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Vaginoplasty and the role of autologous buccal mucosa

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

The combination of neoadjuvant cretostimogene grenadenorepvec plus nivolumab was safe and efficacious in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC), according to data from the phase 1b CORE-002 trial (NCT04610671) published in 

The data were concurrently presented at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in Houston, Texas.

According to the authors, this combination may offer a potential alternative to cisplatin-based chemotherapy for these patients.

 publication underscores cretostimogene’s compelling safety profile and provide preliminary evidence supporting the potential use as a combination therapy for patients with different types of bladder cancer,” said Vijay Kasturi, MD, chief medical officer of CG Oncology, in a news release on the data.

 “Cretostimogene’s dual mechanism of action positions it to potentially work well as either a monotherapy or in combination because it selectively replicates and destroys cancer cells while simultaneously amplifying the immune response against bladder tumors. Cretostimogene targets bladder cancer cells, without harming normal cells in the bladder.”

Overall, safety data from the trial showed no instances of dose limiting toxicities. There was 1 patient who discontinued treatment following an adverse event (AE), although the AE was not thought to be due to treatment.

Grade 3 or higher treatment-emergent AEs occurred in 57% of patients. The majority of these, according to the authors, were due to complications from RC-PLND. The most frequent treatment-related AEs attributed to cretostimogene included grade 1/2 catheter leakage (24%), bladder spasms (14%), and dysuria (14%).

Data also showed a pathological complete response (pT0N0) rate of 42.1%, which the authors note is similar to the response rate seen with standard-of-care cisplatin-based chemotherapy and significantly higher than what has been reported with nivolumab monotherapy. Pathologic response was found to be associated with baseline free E2F activity as well as tumor mutational burden. A link was not observed between pathologic response and PD-L1 status.

No patients achieved a partial response (<pT2N0) in the study. Disease downstaging within the bladder occurred in 2 patients, however these patients did harbor pelvic nodal metastases. Additionally, at 1 year, the recurrence-free survival rate was 70.4%.

The authors also observed, “Although T cell infiltration was broadly induced following intravesical oncolytic virotherapy, the formation and maturation of tertiary lymphoid structures were specifically associated with complete response, emphasizing the importance of adaptive humoral immune responses.”

In total, the study enrolled and treated 21 adult patients with cT2-4aN0-1M0 MIBC who were ineligible for or refused cisplatin-based chemotherapy. For the study, patients received 6 weekly intravesical instillations of cretostimogene (1 × 1012 viral particles) plus 480 mg intravenous nivolumab at weeks 2 and 6.

The primary outcome measure for the study was safety. The secondary outcome measure was anti-tumor efficacy of the combination, as measured by the pathologic complete response rate and 1-year recurrence-free survival.

Final completion of the CORE-002 trial is anticipated for February 2025.

“The CORE-002 study lent us insights towards the safety, efficacy, and mechanism of action of intravesical oncolytic immunotherapy—cretostimogene with nivolumab. We learned that this combination was not only well tolerated, but also able to provide 42% pathologic complete response, on par with standard-of-care cisplatin chemotherapy in healthier patients,” said lead author Roger Li, MD, a genitourinary oncologist at Moffitt Cancer Center, in correspondence with 

®. “We also learned about potential biomarkers that can be used to select for patients more likely to respond to therapy—those with higher baseline tumor mutational burden, and E2F target expression. In addition, there were exciting insights we found as far as the tumor specific T- and B-cell activities that may be leveraged in future immunotherapeutic trials. Together, the data point to the exciting potential for this combination regimen to be used to treat patients with muscle-invasive bladder cancer.”

In addition to CORE-002, cretostimogene grenadenorepvec is also being assessed in the phase 3 BOND-003 trial (NCT04452591) for patients with high-risk non-muscle invasive bladder cancer (NMIBC) who are unresponsive to BCG. Results from this trial are expected by the end of 2024. The therapy is also being assessed in the phase 3 PIVOT-006 trial (NCT06111235) for patients with intermediate-risk NMIBC.

