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It's not clear yet whether transvaginal mesh offers superior anatomic or symptomatic outcomes compared to traditional apical suspension repairs.

Transvaginal mesh: Further study of risks, benefits needed

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

Use of the oral HIF-2α inhibitor belzutifan (Welireg) was associated with improved progression-free survival (PFS) and objective response rate (ORR) vs everolimus (Afinitor) in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to data presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain.

The data, from the final analysis of the phase 3 LITESPARK-005 (NCT04195750) trial, were presented by Brian Rini, MD, chief of Clinical Trials, Ingram Professor of Cancer Research, and professor of medicine (hematology/oncology) at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. Said Rini in his presentation, “As presented at this meeting last year and subsequently recently published,

 belzutifan improved PFS and response rate compared to everolimus in patients with refractory RCC…Progression-free survival at the first interim analysis [showed] a hazard ratio of 0.75 [with] a significant 

<.001] and a response rate advantage of nearly 22% vs 3.5% and a significant 

<.0001]. Based on these initial results, belzutifan was approved in the US for refractory kidney cancer following PD-(L)1 inhibitor and VEGFR-TKI.”

Patients were eligible for the study if they had advanced ccRCC and had received 1 to 3 prior systemic treatment regiments, including at least 1 PD-(L)1 inhibitor and at least 1 VEGFR-TKI. Participants were randomly assigned 1:1 to receive belzutifan, 120 mg or everolimus, 10 mg QD until disease progression or unacceptable adverse events (AEs). Primary end points of the study included PFS per RECIST 1.1 by central review as well as overall survival (OSS).

“ORR per RECIST 1.1 by central review was a key secondary end point. Duration of response (DOR) and safety were secondary end points,” wrote the authors in the study’s abstract.

A total of 372 patients were treated with belzutifan and 360 patients were treated with everolimus. Treatment is ongoing in 54 (14.5%) patients in the belzutifan arm vs 5 (1.4%) in the everolimus arm. Of the 318 patients receiving belzutifan who discontinued treatment, progressive disease was the reason for 255 (85.5%) of patients and AE was the reason in 23 (6.2%) patients. Of the 355 patients receiving everolimus who discontinued treatment, progressive disease was the reason for 248 (68.9%) patients and AE was the reason in 55 (15.3%) patients.

Rini said he and his co-investigators examined the 54 patients still receiving treatment with belzutifan “just to see if we could characterize them by their baseline characteristics.” Although comparable in age vs the intent-to-treat (ITT) population for both the belzutifan and everolimus arms, this patient group had a higher percentage of favorable IMDC risk (31.5% in the 54 patients compared with 21.7% in the ITT belzutifan population and 22.6% in the ITT everolimus population. In addition, rate of prior nephrectomy was higher in the 54 patients at 83.3% vs 69.8% and 69.6% in the ITT belzutifan and everolimus arms, respectively.

Regarding PFS, “benefit was maintained with belzutifan vs everolimus (median 5.6 mo vs 5.6 mo; HR 0.75; 95% CI 0.63–0.88),” wrote the authors. PFS was 33.7% at 12 months in the belzutifan arm vs 17.6% in the everolimus arm and 17.5% at 24 months in the belzutifan arm vs 4.1% in the everolimus arm.

Median OS was 21.4 months (range, 18.2 to 24.3 months) in the belzutifan arm vs 18.2 months (range, 15.8-21.8 months) in the everolimus arm (HR=0.92, 95% CI: 0.77-1.10, 

ORR was 22.7% in the belzutifan arm vs 3.5% in the everolimus arm, and median DOR was 19.3 months (range, 1.9+-40.1+ months) vs 13.7 months in the everolimus arm (range, 3.8-29.5+ months).

