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Study findings have implications for noninvasive markers to predict the course of UCC

Bladder Ca biomarkers and BCG: New knowledge of the urinary microbiome

Dr. De La Cerda provides an overview of a patient case involving a 68 year-old male presenting with severe back pain, with an analysis of the clinical presentation, workup, and medical history.

Bone Predominant mCRPC Patient Case

Video content above is prompted by the following:

What are your initial impressions of the case?

Video Series

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

Ferring Pharmaceuticals has announced the opening of the first clinical trial sites for 2 studies within the ABLE clinical trial program of nadofaragene firadenovec-vncg (Adstiladrin) in non–muscle invasive bladder cancer (NMIBC), the company announced in a news release.

The company also reported the launch of the phase 1/2 LUNAR trial (NCT06668493) to explore the safety, tolerability, and efficacy of nadofaragene instilled to the renal pelvis in patients with low-grade upper tract urothelial cancer (LG-UTUC).

Nadofaragene was approved by the FDA in December 2022 for the treatment of patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ with or without papillary tumors.

“The availability of an innovative locally delivered gene therapy has the potential to be organ sparing for appropriate NMIBC and UTUC patients,” said Joern Jakobsen, MD, PhD, vice president and head of global research and medical for Uro-Oncology and Urology at Ferring Pharmaceuticals, in the news release.

 “The extension of the ADSTILADRIN clinical trial program—with a focus on IR [intermediate risk] NMIBC and LG UTUC where there is a desperate need for new treatments, and generation of mono and combination therapy data, including re-induction, for high-risk BCG-unresponsive NMIBC—is key to understanding how ADSTILADRIN may be able to help even more patients.”

The first study opening enrollment within the ABLE platform includes the phase 2 ABLE-22 trial (NCT06545955), which is exploring nadofaragene as a monotherapy or in combination with chemotherapy (gemcitabine and docetaxel) or an immune checkpoint inhibitor (pembrolizumab [Keytruda]) in patients with high-risk BCG-unresponsive NMIBC. In total, the trial plans to enroll 150 patients across sites in the US.

The primary end point is the complete response rate, assessed for up to 12 months. Secondary end points include the durability of complete response, cystectomy-free survival, overall survival, and the incidence of adverse events. Primary completion of the study is anticipated for July 2026.

Additionally, the first clinical trial sites were activated in the phase 3B ABLE-32 trial (NCT06510374), which is evaluating the safety and efficacy of nadofaragene vs observation in patients with IR NMIBC. The randomized controlled study will enroll approximately 454 patients across study sites in the US.

The primary outcome measure is recurrence-free survival at 24 months. The frequency of adverse events is a secondary end point. Primary completion of the trial is expected for August 2028.

Ferring has also initiated the phase 1/2 LUNAR trial (NCT06668493), which is seeking to enroll 20 adult patients with LG-UTUC.

 The study will begin with a safety lead-in period, instilling only the first 6 patients in the study. All patients will receive instillations of nadofaragene into the renal pelvis.

The primary outcome measures include the number of treatment-emergent adverse events as well as the complete response rate at 3- and 6-month time points. Completion of the study is anticipated for November 2029.

In addition to these 3 studies, nadofaragene is also being assessed in the ongoing ABLE-41 trial (NCT06026332), a real-world evidence study to assess the early utilization, experiences, and outcomes of the agent in the routine care setting. Patients are eligible for inclusion in the observational study if they have NMIBC and have not previously received nadofaragene in a clinical trial.

The first patient was enrolled in the study in September 2023. The target enrollment is approximately 400 patients. Final completion of the trial is anticipated for December 2025.

1. Ferring advances three studies in ADSTILADRIN (nadofaragene firadenovec-vncg) clinical trial program. News release. Ferring Pharmaceuticals. December 3, 2024. Accessed December 3, 2024. https://www.businesswire.com/news/home/20241203511070/en/Ferring-Advances-Three-Studies-in-ADSTILADRIN%C2%AE-nadofaragene-firadenovec-vncg-Clinical-Trial-Program

2. A trial to evaluate intravesical nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy in participants with high-grade BCG unresponsive non-muscle invasive bladder cancer (ABLE-22). ClinicalTrials.gov. Updated November 14, 2024. Accessed December 3, 2024. https://www.clinicaltrials.gov/study/NCT06545955

3. Trial of nadofaragene firadenovec vs observation in participants with intermediate risk non-muscle invasive bladder cancer (ABLE-32). ClinicalTrials.gov. Updated November 26, 2024. Accessed December 3, 2024. https://www.clinicaltrials.gov/study/NCT06510374

