Jason M. Broderick

The FDA has updated the label for mitomycin-containing reverse thermal gel (Jelmyto) in low-grade upper-tract urothelial cancer (LG-UTUC) by extending the in-use period for pyelocalyceal solution admixture from 8 hours to 96 hours (4 days) following reconstitution of the product, according to UroGen, the developer of the treatment.

“This extension expands access to Jelmyto and gives our customers greater flexibility in choosing when to mix and schedule instillations. It also prepares us for managing future growth based on increased patient volume.” Jeff Bova, chief commercial officer, UroGen, stated in a press release.

“This label change for Jelmyto gives physicians and patients the option to treat in the morning, whereas, in most cases, the afternoon was the only option before the change,” Rian Dickstein, MD, chairman of Urology, University of Maryland Baltimore Washington Medical Center, added in the press release. “Previously, centers with mixing partners had to have Jelmyto mixed and sent by courier in the morning, now this extension provides added convenience of opening up additional scheduling options, which is very important as it enables us to more efficiently manage patient care.”

The FDA approved mitomycin gel for LG-UTUC in April 2020, based on findings from thephase 3 OLYMPUS trial (NCT02793128).

 Long-term data from OLYMPUS presented at the 2021 AUA Annual Meeting showed that mitomycin gelinduced a durable recurrence-free survival benefit in patients with LG-UTUC.

As of March 4, 2021, the median duration of response (DOR) achieved with mitomycin gel induction therapy was 28.1 months (95% CI, 14.6-37.1) in 15 evaluable patients. Eighty percent of patients (n = 12) experienced a durable response, defined as having no evidence of recurrence or not having to undergo radical nephroureterectomy.

Twenty percent of patients (n = 3) did not experience a durable response because of disease recurrence (13%; n = 2). One patient needed to undergo radical nephroureterectomy (7%); however, notably, this was performed because of ureteral stricture rather than disease recurrence.

Patients who experienced recurrence underwent endoscopic ablation. None of the patients with disease recurrence progressed to high-grade disease. At the time of the last follow-up, the disease-specific survival rate was 100%.

The open-label, single-arm, phase 3 OLYMPUS trial enrolled a total of 71 patients with LG-UTUC who had never undergone treatment or who had recurrent low-grade, noninvasive disease with at least 1 measurable papillary tumor.

Study participants received mitomycin gel once a week for the duration of 6 weeks followed by a 4- to 6-week grace period. In this period, patients were assessed for the primary efficacy end point of CR rate at their primary disease evaluation (PDE) visit. If patients experienced a CR to treatment, they went on to receive the gel monthly for up to 11 additional months.

Patients were determined to have a complete response (CR) if ureteroscopy and cytology were entirely normal. If there were any abnormalities, patients underwent a biopsy by which this was determined to be either recurrence or a CR.

A key secondary end point of the trial was durable response at the 12-month follow-up visit, and other end points included durability of response with mitomycin gel at 3, 6, and 9 months following the PDE visit. As part of the long-term follow-up, investigators examined duration of response, disease recurrence, disease progression, and death.

The primary analysis of the trial was done on the intention-to-treat (ITT) population, which comprised patients who were given 1 or more instillation of the gel. Secondary analyses were conducted in patients who achieved a CR at the time of their PDE visit, and long-term follow-up analyses looked at those who had a CR at 12 months following their PDE visit.

Of the 71 patients enrolled to the study (ITT population), 10 discontinued mitomycin gel (9 because of adverse effects [AEs] and 1 because of withdrawn consent), and 19 did not achieve a CR by their PDE visit. A total of 42 patients in the ITT population experienced a CR to treatment at the time of their PDE visit, which translated to a CR rate of 59.2% (95% CI, 46.8%-70.7%). Of these patients, 1 withdrew consent, 10 discontinued treatment, and 8 experienced disease recurrence.

Twenty-three patients maintained their CR at 12 months, translating to a CR rate of 56.1% (95% CI, 39.7%-71.5%). Five of these patients were at sites where follow-up protocol was not yet initiated, 2 did not have data available, and 1 was lost to follow-up. The data presented at the 2021 AUA Annual Meeting were for the remaining 15 evaluable patients.

1. FDA Authorizes an Extension of the In-Use Period for UroGen Pharma’s JELMYTO® Admixture to 96 Hours Following Reconstitution. Published online September 29, 2022. Accessed September 29, 2022. https://bwnews.pr/3UOGbfL

2. FDA approves first therapy for treatment of low-grade upper tract urothelial cancer. News release. FDA. April 15, 2020. Accessed September 13, 2021. https://bit.ly/3liG6jn.