Regarding AEs, the median duration of therapy was 7.6 months (range, 0.1-45.9 months) in the belzutifan arm vs 3.9 months (range, 0.03-41.8 months) in the everolimus arm. A total of 369 (99.2%) patients experienced an all-cause AE in the belzutifan arm vs 357 (99.2%) of patients in the everolimus arm. Of these 234 (62.9%) were grade 3 or higher in the belzutifan arm vs 226 (62.8%) in the everolimus arm.

In his concluding remarks, Rini said, “Belzutifan continues to show progression-free survival and overall objective response rate benefits vs everolimus, including, and I think importantly, durable responses that are lasting more than 2 years with more than 2-year minimum follow up. More patients remain on treatment with belzutifan compared to everolimus...These final analysis results of LITESPARK-005 support belzutifan as a treatment option in refractory kidney cancer after checkpoint inhibitor and VEGFR-TKI therapy.”

1. Rini B, Suarez C, Albiges L, et al. Final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC). Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA74. https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=LBA74

2. Chouieri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. 

2024;391(8):710-721. doi:10.1056/NEJMoa2313906

"These final analysis results of LITESPARK-005 support belzutifan as a treatment option in refractory kidney cancer after checkpoint inhibitor and VEGFR-TKI therapy," says Brian Rini, MD.

Belzutifan is associated with PFS and ORR gains in advanced kidney cancer

The investigational oral HIF-2α inhibitor NKT2152 showed strong anti-tumor activity in a population of patients with heavily pretreated advanced clear cell renal cell carcinoma, according to findings from an ongoing phase 1/2 study (NCT05119335).

“In sporadic clear cell renal cell carcinoma, the majority of these tumors will have some functional inactivation in [Von Hippel-Lindau], which will result in upregulation of HIF-1α and HIF-2α, which is targetable. And there’s an agent that’s already been approved in this setting, but this is another agent that will interact with HIF-2α, prevent HIF-2 and HIF-1β heterodimerization, and will then prevent the downstream transcription of these various HIF-dependent genes,” explained presenter Eric Jonasch, MD, professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston. Jonasch presented the data at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain.

The trial included a dose-escalation group comprised, a clinical pharmacology group examining drug-drug interactions and urine metabolites, a dose expansion group, and a post-belzutifan (Welireg) group. A total of 113 patients have been enrolled in the trial, with 46 (41%) patients receiving ongoing treatment. Forty-four (39%) patients have discontinued the trial due to disease/clinical progression. For the part 1 dose escalation, median follow-up was 20.8 months (range, 10.3-31.2 months), and overall median follow-up was 13.5 months (range, 0.23-31.2 months).

The study incorporated 4 daily dose and 4 loading/maintenance dosing regimens.

“The study started off looking at daily dosing. It started off with 200 and then looked at 50, 100, and 300 mg. And as it was apparent that there was significant accumulation of this agent to due to long half-life, loading and maintenance regimens…were then investigated. These included loading for a period of time followed by daily dosing as well as loading followed by weekly dosing,” Jonasch said. The phase 2 expansion included 2 randomized dose evaluation regimens consisting of 200 mg QD for 14 days, then 50 mg QD and 100 mg QD for 7 days, then 100 mg QW.

Across the entire patient population, 41 (36.3%) patients were IMDC poor risk. A total of 106 (93.8%) patients had received prior VEGF-TKI therapy, 110 (97.3%) had received a prior immunotherapy, and 32 (28.3%) patients had received a prior mTOR inhibitor.

Jonasch reported that the pharmacokinetics were dose linear and time independent, with a median half-life of 38 days.

The investigators also evaluated EPO inhibition. EPO, Jonasch explained, is a HIF-2α client gene.

“We saw that there was significant and sustained EPO suppression at all dose levels. [The] maximal was 72%,” Jonasch said.

Across the entire cohort, the objective response rate (ORR) was 20% compared with 26.3% in the dose escalation cohort. ORR was higher in patients IMDC favorable status (33.3%) vs IMDC poor (11.4%), and was 35.6% in patients who were mTOR naïve.