4. Low-grade UTUC treated with nadofaragene firadenovec administered to renal pelvis (LUNAR). ClinicalTrials.gov. Updated October 31, 2024. Accessed December 3, 2024. https://www.clinicaltrials.gov/study/NCT06668493

5. ADSTILADRIN early utilization and outcomes in the real world setting (ABLE-41). ClinicalTrials.gov. Updated November 13, 2024. Accessed December 3, 2024. https://clinicaltrials.gov/study/NCT06026332

Ferring Pharmaceuticals has initiated clinical trials for nadofaragene firadenovec-vncg (Adstiladrin) in non–muscle invasive bladder cancer (NMIBC) and low-grade upper tract urothelial cancer (LG-UTUC). The ABLE-22 trial explores nadofaragene as monotherapy or combined with chemotherapy or immunotherapy in high-risk BCG-unresponsive NMIBC. The ABLE-32 trial compares nadofaragene to observation in intermediate-risk NMIBC. The LUNAR trial assesses safety and efficacy in LG-UTUC. Additionally, the ABLE-41 trial evaluates real-world outcomes. These studies aim to expand treatment options and improve patient outcomes.

Ferring has announced the opening of the first clinical trial sites for 2 studies within the ABLE clinical trial program as well as the launch of the phase 1/2 LUNAR trial. 

Trials launch of nadofaragene firadenovec in bladder cancer

Nogapendekin alfa inbakicept-pmln (Anktiva; N-803) plus BCG demonstrated a high rate of complete response in patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), according to updated data from the ongoing QUILT 3.023 trial (NCT03022825).

The preliminary findings, shared in a news release by ImmunityBio, encompass the first 100 patients enrolled and treated in the phase 2/3 study. At the time of data cutoff (November 2024), 71% of patients achieved a complete response following treatment. Among the responders, the duration of response ranged as long as 54 months.

According to ImmunityBio, “This data update will be submitted to the European Medicines Agency (EMA) in a Marketing Authorization Application (MAA) for ANKTIVA in the European Union (EU), which is anticipated during Q4 2024.”

The agent was approved by the FDA in April 2024.

“We are encouraged by the consistent complete response rates observed in our expanded patient cohort,” said Patrick Soon-Shiong, MD, executive chairman and global chief scientific and medical officer of ImmunityBio, in the news release.

 “These results highlight the potential of ANKTIVA to transform the treatment landscape for patients with BCG-unresponsive NMIBC CIS, offering hope for improved outcomes and cystectomy avoidance, especially with the prolonged duration of response now ranging as much as 54 months in this 100-patient analysis. Duration of complete response is the key efficacy element in driving cystectomy avoidance in this BCG-unresponsive population. I am pleased that this updated ANKTIVA data confirms that one of the highest durable responses is achieved when compared to other approved products in this indication.”

Overall, the phase 2/3, open-label, multicenter study is assessing the use of Anktiva across 3 patient cohorts. Cohorts A and C in the trial include patients with BCG-unresponsive bladder CIS with or without Ta/T1 papillary tumors who received Anktiva plus BCG (cohort A; n = 84) or Anktiva alone (cohort C; n = 10). The trial also enrolled patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC who received Anktiva plus BCG in cohort B (n = 77).

Findings from cohort A of the study were the basis of the approval for the agent earlier this year.

The primary end point for the trial is the incidence of complete response at 3 and 6-month timepoints for cohorts A and C, and disease-free survival at 12 months for cohort B. Secondary end points for cohort A are durability, cystectomy avoidance, progression-free survival, disease-specific survival, and overall survival.

Previous data on the QUILT-3.032 trial were published in 

In cohort A, 71% (95% CI, 59.6% – 80.3%) of patients achieved a CR with a median follow-up of 23.9 months. The median duration of CR was 26.6 months (95 CI, 9.9 months – not reached). Among those with a CR at 24 months, the probability of avoiding a cystectomy was 89.2%, and the probability of disease-specific survival was 100%, per Kaplan-Meier estimates.

In cohort B (n = 72), the disease-free survival (DFS) rate was 55.4% (95% CI, 42% - 66.8%) at 12 months, with a median DFS of 19.3 months (95% CI, 7.4 months – not reached). At the time of the FDA approval, the complete response rate was 62% to 73% among the 77 evaluable patients included in the analysis. The duration of complete response was longer than 47 months at the time of data cutoff, which exceeded the threshold for meaningful clinical results per a panel of experts at the International Bladder Cancer Group. Among patients with a complete response, 58% demonstrated a duration of response (DOR) of 12 months or longer, and 40% demonstrated a DOR of 24 months or longer.

