Will Subcutaneous PD-1/PD-L1 Inhibitors Be a Game Changer?

By this fall, the FDA may approve a subcutaneous (SC) injection of the world’s top-selling cancer drug, pembrolizumab (Keytruda; Merck), that can be delivered to patients in 5 minutes or less. It is a change that Merck’s Marjorie Green, MD, senior vice president and head of oncology clinical development, predicts will “build on this breakthrough medicine to give patients and those who treat them better experiences.”1

With Bristol Myers Squibb (BMS) now rolling out the SC version of rival nivolumab (Opdivo Qvantig), the shift from 30-minute intravenous (IV) infusion to 5-minute SC injection could be one of the most important milestones for immunotherapy since the FDA approved this pair of PD-1 inhibitors in 2014.2-4

Those first approvals, both for advanced melanoma,3,4 launched a drug class that forever changed cancer care. Including PD-L1 inhibitors, this category had estimated sales of $48.7 billion in 2024.5 Some analysts believe that figure could triple in the next decade.5,6

With more than 70 approved indications between them, pembrolizumab has more than half the global PD-1/PD-L1 market, and nivolumab takes another quarter, based on recent estimates.6-8 It is little wonder that many oncologists are buzzing about this next step in the evolution of immunotherapy.

Melissa Johnson, MD | Image: SCRI Oncology Partners

Dani Castillo, MD | Image: City of Hope

Scott A. Soefje, PharmD, MBA, BCOP | Image: Mayo Clinic

Enriqueta Felip, MD, PhD | Image: ESMO

Raghava Reddy Induru, MD | Image: Atrium Health

“As a clinical investigator, and as a physician, the idea of [subcutaneous] pembrolizumab is just magical,” Melissa Johnson, MD, director of lung cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, said in an interview with Evidence-Based Oncology (EBO). It would be “so wonderful,” she said, to spare patients IV infusions.

Dani Castillo, MD, assistant clinical professor, Department of Medical Oncology & Therapeutics Research for City of Hope, in Duarte, California, said the December 27, 2024, approval of nivolumab and hyaluronidase-nvhy for SC injection (SC nivolumab)2 has generated excitement about the opportunity to treat patients outside infusion centers, thus improving access. “In the future, the patient may be able to do this at home, improving patient convenience and also health care resource utilization,” she said in an interview with EBO.

Community practitioners Castillo speaks with look forward to having an SC option for PD-1s, and they anxiously await a permanent J-code to ease prior authorization and billing (BMS reports this will occur by July 1, 20259). “They are excited about how this formulation will change their practice—they can bring this to more patients,” she said.

But for each community practice or academic center, deciding whether to offer SC versions of PD-1/PD-L1 inhibitors will rest on far more than drug delivery time, experts say. Both studies and interviews with EBO show that adoption of SC formulations of PD-1/PD-L1 inhibitors will also hinge on drug pricing and whether institutions see overall value in converting.

For pembrolizumab especially, size matters. The footprint of the top-selling PD-1 inhibitor is so large that changing how it is delivered will require overhauling finely tuned systems and preparation schedules, which must be considered.

“There is a cost to making a change,” said Scott A. Soefje, PharmD, MBA, BCOP, director of pharmacy, Cancer Care Services at Mayo Clinic in Rochester, Minnesota. Inventory management, updating treatment plans, and educating staff all cost money. “It’s not always as easy as people think it is,” he said.

Soefje and other clinical pharmacists must weigh all these factors against the benefits of clinic time saved, a more convenient dosing schedule for patients, and the potential for home infusion to reach patients who otherwise would lack access to immunotherapy.1,2,10

“That’s the biggest unknown at this point,” said Soefje, who spoke with EBO in mid-April. “Is it worth changing?”

How SC versions of PD-1/PD-L1 drugs are priced will matter greatly with biosimilars scheduled to arrive in 2028, he said. If patients become acclimated to SC delivery, they will balk if payers require a return to IV formulations to save money. “We’ve seen this with other drugs,” notably rituximab, Soefje said. “Biosimilars will cause the IV prices to go down, but what happens if the [SC] prices don’t change?”