“Median duration of response has not yet been reached,” Jonasch said. Median progression-free survival was 7.4 months across the entire cohort and 9.2 months in the dose escalation cohort.

Approximately 92% of patients experienced an adverse event, including anemia in 71% of patients, fatigue in 30%, and hypoxia in 25%.

“Dose-limiting toxicities included fatigue and hypoxia,” Jonasch said.

In his concluding remarks, Jonasch said, “NKT2152 demonstrated robust anti-tumor activity in a heavily pretreated, high-risk advanced clear cell renal cell carcinoma population. Objective response rate in the 100 overall patient group was 20%, with progression-free survival of 7.4. In the part 1, with dose escalation, we saw an objective response rate of 26.3% and a PFS of 9.2 months. In patients with no prior mTOR treatment, objective response rate was 35%, and PFS was 12.7 months…We have 2 dose regimens that are undergoing further evaluation and comparison.”

1. Jonasch E, McGregor BA, Msaouel P, et al. NKT2152, a novel oral HIF-2α inhibitor, in participants (pts) with previously treated advanced clear cell renal carcinoma (accRCC): Preliminary results of a phase I/II study. Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract 1690O. https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=1690O

“NKT2152 demonstrated robust anti-tumor activity in a heavily pretreated, high-risk advanced clear cell renal cell carcinoma population," said Eric Jonasch, MD.

NKT2152 shows strong efficacy in advanced clear cell renal cell carcinoma

The combination of enzalutamide (Xtandi) plus radium-223 (Ra223, Xofigo) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases is both safe and associated with significantly improved radiological progression-free survival (rPFS), according to findings from the EORTC-GUCG 1333/PEACE-3 (NCT02194842) trial.

“Abiraterone [Zytiga] and enzalutamide, both androgen receptor pathway inhibitors, are the standard-of-care options for first-line treatment of patients with metastatic castration-resistant prostate cancer who progress on androgen deprivation therapy [ADT] and have not received an [androgen receptor pathway inhibitors] in [the] hormone-sensitive setting.

 Of note, the current standard of care for metastatic hormone-sensitive disease is the combination of ADT plus an [androgen receptor pathway inhibitor]. However, real-life evidence shows that globally, still, many patients receive ADT only. In the setting of first-line metastatic castration-resistant prostate cancer, no combination so far has shown benefit for both radiological progression-free survival and overall survival compared to abiraterone or enzalutamide monotherapy,” said first author Silke Gillessen, MD, medical oncologist at the Oncology Institute of Southern Switzerland, Bellinzona, at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain.

Gillessen further noted that in the 2013 ALSYMPCA trial (NCT00699751), Ra223 increased OS in patients with castration-resistant prostate cancer.

“However, this was in a time before the introduction of abiraterone and enzalutamide,” Gillessen said.

In addition, the ERA-223 trial (NCT02043678) evaluated the combination of abiraterone plus Ra223 vs abiraterone plus placebo. The investigators did not find a benefit symptomatic skeletal event-free survival or OS, and an increase in fractures was observed.

Patients were eligible for inclusion in PEACE-3 if they had mCRPC and bone metastases, were asymptomatic or mildly symptomatic, had a WHO performance status of 0 or 1, had not received prior treatment with enzalutamide, Ra223, apalutamide (Erleada), or darolutamide (Nubeqa), no known visceral metastases, and were receiving ongoing ADT. Patients were randomly assigned 1:1 to standard-of-care enzalutamide, 160 mg once daily or enzalutamide, 160 mg once daily plus Ra223 every 4 weeks for 6 cycles. The primary end point was investigator-assessed rPFS. Key secondary end points included safety, OS, time to next systemic treatment progression, and time to first symptomatic skeletal event. Following the ERA-223 trial, the use of bone-protecting agents was made mandatory. The investigators targeted a 32% improvement in rPFS as the primary objective.