In cohort C, data from the published study in 2022 showed that 20% of patients achieved a complete response at 3-month follow-up. Only 1 patient maintained a CR at 6 months. Six patients underwent reinduction. The median follow-up for all patients was 7.9 months at the time of data cutoff.

Regarding safety, 86% of treatment-emergent adverse events (TEAEs) from the combination therapy were grade 1 to 2, with 3 grade 3 immune-related TEAEs.

The QUILT 3.023 study remains ongoing to assess the durability of response and overall survival. Final study completion is expected in October 2028.

1. ImmunityBio completes ANKTIVA’s post-approval enrollment of the 100th patient in BCG unresponsive NMIBC CIS trial and reports a complete response rate of 71% with a durable duration of response ranging up to 54 months. News release. ImmunityBio. Published online and accessed November 19, 2024. https://www.businesswire.com/news/home/20241119975432/en/ImmunityBio-Completes-ANKTIVA%E2%80%99s-Post-Approval-Enrollment-of-the-100th-Patient-in-BCG-Unresponsive-NMIBC-CIS-Trial-and-Reports-a-Complete-Response-Rate-of-71-with-a-Durable-Duration-of-Response-Ranging-Up-to-54-Months

2. QUILT-3.032: A multicenter clinical trial of intravesical bacillus calmette-guerin (BCG) in combination with ALT-803 (N-803) in patients with BCG unresponsive high grade non-muscle invasive bladder cancer. ClinicalTrials.gov. Last updated April 8, 2024. Accessed November 19, 2024. https://clinicaltrials.gov/study/NCT03022825

3. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 superagonist NAI in BCG-unresponsive non-muscle-invasive bladder cancer. 

. 2023;2(1):EVIDoa2200167. doi:10.1056/EVIDoa2200167

Nogapendekin alfa inbakicept-pmln (Anktiva; N-803) combined with BCG shows promising results in treating BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). The QUILT 3.023 trial reports a 71% complete response rate among the first 100 patients, with some responses lasting up to 54 months. The trial's findings support the potential of ANKTIVA to improve outcomes and avoid cystectomy. The study, which includes three patient cohorts, continues to evaluate response durability and overall survival, with completion expected in October 2028.

At the time of data cutoff, 71% of patients achieved a complete response following treatment. 

QUILT 3.032 trial: Anktiva achieves high response rate in BCG-unresponsive NMIBC

I have a question about G2211. As a pediatric urologist, am I allowed to report this code for patients who meet the criteria regardless of payer? Our practice has encouraged it to be used for adult urology patients who have Medicare but not in pediatric urology patients because they are not of Medicare age, and they believe this is a Medicare-specific code.

We had addressed the definition and use of the Healthcare Common Procedure Coding System (HCPCS) code G2211 in previous 

 articles, including that of May 1, 2024.

 As a quick reminder, the HCPCS G2211 add-on code descriptor is the following:

“Visit complexity inherent to evaluation and management associated with medical care services that serve as the continuing focal point for all needed health care services and/or with medical care services that are part of ongoing care related to a patient’s single, serious condition or a complex condition. (Add-on code, list separately in addition to office/outpatient evaluation and management visit, new or established)”

HCPCS codes can be used and accepted by any insurer. The insurer’s payment policies will determine whether it gets reimbursed. From our standpoint, it is reasonable to add this HCPCS code to any patient who meets the appropriate criteria, notwithstanding their insurance coverage. If a practice has determined in writing that there are insurers whose policies advised that they will not accept this code, it seems reasonable not to report that code to that insurer even when criteria are met.

1. Rubenstein J, Painter M. Medicare’s G2211 and thoughts on how to best use it in urology. 

May 1, 2024. Accessed December 16, 2024. https://www.urologytimes.com/view/medicare-s-g2211-and-thoughts-on-how-to-best-use-it-in-urology

Send coding and reimbursement questions to Jonathan Rubenstein, MD, and Mark Painter c/o

The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules.

"If a practice has determined in writing that there are insurers whose policies advised that they will not accept this code, it seems reasonable not to report that code to that insurer even when criteria are met," write Jonathan Rubenstein, MD, and Mark Painter.

Petar Bajic, MD

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