The specter of biosimilars is top of mind for both Merck and BMS, according to published reports.11,12 BMS aims to convert at least 30% of IV users to the SC formulation, although limits in the FDA approval will prevent use of its SC version in some combinations with IV therapy.12

First SC Formulations Have Launched
In the US, the shift to SC delivery of PD-1/PD-L1s kicked off in September 2024, when the FDA approved PD-L1 inhibitor atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza; Genentech) for SC injection.13 The formulation arrived in the United Kingdom in August 2023 and is now available in more than 60 countries. In an email, a Genentech spokesperson said the conversion rate—which is SC use as a percentage of the total—has climbed to 50% in early-launch countries.

Uptake of SC atezolizumab in the US was “as expected” after 7 months, the spokesperson said. The SC formulation “is reimbursed by major US payers, and we will continue collaborating with all stakeholders to facilitate broad access for patients,” the email said.

Following its approval, SC nivolumab reached the market in the first quarter of 2025, and in early May, BMS officials told EBO in an email that early uptake was “in line with our expectations.” First-quarter results show sales of SC nivolumab at $9 million,9 but clinicians who spoke with EBO said that uptake cannot be accurately assessed until J-codes are in place.

Meanwhile, the deadline for FDA action on Merck’s biologics license application for SC pembrolizumab is September 23, 2025,14 and Reuters reports that a launch is planned for October 1, 2025.15

Shorter Delivery Times, Same Efficacy
The biggest selling point of SC formulations of PD-1s is that patients receive therapy in 5 minutes or less, compared with 30 minutes for IV delivery. Pharmaceutical sponsors claim a shift to SC delivery can free up space in cancer clinics, and both BMS and Merck tout SC delivery schedules that double the time between treatments.1,16

If experience with atezolizumab is any guide, patients and physicians will find SC formulations are a home run. Data from IMscin002 (NCT05171777), a phase 2, randomized, open-label, crossover trial of SC and IV atezolizumab, showed that switching from IV to SC atezolizumab cuts delivery time from 40 to 7 minutes, on average. Results also showed that 70.7% of patients preferred the SC formulation, and 79.4% of SC patients stuck with this version during the study’s continuation period. Among providers, 75.2% felt SC atezolizumab was more convenient than IV. 17

CheckMate-67T. BMS’ phase 3 study (NCT04810078), presented in January 2024, found that SC nivolumab was noninferior to IV in measures of pharmacokinetics (PK) and overall response rate. The study compared patients receiving SC nivolumab every 4 weeks with those receiving IV treatment every 2 weeks.18

MK-3475A-D77. Data from Merck’s pivotal phase 3 trial of pembrolizumab with berahyaluronidase alfa (NCT05722015) were presented March 27, 2025, at the European Lung Cancer Congress. They showed SC pembrolizumab with chemotherapy every 6 weeks met end points on measures of PK and progression-free survival consistent with IV pembrolizumab and chemotherapy given every 3 weeks, in patients receiving first-line treatment for metastatic non–small cell lung cancer (NSCLC).19

“The median injection time for [SC] pembrolizumab was only 2 minutes for a volume of 4.8 mL,” study author Enriqueta Felip, MD, PhD, head of the Thoracic Tumors Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain, said in an interview with EBO. “This is important for patients.”
A time-in-motion study showed that overall “chair time” was 59.0 minutes for SC pembrolizumab vs 117.2 minutes for IV pembrolizumab, a reduction of 49.7%; the analysis also found the SC version cut total treatment room time by 47.4%.1