3. Kleinman N, Pierorazio P, Raman JD, et al. Long-term recurrence-free survival following UGN-101 treatment for low-grade upper tract urothelial carcinoma. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-10

Articles

The FDA has updated the label for mitomycin-containing reverse thermal gel (Jelmyto) in low-grade upper-tract urothelial cancer by extending the in-use period for pyelocalyceal solution admixture.

FDA updates label for mitomycin gel in UTUC

The FDA has accepted a new drug application (NDA) for the radiohybrid PSMA-PET imaging agent 

F-rhPSMA-7.3for diagnostic imaging of prostate cancer, according to Blue Earth Diagnostic, the developer of the agent.

The NDA is supported by findings from a phase 1 trial and two phase 3 trials, SPOTLIGHT and LIGHTHOUSE. The SPOTLIGHT data were shared at medical conferences earlier this year; however, the findings from LIGHTHOUSE have not yet been made available.

“Prostate cancer is a leading cause of male cancer-related death worldwide, and accurate localization and staging of the disease is critical in establishing optimal medical management strategies,” Eugene Teoh, MBBS, MRCP, FRCR, DPhil, chief medical officer of Blue Earth Diagnostics, stated in a press release. “We believe that the performance of 

F-rhPSMA-7.3, its high PSMA binding affinity and potential for low bladder activity will make it a valuable diagnostic tool that is radiolabeled with 18F for high image quality and readily available patient access.”

The latest data from the phase 3 SPOTLIGHT trial presented earlier this year at the 2022 AUA Annual Meeting showed that compared with baseline conventional imaging, PET imaging with 

F-rhPSMA-7.3 frequently led to post-scan disease upstaging in men with prostate cancer recurrence.

Among 250 of 366 men in the efficacy analysis population who had negative baseline conventional imaging, 

F-rhPSMA-7.3 showed a correct detection rate between 45% and 47%, which is the percentage of patients scanned with at least one true positive PET finding compared with the Standard of Truth of histopathology or confirmatory conventional imaging. Notably, upstaging results were found to vary based on prior treatment and anatomical region.

Initial data from SPOTLIGHT (NCT04186845) previously presented at the 2022 Genitourinary Cancers Symposium showed that the overall detection rate in patients who had an evaluable 

F-rhPSMA-7.3 scan was 83% by majority read.

SPOTLIGHT enrolled male patients who were at least 18 years of age and received prior curative intent treatment for localized prostate cancer. Patients were required to have elevated PSA that could indicate biochemical recurrence and be eligible for salvage therapy.

F-rhPSMA-7.3 was administered at a dose of 296 MBq/8 mCi, and PET/CT scans were given between 50 and 70 minutes following injection. Scans were then evaluated by 3 blinded central readers. The Standard of Truth was histopathology or confirmatory conventional imaging. Biopsies took place with 60 days following PET scans, and confirmatory imaging was conducted within 90 days.

Of the 420 patients who consented for the trial, 391 received 

F-rhPSMA-7.3, of which 389 underwent an evaluable PET/CT scan. Furthermore, 366 patients had sufficient data to determine Standard of Truth; these patients comprised the efficacy-evaluable population. Specifically, 69 patients had Standard of Truth determined by histopathology compared with imaging in 297 patients.

In this population, the mean age was 68.4 years (range, 43-85). The median PSA was 1.27 ng/mL (range, 0.03-134.6), and most patients had a Gleason grade group of 3 (30%).

F-rhPSMA-7.3 detection rate was 88% compared with a correct detection rate of 57%.

In patients with negative baseline conventional imaging in the prostate bed region, between 3.5% and 8.0% of patients post prostatectomy showed true positive detections compared with between 39% and 41% of patients post radiation therapy.

In patients with negative baseline conventional imaging in the pelvic lymph node region, between 18% and 21% of patients post prostatectomy showed true positive detections vs 6.5% of patients post radiation. In patients with negative baseline conventional imaging in the extra-pelvic region, between 21% and 26% of patients post prostatectomy showed true positive detections vs between 20% and 30% of patients post radiation.

