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"The emulation framework lends the design and conduct of observational analyses some of the rigor required for the planning of a randomized trial. In doing so, it provides an innovative and principled approach to improve the evidence base on the comparative effectiveness of interventions," writes Boris Gershman, MD, and Aaron Fleishman, MPH.

Emulating target trials using observational evidence to inform clinical decision-making

The FDA has accepted a Biologics License Application (BLA) seeking approval of nivolumab (Opdivo) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20), or subcutaneous nivolumab, for the treatment of patients with all previously approved solid tumor indications for nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Nivolumab is currently approved under several indications, including in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.

 According to a news release from Bristol Myers Squibb,

 approval of the formulation would make it the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in the news release.

 “Opdivo is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV Opdivo but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30-to-60-minute infusion.”

The BLA submission is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time average nivolumab serum concentration over 28 days (C

; geometric mean ratio [GMR}, 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,

 also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR), compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus rHuPH20 every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C

 of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

Final completion of the CheckMate-67T study is expected in January 2026.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 7, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Published online and accessed May 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, 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. 

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated March 1, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT04810078

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024. 

News

FDA accepts BLA for subcutaneous nivolumab in solid tumors

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy.

During cystoscopy, a rim of calcification was seen along the right ureteric ridge (figure 1a). A biopsy of this area was taken with the pathology shown in figure 1b.

B. Squamous cell carcinoma of the bladder

A 35-year-old male from Sudan presented with a 1-cm obstructing ureteral stone and curvilinear calcification in the bladder wall, as seen on KUB imaging. The patient underwent ureteroscopy and laser lithotripsy. During cystoscopy, calcification was observed along the right ureteric ridge. A biopsy was performed on this area to further investigate the pathology. The findings from the biopsy are crucial for understanding the underlying condition contributing to the calcification and obstruction, which may have implications for the patient's treatment and management.

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy. During cystoscopy, a rim of calcification was seen along the right ureteric ridge. What is the diagnosis?

Residents Corner

Quiz: Sandy patch on cystoscopy

Ellen Cahill, MD, discusses the use of chaperones for genitourinary exams

What’s required for incorporating chaperone use in genitourinary exams

 discusses the use of chaperones for genitourinary exams. She presented the study “The Use of Chaperones for Genitourinary Exams: A Survey of Society for the Study of Male Reproduction (SSMR) Members,” at the 2024 Sexual Medicine Society of North American Fall Scientific Meeting in Scottsdale, Arizona. Cahill is a urology resident at Yale School of Medicine in New Haven, Connecticut.

Although some respondents reported that chaperones added minimal time to visits, others indicated that it could be more time-consuming. How can practices balance the need for patient comfort and protection with the goal of maintaining efficiency?

Efficiency is hugely important, and anything that we add to our practice, we do have to make sure it's not inconvenient to us. I think it requires the adequate staff, and then also the development of a practice pattern for how chaperones are used. You need enough people to serve as your chaperones around. You don't want to be looking out into the hallway and you don't see anybody. You need to know who's going to serve as your chaperone. Is it going to be the techs, the nurses? It kind of depends on the practice setting. And then you need buy-in from all the staff to make sure that you understand how it's going to impact your workflow. Is it that they're going to room the patient, you're going to see the patient, and then you're going to make sure you have somebody outside of the room ready to go for the chaperone portion of the exam? How long are they going to spend with you, and making sure it doesn't interfere with them being able to room your next patient? I think at Yale, it's actually been able to be incorporated pretty well. We have another abstract here from my co -resident, Dr Sharath Reddy, who surveyed Yale urologists specifically, and most of our physicians felt that the policy worked out well for them and was quite efficient. We do have a lot of staff, so we just have to make sure that we always have somebody available. And typically we do, it doesn't add much time to the visit.

This transcript was AI generated and edited by human editors for clarity.

The use of chaperones during genitourinary exams is a topic of discussion among medical professionals, balancing patient comfort and practice efficiency. While some practitioners find chaperones minimally time-consuming, others see them as potentially disruptive. Effective implementation requires adequate staffing and clear practice patterns. Staff buy-in is crucial to ensure workflow integration without hindering patient throughput. At Yale, the chaperone policy has been successfully integrated, with sufficient staff ensuring minimal impact on visit duration. The experience highlights the importance of strategic planning and resource allocation in medical practice.

"I think it requires the adequate staff, and then also the development of a practice pattern for how chaperones are used," says Ellen Cahill, MD.