Although significant, the time savings are less dramatic than those seen in some SC conversions. Soefje led the study that showed patients with multiple myeloma saved 3 hours of chair time when they switched from IV to SC daratumumab (Darzalex Faspro; Janssen), an anti-CD38 monoclonal antibody.20 This conversion is considered the model that PD-1 sponsors believe will help them retain market share once biosimilars arrive.21 Of course, adding an SC formulation does not prevent new rivals from doing the same. At press time, a rival anti-CD38 therapy, isatuximab (Sarclisa; Sanofi), is poised to present results from its phase 3 IRAKLIA study (NCT05405166) of an on-body delivery system at the American Society of Clinical Oncology Annual Meeting.22 BeOne Medicines’ phase 1 results on its SC version of tislelizumab (Tevimbra) are due this summer (NCT06091943), after the PD-1 inhibitor entered the market priced 10% below pembrolizumab.23

Raghava Reddy Induru, MD, based in Albemarle, North Carolina, for Atrium Health Levine Cancer Institute, offered an impassioned endorsement of SC therapy in March 2025, during the Association of Cancer Care Centers’ business meeting.10 Induru shared stories of patients who would not be treated at all without SC formulations—however, most did not involve patients receiving PD-1 inhibitors.

The most important consideration is what the patient wants, he said, and with the arrival of SC options, home administration of therapy is not out of the question. Although IV administration still has some advantages, Induru said, “Patient preference has to be the key.”

Assessing Time, Cost Savings
Soefje said he understands pharma’s argument that points to chair time as the key measure of time savings. “I suspect if we could guarantee [saving] an hour every time we administer the drug, we would find that meaningful,” he said. However, he says there are many other considerations when running a cancer clinic.

Because Mayo Clinic uses large quantities of pembrolizumab, pharmacists prepare the IV product in batches, which Soefje said remain stable up to 96 hours when refrigerated. This takes place during downtime at the clinic, he said, so it does not interrupt the workflow.

Mayo Clinic is likely to consider the total chair time as well as drug delivery time, and evaluate these results against an efficient system that has a bag of IV therapy prepared for patients before they arrive. “We don’t intend to do the same thing with subcutaneous [formulation], so that means that subcutaneous syringe is going to fall into our normal work queue, which is a 45-minute prep time,” Soefje said.

Again, the experience with atezolizumab may offer insights. A 2024 analysis by Moeller et al of costs and benefits of SC checkpoint inhibitors in NSCLC cited an in-hospital study comparing formulations of atezolizumab.24 The authors found that the overall time savings was negligible, given the need for 30 minutes of observation after drugs are administered. However, other studies say observation periods for checkpoint inhibitors post injection can be shortened after the early doses, if patients show no adverse effects.25
Writing in 2024, Moeller et al noted that the doses for the SC formulations are larger than the IV versions, which could make savings difficult to achieve.24 However, Managed Healthcare Executive reported that during the SC nivolumab launch, a BMS spokesperson said the 2 versions would have pricing parity: IV nivolumab, with a dose of 240 mg every 2 weeks, has a list price of $7635 per infusion, whereas the SC nivolumab injection of 480 mg every 4 weeks lists for $15,269.26

Even home administration is not straightforward, Soefje said. Mayo Clinic’s Florida group is studying the use of SC therapy at home to evaluate whether it offers a better solution than home IV infusion. However, Soefje knows that in some home infusion scenarios, the nurse sets up the IV and leaves, having taught the patient to disconnect themselves. SC administration, by contrast, requires the nurse to push the therapy through the syringe. (Enable Injections, developer of the on-body delivery system being studied with isatuximab, points to a survey that shows nurses much prefer this modality over a syringe, because it is “hands free.”27)

For Johnson, home administration would be reserved only for patients who are very stable on therapy, to allow breaks from long drives to the clinic. She does not support drug delivery at home because patients are bedridden. “Those are patients that are at high risk for complications from their therapy or their cancer. So those are the ones I want to see,” Johnson said.

These are questions that must be studied, Soefje said. For now, he believes uptake of the SC versions of nivolumab and pembrolizumab will be similar to that of rituximab and trastuzumab. “Some sites are going to love them and use them all the time. Other sites are saying, ‘It’s not worth it.’ I don’t think it’s a slam dunk.”

