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1rem

Authors

Lu is a board-certified anatomic pathologist and medical director of GoPath Laboratories LLC and GoPath Pathology Associates S.C., Buffalo Grove, Illinois.

"Liquid biopsy analysis provides a noninvasive and facile tool for early detection, diagnosis, and recurrence surveillance of urological cancer," writes Jim Lu, MD, PhD.

Molecular diagnostic practice in prostate and bladder cancers

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

Defining mCSPC: Diagnostic Criteria, Imaging Approaches, and Patient Identification

Video content above is prompted by the following:

How do you define mCSPC and mHSPC? How are they different? (

Metastatic castration-sensitive prostate cancer (mCSPC) and metastatic hormone-sensitive prostate cancer (mHSPC) are terms used to describe prostate cancer that has spread beyond the prostate gland and still responds to hormone therapy. The distinction between mCSPC and mHSPC is subtle, often used interchangeably, but may vary based on specific clinical guidelines or contexts. Both conditions are characterized by the presence of metastases and sensitivity to androgen deprivation therapy (ADT), with treatment strategies focusing on ADT combined with other systemic therapies to improve patient outcomes.

Panelists discuss how metastatic castration-sensitive prostate cancer (mCSPC) is defined by its sensitivity to androgen deprivation therapy, while metastatic hormone-sensitive prostate cancer (mHSPC) emphasizes the cancer’s responsiveness to hormone treatment, highlighting the nuanced differences in patient management strategies.

Emerging Trends and Rising Prevalence of  mCSPC

What is the prevalence of mCSPC? What trends have emerged in recent years?

Metastatic castration-sensitive prostate cancer (mCSPC) is increasingly prevalent due to improved diagnostic techniques and an aging population. Recent trends indicate a shift towards earlier detection and treatment, with a focus on personalized therapeutic strategies. Advances in imaging and biomarker identification have contributed to better disease characterization, enabling more precise treatment approaches. Additionally, there is a growing emphasis on understanding the molecular and genetic underpinnings of mCSPC, which is driving the development of novel targeted therapies. These trends highlight the importance of continued research and innovation in managing mCSPC.

Panelists discuss how the prevalence of metastatic castration-sensitive prostate cancer (mCSPC) has been increasing, potentially influenced by changes in prostate-specific antigen screening recommendations and rising diagnoses of metastatic hormone-sensitive prostate cancer.

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy.

During cystoscopy, a rim of calcification was seen along the right ureteric ridge (figure 1a). A biopsy of this area was taken with the pathology shown in figure 1b.

B. Squamous cell carcinoma of the bladder

A 35-year-old male from Sudan presented with a 1-cm obstructing ureteral stone and curvilinear calcification in the bladder wall, as seen on KUB imaging. The patient underwent ureteroscopy and laser lithotripsy. During cystoscopy, calcification was observed along the right ureteric ridge. A biopsy was performed on this area to further investigate the pathology. The findings from the biopsy are crucial for understanding the underlying condition contributing to the calcification and obstruction, which may have implications for the patient's treatment and management.

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy. During cystoscopy, a rim of calcification was seen along the right ureteric ridge. What is the diagnosis?

Residents Corner

Quiz: Sandy patch on cystoscopy

-selective tyrosine kinase inhibitor, demonstrated initial efficacy while maintaining a favorable tolerability profile in patients with metastatic urothelial carcinoma (mUC), according to interim data from the phase 1/2 SURF301 trial (NCT05544552).

The data were presented at the 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

 alterations are known to drive tumor biology in a subset of urothelial cancer. While pan-

 inhibitors have demonstrated benefit and are approved for use in 

-altered urothelial cancer, they are associated with multiple intolerable on-target toxicities that limit their clinical utility,” said Ben Tran, MD, associate professor at the Peter McCallum Cancer Centre in Melbourne, Australia, in a news release on the data.

 “There remains an unmet need to deliver improved precision medicine for urothelial cancer patients that allow patients to not only live longer, but live better.”

In total, 41 patients were included in the preliminary analysis at the time of data cutoff. For the trial, TYRA-300 was evaluated across 6 dose levels, ranging from 10 mg to 120 mg once daily.

-altered mUC, anti-tumor activity was observed across all patients who were treated at the dose levels of 90 mg and higher. In these cohorts, 54.5% of patients (6 of 11) achieved a partial response. This consisted of 5 patients (50%) in the 90 mg cohort and 1 patient (100%) in the 120 mg cohort. Three partial responses were still ongoing at the time of data report.