Cretostimogene was previously granted fast track and breakthrough therapy designations by the FDA in December 2023 for patients with high-risk NMIBC.

1. Li R, Villa NY, Yu X, et al. Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial. 

2. Li R, Li T, Villa NY, et al. Oncolytic virotherapy combined with nivolumab elicits complete responses in muscle-invasive bladder cancer in association with the formation of tertiary lymphoid structures. Presented at: 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC). November 6-10, 2024. Houston, Texas. Abstract 596

3. CG Oncology announces Nature Medicine publication of phase 1b study results evaluating cretostimogene grenadenorepvec in combination with nivolumab in muscle-invasive bladder cancer. News release. CG Oncology Inc. Published online and accessed November 11, 2024. https://ir.cgoncology.com/news-releases/news-release-details/cg-oncology-announces-nature-medicine-publication-phase-1b-study

4. Study of CG0070 combined with nivolumab in cisplatin ineligible patients with MIBC. ClinicalTrials.gov. Last updated July 10, 2024. Accessed November 11, 2024. https://clinicaltrials.gov/study/NCT04610671

The combination of neoadjuvant cretostimogene grenadenorepvec and nivolumab demonstrated safety and efficacy in cisplatin-ineligible muscle-invasive bladder cancer (MIBC) patients, as shown in the phase 1b CORE-002 trial. The treatment achieved a 42.1% pathological complete response rate, comparable to cisplatin-based chemotherapy. Safety data revealed no dose-limiting toxicities, with grade 3 or higher treatment-emergent adverse events in 57% of patients. The study highlighted potential biomarkers for response prediction and emphasized the role of adaptive humoral immune responses. Further trials are ongoing to explore its broader applicability.

"Together, the data point to the exciting potential for this combination regimen to be used to treat patients with muscle invasive bladder cancer," says Roger Li, MD.

Cretostimogene grenadenorepvec plus nivolumab shows promise in cisplatin-ineligible MIBC

Primary chemoablation with UGN-101 (Jelmyto), a mitomycin reverse thermal gel, demonstrated favorable long-term durability in patients with low-grade upper tract urothelial carcinoma (UTUC), according to long-term data from the phase 3 OLYMPUS trial (NCT02793128) published in 

UGN-101 was approved by the FDA in April 2020 based on data from this study.

In total, the OLYMPUS trial enrolled 71 patients, of whom 42 achieved a complete response following 6 weekly doses of UGN-101. Of those, 41 continued to be followed for 12 months following the initial response.

At a median follow-up of 28.1 months, the median duration of response (DOR) was 47.8 months (95% CI 13.0, not estimable) among those who achieved an initial complete response.

Additionally, at study completion, 49% of patients (n = 20) opted to undergo long-term follow-up for up to 5 years until disease recurrence, progression, or death. The median follow-up among these patients was 53.3 months. Of these, 75% showed no evidence of recurrence at last follow-up. The median DOR was not estimable due to a low event rate.

“The median DOR of 47.8 months in patients who achieved complete response with JELMYTO provides evidence of robust durability in maintaining control of low-grade UTUC over an extended period,” said lead author Phillip Pierorazio, MD, chief in the Section of Urology at Penn Presbyterian Medical Center and professor of surgery at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylanvia, in a news release on the findings.

 “The AUA/SUO recommend that urologists use kidney-sparing techniques as the preferred management strategy for patients with low-grade UTUC when possible. JELMYTO, with this evidence for extended durability of complete response, offers the opportunity for durable recurrence-free intervals.”

Previous data from the OLYMPUS trial showed that 56% of patients (23/41) remained in complete response at 12-month follow-up.

 Of those, 6 of 12 (50%) patients did not receive any maintenance instillations and 17 of 29 (59%) patients received at least 1. The estimated durability of response was 82% (95% CI, 66-91) at 12 months, per Kaplan-Meier.

Regarding safety, the most common treatment-emergent adverse event (TEAE) was ureteric stenosis, reported in 44% (31/71) of all patients in the study. A higher number of UGN-101 instillations was associated with an increased incidence of urinary TEAEs.

