In December 2024, the FDA approved a subcutaneous formulation of the immune checkpoint inhibitor nivolumab across adult, solid tumor nivolumab indications as monotherapy, monotherapy maintenance following completion of nivolumab (OPDIVO) plus ipilimumab (YERVOY) combination therapy, or in combination with chemotherapy or cabozantinib. Patients can now receive the original intravenous version of nivolumab (OPDIVO) or the subcutaneous injection, nivolumab + hyaluronidase (OPDIVO Qvantig). The enzyme hyaluronidase is used for subcutaneous drug formulations to increase drug absorption and dispersion in tissues.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 ones, and there are also advantages for healthcare providers and medical systems.2
Considerations regarding efficacy, adverse reactions, preparation/administration time, cost, as well as patient preferences and access to care, are discussed here.
Efficacy
In the CHECKMATE-67T multicenter, randomized, open-label study in adult patients with advanced or metastatic renal cell carcinoma, 247 patients received nivolumab + hyaluronidase (OPDIVO Qvantig), and 245 patients received intravenous nivolumab. Objective response rate (ORR), progression-free survival, disease control rate, and overall survival were all comparable for the subcutaneous and intravenous formulations, and noninferiority was demonstrated for pharmacokinetics and for ORR. 3,4
Adverse Reactions
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 Importantly, an advantage of subcutaneous formulations is the lack of needing venous access and a permanent port, which is associated with risks such as infection and thrombosis.5 In addition, the percentage of patients with grade 3 and 4 adverse reactions was lower with the subcutaneous versus the intravenous formulation (40.1% versus 46.5%).4
Only a few adverse reactions were more common in patients receiving the subcutaneous formulation. Adverse reactions that were more common with subcutaneous versus intravenous nivolumab were as follows: constipation (6% vs. 8%), rash (13% vs. 15%), and vomiting (4.9% vs. 6%). Injection site reactionswith 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.3,4
Preparation and Administration Time and Cost and Resource Implications
Intravenous nivolumab is administered as an infusion over 30 minutes, while the subcutaneous injection is administered over 3 to 5 minutes by a health care professional.3 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.6
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.2,6
Results from a trial comparing subcutaneous versus intravenous trastuzumab/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 that 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).7
Direct and indirect costs are also 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
Patient Preferences and Access to Care
Patients typically prefer subcutaneous administration over intravenous infusion, and greater patient satisfaction has been observed as well. For example, 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.8
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. Furthermore, if self-administration at home becomes an option in the future, access to immunotherapy could be expanded even further in the community, particularly for patients who live far from treatment centers and those who require long-term maintenance therapy.6,9 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.8
Conclusions
The approval of subcutaneous nivolumab provides patients with a new option to improve treatment satisfaction. In addition, the approval of pembrolizumab and berahyaluronidase alfa-pmph (KEYTRUDA Qlex) injection, further supports the role of subcutaneous immunotherapies. The availability and use of subcutaneous cancer immunotherapies is associated with improved healthcare utilization and decreased costs. Furthermore, access to therapy in patients overall as well as those in rural/underserved communities may be optimized.
For More Information
- OPDIVO Qvantig Toolkit – Access our toolkit to support your clinical practice here.
- OPDIVO Qvantig Patient Action Plan – Download the patient action plan to help guide discussions and care planning here.
References
1. 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(1):98-106.
2. 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.
3. OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy) injection [prescribing information]. Bristol Myers Squibb. Princeton, NJ 08543. Available at: https://packageinserts.bms.com/pi/pi_opdivo-qvantig.pdf. Accessed 6.24. 2025. Revised 5.2025.
4. Albiges L, Bourlon MT, Chacón M, et al. Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol. 2025;36(1):99-107.
5. Machat S, Eisenhuber E, Pfarl G, Stübler J, Koelblinger C, Zacherl J, Schima W. Complications of central venous port systems: a pictorial review. Insights Imaging. 2019 Aug 28;10(1):86.
6. 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(3):267-269.
7. Waks AG, Chen EL, Graham N, et al: Subcutaneous versus intravenous trastuzumab/ pertuzumab: A time and motion substudy of a phase II trial of adjuvant trastuzumab/ pertuzumab for stage I HER2+ breast cancer (ADEPT trial). JCO Oncol Pract. 2025;21:351-357.
8. Epstein, R., Krenitsky, J. & Sarocco, P. Real-World Quantitative Insights into the Treatment Experience of Patients with Cancer in the USA with Subcutaneous Versus Intravenous Drug Delivery. Oncol Ther. 2025;13:695–710.
9. From Infusion to Injection: The Promise of Subcutaneous Nivolumab. GU Oncology Now. February 25, 2025. Available at: https://www.guoncologynow.com/post/from-infusion-to-injection-the-promise-of-subcutaneous-nivolumab
