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1rem

Authors

Leading West Michigan practice now affiliated with nation’s largest urological healthcare management company

Urologic Consultants has joined Solaris Health

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

Innovations in NMIBC Treatment: The Synergy of BCG and PD-1/PD-L1 Inhibitors

Video content above is prompted by the following:

How might the combination of BCG and PD-1/PD-L1 inhibitors affect antitumor activity compared with using each agent alone?

What is the rationale for using these therapies in combination?

How do you think the combination therapies will evolve treatment of non–muscle-invasive bladder cancer (NMIBC)?

How would the use of PD-1/PD-L1 inhibitors plus BCG in high-risk NMIBC impact patient flow in urology practice?

THE SPEAKER WILL HIGHLIGHT THE IMPORTANCE OF A MULTIDISCIPLINARY APPROACH

Combining BCG with PD-1/PD-L1 inhibitors may enhance antitumor activity compared to monotherapy, leveraging complementary mechanisms of action. BCG stimulates an immune response, while PD-1/PD-L1 inhibitors prevent immune evasion by tumors. This combination could revolutionize non–muscle-invasive bladder cancer (NMIBC) treatment, offering improved outcomes for high-risk patients. The integration of these therapies in urology practice may necessitate adjustments in patient management and flow, emphasizing the need for a multidisciplinary approach to optimize treatment strategies and patient care.

Panelists discuss how combining BCG with PD-1/PD-L1 inhibitors may enhance antitumor activity compared with using each agent alone, emphasizing the rationale for this combination therapy and its potential to evolve treatment strategies for non–muscle-invasive bladder cancer (NMIBC) while also considering the implications for patient flow in urology practice and the necessity of a multidisciplinary approach.

Exploring PD-1/PD-L1 Pathways and Innovative Treatments for NMIBC 

What is the role of the PD-1/PD-L1 pathways in cancer immunotherapy?

What agents are being investigated in the BCG-naive and unresponsive setting? Gene therapy, intravesical?

The PD-1/PD-L1 pathways play a crucial role in cancer immunotherapy by modulating immune responses, allowing cancer cells to evade immune detection. These pathways involve the interaction between the PD-1 receptor on T-cells and the PD-L1 ligand on tumor cells, leading to T-cell inactivation. In the BCG-naive and unresponsive settings, various agents are under investigation, including gene therapy and intravesical treatments. These approaches aim to enhance immune response and improve therapeutic outcomes in patients who do not respond to traditional Bacillus Calmette-Guérin (BCG) therapy.

Panelists discuss how the PD-1/PD-L1 pathway plays a crucial role in cancer immunotherapy, outlining its mechanisms of action and highlighting the agents currently being investigated for patients who are BCG-naive or unresponsive, including gene therapy and intravesical options.

NMIBC Treatment Insights: Standard of Care, BCG Immune Response, and Patient Outcomes

What are the standard treatment options for non–muscle-invasive bladder cancer (NMIBC)? 

What are the management options for patients with intermediate and high-risk NMIBC?

Can you explain the mechanism of action of BCG treatment in stimulating the immune response against bladder cancer?

In an ideal treatment paradigm with single-agent BCG, what are the best outcomes for patients with high-risk NMIBC?

What are the rates of recurrence and progression?

What do you feel the rates of progression are in the real world vs what you see in your practice?

Non–muscle-invasive bladder cancer (NMIBC) is primarily managed through transurethral resection of bladder tumor (TURBT) followed by intravesical therapy. Bacillus Calmette-Guérin (BCG) is a standard treatment, especially for intermediate and high-risk patients, due to its ability to stimulate an immune response against cancer cells. The ideal treatment paradigm with BCG aims for reduced recurrence and progression rates. However, real-world progression rates may differ from clinical practice observations, highlighting the need for personalized treatment strategies and ongoing monitoring to optimize patient outcomes.

Panelists discuss how standard treatment options for non–muscle-invasive bladder cancer (NMIBC) include BCG therapy, exploring its mechanism of action in enhancing the immune response while also examining management strategies for intermediate and high-risk patients, optimal outcomes with single-agent BCG, and the discrepancies between observed rates of recurrence and progression in clinical practice and reported data.

Exploring NMIBC: Overview, Symptoms, Risk Factors and Staging  

What is non–muscle-invasive bladder cancer (NMIBC)?

What are the common symptoms and signs of NMIBC?

What diagnostic procedures are typically used to confirm a case of NMIBC?

What is the economic burden of this disease for health care systems and insurance companies?

What are the main risk factors associated with the development of NMIBC? 

Smoking as a risk factor for the development of bladder cancer

No clear genetic association (that we know of so far)

What are the different stages and grades of NMIBC?Grabe-Heyne 2023

What is the importance of getting the stage correct? (PMID 38994181)

Ensuring appropriate treatment based on patient stage

How often do you feel that patients are incorrectly staged? How does that then affect the patient treatment journey?

