The Importance of Subcutaneous Checkpoint Inhibitors for Cancer
Subcutaneous formulations of immunotherapies have the potential to save time and reduce efforts for both patients and healthcare providers. These formulations save patients and providers 30 or more minutes in treatment time because they simply take less time to administer. They can also make treatment more accessible for some patients by reducing the frequency of hospital visits and the need to travel long distances to infusion centers. This benefit is especially relevant for patients who live in rural or underserved communities. Subcutaneous checkpoint inhibitors can be administered by a healthcare provider in multiple settings such as an infusion center or clinic, providing flexibility particularly for patients who live far from treatment centers and those who require long-term maintenance therapy.¹’¹⁹ When surveyed, patients have indicated their satisfaction with subcutaneous treatment versus infusion.
Rationale for the Development of Subcutaneous Checkpoint Inhibitors
Reducing treatment preparation and administration time to improve quality of life for patients, care partners, and clinical staff, as well as to free up space for infusions, has recently become a focus of attention.1 Intravenous administration of immunotherapies can be a burden to patients and the healthcare system, which supports the rationale for developing new formulations. Results from prior studies indicate that patients prefer subcutaneous formulations over intravenous (IV) ones, and there are also advantages for healthcare providers and medical systems.2 IV infusions generally must be administered in a cancer center or hospital outpatient setting and the administration time is 30 minutes or more, which can be burdensome to both patients and the healthcare system. On the other hand, subcutaneous therapies may be administered in an office setting or clinic, and the administration takes only a few minutes. For patients who do not live near a cancer center or hospital, subcutaneous injections can also save travel time and increase access to therapy. Importantly, the subcutaneous formulations combine the same checkpoint inhibitor as in the IV infusions with the enzyme hyaluronidase which is used for subcutaneous drug formulations to increase drug absorption and dispersion in tissues.3
FDA-Approved Subcutaneous Checkpoint Inhibitors and Indications
Atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza)
The anti PD-L1 checkpoint inhibitor atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza) was approved in September 2024 as monotherapy, in combination with chemotherapy, and in combination with targeted therapies. 4,5
The approved indications are:
- Unresectable or metastatic melanoma
- Non-Small Cell Lung Cancer
- Small Cell Lung Cancer
- Hepatocellular Carcinoma
- Alveolar Soft Part Sarcoma
- Muscle Invasive Bladder Cancer
Nivolumab and hyaluronidase-nvhy (Opdivo Qvantig)
In December 2024, the FDA approved a subcutaneous formulation of the anti-PD-1 checkpoint inhibitor nivolumab as onotherapy, monotherapy maintenance following completion of nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy, or in combination with chemotherapy or cabozantinib.6,7
The approved indications are7:
- Unresectable or metastatic melanoma
- Stage IIB, Stage IIC, Stage III, or Stage IV melanoma
- Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch
- repair deficient (dMMR) colorectal cancer
- Esophageal cancer
- Gastric cancer, gastroesophageal junction cancer, and esophageal
- adenocarcinoma
- Hepatocellular carcinoma
- Non-small cell lung cancer
- Renal cell carcinoma
- Squamous cell carcinoma of the head and neck
- Urothelial carcinoma
Pembrolizumab and Berahyaluronidase alfa-pmph (Keytruda Qlex)
In September 2025, the anti-PD-1 checkpoint inhibitor pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) injection was approved.8,9
The approved indications are9:
- Advanced melanoma
- Stage IIB, IIC, and III melanoma
- Advanced non-small cell lung cancer
- Advanced malignant pleural mesothelioma
- Head and neck squamous cell cancer
- Advanced Merkel cell carcinoma
- Metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient
- (dMMR) solid tumors
- Advanced renal cell carcinoma
- MSI-H, dMMR, or advanced endometrial carcinoma
- Advanced tumor mutational burden-high solid tumors
- Advanced cutaneous squamous cell carcinoma
- Triple negative breast cancer
- Urothelial cancer
- MSI-H or dMMR colorectal cancer
- Gastric or gastroesophageal junction adenocarcinoma
- Advanced esophageal cancer
- Advanced cervical cancer
- Hepatocellular carcinoma
- Advanced biliary tract cancer
- Advanced ovarian cancer
Administration Information for Subcutaneous Checkpoint Inhibitors 5,7,9
| Atezolizumab and hyaluronidase-tqjs | Nivolumab and hyaluronidase-nvhy | Pembrolizumab and berahyaluronidase alfa-pmph | |
|---|---|---|---|
| How supplied | – 1,875 mg atezolizumab and 30,000 units hyaluronidase per 15 mL (125 mg/2,000 units per mL) | – 300 mg nivolumab and 5,000 units hyaluronidase per 2.5 mL (120 mg/2,000 units per mL) – 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 | – 395 mg pembrolizumab and 4,800 units berahyaluronidase alfa per 2.4 mL (165 mg/2,000 units per mL) – 790 mg pembrolizumab and 9,600 units berahyaluronidase alfa per 4.8 mL (165 mg/ 2,000 units per mL) |
| Recommended dose in adult and pediatric patients weighing >40 kg and duration of injection | – 1,875 mg/30,000 units over approximately 7 minutes every 3 weeks | As monotherapy: – 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks over 3 to 5 minutes As combination therapy: – 600 mg/10,000 units every 2 weeks, 900 mg/15,000 units every 3 weeks, or 1,200 mg/20,000 units every 4 weeks over 3 to 5 minutes | – 395 mg/4,800 units over 1 minute every 3 weeks – 790 mg/9,600 units over 2 minutes every 6 weeks |
| Injection site | Thigh | Abdomen or Thigh | Abdomen or Thigh |
Clinical Considerations: Efficacy and Safety
Atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza) 5,6,10
Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the IMscin001 trial in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had not received cancer immunotherapy and who had disease progression after chemotherapy. In total, 371 patients were randomized to receive subcutaneous atezolizumab and hyaluronidase-tqjs or intravenous atezolizumab. There were no significant differences in ORR, PFS, or OS between the different formulations. The safety profile was also consistent with the IV formulation. Approximately 4.5% of patients experienced local injection site reactions that were all grade 1 or grade 2 in severity.
Nivolumab and hyaluronidase-nvhy (Opdivo Qvantig) 7,11
In the CHECKMATE-67T study in adult patients with advanced or metastatic renal cell carcinoma, 247 patients received nivolumab + hyaluronidase-nvhy, and 245 patients received intravenous nivolumab. Objective response rate, progression-free survival, disease control rate, and overall survival were all comparable for the subcutaneous and intravenous formulations.
The safety profile of the subcutaneous formulation was shown to be consistent with the intravenous formulation and no new safety signals were identified. 3,4 Injection site reactions with the subcutaneous formulation occurred in 8% of patients. Importantly,
these injection site reactions were mild (grade 1 and 2 in severity), resolved, and did not lead to treatment discontinuation.
Pembrolizumab and Berahyaluronidase alfa-pmph (Keytruda Qlex) 8.9,12
In total, 377 participants were randomized to receive subcutaneous or intravenous pembrolizumab in the MK-3475A-D77 trial in patients with treatment-naïve metastatic non-small cell lung cancer (NSCLC) with no EGFR, ALK or ROS1 genomic tumor
aberrations. Patients also received platinum doublet chemotherapy. The overall response rate was similar for subcutaneous or intravenous pembrolizumab. In addition, significant differences were not observed in progression-free survival and overall survival. The safety profile was also consistent for both treatments. Injection-site reactions with the subcutaneous formulation were observed in 2.4% of patients. They were all grade 1 in severity and considered not serious, and they did not result in patients discontinuing treatment.
