At the American Urological Association (AUA) 2022 meeting in New Orleans, the Friday plenary session highlighted 3 key late-breaking abstracts that warrant awareness by all practicing clinicians treating patients with urologic malignancy.
The first abstract, entitled “IL-15RαFc superagonist N-803 with BCG in BCG unresponsive non-muscle invasive bladder cancer (nMIBC) CIS and papillary cohorts,”1 was presented by Karim Chamie, MD, associate professor of urology at UCLA. Dr. Chamie explained that the current standard of care for high-risk patients with nMIBC is bacillus Calmette-Guérin (BCG), due to its ability to induce trained immunity of T cells and natural killer (NK) cells. Anktiva (N-803 compound; ImmunityBio) is a superagonist complex2 composed of an interleulin-15 (IL-15)-like peptide and a fusion protein, allowing for stimulation of activation of T cells and NK cells. Dr. Chamie explained that the concept explored in the QUILT 3032 trial was to identify if addition of N-803 to BCG in patients with BCG-unresponsive disease would result in improved results.
The trial enrolled patients with histologically confirmed disease recurrence after BCG therapy and stratified patients into carcinoma in situ (CIS) and papillary cohorts. According to Dr. Chamie, BCG unresponsive disease was defined as persistent or recurrent CIS with or without Ta/T1 disease within 12 months of BCG therapy. The patients enrolled in the trial received BCG 50 mg plus N-803 compound intravesically instilled weekly for 6 weeks. The investigators sought to identify several parameters, including safety of the compound as well as a primary endpoint of complete response (CR) and secondary endpoints of duration of complete response, time to cystectomy, and cystectomy avoidance.
Dr. Chamie explained that the mean age of all patients was approximately 72 years of age, with the majority (>70%) of patients being male and with good performance status. In reviewing the safety outcomes, Dr. Chamie explained that overall, N-803 was very well tolerated, with only 1% of the patient population experiencing treatment-related adverse events (AEs). The majority of AEs were low-grade issues such as dysuria, and no patients were found to have elevated systemic IL-15 levels, noted Dr. Chamie.
The clinical results of the trial were promising. For cohort A (patients with CIS), Dr. Chamie explained that 71% of patients experienced a CR, with a median CR duration of 24.1 months. Furthermore, patients who experienced therapeutic response had a lower cystectomy rate than those who did not (7% vs 15%). Most patients experienced progression-free survival (PFS) of 91% at 24 months. Even more impressively, Dr. Chamie presented a forest plot demonstrating that the improvement in response was sustained throughout all subgroup analyses (ie, age, race, gender).
For cohort B (patients with papillary recurrence), Dr. Chamie explained that investigators focused on disease-free survival (DFS) because these patients mostly had transurethral resections for definitive therapy. A median DFS was 23.6 months, with a DFS rate of 57% at 12 months and 48% at 24 months. Most patients (73 of 77) were spared radical cystectomy. Dr. Chamie concluded by reiterating that the outcomes of this trial were favorable, with 100% and 98% rates overall survival at 2 years for both the CIS and papillary cohorts, respectively.
SPOTLIGHT Study Phase 3
The second abstract highlighted was “Impact of 18F-rhPSMA-7.3 PET on upstaging of patients with prostate cancer recurrence: results from the prospective, phase 3 multicenter SPOTLIGHT study,”3 which was presented by Mark Fleming, MD, of Virginia Oncology Associates.
Dr. Fleming began by explaining the molecular advantages of 18F-rhPSMA-7.3, a fluorine-18 (18F)- based high-affinity prostate-specific membrane antigen (PSMA)-targeted PET pharmaceutical. He specifically cited 2 features: low bladder activity and improved spatial resolution of positron emission tomography (PET) images compared with gallium-68 (68Ga) PSMA scans.4 Dr. Fleming also cited production advantages of 18F as well as the ability to produce it in larger quantities, with a longer half-life for clinical use than its comparators. Additionally, he remarked that the compound also can be bound to α- or ß-emitted radiopharmaceuticals for theranostics therapy.
The SPOTLIGHT study (NCT04186845)5 sought to investigate the utility of 18F-rhPSMA-7.3 diagnostic scans in patients who had received prior localized therapy for prostate cancer (ie, prostatectomy or radiation) and subsequently experienced rising PSA levels that were considered suspicious for biochemical recurrence (BCR). All patients enrolled in the study had negative results on conventional imaging. Dr. Fleming explained that the scans were obtained approximately 50 to 70 minutes after injection of the radiotracer, and all images were evaluated by 3 radiologists. The findings on diagnostic PET scan were confirmed by biopsy or by confirmation on conventional imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI). The investigators sought to identify patients with true- positive disease recurrence that led to upstaging in patients who had negative baseline findings on conventional imaging.
