Chris Ryan

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

Articles

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

A treatment regimen in which nivolumab (Opdivo) monotherapy is followed by a combination of nivolumab and ipilimumab (Yervoy) was associated with improved responses for patients with advanced renal cell carcinoma (RCC).

The data were derived from final results of the phase 2 TITAN-RCC trial (NCT02917772) presented at ESMO Congress 2022.

Data showed that nivolumab followed by nivolumab/ipilimumab resulted in an overall response rate (ORR) of 34%, which included a complete response (CR) rate of 7%, a partial response (PR) rate of 27%, and a stable disease (SD) rate of 26%; 39% of patients had progressive disease (PD). Patients who received only single-agent nivolumab experienced a ORR of 24%, which included a CR rate of 1%, a PR rate of 23%, a SD rate of 25%, and a PD rate of 15%. Additionally, 24% of patients who received nivolumab alone had early PD and received a nivolumab/ipilimumab boost at week 8. Of 207 enrolled patients, 139 received at least 1 nivolumab/ipilimumab boost cycle.

For patients treated in the first-line setting, the ORR with nivolumab monotherapy followed by nivolumab/ipilimumab boosting was 36%, which included a CR rate of 7%, a PR rate of 28%, a SD rate of 28%, and a PD rate of 35%. Those administered nivolumab alone experienced an ORR of 28%, which was comprised of a CR rate of 2%, a PR rate of 27%, a SD rate of 27%, and a PD rate of 12%. Twenty percent of patients who received nivolumab alone had early PD and required a boosting cycle at week 8.

In the second-line setting, nivolumab monotherapy followed by nivolumab/ipilimumab boosting resulted in an ORR of 32%, which included a CR rate of 6%, a PR rate of 26%, a SD rate of 23%, and a PD rate of 43%. Nivolumab alone produced an ORR of 18%, which comprised a PR rate of 18%, a SD rate of 23%, and a PD rate of 18%. Twenty-eight percent of patients who received nivolumab alone required a boosting cycle at week 8 following early PD.

“TITAN-RCC provides further evidence to the added value of ipilimumab in combination with nivolumab in advanced RCC,” lead study author Marc-Oliver Grimm, MD, of Jena University Hospital, said in a presentation of the data. “In the first-line [setting], boosting significantly—based on our assumptions—improved ORR, and activity parameters are, however, inferior in the TITAN-RCC regimen if we compare that with a direct start with nivolumab/ipilimumab, as it is approved. In the second-line [setting], boosting numerically improved ORR, and activity parameters suggest superiority to have the adaptive approach of TITAN-RCC compared with nivolumab monotherapy, as it is approved and used today.”

TITAN-RCC enrolled patients with histologically confirmed locally advanced or metastatic RCC with a clear cell component who were intermediate/high risk by International mRCC Database Consortium criteria. Patients were permitted to be treatment naïve or have received 1 prior therapy with a TKI. Other inclusion criteria included having measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of at least 70, and an evaluable tumor sample to test PD-L1 expression.

Once enrolled, all patients received induction treatment with 240 mg of intravenous nivolumab given every 2 weeks for 8 cycles. Patients who achieved a CR or PR continued nivolumab maintenance at 240 mg every 2 weeks or 480 mg every 4 weeks.

Patients who had early PD at week 8 or SD/PD after nivolumab induction received 2 boosting cycles of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks. Patients who achieved a CR or PR following the 2 boosting cycles shifted to nivolumab maintenance, and patients who still had SD or PD received 2 more nivolumab/ipilimumab boosting cycles. Patients with a CR, PR, or SD following the third and fourth boosting cycles moved to nivolumab maintenance, and patients with PD were deemed to have immunotherapy resistance.

The primary end point of the trial was ORR, and secondary end points were comprised of progression-free survival (PFS), overall survival (OS), remission rates after boosting cycles, safety, and quality of life.

Among all patients treated, the median age was 65 years (range, 20-87), and 71% were male. Additionally, 18% of patients had a Karnofsky performance status of less than 80%, 66% had their initial RCC diagnosis within 12 months, 53% had hemoglobin below the lower limit of normal, 19% had a platelet count above the upper limit of normal (ULN), 13% had an absolute neutrophil count above ULN, and 13% had calcium above ULN. Thirty percent of patients had a PD-L1 expression of at least 1%.