Impact of Subcutaneous Checkpoint Inhibitors on Preparation, Administration,
Chair Time, Costs, and Resources
Overview of Factors Impacted by Subcutaneous Administration
| Factors | Impact |
|---|---|
| Preparation and administration time | Less time |
| Chair time/utilization | Decreased |
| Staffing needs | Potentially reduced |
| Costs | Potentially reduced |
Preparation, Administration Time, and Chair Time/Utilization
Results from a trial comparing subcutaneous versus intravenous trastuzumab and pertuzumab in breast cancer showed that the mean treatment time, including drug administration and observation time, was 61.8 minutes shorter (22.5 versus 84.3
minutes; P < .0001) with subcutaneous administration compared with IV administration. The mean total patient treatment experience time, which includes time spent waiting for treatment initiation and time spent undergoing treatment, was 81.8 minutes shorter for subcutaneous administration (96 versus 177.8 minutes; P < .0001). Workflow time for the pharmacy was also 78.2 minutes shorter for subcutaneous administration (41 versus 119.2 minutes; P < .0001).13
While significant time savings are possible with subcutaneous therapies, it is important to acknowledge other considerations. For example, patients still need to arrive early for laboratory tests, as well as wait for the results and have them reviewed before an
injection can take place. In addition, more time is required for those patients who also require intravenous chemotherapy.14
Staffing Needs
The ability to optimize utilization of healthcare resources and reduce administrative tasks are benefits of subcutaneous formulations. The time savings may be factored into nurse workflows, which is especially important when there are nursing shortages. Furthermore, pharmacy professionals benefit from shorter processing times with subcutaneous formulations.1,2
Costs
Direct and indirect costs may be lower with subcutaneous administration. According to results from one publication, reductions in direct costs for preparation of subcutaneous formulations of cancer therapies compared to IV formulations ranged from 6.6% to
50.1%, and reductions in administration costs ranged from 4.5% to 95.3%. In addition, indirect costs associated with productivity loss were lower with subcutaneous versus IV administration because the time required to receive subcutaneous therapy was shorter. Utilization and cost of medical resources was also shown to decrease with subcutaneous formulations.2
Impact of Subcutaneous Checkpoint Inhibitors on Patient Preferences and Access to Care
Overall Considerations for Patient Preference
Patients typically prefer subcutaneous administration over intravenous infusion, and greater patient satisfaction has been observed as well. In addition, results from a review publication showed that more than 68% of patients had greater satisfaction with subcutaneous formulations of cancer therapies. Shorter administration time, less pain at the injection site, more comfort, less anxiety, not needing or considering the possibility of requiring venous access, fewer adverse reactions, and feeling less sick are all reasons for preferring subcutaneous therapies. 2 Results from a publication on survey results from 201 patients experienced with
subcutaneous and intravenous cancer treatments showed that 89.6% of patients preferred subcutaneous therapy and 5.5% of patients preferred IV therapy. In addition, patients were typically more satisfied with subcutaneous treatment (78.6% versus
33.3% for intravenous therapy). Appointment travel time, total time spent at a treatment facility, reduced treatment burden, improved independence and convenience, as well as the ability to cope with their illness were factors affecting satisfaction with treatment.15
Specific Patient Preference Results for Atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza)
In the Phase II IMscin002 study, 179 patients with resected NSCLC who had completed adjuvant chemotherapy without evidence of recurrence, and chemotherapy-naïve patients with metastatic NSCLC, were randomized to receive subcutaneous atezolizumab and then IV atezolizumab or IV atezolizumab and then subcutaneous atezolizumab. After cycle 3, patients switched administration routes, and then following cycle 6, the patients chose the route of administration for the continuation period. Results showed that 71% of patients preferred subcutaneous atezolizumab compared to intravenous atezolizumab, and the most common reasons were less time in the clinic, increased comfort during treatment, and reduced emotional distress. In total, 4 out of 5 patients (79%) chose to continue with subcutaneous therapy after having experience with both formulations.16
Specific Patient Preference Results for Nivolumab and hyaluronidase-nvhy (Opdivo Qvantig)