"This event marks a significant milestone in advancing our robust prostate cancer portfolio, and we are very pleased that the FDA has accepted our NDA submission for the use of 

F-rhPSMA-7.3 PET imaging in prostate cancer patients," David E. Gauden, DPhil, chief executive officer of Blue Earth Diagnostics, stated in this press release 

"We look forward to working with the Agency throughout the review process, with the goal of having an approved product that is widely available and accessible across the United States. Subject to FDA approval, we believe that 

F-rhPSMA-7.3 PET imaging may be clinically useful in the management of men affected by prostate cancer across the care continuum. All of us at Blue Earth want to express our sincere gratitude to the many patients, physicians, clinical trial sites and collaborators who have worked closely with us to progress 

F-rhPSMA-7.3, and to having successfully completed our phase 3 clinical trials despite all the challenges presented by the COVID-19 pandemic," added Gauden.

Dr. Fleming on imaging agent 18F-rhPSMA-7.3 and SPOTLIGHT trial in prostate cancer

Reader reproducibility high with 18F-rhPSMA-7.3 image interpretation in prostate cancer

1. Blue Earth Diagnostics Announces FDA Acceptance of New Drug Application for 18F-rhPSMA-7.3, a Radiohybrid Prostate-Specific Membrane Antigen-Targeted PET Imaging Agent for Prostate Cancer. Posted online September 28, 2022. Accessed September 29, 2022. https://bwnews.pr/3y4rbRf

2. Fleming MT. Impact of 18F-rhPSMA-7.3 PET on upstaging of patients with prostate cancer recurrence: results from the prospective, phase 3, multicenter, SPOTLIGHT study. Presented at: 2022 AUA Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract PLLBA-02.

3. Schuster DM. Detection rate of 18F-rhPSMA-7.3 PET in patients with suspected prostate cancer recurrence: results from a phase 3, prospective, multicenter study (SPOTLIGHT). J Clin Oncol. 2022(suppl 6):9. doi:10.1200/JCO.2022.40.6_suppl.009

The application is supported by findings from a phase 1 trial and two phase 3 trials, SPOTLIGHT and LIGHTHOUSE. 

FDA accepts application for 18F-rhPSMA-7.3 for prostate cancer

The first patient has been enrolled in the phase 2 ProstACT TARGET study (NCT05146973), which is exploring TLX591 (177Lu-DOTA-rosopatamab) in combination with external beam radiation therapy (EBRT) in patients with biochemically recurrent, oligometastatic, PSMA-positive prostate cancer, according to Telix Pharmaceuticals and GenesisCare, the codevelopers of the investigational antibody.

The first patient was enrolled at GenesisCare's integrated cancer centre at the St John of God Hospital Murdoch campus in Western Australia. Overall, the study has a target enrollment of 50 patients across multiple clinical sites in Australia.

"I'm excited to commence this important study that builds on the momentum of ProstACT SELECT. With previous studies having confirmed the preliminary efficacy and safety profile of TLX591, GenesisCare is pleased to partner with Telix to further their therapeutic antibody-based program, which has potential to improve health outcomes for thousands of men living with prostate cancer in Australia and worldwide," TARGET principal investigator Nat Lenzo, BSc, MBBS, GenesisCare Group Medical Director (Theranostics), stated in a press release.

Some of the additional inclusion criteria for the TARGET study are ECOG performance status of 0-2, Gleason score ≥7 at primary presentation, previous radical prostatectomy with curative intent, and no prior chemotherapy. The study defines biochemical relapse per EAU-ESTRO-SIOG guidelines (serum PSA > 0.2 ng/mL, confirmed by repeat measurements) and oligometastatic disease as ≤5 metastatic lymph nodes.

The primary outcome measure is PSA progression-free survival, defined as the time period from enrollment to PSA level increasing by >25%. The estimated primary completion date is June 30, 2023.

"Enrolling a first patient in the ProstACT TARGET study is a significant milestone in Telix's overall clinical mission to support men with prostate cancer at every step in their journey with a PSMA antibody approach to targeted radiation therapy. Alongside ProstACT SELECT, this program will add value and clinical insight to Telix's antibody therapy candidate TLX591, as we progress global regulatory submissions for the ProstACT GLOBAL phase 3 study. We wish to express our gratitude to Professor Nat Lenzo and his clinical team, as well as the patients who will contribute to the study," Dr. Colin Hayward, chief medical officer, Telix, stated in the press release.

1. First Patient Enrolled in ProstACT TARGET Study. Published online September 26, 2022. Accessed September 27, 2022. https://prn.to/3LKq9iZ

2. External Beam Therapy With Theranostic Radioligand Therapy for Oligometastatic Prostate Cancer (ProstACT TARGET). NIH ClinicalTrials.gov. NCT05146973. First posted December 7, 2021. Last updated July 20, 2022. https://clinicaltrials.gov/ct2/show/NCT05146973

The phase 2 ProstACT TARGET study is exploring TLX591 (177Lu-DOTA-rosopatamab) in combination with external beam radiation therapy.