The disease control rate, consisting of partial response plus stable disease, was 100% among patients with mUC who received TYRA-300 at 90 mg or higher.

According to the authors, the therapy was also generally well-tolerated. There were 4 (10%) serious adverse events (AEs) related to TYRA-300 across all dose levels (10 mg to 120 mg). Of these, 1 was a grade 3 dose-limiting toxicity in the 90 mg cohort, and 2 were grade 3 treatment-related AEs (TRAEs) of increased ALT in the 90 mg cohort, 1 of which led to the discontinuation of treatment.

Overall, AEs of any grade occurred in 78% of patients (n = 32), and AEs of grade 3 or higher occurred in 20% of patients (n = 8). There were no grade 4 or higher TRAEs. No dose-limiting toxicities were reported among patients in the highest dose cohort of 120 mg at the time of data cutoff.

“These first results from the phase 1 clinical trial of TYRA-300 show compelling activity in patients whose cancer has progressed despite being heavily treated with other therapies previously,” said Timothy A. Yap, MBBS, PhD, FRCP, from the University of Texas MD Anderson Cancer Center in Houston and co-chair of the EORTC-NCI-AACR Symposium.

 “The fact that TYRA-300 seems able to specifically target cancers with 

 mutations or fusions, with fewer side effects than other drugs, gives us hope that patients with hard-to-treat advanced bladder and other cancers that also have 

 mutations or fusions may be able to benefit from a kinder and more effective therapy once these results have been validated in further clinical trials.”

Overall, the ongoing SURF301 trial is enrolling participants with mUC and other solid tumors who harbor 

 gene alterations. At the time of data cutoff, 61% of patients (n = 25) in the trial had mUC. Among all patients with 

-altered mUC, 76% had received at least 3 prior lines of therapy. 

The median age among all participants was 66 years. Enrollment for the trial is taking place at 21 clinical trial sites across the United States, Europe, and Australia.

For phase 1 of the study, patients will receive TYRA-300 at dose levels ranging from 10 mg – 120 mg once or twice daily. In phase 2, patients will receive TYRA-300 at the recommended phase 2 dose level determined in the first phase.

The primary end points for phase 1 include the incidence of dose-limiting toxicities and adverse events, as well as other safety parameters. Secondary end points include pharmacokinetic parameters, overall response rate, duration of response, duration of complete response, time to response, and progression-free survival.

Phase 1 of the study remains ongoing to determine the maximum tolerated dose.

"The initial results from TYRA-300 are very encouraging. I believe TYRA-300 has the potential to be a next generation targeted therapy, with high selectivity for 

 “These early data provide support that TYRA-300 can deliver improved anti-tumor activity and tolerability for our 

-altered urothelial cancer patients. TYRA-300 has real potential to improve outcomes, and I look forward to its continued development in all 

1. Tran B, Zhang A, Hansen A, et al. Preliminary safety and anti-tumor activity of TYRA-300, a highly selective FGFR3 inhibitor, in participants with advanced solid tumors with activating FGFR3 mutations/fusions (SURF301). Presented at: 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics. October 23-25, 2024. Barcelona, Spain. Abstract 500LBA

2. Tyra Biosciences reports interim clinical proof-of-concept data for TYRA-300, an investigational oral FGFR3-selective inhibitor, in phase 1/2 SURF301 study in patients with metastatic urothelial cancer (mUC). News release. Tyra Biosciences, Inc. October 24, 2024. Accessed October 31, 2024. https://ir.tyra.bio/news-releases/news-release-details/tyra-biosciences-reports-interim-clinical-proof-concept-data

3. Patients with advanced bladder cancer with alterations in the FGFR3 gene respond well to investigational drug, TYRA-300. News release. October 25, 2024. Accessed October 31, 2024. https://event.eortc.org/ena2024/2024/10/25/patients-with-advanced-bladder-cancer-with-alterations-in-the-fgfr3-gene/

4. Safety and preliminary anti-tumor activity of TYRA-300 in advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations (SURF301). ClinicalTrials.gov. Updated October 3, 2024. Accessed October 31, 2024. https://clinicaltrials.gov/study/NCT05544552

TYRA-300, an investigational FGFR3-selective tyrosine kinase inhibitor, shows promising efficacy and tolerability in metastatic urothelial carcinoma (mUC) patients, according to interim data from the SURF301 trial. The trial demonstrated a 54.5% partial response rate in patients receiving doses of 90 mg or higher, with a 100% disease control rate. The therapy was generally well-tolerated, with no grade 4 or higher treatment-related adverse events. These findings suggest TYRA-300's potential as a targeted therapy for FGFR3-altered cancers, warranting further clinical investigation.