Four percent of patients had favorable-risk disease, 71% had intermediate-risk disease, and 25% had high-risk disease. Among those who received prior first-line therapy, 72% received sunitinib (Sutent), 22% received pazopanib (Votrient), and 5% received another agent.

Among patients in the first-line setting who received boosting with nivolumab/ipilimumab in week 8 (n = 49), the best response rate was 33%, which included a CR rate of 2%, a PR rate of 14%, and a SD rate of 16%. The median duration of response (DOR) for those who achieved a CR, PR, or SD was not estimated (NE; 27.8 months), 8.3 months (range, 5.3-30.5), and 6.2 months range, 2.8-8.5), respectively. Among patients in the first-line setting who were boosted beyond week 16 (n = 17), the best response rate was 53%, which included a PR rate of 18% and a SD rate of 35%; the DOR for patients who had a PR or SD was NE (95% CI, 4.2-22.1) and 15.7 (95% CI, 2.6-28.4), respectively.

For patients who were boosted in the second-line setting in week 8 (n = 59), the best response rate was 37%, which comprised a CR rate of 5%, a PR rate of 12%, and a SD rate of 20%. The DOR following the boost in patients who achieved a CR, PR, or SD was NE (range, 4.9-40.4), 18.2 months (range, 2.8-20.0), and 5.2 (range, 1.6-27.7), respectively. In patients in the second-line setting who were boosted beyond week 16 (n = 11), the best response rate was 55%, which comprised a PR rate of 18% and a SD rate of 36%; the DOR in those who had a PR or SD was NE (95% CI, 4.1-11.1) and NE (95% CI, 2.7-73), respectively.

The median PFS was 6.0 months (95% CI, 3.7-10.1) for patients in the first-line setting and 3.7 months (95% CI, 1.8-4.5) for patients in the second-line setting. The median OS for those 2 groups was 36.1 months (95% CI, 27.2-46.7) and 33.7 months (95% CI, 21.6–not calculable), respectively.

“Please note, however, that due to the study design, [the PFS data] mainly reflect nivolumab monotherapy,” Grimm explained.

Although Grimm did not present full safety data, he noted that no new safety signals were identified.

1. Grimm M-O, Esteban E, Barthelemy P, et al. Efficacy of a tailored approach with nivolumab and nivolumab/ipilimumab as immune-therapeutic boost in metastatic renal cell carcinoma – final results of TITAN-RCC. 

. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072

Data showed that nivolumab followed by nivolumab/ipilimumab resulted in an overall response rate of 34%.

Combination nivolumab/ipilimumab after nivolumab monotherapy shows benefit in advanced RCC

Inter- and intra-reader reproducibility results with the novel PET imaging agent 18F-rhPSMA-7.3 showed high concordance when used in patients with biochemically recurrent prostate cancer, according to findings from the phase 3 SPOTLIGHT trial presented at the 2022 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting.

The overall inter-reader agreement for 18F-rhPSMA-7.3 PET/CT was above 75% and was highest for the pelvic lymph node region at above 87%. The overall intra-reader agreement was higher than 85%.

“Biochemically recurrent prostate cancer can be locally recurrent disease, metastatic disease, or both. Therefore, optimal assessment of the extent and location of recurrent prostate cancer is critical for clinical decision-making by physicians and patients,” Phillip Kuo, MD, PhD, Departments of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona, on behalf of the SPOTLIGHT study group, stated in a news release.

“Unfortunately, recurrence of prostate cancer is common. Conventional imaging, such as CT and bone scintigraphy, is often negative particularly when PSA is still low, so the demonstrated performance of PSMA-PET imaging fits an important unmet need. But no matter how good the radiotracer or scanner, reliable and consistent interpretation of PET imaging is foundational and has the potential to substantially impact patient care. These findings from the SPOTLIGHT study showed high inter-reader and intra-reader agreement for interpretation of 18F-rhPSMA-7.3 PET/CT scans in the setting of biochemical recurrence. Such high reproducibility, particularly for extra-prostatic regions, is clinically valuable, due to the potential of these findings to influence patient management,” added Kuo.

The multicenter, single-arm SPOTLIGHT (NCT04186845) 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. 18F-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.