In the phase 2, open-label, multicenter CA224-1044 study, adults (n=50) with completely resected Stage IIB/C, III, or Stage IV melanoma received intravenous nivolumab once every 4 weeks for 2 cycles followed by subcutaneous nivolumab every 4 weeks until disease recurrence, unacceptable toxicity, or 1 year of total treatment duration. The results showed that 71% of patients preferred the subcutaneous delivery of nivolumab versus the intravenous formulation.17
Specific Patient Preference Results for Pembrolizumab and Berahyaluronidase alfa-pmph (Keytruda Qlex)
In the 2-arm, open-label 3475A-F11 crossover study, patient preference for subcutaneous pembrolizumab or intravenous pembrolizumab was assessed in 147 patients. Patients received subcutaneous pembrolizumab every 3 weeks or intravenous
pembrolizumab IV 200 mg Q3W (arm B) for 3 cycles before crossing over to the other administration route for 3 cycles. After 6 cycles, patients could choose to continue with the subcutaneous or intravenous formulation. In total, 65% of patients preferred
subcutaneous pembrolizumab. Reasons for the preferring this formulation were less clinic time, more comfort during administration, less injection site pain, and less emotional distress. In total, 68% of patients chose to continue with subcutaneous
pembrolizumab and 32% chose to continue with intravenous pembrolizumab.18
Considerations Regarding Access to Care
Importantly, availability and incorporation of subcutaneous formulations of immunotherapies in treatment plans has the potential to make therapy more accessible by reducing the frequency of hospital visits and the need to travel long distances to infusion centers. This is especially relevant for patients who live in rural/underserved communities. Subcutaneous checkpoint inhibitors can be administered by a healthcare provider in multiple settings such as an infusion center, a doctor’s office, or community, which provides flexibility particularly for patients who live far from treatment centers and those who require long-term maintenance therapy. 1,19 Over 80% of patients who answered the survey mentioned above stated that they perceived a potential benefit
when asked about hypothetically receiving at-home subcutaneous injections.
AIM Resources for Healthcare Providers
Subcutaneous Versus Intravenous Nivolumab Formulations: Important Considerations for Patient Care
FAQs about Subcutaneous Checkpoint Inhibitors for Healthcare Providers
Information about FDA-approved immunotherapies
AIM with Immunotherapy Toolkits
AIM Resources for Patients
Subcutaneous Immunotherapies for Melanoma: What You Need to Know
FAQs about Subcutaneous Checkpoint Inhibitors for Patients
Information about FDA-approved immunotherapies
Publications on Subcutaneous Checkpoint Inhibitors
Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol. 2025;36:99-107.
References
- Gupta A, Tregear M, Pace MB et al. Stick With Intravenous or Give Subcutaneous a Shot? Time and Other Considerations When Evaluating Cancer Drug Formulations. JCO Oncol Pract. 2024;219:267-269.
- Parra A, Hernandez C, Prieto-Pinto L et al. Evaluation of the economic benefits, administration times, and patient preferences associated with the use of biotechnological drugs administered subcutaneously and intravenously in
patients with cancer: A systematic review. Expert Rev Pharmacoecon Outcomes Res. 2023;1017-1026. - Locke KW, Maneval DC, LaBarre MJ. ENHANZE ® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv. 2019;26:98-106.
- FDA approves atezolizumab and hyaluronidase-tqjs for subcutaneous injection. September 12, 2024. Available at:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-and-hyaluronidase-tqjs-subcutaneous-injection - TECENTRIQ HYBREZA. Prescribing information. Genentech, Inc.; 2026. Accessed June 25, 2026. Available at:
https://www.gene.com/download/pdf/tecentriq_hybreza_prescribing.pdf - U.S. Food and Drug Administration Approves Opdivo Qvantig™ (nivolumab and hyaluronidase-nvhy) Injection on December 27, 2024. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
nivolumab-and-hyaluronidase-nvhy-subcutaneous-injection - OPDIVO QVANTIG. Prescribing information. Bristol Myers Squibb; 2026. Accessed June 25, 2026. Available at:
https://packageinserts.bms.com/pi/pi_opdivo-qvantig.pdf - FDA Approves Merck’s KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) Injection for Subcutaneous Use in Adults Across Most Solid Tumor Indications for KEYTRUDA® (pembrolizumab). Available at:
https://www.merck.com/news/fda-approves-mercks-keytruda-qlex-pembrolizumab-and-berahyaluronidase-alfa-pmph-injection-for-subcutaneous-use-in-adults-across-most-solid-tumor-indications-for-keytrudapem/#:~:text=In%20descriptive%20efficacy%20analyses%2C%20overall,(including%20corneal%20graft)%20rejection - KEYTRUDA QLEX. Prescribing information. Merck & Co.; 2026. Accessed June 25, 2026. Available at:
https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_
pi.pdf