Overall, the prospective, open-label, single-arm OLYMPUS trial enrolled patients with low-grade UTUC to assess the efficacy, safety, and tolerability of UGN-101. Participants were enrolled across clinical trial sites in the United States and Isreal.

Those enrolled in the study received 6 once weekly instillations of the therapy in a retrograde fashion. Those who achieved a complete response continued to receive UGN-101 once monthly for up to 11 instillations or until the first recurrence.

The primary end point was the number of patients who achieved a complete response at the end of treatment period. Secondary end points included the durability of complete response, clinical benefit for patients who achieved a partial response, and pharmacokinetic measures.

UGN-101 is continuing to be explored in the JELMYTO uTRACT Registry (NCT05874921) to obtain longitudinal real-world usage data in patients with UTUC. As of July, 191 patients have been enrolled across 19 sites. Enrollment for the registry remains ongoing, with a goal of enrolling 400 patients.

1. Pierorazio PM, Kleinmann N, Shabsigh A, et al. Long-Term Outcomes of Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma (LG UTUC) with UGN-101, A Mitomycin Reverse Thermal Gel. 

. 2024:101097JU0000000000004331. doi:10.1097/JU.0000000000004331

2. New data from a long-term follow-up study to the OLYMPUS trial show median duration of response of four years in patients who achieved a complete response with JELMYTO. News release. UroGen Pharma Ltd. Published online and accessed November 26, 2024. https://investors.urogen.com/news-releases/news-release-details/new-data-long-term-follow-study-olympus-trial-show-median

3. Matin SF, Pierorazio PM, Kleinmann N, et al. Durability of response to primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel: OLYMPUS trial final report. 

. 2022;207(4):779-788. doi:10.1097/JU.0000000000002350

4. The OLYMPUS Study - Optimized DeLivery of Mitomycin for Primary UTUC Study (Olympus). ClinicalTrials.gov. Last updated December 22, 2020. Accessed November 26, 2024. https://clinicaltrials.gov/study/NCT02793128

5. uTRACT Jelmyto Registry: A registry of patients with upper tract urothelial cancer (UTUC) treated with Jelmyto (uTRACT). ClinicalTrials.gov. Last updated December 5, 2023. Accessed November 26, 2024. https://clinicaltrials.gov/study/NCT05874921

UGN-101 (Jelmyto), a mitomycin reverse thermal gel, has shown promising long-term efficacy in treating low-grade upper tract urothelial carcinoma (UTUC), as evidenced by the phase 3 OLYMPUS trial. The trial demonstrated a median duration of response of 47.8 months among patients achieving complete response. The study also highlighted the importance of kidney-sparing techniques, with 75% of patients showing no recurrence at last follow-up. However, ureteric stenosis was a common adverse event. UGN-101 is further being studied in the JELMYTO uTRACT Registry for real-world data.

“The median DOR of 47.8 months in patients who achieved complete response with JELMYTO provides evidence of robust durability in maintaining control of low-grade UTUC over an extended period,” says Phillip Pierorazio, MD. 

UGN-101 demonstrates long-term durability in low-grade UTUC

Sakti Das, MD, a friend, a mentor (guru), and an inspiration to me, passed away recently. I can go on with the accolades, as this gentle soul meant so much to so many. It is traditional to highlight his accomplishments in his field of urology. (Please see the Western Section of the American Urological Association [AUA] tribute by Tupper Stevens, MD, at 

). However, I would like to focus on the humanitarian and artistic aspects of his life and share why his being meant so much.

Das hailed from the land of Rabindranath Tagore, Calcutta. His prose, conversations, and writings were poetic. As a resident, I became aware of him through his publications in the

. When I eventually met Das at an AUA annual meeting, his smile and demeanor were captivating. I had to push through the hordes of admirers to get close to him. Once he befriended you, you were a recipient of his largesse of knowledge, history, and path in life. His writings and paintings are part of the William P. Didusch Center for Urologic History, including well over 200 publications, books, etc.