A total of 446 patients from 12 countries were enrolled from November 2015 to March 2023. Median follow-up was 42.2 months. Gillessen noted that patient characteristics were “generally well balanced,” but noted that there were more patients with increased alkaline phosphatase in the enzalutamide-alone arm.

“All 224 patients in the enzalutamide-alone arm started enzalutamide. In the combination arm, 3 patients started enzalutamide but not radium, and 4 patients didn’t start any treatment. Of note, from the patients who started the radium, almost 90% received all of the 6 planned cycles,” Gillessen noted.

Regarding rPFS, “The risk of radiological progression or death was reduced by 31% in favor of the combination of radium-223 plus enzalutamide. This was statistically significant, with a 

value of .0009. In absolute terms, at 2 years, 36% of the patients in the enzalutamide-alone were free of radiological progression compared with 45% in the combination arm,” Gillessen reported.

Median OS was 35.0 months in the enzalutamide-alone arm vs 42.3 months in the combination arm.

“Due to the nonproportional hazards, the IMDC recommended to continue to the final overall survival analysis, despite this positive result, to confirm the observed treatment effect,” Gillessen said.

Regarding time to next systemic treatment, 51% of patients in the enzalutamide-alone arm started a new systemic treatment at 2 years vs 31% of patients in the combination group. There was no difference in time to pain progression or time to symptomatic skeletal event.

In terms of adverse events (AEs), “In general, the combination was very well tolerated. Only a few patients had to stop treatment due to toxicity,” Gillessen said. The investigators reported no drug-related deaths. The most common grade 3-5 treatment-emergent AEs included hypertension, fatigue, fracture, anemia, and neutropenia.

In her concluding remarks, Gillessen said, “The combination of enzalutamide and 6 cycles of radium-223 shows a statistically significant improvement in rPFS, with a 31% reduction in radiological progression or death…These results support the combination of enzalutamide plus radium-223 plus a bone-protecting agent as a potential new first-line mCRPC treatment option for patients with prostate cancer and bone metastases who have not received a prior androgen receptor pathway inhibitor.”

1. Gillessen S, Choudhury A, Saad F, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA1. https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=LBA1

2. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. 

2013;368(2):138-148. doi:10.1056/NEJMoa1209096

3. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. 

2014;371(5):424-433. doi:10.1056/NEJMoa1405095

4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. 

. 2013;369:213-223. doi:10.1056/NEJMoa1213755

5. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial

2019;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X

Enzalutamide plus Ra223 significantly boosts rPFS in mCRPC

Findings from an analysis of the phase 3 CheckMate 9ER trial (NCT03141177) presented during the 

 showed that patients with advanced renal cell carcinoma (RCC) who received frontline nivolumab (Opdivo) plus cabozantinib (Cabometyx) achieved a 1.5-times longer mean time surviving treatment-free before the initiation of second-line therapy vs those who received sunitinib (Sutent).

Over the 48-month period following random assignment, patients in the intention-to-treat (ITT) population who received the combination (n = 323) experienced a mean treatment-free survival (TFS) of 7.0 months compared with 4.6 months in the sunitinib arm (n = 328), for a difference of 2.4 months (95% CI, 0.8-3.9). Patients without a grade 2 or higher treatment-related adverse effect (TRAE) experienced a mean TFS of 3.0 months vs 2.3 months, respectively. Those who experienced a grade 2 or higher TRAE experienced a mean TFS of 3.9 months vs 2.3 months. The 48-month mean overall survival (OS) was 35.1 months in the doublet arm vs 30.7 months in the sunitinib arm. The mean times on protocol treatment were 22.6 months compared with 14.1 months, respectively.

Additionally, the 48-month OS rates were 49.2% in the nivolumab plus cabozantinib arm vs 40.2% in the sunitinib arm, and the 48-month TFS rates were 33.3% compared with 12.9%, respectively.

“There are multiple immunotherapy-based combination treatments with similar efficacies approved for first-line treatment of advanced RCC. Therefore, it’s important to characterize patient survival time after treatment initiation,” Charlene Mantia, MD, a medical oncologist at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, said during a presentation of the findings. “Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib.”