In reviewing the results, Dr. Fleming explained that ultimately, 389 patients underwent 18F-rhPSMA-7.3 PET/CT imaging. The mean age of the population was 68.4 years, and the median BCR suspicion PSA was 1.27. The majority of the cohort comprised patients with Gleason grade group 3 disease. Of these patients, 366 had enough data for the exploratory analysis, with Dr. Fleming reporting a corrected detection rate of 57% for patients receiving this scan. A total of 68% of the patients in the analysis had negative baseline conventional imaging results before therapy. Subsequent imaging with 18F-rhPSMA-7.3 PET/CT at the time of concern for BCR resulted in a corrected detection rate ranging from 45% to 47%, suggesting that despite negative conventional imaging, these patients were upstaged to locally advanced or metastatic disease based on the findings of the PET/ CT scan. The results of the exploratory analysis were substratified by anatomic region by Dr. Fleming. In the prostate bed, detection rates were markedly higher for those patients who had undergone radiotherapy (39%- 41%) compared with prostatectomy (3.5%-8%); however, this difference was diminished in the pelvic lymph node region (18%-21% vs 6.5%) and extrapelvic regions (21%- 26% vs 20%-30%).
In concluding remarks, Dr. Fleming summarized that the rhPSMA scan often detected upstaging of prostate cancer stage, especially after negative findings on conventional imaging. This effect was markedly notable in patients who had undergone radiotherapy compared with prostatectomy. According to Dr. Fleming, before therapy for BCR, the utility of the 18F-rhPSMA-7.3 scan may allow clinicians to localize areas of disease and help guide treatment decisions.
A Novel Gene Therapy for Incontinence
The third abstract highlighted was “Efficacy and safety of a novel gene therapy (URO-902; pVAX/hSlo) in female patients with overactive bladder and urge urinary incontinence: results from a phase 2a trial”6 presented by Kenneth M. Peters, MD, of Oakland University William Beaumont School of Medicine.
Dr. Peters briefly explained the mechanism of URO-902, a novel gene therapy that, when injected into the detrusor muscle, is posed to reduce bladder hypercontractility by increasing potassium channel expression. The results of an interim analysis of an ongoing multicenter randomized controlled trial evaluating the efficacy of URO-902 were reviewed. Dr. Peters explained that the trial sought to enroll women patients between 40 and 79 years of age with overactive bladder (OAB) and urge urinary incontinence (UUI) refractory to oral medications. Patients enrolled in this trial were randomized to URO-902 instillation of 24 mg or 48 mg, or placebo.
The mean age of patients enrolled was 64.7 years. Most patients had >3 urge urinary incontinence episodes per day and had received prior onabotulinum toxin injection. Although not final, the exploratory analysis of this trial demonstrated several promising markers for URO-902 as a treatment option for patients with OAB and UUI. Dr. Peters remarked that patients receiving treatment with URO-902, regardless of dose, had a statistically significant decrease in OAB-q symptom bother score. The safety profile of the URO-902 therapy was also very favorable, with no patients experiencing AEs leading to discontinuation. Although this was a preliminary exploratory analysis of this medication, the early results of this trial demonstrate that URO-902 may be an emerging effective therapy for patients with refractory OAB.
- Chang S, Chamie K, Hidalgo H, et al. Final clinical results of pivotal trial of IL-15RΑFC superagonist N-803 with BCG IN BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) CIS and papillary cohorts. J Urol. 2022;207(suppl 5 (2022):e1047. Abstract PLLBA-01. doi: 10.1097/JU.0000000000002671.01
- ImmunityBio submits biologics license application for N-803 plus BCG for patients with BCG-unresponsive non-muscle invasive bladder cancer carcinoma in situ [news release] Immunity Bio website. https://immunitybio.com/immunitybio-submits-biologics-license-application-for-n-803-plus-bcg-for-patients-with-bcg-unresponsive-non-muscle-invasive-bladder-cancer-carcinoma-in-situ/. Accessed June 23, 2022.
- Fleming M. Impact of 18F-RHPSMA-7.3 PET on upstaging of patients with prostate cancer recurrence: results from the prospective, phase 3, multicenter, SPOTLIGHT study. J Urol. 2022;207(suppl 5): e1047. Abstract PLLBA-02. doi: 10.1097/JU.0000000000002671.02
- Wurzer A, Di Carlo D, Schmidt A, et al. Radiohybrid ligands: a novel tracer concept exemplified by 18F- or 68Ga-labeled rhPSMA inhibitors. J Nucl Med. 2020;61(5):735-742. doi: 10.2967/jnumed.119.234922
- ClinicalTrials.gov. Imaging Study to Investigate Safety and Diagnostic Performance of rhPSMA 7.3 (18F) PET Ligand in Suspected Prostate Cancer Recurrence (SPOTLIGHT). https://clinicaltrials.gov/ct2/show/NCT04186845. Accessed June 22, 2022. NCT identifier ClinicalTrials.gov Identifier: NCT04186845.
- Peters K, Enemchukwu E, Kalota S, et al. Efficacy and safety of a novel gene therapy (URO-902; pVAX/hSlo) in female patients with overactive bladder and urge urinary incontinence: results from a phase 2A trial. J Urol. 2022;207(suppl 5): e1048. Abstract PLLBA-03. doi: 10.1097/JU.0000000000002671.03