Das was influenced by Mother Teresa from Calcutta; serving and educating those in need was his karma. There are few places in the world where he did not travel to operate, teach, and open a school or an orphanage, and he inspired and cajoled others to follow. Das joined the modern-day “Mother Teresa of urology,” Catherine R. deVries, MD, MS, to make International Volunteers in Urology a medium through which many could serve. Named Humanitarian of the Year by the Urology Care Foundation in 2022, he perhaps received much more in the blessing from those he served. Below, I share with you the many messages I have received.

“I will miss his stimulating Tagore quotes, his humility, and [his] zest for contributing to the well-being of our planet.”

“Sakti was a humble, vibrant being of light, radiating love and care wherever he was. We are blessed to have basked in his light and encouragement.”

“I am incredibly grateful to have crossed paths and to have been taken under his wing as a student years ago. Sakti [not only] shared his technical skills but also [his] life philosophy.”

“May the love, patience, and generosity Sakti showed each of his many mentees ripple forth from those whose lives he has touched to touch the lives of many to come.”

“He was an amazing friend, [a] colleague of my husband, and a wonderful human being. Through his philanthropy, he was a shining light in the dark spots that sometimes occur in this world. Whether it was building schools for girls or doing hypospadias surgeries, he gave his time, [his] expertise, and his heart. He was an amazing man, and I am honored that my husband and I could call him a friend.”

“He personified his personal motto of ‘I serve, therefore I am.’ He was a multifaceted person. His humility, generosity, and genuine concern for all, as well as [his] willingness to act quickly and create meaningful changes, touched many lives. We borrowed his personal motto, converted it to ‘We serve, therefore we are,’ and created the nonprofit Caring Hands [Foundation]. He championed many causes. We embraced them and built many schools, orphanages, old-age homes, etc. He has been the inspiration and nurturing guide for Caring Hands. We still have a few projects that Sakti brought to us in the pipeline. How I wish things just went on like before! But life must go on. We will keep his service legacy alive and carry on his work in Caring Hands.”

“The passing of Dr Sakti Das, a giant in the field of urology, leaves a profound void not just in the medical community but [also] in the hearts of those privileged to have been mentored by him. I can’t express how deeply his guidance has impacted my life, both professionally and personally. Growing under his mentorship, reading his works, and working alongside him has been a profound experience. His loss is immeasurable to me, and I will forever carry his teachings and memories with me. He will always remain in my thoughts, and his influence will continue to guide me. I will miss you greatly, sir.”

“He touched many lives across continents as a person, a mentor, [a] teacher, [a] role model, [and a] facilitator. [He was] always willing, supportive, [and] helpful, paving paths [as] a visionary. Certainly, [he] helped me, and [I am] forever grateful for it. He will be missed tremendously. He introduced me to Rabindranath Tagore, who shares these words from 

‘In one salutation to thee, my God, let all my senses spread out and touch this world at thy feet.

Like a rain cloud of July hung low with its burden of unshed showers, let all my mind bend down at thy door in one salutation to thee.

Let all my songs gather together their diverse strains into a single current and flow to a sea of silence in one salutation to thee.

Like a flock of homesick cranes flying night and day back to their mountain nests, let all my life take its voyage to its eternal home in one salutation to thee.’”

I hope these messages have given you a sense of his influence on many of us. I have not even tried to express the feelings of the thousands of patients and school students he transformed.

We communicated frequently, and I was fortunate to spend quality time with Sakti at the last AUA annual meeting. In parting, we both knew it may be the last time we would see each other. In his last message, as was his habit, he ended with a quote: “Let this be my last word, that I trust in thy love.”

PS: If you feel generous, please contribute to the 

"When I eventually met Das at an AUA annual meeting, his smile and demeanor were captivating. I had to push through the hordes of admirers to get close to him," writes Gopal H. Badlani, MD.

Opinion

Paying tribute to Sakti Das, MD

Case 1: A 68-Year-Old Man with Bone-Predominant Metastatic Castration-Resistant Prostate Cancer (mCRPC)  

Video Series

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?

Linda A. Baker, MD

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