Johnson said her enthusiasm about SC PD-1/PD-L1 inhibitors is tempered after speaking with the pharmacist at her practice, SCRI Oncology Partners. She notes that her group evaluated adding SC atezolizumab, but concluded the practice was not using enough of the therapy to justify the cost of putting it on formulary. She anticipates her practice will evaluate SC pembrolizumab this summer.

If evidence shows SC therapy offers patients significant quality-of-life benefits, Johnson urges payers to work with practices to ensure the economics are a fit. “There’s a cost to switching,” she said. “You have to have a critical mass to make the juice worth the squeeze, so to speak.”

References
1. Merck’s investigational subcutaneous pembrolizumab with berahyaluronidase alfa demonstrates noninferior pharmacokinetics compared to intravenous (IV) Keytruda (pembrolizumab) in pivotal 3475A-D77 trial. News release. Merck. March 27, 2025. Accessed May 25, 2025. https://bit.ly/43dSAQz
2. Steinzor P. FDA approves first subcutaneous nivolumab injection in most solid tumors. AJMC. January 2, 2025. Accessed May 25, 2025. https://www.ajmc.com/view/fda-approves-first-subcutaneous-nivolumab-injection-in-most-solid-tumors
3. Merck receives accelerated approval of Keytruda (pembrolizumab), the first FDA-approved anti–PD-1 therapy. September 4, 2014. Accessed May 25, 2025. https://www.merck.com/news/merck-receives-accelerated-approval-of-keytruda-pembrolizumab-the-first-fda-approved-anti-pd-1-therapy/
4. Bristol Myers Squibb receives accelerated approval of Opdivo (nivolumab) from the US Food and Drug Administration. News release. Bristol Myers Squibb. December 22, 2014. Accessed May 25, 2025. https://bit.ly/3HdpKXX
5. Global PD-1 and PD-L1 Inhibitors Market. Insight ACE Analytic. May 14, 2025. Accessed May 25, 2025. https://www.insightaceanalytic.com/report/global-pd-1-and-pd-l1-inhibitors-market-/1115
6. Gores M. In the eye of the storm: PD-(L)1 inhibitors weathering turbulence. IQVIA. May 9, 2022. Accessed May 25, 2025. https://www.iqvia.com/library/white-papers/in-the-eye-of-the-storm-pd-l-1-inhibitors-weathering-turbulence
7. Keytruda: A key to more possibilities for treating your patients. Merck. Accessed May 25, 2025. https://www.keytrudahcp.com/
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9. Q1 2025 results. Bristol Myers Squibb. April 24, 2025. Accessed May 25, 2025. https://www.bms.com/assets/bms/us/en-us/pdf/investor-info/doc_presentations/2025/BMY-2025-Q1-Results-Investor-Presentation.pdf
10. Caffrey M. With sub-Q immunotherapy coming, “patient preference has to be the key.” AJMC. March 9, 2025. Accessed May 25, 2025. https://www.ajmc.com/view/with-sub-q-immunotherapy-coming-patient-preference-has-to-be-the-key-
11. Yasiejko C. Merck’s new Keytruda shot is a rare real-time “product hop.” Bloomberg. May 7, 2025. Accessed May 25, 2025. https://news.bloomberglaw.com/ip-law/mercks-new-keytruda-shot-is-a-rare-real-time-product-hop
12. Liu A. Bristol Myers Squibb celebrates 10 years of Opdivo with FDA approval for subcutaneous version. Fierce Pharma. January 2, 2025. Accessed May 25, 2025. https://www.fiercepharma.com/pharma/bristol-myers-celebrates-10-years-opdivo-fda-approval-subcutaneous-version
13. FDA approves atezolizumab and hyaluronidase-tqjs for subcutaneous injection. FDA. September 12, 2024. Accessed May 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-and-hyaluronidase-tqjs-subcutaneous-injection