Study launches of novel PSMA-targeting antibody in biochemically recurrent prostate cancer

In patients with recurrent, intermediate-risk, low-grade bladder tumors, outpatient laser destruction of the tumors is noninferior to conventional inpatient transurethral resection of bladder tumor (TURBT), according to findings from the phase 3 Laser trial published in 

The 4-month recurrence-free survival was 8% (95% CI, 8%-24%) higher after laser photocoagulation of bladder tumor(PC-BT) versus TURBT in general anesthesia (TURBT-GA). This met the primary end point of the trial, which was a predefined noninferiority criterion of 15%. PC-BT was also shown to be less burdensome to patients compared with TURBT-GA.

In the study, the outpatient group received laser-mediated ablation of bladder tumors under local anesthesia performed through PC-BT using a 980 nm diode laser. The inpatient group received the gold standard TURBT-GA. Both procedures were performed using photodynamic diagnosis guidance which was done with blue light cystoscopy and Hexvix (Photcure).

"The study outcomes clearly demonstrate that for patients with small low grade stage Ta bladder tumors the procedure can be safely moved from the OR to the office, thereby reducing the burden for patients stemming from general anesthesia and cost related to hospital stays. Safety is the most important term here. Our team find that blue light cystoscopy with Hexvix in the outpatient department support the identification of small bladder tumors which therefore safely can be removed with laser before they become too large for outpatient treatment," lead investigator Gregers G. Hermann, MD, DM Sc, consultant urologist, Department of Urology, Herlev/Gentofte Hospital, Denmark, stated in a news release.

Explaining the rationale for the study, Hermann and his coauthors wrote, “Transurethral resection of recurrent low-grade intermediate-risk Ta bladder tumor in general anesthesia is burdensome to patients and health care system. Laser technologies enable treatment in office-based settings, reducing morbidity and costs.”

The prospective, randomized, noninferiority phase 3 Laser III trial (NCT02886026) enrolled patients with histologically verified Ta low-grade bladder tumor recurrence. Overall, there were 206 patients randomized to the trial from 2016 to 2020 in the Capital Region of Denmark. Of these patients, 176 completed treatment and were available for follow-up per the study protocol.

Patients reported a pain score (1-10) of 2.4 (interquartile range, 0.8-3.3) during PC-BT. The TURBT-GA group had a postoperative lower urinary tract symptom score (0–100) that was 13.9 points (95% CI, 6.9-21.0; 

 <.001) higher compared with the PC-BT group. Also, the occurrence of minor complications was 8.1% (95% CI, 1.0%-14.6%; 

 = .026) higher following TURBT-GA versus PC-BT.

The study investigators plan to share 12-month follow-up data in a separate paper.

"We expect to see more scientific studies investigating how some of the more intensive procedures like TURBTs can be reduced, avoided, or made more bearable for patients. In non-muscle-invasive bladder cancer especially, where most patients are over 55 years old, research into reducing patient burden is of great importance. We believe BLC with Hexvix/Cysview can help responsible researchers in these efforts by minimizing the concern of uncertainty when it comes to detecting the tumors," Dan Schneider, president and CEO of Photocure, stated in the news release.

1. New study demonstrates that tumor removal in the outpatient setting is as good as TURBT under general anesthesia. Published online September 20, 2022. Accessed September 23, 2022.

2. Pedersen GL, Erikson MS, Mogensen K, Rosthøj S, Hermann GG. Outpatient Photodynamic Diagnosis-guided Laser Destruction of Bladder Tumors Is as Good as Conventional Inpatient Photodynamic Diagnosis-guided Transurethral Tumor Resection in Patients with Recurrent Intermediate-risk Low-grade Ta Bladder Tumors. A Prospective Randomized Noninferiority Clinical Trial [Published online ahead of print September 1, 2022]. 

The phase 3 Laser trial showed that outpatient laser photocoagulation of bladder tumors is as effective as conventional inpatient TURBT in patients with Ta low-grade bladder cancer recurrence. 

Jason M. Broderick

Articles

FDA updates label for mitomycin gel in UTUC

FDA accepts application for 18F-rhPSMA-7.3 for prostate cancer

Study launches of novel PSMA-targeting antibody in biochemically recurrent prostate cancer

Outpatient laser destruction of recurrent bladder tumors noninferior to inpatient TURBT