Anti-tumor activity was observed across all patients with FGFR3-altered metastatic urothelial carcinoma who were treated at the dose levels of 90 mg and higher. 

TYRA-300 shows encouraging safety, efficacy in FGFR3+ metastatic urothelial carcinoma

Recent data presented at Pelvic Floor Disorders Week 2024 showed no significant association between the use of vaginal estrogen for the management of genitourinary syndrome of menopause (GSM) and subsequent major adverse cardiovascular events (MACE).

An additional study presented at the meeting showed no significant association between the use of systemic (non-vaginal) estrogen for vasomotor symptoms of menopause (VMS) and subsequent venous thromboembolic events (VTE).

According to the authors, vaginal estrogen therapies contain a listed contraindication for a history of myocardial infarction and stroke, as well as a black-box warning for increased risk of deep vein thrombosis. The current studies sought to assess the risk of these events in women who did and did not receive vaginal or systemic estrogen within 1 year following their diagnosis.

In total, the retrospective cohort analysis comparing vaginal estrogen and subsequent MACE included 549,925 women from the TriNetX database who received a diagnosis of GSM between April 2004 and April 2024. Among all patients, 53.8% received vaginal estrogen.

After propensity score matching, each study arm included 65,243 high-risk women (a diagnosis of MACE between 3 and 24 months prior to first GSM diagnosis) and241,326 low-risk women (no history of MACE). A subsequent MACE diagnosis included myocardial infarction, stroke, and cardiovascular death.

Among all high-risk women, a subsequent MACE diagnosis occurred in 23% of patients who received vaginal estrogen vs 23% of patients who were not treated with vaginal estrogen (HR, 0.990; 95% CI, 0.936 to 1.048; 

 = .423). In low-risk women, a subsequent MACE diagnosis occurred in 6.2% of patients who received vaginal estrogen vs 7.4% of patients who did not receive vaginal estrogen (HR, 0.938; 95% CI, 0.918 to 0.959; 

Similar results were seen when comparing the use of systemic estrogen for VMS and subsequent VTE.

In total, the retrospective study identified 526,144 women from the TriNetX database who received a diagnosis of VMS between April 2004 and April 2024. Among these patients, 7.4% received systemic estrogen. After propensity score matching, each study arm included564 high-risk women (a diagnosis of tobacco use by ICD-10 code any time prior to first VMS diagnosis) and 38,583 low-risk women (no history of prior tobacco use).

Among all high risk-women, subsequent VTE occurred in 2.0% of patients who received systemic estrogen compared with 2.8% of patients who did not receive systemic estrogen (HR, 0.774; 95% CI, 0.359 to 1.670; 

 = .750). Among low-risk women, subsequent VTE was experienced by 1.6% of patients who received systemic estrogen compared with 2.1% of patients who did not receive systemic estrogen (HR, 0.986; 95% CI, 0.887 to 1.097; 

“These findings support the safety of vaginal estrogen for treatment of local menopause symptoms, even in high-risk women,” concluded lead author Gabriella M. Rustia, MD, a female pelvic medicine and reconstructive surgery fellow at University Hospitals in Cleveland, Ohio, in correspondence with 

. “Further research should elucidate current practice patterns with systemic hormone replacement specific to route and dose of administration such as patch or oral routes.”

1. Rustia GM, Rahman A, Rhodes S, Sheyn D. Major adverse cardiovascular events with and without vaginal estrogen therapy. Presented at: Pelvic Floor Disorders Week 2024. October 22-25, 2024. Washington, DC

2. Rustia GM, Rhodes S, Sheyn D. Rate of venous thromboembolic events with and without systemic estrogen therapy. Presented at: Pelvic Floor Disorders Week 2024. October 22-25, 2024. Washington, DC

Recent studies presented at Pelvic Floor Disorders Week 2024 indicate no significant link between vaginal estrogen use for genitourinary syndrome of menopause (GSM) and major adverse cardiovascular events (MACE), nor between systemic estrogen for vasomotor symptoms (VMS) and venous thromboembolic events (VTE). The retrospective cohort analysis involved over half a million women from the TriNetX database. Results showed similar MACE and VTE rates in both high-risk and low-risk groups, regardless of estrogen therapy. These findings suggest the safety of estrogen therapies, even in high-risk populations.

“These findings support the safety of vaginal estrogen for treatment of local menopause symptoms, even in high-risk women,” says Gabriella M. Rustia, MD.

Jim Lu, MD, PhD

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