The analysis presented at SNMMI assessed overall image interpretation agreement between the 3 blinded readers as well as image interpretation agreement for the regions of the prostate/prostate bed, pelvic lymph nodes, and other (extra-pelvic) sites (lymph nodes outside pelvis, soft tissue/parenchyma, and bones).

Agreement was high across all readers. When assessed by region, prostate/prostate bed reproducibility was lower than reproducibility for other regions; however, the study researchers noted that, “the high reproducibility for extra-prostatic regions is clinically valuable due to the potential of these findings to influence patient management.”

Data from the SPOTLIGHT trial previously presented at the 2022 AUA Annual Meeting showed that compared with baseline conventional imaging, PET imaging with 18F-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, 18F-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.

Prior data from the SPOTLIGHT trial were also presented at the 2022 Genitourinary Cancers Symposium, showing that the overall detection rate in patients who had an evaluable 18F-rhPSMA-7.3 scan was 83% by majority read.

1. Blue Earth Diagnostics Announces Reader Reproducibility Results from Phase 3 SPOTLIGHT Trial of Investigational PET Imaging Agent 18F-rhPSMA-7.3 in Biochemical Recurrence of Prostate Cancer. Published online June 15, 2022. Accessed June 15, 2022. https://bwnews.pr/3O8Yto0

“These findings from the SPOTLIGHT study showed high inter-reader and intra-reader agreement for interpretation of 18F-rhPSMA-7.3 PET/CT scans in the setting of biochemical recurrence,” said Phillip Kuo, MD, PhD. 

Compared with baseline conventional imaging, PET imaging with 18F-rhPSMA-7.3 frequently led to post-scan disease upstaging in men with prostate cancer recurrence, according to the latest data from the phase 3 SPOTLIGHT trial presented at the 2022 AUA Annual Meeting.

Among 250 of 366 men in the efficacy analysis population who had negative baseline conventional imaging, 18F-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.

“We have hoped to have another option [to evaluate] patients for PSA [prostate specific antigen] recurrences, whether it was those with localized disease post prostatectomy or radiation therapy, [in addition to] what we can [currently] provide. We can find these tumor recurrences and options for treatment to salvage [these patients] better and earlier, and that is huge to both physicians and, most importantly, our patients,” said presenting author Mark Fleming, MD, Virginia Oncology Associates, US Oncology Research.

18F-rhPSMA-7.3 is an investigational prostate‐specific membrane antigen (PSMA)–targeted radiohybrid (rh) PET imaging agent. The agent has a longer half-life, a scope for larger batch productions, and improved spatial resolution in PET images compared with gallium 68.

Prior data from SPOTLIGHT (NCT04186845) presented at the 2022 Genitourinary Cancers Symposium showed that the overall detection rate in patients who had an evaluable 18F-rhPSMA-7.3 scan was 83% by majority read.

18F-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 18F-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.

Additional data showed the 18F-rhPSMA-7.3 detection rate was 88% compared with a correct detection rate of 57%.

“It was very interesting for me, as you look closer to the data, that patients who had prostatectomy [were] different than patients who had radiation in the sites of disease,” Fleming said.

Based on the updated data from SPOTLIGHT, 18F-rhPSMA-7.3 could represent a way to better define sites of disease recurrence and identify salvage therapies for the right patients.

“[SPOTLIGHT] showed that we are able to upstage patients [with 18F-rhPSMA-7.3], that we are able to find disease that was missed [by conventional imaging] and gave a false sense of reassurance to patients that they didn’t have recurrence of the disease,” Fleming concluded.

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.

Blue Earth Diagnostics announces additional results from phase 3 SPOTLIGHT trial of investigational PET imaging agent 18F-rhPSMA-7.3 in biochemical recurrence of prostate cancer. News release. Blue Earth Diagnostics. May 13, 2022. Accessed May 13, 2022. https://bwnews.pr/3wu1Cr9

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). 

. 2022(suppl 6):9. doi:10.1200/JCO.2022.40.6_suppl.009

Compared with baseline conventional imaging, PET imaging with 18F-rhPSMA-7.3 frequently led to post-scan disease upstaging in men with prostate cancer recurrence, according to the latest data from the phase 3 SPOTLIGHT trial.

Chris Ryan

Articles

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

Combination nivolumab/ipilimumab after nivolumab monotherapy shows benefit in advanced RCC

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

Novel PET imaging agent 18F-rhPSMA-7.3 increases upstaging in recurrent prostate cancer