Non–muscle-invasive bladder cancer (NMIBC) is characterized by tumors that have not invaded the muscle layer of the bladder. Common symptoms include hematuria, frequent urination, and dysuria. Diagnostic procedures typically involve cystoscopy, urine cytology, and imaging studies. The economic burden of NMIBC is significant due to frequent surveillance and treatment costs. Major risk factors include smoking and occupational exposures, with no clear genetic associations identified. Accurate staging is crucial for appropriate treatment, as incorrect staging can lead to suboptimal management and impact patient outcomes.

Panelists discuss how non–muscle-invasive bladder cancer (NMIBC) presents with specific symptoms and diagnostic procedures, emphasize the significant economic burden on health care systems, and highlight key risk factors like smoking and occupational exposure while also addressing the critical importance of accurate staging for guiding treatment decisions and the potential consequences of incorrect staging on patient outcomes.

Overall device-related problems and event rates for polyethylene glycol (PEG) hydrogel spacers (SpaceOAR) consistently remained below 1% relative to the estimated device usage in patients with prostate cancer, according to data from a real-world analysis presented during a poster session at the 

2024 American Society for Radiation Oncology Annual Meeting

PEG hydrogel spacers are used to reduce toxicity to the rectum in patients undergoing radiotherapy for prostate cancer.

The results were presented by Michael R. Folkert, MD, PhD, who is the chief of brachytherapy and a professor of radiation oncology at the Fred Hutchinson Cancer Center at the University of Washington School of Medicine in Seattle.

According to the authors, “Previously published analyses of PEG hydrogel spacers using the [FDA’s] Manufacturer and User Facility Device Experience (MAUDE) passive surveillance database have not taken into account the real-world volume of spacers placed as part of standard of care following approval. To contextualize the MAUDE reports for the spacers, we assessed the device-related issues and patient event rates from the database, factoring in a conservative estimate of total spacer units used in the US.”

For the analysis, the investigators assessed a total of 1005 safety reports for PEG hydrogel spacers in the context of an estimated 251,836 units sold from January 2015 to September 2023. This translates to an overall report rate per unit sold of 0.40% (range, 0.00% in 2015 to 0.57% in 2023) during the study period. The highest incidence of medical device reports was in 2022, with a yearly report rate of 0.68% (n = 340).

Among all reports, 743 (0.30% of total units sold) reported device issues were due to an issue with placement/positioning of the device, and 212 (0.08% of total units sold) reported device issues were due to an “adverse event without identified device or use problem.”

Of those related to an issue with placement/positioning of the device, approximately 60% of patient events reported had “no clinical signs, symptoms, or conditions” and “no consequences or impact to patient” (456 reports, 0.18% of total units sold). A total of 158 reports related to placement/positioning of the device were due to pain/discomfort (0.06% of total units sold).

Overall, the most frequently reported patient events included 440 for “no clinical signs, symptoms, or conditions” (0.17% of total units sold) and 278 for “pain/discomfort” (0.11% of total units sold). Other commonly reported events included infection (132 reports, 0.05% of total units sold), fistula (92 reports; 0.03% of total units sold), hemorrhage/blood loss/bleeding (83 reports; 0.03% of total units sold), and urinary dysfunction (77 reports; 0.03% of total units sold).

Based on these data, the authors note that a majority of reported device-related problems and events for PEG hydrogel spacers appear to have little or no reported clinical consequence.

They concluded, “Although still a valuable source of information, given the known limitations of MAUDE, additional real-world evidence may help support making informed decisions involving the incorporation of this technology into prostate cancer treatment to potentially mitigate rectal toxicity in men undergoing radiotherapy for prostate cancer.”

1. Folkert MR, Shin Y, Vannan D, Rojanasarot S. Real-world medical device reports of PEG hydrogel spacers: Analysis of the FDA Manufacturer and User Facility Device Experience (MAUDE) Database. Presented at: American Society for Radiation Oncology Annual Meeting. September 29-October 2, 2024. Washington, DC. Poster 3169. https://www.redjournal.org/article/S0360-3016(24)01935-7/fulltext

Polyethylene glycol (PEG) hydrogel spacers, used to reduce rectal toxicity in prostate cancer radiotherapy, show device-related problems and event rates consistently below 1% in real-world usage. An analysis of 1005 safety reports from 251,836 units sold between 2015 and 2023 revealed a 0.40% report rate. Most issues were related to device placement, with minimal clinical consequences. Common patient events included pain, infection, and urinary dysfunction. Despite limitations of the MAUDE database, further real-world evidence could enhance decision-making for incorporating this technology in treatment.

The overall report rate per unit sold of the PEG hydrogel spacers was 0.40%.

Solaris Health

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