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An expert panel discusses the case of a 65-year-old Caucasian male who is noted to have an incidental 3-cm right renal mass, enhancing on a contrasted CT scan as part of a routine follow-up for his metastatic castration-resistant prostate cancer, diagnosed in 2017 and currently undergoing therapy.

Case review: An incidentally discovered renal mass

Determining grade of disease is important, as nephron-sparing approaches may be feasible.

Upper tract transitional cell carcinoma: Diagnostic and therapeutic considerations

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

The Evolving Role of Radium-223 in mCRPC and the Impact of Combination Therapies

Video Content above is prompted by the following:

What are the challenges, historically, that the PEACE III study addresses?

Discuss reasons for the relatively poor uptake of radium-223 (Xofigo) in the clinic.

Radium alone doesn’t control prostate-specific androgen (PSA), nor does docetaxel. PSA control is addressed by androgen receptor inhibitor (ARI).

Layered radium-223 and enzalutamide plus ARI will control PSA, so radium-223 can be administered without being questioned or second-guessed.

Similar to the ARASENS trial, maintain relationship and management and share care with med oncology for docetaxel.

Discuss the rationale for combining radium-223 with androgen receptor–targeted therapy (enzalutamide). (Sartor et al [2018]; Shore et al [2020])

Allows for 2 distinct mechanisms of action.

The PEACE III study addresses historical challenges in prostate cancer treatment by exploring the combination of radium-223 with androgen receptor-targeted therapies like enzalutamide. This approach aims to improve PSA control, which radium-223 and docetaxel alone do not achieve. The study seeks to enhance the clinical uptake of radium-223 by demonstrating its efficacy when combined with androgen receptor inhibitors. This combination leverages two distinct mechanisms of action, potentially improving patient outcomes. Collaboration with medical oncology for docetaxel management is emphasized, similar to the ARASENS trial.

Panelists discuss how combining radium-223 with androgen receptor–targeted therapy like enzalutamide addresses historical challenges in treating metastatic castration-resistant prostate cancer, including poor radium-223 uptake, prostate-specific androgen–level control issues, and the need for multimodal treatment approaches.

Investigator Perspectives

Video Series

Advancing Prostate Cancer Treatment With Lutetium 617 and PSMA PET Imaging

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Neal Shore, MD, FACS, discusses the evolving use of follow-up PSMA PET scans and the recent FORE trial, which showed that Lutetium-177 improves radiographic progression-free survival and PSA levels in prechemotherapy patients with mCRPC, with more data on overall survival and quality of life expected.

An expanded access program (EAP) for cretostimogene grenadenorepvec has been initiated for adult patients in the US with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) who meet certain program eligibility criteria, CG Oncology, the developer of the therapy, announced in a news release.

EAPs grant availability to investigational therapeutics for patients outside of clinical trials for whom there is no comparable or satisfactory alternative options. According to the company, the first patient has been dosed with cretostimogene through the open-label EAP, and enrollment for the program is currently ongoing (NCT06443944).

“Bladder cancer is a highly recurrent disease with few treatment options available to patients,” said Ambaw Bellete, president and chief operating officer of CG Oncology, in the news release.

 “This program reflects our commitment to patients afflicted with NMIBC and our desire to ensure that they have efficient access to cretostimogene, our novel oncolytic immunotherapy candidate.”

Patients included in the EAP will first receive an induction course of cretostimogene. If there is no disease recurrence present at week 13, patients will then receive 3 weekly treatments up to week 15. If there is disease present at week 13, patients may undergo a second induction course. If no further disease is present after, patients will then receive 3 weekly treatment cycles every 12 weeks through month 12, and then 3 weekly treatment cycles every 6 months to month 24 or until treatment discontinuation.

Cretostimogene grenadenorepvec is an intravesical oncolytic immunotherapy currently under investigation in phase 3 trials. BOND-003 (NCT04452591) is a phase 3 trial exploring the therapy in patients with BCG-unresponsive NMIBC. PIVOT-006 (NCT06111235) is a phase 3 study evaluating the therapy in patients with intermediate-risk NMIBC following TURBT. Cretostimogene is also being assessed in combination with nivolumab in an investigator-initiated trial for patients with muscle-invasive bladder cancer.

Phase 3 data from the BOND-003 trial of cretostimogene grenadenorepvec in patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS) were recently presented at the 

2024 American Urological Association Annual Meeting

Overall, the study showed that the novel oncolytic immunotherapy induced complete responses (CRs) in three-fourths of patients with BCG-unresponsive NMIBC with CIS.

