N ≈ 286; NCT05297565). The coprimary endpoints of the study are C_avgd28 and C_minss. The SC regimen in this trial was tested using an auto-injector pen and the study was stopped before reaching completion—not because of safety or efficacy concerns, but because SC nivolumab is no longer administered using an auto-injector pen. It is now administered using a vial and a syringe just like any other SC medicine without an injector device attached to it.

The phase III RELATIVITY-127 study is exploring SC nivolumab in combination with the anti-LAG3 antibody relatlimab plus hyaluronidase vs IV nivolumab plus relatlimab in patients aged 12 years or older with previously untreated or metastatic melanoma with measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 (N = 570; NCT05625399). The coprimary endpoints of the study are C_avgd28 of SC nivolumab and relatlimab both up to 28 days and C_minssd28 of nivolumab and relatlimab both up to 4 months. This trial is important because it is evaluating a formulation that has not yet been widely used (nivolumab plus relatlimab).

A phase II, open-label, 2-cohort, patient preference study is evaluating the crossover from IV nivolumab plus relatlimab to SC nivolumab in combination with relatlimab plus hyaluronidase (cohort 1a/b) and crossover from IV nivolumab monotherapy to SC nivolumab plus hyaluronidase (cohort 2a/b) in patients aged 18 years or older with high-risk advanced resected or previously untreated metastatic melanoma (N = 100; NCT06101134). Patients with autoimmune disease, disease in the eyes, brain, mucous membranes, or being treated with steroids did not qualify for enrollment. Similar to the patient preference study mentioned earlier, the primary endpoint was the number of participants preferring SC administration of nivolumab based on a patient experience and preference questionnaire. Secondary endpoints include safety and laboratory abnormalities.

Implementing Current Indications of SC ICI Through Effective Engagement and Education of the Multidisciplinary Care Team
Saby George, MD, FACP:
When thinking about implementing the current indications for SC ICI, the following takeaways come to mind.

• Is the patient starting immunotherapy for the first time? This is often the easier situation because the patient is not already established on an IV ICI protocol.
• We should discuss with the patient that there are 2 ICI formulations (SC or IV) available for treatment of their cancer.
• Available and emerging data suggest equivalency for the SC and IV formulations with regard to safety and efficacy and there are data to suggest that patients may favor the SC formulation because of reduced time in the infusion center and avoiding delays.
• SC administration might also be preferred by pharmacists because preparation and administration has been standardized and injections do not take a long time.
• SC ICI is still administered in the clinic/within the infusion center.
• SC ICI is also a good option in low-resources settings where patients cannot afford to travel, the cost of treatment might be high, etc.

Evan J. Lipson, MD:
From a time-savings perspective, it has been estimated that with an IV formulation the patient takes approximately 45 minutes of “chair time” including travel logistics, IV preparation, and infusion time. By contrast with a 5-minute injection and approximately 10-minute procedure time there is an estimated 26 hours of time savings per patient per year when giving SC ICI as monotherapy. Again, when used in combination with other non-SC agents and/or chemotherapy the time might vary with those as well.

The bottom line is that we can open up more “chair time” and therefor treat more patients.  

Patrick Forde, MD, PhD:
Another consideration is that oncologists and pharmacists need to work together to reach agreement on which patients should be considered for SC ICI vs IV ICI.

Saby George, MD, FACP:
Lastly, SC ICIs and IV ICIs are presently priced similarly with regard to reimbursement. This may vary somewhat based on whether your organization uses a “Group Purchase Organizations” where you would get a more favorable bulk pricing or discount this way.

Patrick Forde, MD, PhD:
It is my understanding that the actual drug costs—which our patients rarely see directly—have not changed. As long as these treatments are administered in the clinic, I think the reimbursement process will remain quite similar. In the future, if there is some movement towards administration outside of the hospital or clinic setting, reimbursement might be different. But there are currently no data for SC ICI in the outpatient setting.  

Your Thoughts
What are your current questions and/or challenges related to the integration of SC ICI into the care of your patients with cancer?

Visit the program page, access the text module and associated slides with more detailed information on SC ICIC, and register for an upcoming pharmacist series webinar to hear from a clinical pharmacist and managed care pharmacist on successful integration of SC ICIs into the care of patients with cancer.