Mark D. Tyson, II, MD, MPH, is a urologic oncologist at Mayo Clinic.

Mark D. Tyson, II, MD, MPH, discusses challenges choosing between nadofaragene firadenovec, nogapendekin alfa, and pembrolizumab in BCG-unresponsive NMIBC.  

"[Which of these 3 agents to choose] is a tough question. The days for pembrolizumab monotherapy are coming to an end. Pembrolizumab monotherapy was a reasonable option, but now we have 2 intravesical therapies, which have demonstrated just as good or even slightly better efficacy in clinical trials, and certainly better tolerability."

Mark D. Tyson, II, MD, MPH, a urologic oncologist at Mayo Clinic, discusses factors informing the selection between nadofaragene firadenovec-vncg (Adstiladrin), nogapendekin alfa inbakicept-pml (Anktiva), and pembrolizumab (Keytruda) for the treatment of patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC).

According to the National Comprehensive Cancer Center guidelines, nadofaragene firadenovec, nogapendekin alfa, and pembrolizumab are all viable treatment options for patients with NMIBC who are not considered candidates for BCG or cystectomy. However, selecting between these therapies remains a challenge, Tyson begins.

Pembrolizumab monotherapy, which was once a reasonable option for patients unwilling to undergo cystectomy or further intravesical therapy, is becoming less relevant as intravesical therapies gain prominence, he asserts. Both nadofaragene firadenovec and nogapendekin alfa have demonstrated comparable or potentially superior efficacy vs pembrolizumab in clinical trials, with more favorable tolerability profiles due to the absence of systemic immune-related adverse effects, Tyson notes.

The choice between these intravesical agents involves logistical considerations, he continues. Nadofaragene firadenovec is administered once every 90 days as a monotherapy, whereas nogapendekin alfa is given in combination with BCG using the conventional induction and maintenance regimen, Tyson clarifies. If BCG supply is limited, nadofaragene firadenovec may be the preferred option, according to Tyson. Conversely, nogapendekin alfa demonstrated the highest complete response rate at 1 year in an FDA-defined population, which is approximately 2 times higher than that observed with nadofaragene firadenovec, Tyson adds. Although these response rates suggest a potential efficacy advantage with nadofaragene firadenovec over nogapendekin alfa, direct comparative studies have not been conducted, and definitive conclusions regarding superiority cannot yet be made, he states.

Given the absence of head-to-head trials, the decision between these agents ultimately comes down to individual patient preferences, treatment logistics, and institutional considerations, Tyson says. In clinical practice, both therapies are available, allowing for shared decision-making, he details. Some patients may prefer the less frequent dosing schedule of nadofaragene firadenovec, whereas others may be drawn to the response rates observed with nogapendekin alfa, Tyson concludes.

Videos

Mark D. Tyson, II, MD, MPH, discusses challenges choosing between nadofaragene firadenovec, nogapendekin alfa, and pembrolizumab in BCG-unresponsive NMIBC.

Dr Tyson on Factors Influencing the Selection of Nadofaragene Firadenovec in BCG-Unresponsive NMIBC

Mark D. Tyson, II, MD, MPH, discusses findings from the phase 3 BOND-003 trial in BCG-unresponsive non–muscle-invasive bladder cancer with CIS.

Dr Tyson on the Phase 3 BOND-003 Trial in BCG-Unresponsive NMIBC With CIS

Mark D. Tyson, II, MD, MPH, a urologic oncologist at Mayo Clinic, discusses findings from the phase 3 BOND-003 trial (NCT04452591) in patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS).

BOND-003 was an open-label, single-arm study of cretostimogene grenadenorepvec in patients with high-risk BCG-unresponsive NMIBC with CIS. At the April 1, 2024, data cutoff, efficacy-evaluable patients (n = 105) achieved a complete response (CR) rate of 75.2% (95% CI, 65%-83%). Tyson noted that beyond the CR findings, treatment with cretostimogene conferred durable responses; 53.8% of patients who received repeat induction converted to CR. Additionally, 29 patients experienced a duration of response (DOR) of at least 1 year, including 14 patients with a DOR of at least 21 months.

The primary end point of the trial is CR rate at any time. Secondary end points include 12-month CR rate, DOR, progression-free survival, cystectomy-free survival (CFS), and safety.

BOND-003 enrolled a total of 112 patients from North America and the Asia-Pacific region. Eligible patients needed to be at least 18 years old, have pathologically confirmed high-risk NMIBC with carcinoma in situ with or without Ta/T1 disease that is unresponsive to BCG, and have an ECOG performance status of 2 or less.

At baseline, most patients were White (61%), male (74%), and more than 65 years old (83%). The median age was 74 years (range, 43-90) and the median number of previous BCG installations was 12 (range, 7-66).

Regarding safety, no grade or higher 3 treatment-related adverse effects (TRAEs) occurred and there were no deaths. Any-grade TRAEs were reported in 62.5% of patients; the most common TRAEs were bladder spasm (23.2%), pollakiuria (19.6%), dysuria (15.2%), micturition urgency (15.2%), and hematuria (14.2%). Serious adverse effects (AEs) consisted of cystitis (1.8%) and clot retention (1.8%) and 1 patient discontinued treatment due to an AE unrelated to treatment. Nearly all (94.5%) patients completed treatment.

Mark D. Tyson, MD, urologic oncologist, Mayo Clinic, discusses 2 trials that have shaped physicians’ opinions on the use of neoadjuvant chemotherapy in patients with bladder cancer.

A Medical Research Council trial showed the benefit of 3 cycles of cisplatin, methotrexate, and vinblastine in the neoadjuvant setting for patients receiving radiation, surgery, or radiation plus surgery. That trial showed 6% significance 8 years into the trial.

The SWOG 8710 trial was much more compelling. There was a 31-month survival benefit for patients in the surgical subset who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (MVAC). The patients in the T3 subset experienced a 40-month benefit.

Tyson states that there’s most likely a beneficial effect of neoadjuvant chemotherapy. Whether or not physicians should give gemcitabine and cisplatin or dose-dense MVAC, and the correct number of cycles is still up for debate. Toxicity management still remains a challenge, especially in MVAC.

Mark D. Tyson, II, MD, MPH

Articles

Dr Tyson on Factors Influencing the Selection of Nadofaragene Firadenovec in BCG-Unresponsive NMIBC

Dr Tyson on the Phase 3 BOND-003 Trial in BCG-Unresponsive NMIBC With CIS

Dr. Tyson on Rationale For Neoadjuvant Chemotherapy in Bladder Cancer