14. Zacks Equity Research. FDA accepts Merck’s filing for subcutaneous version of Keytruda. Yahoo Finance. March 28, 2025. Accessed May 25, 2025. https://finance.yahoo.com/news/fda-accepts-mercks-filing-subcutaneous-152000184.html
15. Erman M. Merck plans to launch US subcutaneous version of Keytruda on October 1. Reuters. March 27, 2025. Accessed May 25, 2025. https://www.reuters.com/business/healthcare-pharmaceuticals/merck-plans-us-launch-subcutaneous-version-keytruda-october-1-2025-03-27/
16. Bristol Myers Squibb receives positive CHMP opinion for the subcutaneous formulation of Opdivo (nivolumab) across multiple solid tumor indications. News release. Bristol Myers Squibb. March 28, 2025. Accessed May 25, 2025. https://bit.ly/3F8SpwV
17. Cappuzzo F, Zvirbule Z, Korbenfeld E, et al. Primary results from IMscin002: a study to evaluate patient preferences and perceptions of health care professionals for atezolizumab subcutaneous versus intravenous for the treatment of NSCLC. JTO Clin Res Rep. 2025;6(5):100815. doi:10.1016/j.jtocrr.2025.100815
18. George S, Bourlon MT, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. J Clin Oncol. 2024;42(suppl 4):LBA360. https://doi.org/10.1200/JCO.2024.42.4_suppl.LBA360
19. Felip E, Rojas CI, Schenker M, et al. Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non–small cell lung cancer: the phase III 3475A-D77 trial. Ann Oncol. Published online March 27, 2025. doi:10.1016/j.annonc.2025.03.012
20. Soefje SA, Carpenter C, Carlson K, et al. Clinical administration characteristics of subcutaneous and intravenous administration of daratumumab in patients with multiple myeloma at Mayo Clinic infusion centers. JCO Oncol Pract. 2023;19(4):e542-e549. doi:10.1200/OP.22.00421
21. Plieth J. A subcutaneous answer to PD-1’s patent problem. ApexOnco OncologyPipeline. August 18, 2023. Accessed May 25, 2025. https://www.oncologypipeline.com/apexonco/subcutaneous-answer-pd-1s-patent-problem
22. Ailawadhi S, Spicka I, Lu J, et al. Isatuximab (Isa) subcutaneous (SC) via an on-body delivery system (OBDS) vs Isa intravenous (IV), plus pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma (RRMM): results of the randomized, noninferiority, phase 3 IRAKLIA study. J Clin Oncol. 2025;43(suppl 16):7506. doi:10.1200/JCO.2025.43.16_suppl.7506
23. Martin G. With tislelizumab, BeiGene brings immunotherapy to more patients in Europe. The Pharma Letter. January 16, 2025. Accessed May 25, 2025. https://www.thepharmaletter.com/with-tislelizumab-beigene-brings-immunotherapy-to-more-patients-in-europe
24. Moeller J, Green MD, Ramnath N. Pros and cons of subcutaneous (SC) versus intravenous (IV) administration of immune checkpoint inhibitors in non–small cell lung cancer. Transl Lung Cancer Res. 2024;13(6):1444-1449. doi:10.21037/tlcr-24-111
25. van Rijssen L, Nagtegaal IEC, Ploos van Amstel FK, et al. Safety of accelerated infusion of nivolumab and pembrolizumab. Eur J Cancer. 2025;220:115373. doi:10.1016/j.ejca.2025.115373
26. Myshko D. FDA approves subcutaneous Opdivo to treat solid tumors. Managed Healthcare Executive®. December 28, 2024. Accessed May 25, 2025. https://www.managedhealthcareexecutive.com/view/fda-approves-subcutaneous-opdivo-to-treat-solid-tumors
27. Desai M, Faiman B, Gorski LA, Miles A, Sterlin V, Curry N. Evaluating nurse preferences for a novel on-body delivery system vs manual syringes for large-volume subcutaneous drug administration: a survey study. Drug Deliv. 2025;32(1):2484278. doi:10.1080/10717544.2025.2484278