Looking at the efficacy analysis, the overall CR rate at any time point for all patients was 75.2% (95% CI, 65%-83%), according to Mark D. Tyson, II, MD, MPH, who presented the data at the meeting.

Cretostimogene also demonstrated durable responses over time as 53.8% of patients who underwent repeat induction converted to CR. Additionally, a duration of response (DOR) of 6 months or longer was maintained in 52 patients, a DOR of 12 months or longer in 29 patients, and a DOR of 21 months or longer in 14 patients. Currently, 8, 22, and 36 complete responders are still pending for those time points, respectively.

Additional data showed a cystectomy-free survival (CFS) of 92.4% at the 1-year time point. None of the patients with a CR had undergone a radical cystectomy, and there was no nodal or metastatic progression observed. Further, the progression-free survival (PFS) at 12 months was 96.7%.

Regarding safety, cretostimogene has been generally well-tolerated with no grade 3 or greater treatment-related adverse events (TRAEs) and no deaths reported. Most AEs were grade 1 or 2. TRAEs occurred in 70 patients (62.5%) with the most common (greater than 10%) being bladder spasm (23.2%), pollakiuria (19.6%), dysuria (15.2%), micturition urgency (15.2%), and hematuria (14.2%).

In total, 2 (1.8%) grade 2 serious AEs––cystitis and clot retention––were observed, and 1 patient discontinued the trial due to an unrelated AE. Moreover, 94.5% of patients completed all expected treatments.

Overall, BOND-003 is an open-label, single-arm, phase 3 trial that enrolled 112 patients with BCG-unresponsive, high-risk NMIBC across sites in North America and the Asia-Pacific region. Those eligible for enrollment were patients aged 18 years and older with pathologically confirmed high-risk NMIBC with CIS +/- Ta/T1 disease that is unresponsive to BCG treatment. Patients were also required to have an ECOG performance status of 0 to 2.

The primary end point being evaluated in the trial is the rate of CRs reached at any time. Investigators are also evaluating the secondary end points of CR rate at 12 months, DOR, PFS, CFS, and safety.

These data led the FDA to grant both fast track and breakthrough designations to cretostimogene grenadenorepvec for the treatment of BCG-unresponsive NMIBC in December 2023.

 CG Oncology and the FDA are continuing to work together to advance cretostimogene grenadenorepvec as a potential backbone therapy in bladder cancer.

1. CG Oncology initiates expanded access program for cretostimogene grenadenorepvec. News release. CG Oncology Inc. Published online and accessed June 18, 2024. https://ir.cgoncology.com/news-releases/news-release-details/cg-oncology-initiates-expanded-access-program-cretostimogene

2. An expanded access program of cretostimogene grenadenorepvec for treatment of NMIBC for patients unresponsive to BCG. ClinicalTrials.gov. Last updated June 5, 2024. https://www.clinicaltrials.gov/study/NCT06443944

3. Tyson M, Uchio E, Nam J, et al. Pivotal results from BOND-003:A phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for the treatment of high risk, BCG-unresponsive non-muscle invasive bladder cancer. Presented at: 2024 American Urological Association Meeting; May 3-May 6, 2022; San Antonio, TX.

4. Study of CG0070 given in patients with non-muscle invasive bladder cancer, unresponsive to Bacillus Calmette-Guerin (BOND-003). ClinicalTrials.gov. Updated May 12, 2023. Accessed May 3, 2024. https://www.clinicaltrials.gov/study/NCT04452591

5. CG Oncology receives both FDA fast track and breakthrough therapy designation for cretostimogene grenadenorepvec in high-risk BCG-unresponsive non-muscle invasive bladder cancer. News release. December 5, 2023. Accessed June 18, 2024.https://cgoncology.com/cg-oncology-receives-both-fda-fast-track-and-breakthrough-therapy-designation-for-cretostimogene-grenadenorepvec-in-high-risk-bcg-unresponsive-non-muscle-invasive-bladder-cancer/

An expanded access program (EAP) for cretostimogene grenadenorepvec has been launched for patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) in the US. This investigational oncolytic immunotherapy has shown promising results in phase 3 trials, with a complete response rate of 75.2% in patients with carcinoma in situ. The therapy demonstrated durable responses and high cystectomy-free survival rates. Safety data indicate it is well-tolerated, with mostly mild adverse events. The FDA has granted fast track and breakthrough designations to expedite its development.

Cretostimogene grenadenorepvec is an intravesical oncolytic immunotherapy currently under investigation in phase 3 trials.

Cretostimogene grenadenorepvec made available through expanded access program

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.

Jeremy D. Handel, MD

Articles

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