Ellen Cahill, MD, discusses what to consider when incorporating chaperones for genitourinary exams

Ellen Cahill, MD, on chaperone use for genitourinary exams

 discusses what to consider when incorporating chaperones for genitourinary exams. She presented the study “The Use of Chaperones for Genitourinary Exams: A Survey of Society for the Study of Male Reproduction (SSMR) Members,” at the 2024 Sexual Medicine Society of North American Fall Scientific Meeting in Scottsdale, Arizona. Cahill is a urology resident at Yale School of Medicine in New Haven, Connecticut.

What factors should be considered when developing standardized guidelines for chaperone use in sexual medicine? How can these guidelines be implemented effectively to ensure consistency and improve the patient-physician experience?

I think it would be really nice if we did have standardized guidelines on who could serve as a chaperone. Like I said, our study showed that there are wide variations. At Yale, we only allow for nurses and techs to be chaperones. We don't allow another physician to be a chaperone, a medical student, a scribe, anything like that. But it really varied in our survey. You also want to consider what exam needs a chaperone. At Yale, we use them for any rectal exam, genitourinary exam, breast exam, any really sensitive exam. And we don't give patients a choice. It's just a policy that we have. Sometimes patients do say, "Do we really need this? Do I have to have this done?" And typically, by just saying, "This is our policy," we don't have issues with that, but it's something that should be considered. Are you going to give the patients a choice, or are you going to have that be your standardized policy, and then just making sure to work it into the workflow, talk to the clinic staff, and figure out how this is going to be implemented by who, and just making sure there's buy-in from everybody.

Standardized guidelines for chaperone use in genitourinary exams are essential to ensure consistency and improve the patient-physician experience. Variations exist in who can serve as a chaperone, with some institutions like Yale allowing only nurses and techs. The decision to use chaperones should consider the type of exam and whether patients have a choice. Effective implementation requires integrating the policy into clinical workflows and securing buy-in from all staff members to ensure smooth operation and adherence to the guidelines.

"I think it would be really nice if we did have standardized guidelines on who could serve as a chaperone," says Ellen Cahill, MD.

Key Trials on PARP Inhibitor Combinations in Metastatic Prostate Cancer: Efficacy and Future Considerations

Video Content above is prompted by the following:

The TALAPRO-2 study authors noted that the use of androgen receptor (AR)–targeted therapy in clinical practice has increased considerably in recent years. How might prior use of AR-targeted therapy affect the effectiveness of this combination?

What are the main safety concerns with use of talazoparib and other PARP inhibitors (eg, anemia, neutropenia, thrombocytopenia)? Would these make you more hesitant to use PARP inhibitors compared with another option?

How do you expect the results found in the TALAPRO-2 trial population to compare to that in the ZZ-First trial (NCT04332744) population (metastatic hormone-naive prostate cancer)?

What future studies are needed to clarify the optimal approaches for different populations of people with metastatic prostate cancer?

The TALAPRO-2 study highlights the increased use of androgen receptor (AR)-targeted therapy in clinical practice and examines its impact on the efficacy of combination treatments. Safety concerns with talazoparib and other PARP inhibitors, such as anemia, neutropenia, and thrombocytopenia, are discussed, raising questions about their use compared to other options. The study also considers how results might differ from the ZZ-First trial, which focuses on metastatic hormone-naive prostate cancer. Future research is needed to determine optimal treatment strategies for various metastatic prostate cancer populations.

Panelists discuss how the increased use of androgen receptor–targeted therapy in clinical practice may impact the effectiveness of PARP inhibitor combinations like talazoparib in the TALAPRO-2 study, while also addressing safety concerns, potential differences in trial populations, and the need for future studies to optimize treatment approaches for various metastatic prostate cancer patient subgroups.

Investigator Perspectives

Video Series

PARP Inhibitors in Metastatic Prostate Cancer: Efficacy, Trials, and Combination Therapies

Discuss efficacy and safety findings from monotherapy trials PARP inhibitors in metastatic prostate cancer harboring homologous recombination repair gene alterations.

PARP inhibitors, particularly olaparib, have shown promise in treating metastatic prostate cancer with homologous recombination repair (HRR) gene alterations. The PROfound trial demonstrated olaparib's efficacy, significantly improving radiographic progression-free survival and overall survival compared to standard treatments. Safety profiles were consistent with known PARP inhibitor effects, with manageable adverse events. These findings underscore the potential of PARP inhibitors as a targeted therapy for patients with HRR gene alterations, offering a personalized treatment approach and highlighting the importance of genetic testing in guiding therapeutic decisions.

Panelists discuss how the PROfound trial (NCT02987543) demonstrated the efficacy and safety of olaparib monotherapy in metastatic prostate cancer patients with homologous recombination repair gene alterations, highlighting its potential as a targeted treatment option and its impact on the landscape of precision medicine in prostate cancer management.

Aaron Fleishman, MPH

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