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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.

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

Exploring NMIBC: Overview, Symptoms, Risk Factors and Staging  

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

Treatment with pazopanib (Votrient) alternated with treatment with bevacizumab (Avastin) demonstrated promising initial efficacy and safety in patients with treatment-naïve metastatic clear cell renal cell carcinoma (ccRCC), according to data from a phase 2 study (NCT01684397) presented at the 

2024 European Society for Medical Oncology Congress

For the trial, patients received the recommended phase 2 dose of pazopanib 800 mg daily on days 1 through 28 plus bevacizumab 10 mg/kg on days 36 and 50 of a 10-week cycle.

According to the authors, “The study was designed to detect a CBR [clinical benefit rate] of 60% vs 45% at alpha = 0.10 and power = 0.80 using a 2-stage design with n = 26+25 (51) pts.” With these criteria, a 45% 12-month CBR—defined as complete response, partial response, and stable disease—translated to a median progression-free survival (PFS) of 11.1 months. A 60% CBR translated to a median PFS of 15.7 months.

The primary end point was the 12-month CBR. Secondary end points included the objective response rate (ORR), overall survival (OS), and safety.

Overall, the authors stated that “the final efficacy rule of ≥28/51 pts having a CBR response at 12 months was met (40/51 = 0.78).”

Additionally, at a median follow-up of 33.1 months, the median PFS was 22.1 months (95% CI, 15.9-27.4). According to a news release on the findings, this PFS was more than double that seen with pazopanib alone. The news release noted, “In clinical trials that supported FDA approval of pazopanib for advanced RCC, the median PFS was 11.1 months.”

Additional findings showed an ORR of 54.9% and a stable disease rate of 43.1%, translating to a CBR of 98%. Progressive disease occurred in 2% (n = 1) of patients. The median OS was 62.9 months (95% CI, 46-NR).

Regarding safety, the regimen was generally well-tolerated. The most common adverse events (AEs) of any grade were diarrhea (70%), hypertension (54%), fatigue (69%), and nausea (51%). The most common grade 3 or 4 AEs included hypertension (33%), ALT elevation (14%), and AST elevation (12%). Among all patients, 6 came off the trial for reasons related to study drug toxicities and 6 came off the trial for other reasons or for unrelated medical conditions. At the time of data report, 5 patients remained on trial.

In total, the multicenter trial enrolled 51 patients with previously untreated metastatic ccRCC across 5 clinical trial sites in the United States. The median age of participants was 65.6 years, and 70.6% of patients in the trial were male.

The study enrolled more patients in the IMDC favorable risk category (31 of 45 patients) due to FDA approval of immunotherapy regimens.

Presenting author Saby George, MD, FACP, professor of oncology and medicine and the Director of Network Clinical Trials at Roswell Park Cancer Center, explained in the news release, “Because immunotherapy options were available to patients in other risk groups, the phase 2 group included more patients in the favorable risk category. The encouraging results suggest that alternating pazopanib with bevacizumab is a promising treatment regimen for renal cell carcinoma patients in the favorable risk group.”

Final completion of the study is anticipated for January 2025.

1. Vaishampayan UN, Hutson A, Groman A, et al. A phase I/ II trial of pazopanib (Paz) alternating (alt) with bevacizumab (Bev) in treatment-naïve metastatic clear cell renal cell carcinoma (mccRCC) patients (pts): Phase II results. Presented at: 2024 European Society for Medical Oncology Congress. September 13-17, 2024. Barcelona, Spain. Abstract 1696P. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/1696P.html.pdf

2. Roswell Park-designed treatment regimen doubles progression-free survival in metastatic kidney cancer. News release. Roswell Park Comprehensive Cancer Center. September 15, 2024. Accessed September 25, 2024. https://www.newswise.com/articles/roswell-park-designed-treatment-regimen-doubles-progression-free-survival-in-metastatic-kidney-cancer

3. Pazopanib hydrochloride and bevacizumab in treating patients with previously untreated metastatic kidney cancer. ClinicalTrials.gov. Last updated January 31, 2024. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT01684397

"The encouraging results suggest that alternating pazopanib with bevacizumab is a promising treatment regimen for renal cell carcinoma patients in the favorable risk group," says Saby George, MD, FACP. 

Pazopanib plus bevacizumab shows promising phase 2 efficacy in ccRCC

, discusses the study, “High resolution molecular imaging to elucidate the contextual mechanisms of BCG resistance in non-muscle invasive recurrent bladder cancer,” which he presented at the 2024 Bladder Cancer Advocacy Network (BCAN) Think Tank in San Diego, California. According to a news release from BCAN, the study utilized both “spatial transcriptomics and imaging mass cytometry in patient tumor samples before and after treatment with BCG to better understand BCG resistance.”

 By doing this, investigators could assess the gene and protein activity in each sample to better understand mechanisms of BCG resistance.

Findings from this study have led to the launch of the phase 2 ENHANCE trial (NCT06503614), which will assess the combination of durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed carcinoma in situ non–muscle-invasive bladder cancer (NMIBC).

Sfakianos is an associate professor of urology and urologic oncology at the Icahn School of Medicine at Mount Sinai in New York, New York.

This transcription has been edited for clarity.

Could you describe the background/rationale for conducting this research?

We've used BCG inside the bladder as the primary treatment for non-muscle invasive bladder cancer for over 30 years now. We really have yet to understand the underlying mechanism of how BCG works. But more importantly, we've not really understood how patients or the tumors themselves become resistant to BCG. So, the idea here was to use novel technologies to get a better understanding of what is happening in the tumor microenvironment to help gauge better treatments and therapies for tumors that have failed BCG therapy.

There are quite a few very interesting findings, both from the standpoint of the tumor and from the standpoint of the immune cells. We've focused mostly on the immune cells because that's what the lab is interested in. What we see from the immune cell standpoint specifically is that there are pockets of immune cells that are expressing immune checkpoints that are very well known to us, like PD-1. But there is also an up-regulation of a specific immune checkpoint called NKG2A, which are more specific to NK cells, but is also present on some T cells. That pathway to us is of interest because this is a pathway that can be targeted.

What future work is planned based on this study?

Interestingly, the findings from this study have already translated into an investigator-initiated clinical trial. The study is called the ENHANCE trial (NCT06503614), and it is IRB approved. ENHANCE is a phase 2 single arm clinical trial combining monalizumab and durvalumab in patients with BCG exposed and unresponsive NMIBC. So, we're combining an NKG2A inhibitor and a PD-1 inhibitor.

This is going to be a multi-institutional trial that is also being funded by BCAN and the BCAN Clinical Trial Award that we received last year for this study. The study will include both patients with carcinoma in situ that's resistant to BCG as well as papillary tumors themselves that are resistant to BCG. We're hoping to start enrolling patients in October.

What are the potential implications of this work?

The potential implications clinically would be to identify a novel treatment combination to treat patients with BCG unresponsive non-muscle invasive bladder cancer. Implications from the research perspective are important because this is a true translational project that has gone from the bench to bedside.

1. Bladder Cancer Advocacy Network announces $600,000 in funding to accelerate bladder cancer research. News release. Bladder Cancer Advocacy Network. July 11, 2022. Accessed September 22, 2024. https://bcan.org/bladder-cancer-advocacy-network-announces-600000-in-funding-to-accelerate-bladder-cancer-research/

"Interestingly, the findings from this study have already translated into an investigator-initiated clinical trial," says John P. Sfakianos, MD.

Imaging study offers insights on mechanism behind BCG resistance in NMIBC

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