CheckMate 9ER was an open-label study that enrolled patients with histologically confirmed untreated advanced or metastatic clear cell RCC who did not receive prior systemic therapy for RCC. However, treatment with 1 prior adjuvant or neoadjuvant therapy was permitted for patients with completely resectable disease if the agent was not VEGF-targeted and if recurrence occurred at least 6 months following treatment.

Patients were randomly assigned 1:1 to receive intravenous nivolumab 240 mg every 2 weeks in combination with oral cabozantinib 40 mg daily or sunitinib 50 mg daily for 4 weeks in 6-week cycles. Treatment in both arms continued until disease progression or unacceptable toxicity, and the maximum duration of nivolumab therapy was 2 years.

The primary end point was progression-free survival by blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, objective response rate, and safety.

In the ITT population, the baseline characteristics were well balanced between the combination and sunitinib arms; the median age was 62 years (range, 29-90) vs 61 years (range, 28-86), respectively. Most patients in both arms were not from North America or Europe (51.1% vs 50.9%), had a Karnofsky performance status (KPS) of 90 or 100 (79.6% vs 73.5%), underwent prior nephrectomy (68.7.% vs 71.0%), and had tumors without sarcomatoid features (89.1% vs 87.1%).

Additional findings from the TFS analysis showed that patients with IMDC favorable-risk disease in the combination (n = 74) and control (n = 72) arms achieved a 48-month mean TFS of 6.1 months vs 4.3 months, respectively, for a difference of 1.8 months (95% CI, –1.1 to 4.6). The mean OS during this time frame was 38.2 months in the nivolumab plus cabozantinib arm vs 38.6 months in the sunitinib arm. Patients spent a mean time of 25.2 months vs 19.9 months on protocol treatment, respectively.

Further, patients with IMDC intermediate- or poor-risk disease in the combination (n = 249) and sunitinib (n = 256) arms achieved a 48-month mean TFS of 7.2 months vs 4.7 months, respectively, for a difference of 2.5 months (95% CI, 0.8-4.3). The 48-month mean OS was 34.2 months vs 28.5 months, respectively, and patients spent a mean time of 21.8 months in the combination arm vs 12.5 months in the sunitinib arm on protocol treatment.

Results from a TFS subgroup analysis showed that the benefit with nivolumab plus cabozantinib vs sunitinib was observed across prespecified subgroups. The largest differences in 48-month mean TFS in favor of the combination were reported among patients with a KPS of 80 or less (5.3 months [95% CI, 2.1-8.5]), IMDC poor-risk disease (4.0 months [95% CI, 0.5-7.5]), and a PD-L1 expression of at least 1% (3.5 months [95% CI, 0.8-6.1]).

“Mean TFS differences were similarly longer for nivolumab plus cabozantinib vs sunitinib across most baseline subgroups analyzed,” Mantia said in conclusion. “TFS was more frequently observed after patients stopped therapy due to adverse effects, study drug toxicity, or prespecified other reasons with nivolumab plus cabozantinib vs sunitinib. We believe that future studies should continue to investigate the impact of having a defined treatment duration for patients. This partitioned OS analysis highlights important aspects of patient survival time that can be considered in making decisions when choosing a first-line treatment for patients.”

1. Mantia C, Jegede O, Viray H, et al. Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC). J Clin Oncol 2024;42(suppl 16):4507. doi:10.1200/JCO.2024.42.16_suppl.4507

2. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994

3. A study of nivolumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). ClinicalTrials.gov. Updated January 17, 2024. Accessed June 4, 2024. https://clinicaltrials.gov/study/NCT03141177

“Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib," says Charlene Mantia, MD. 

Nivolumab plus cabozantinib extends treatment-free survival vs sunitinib in aRCC

The FDA's Antimicrobial Drugs Advisory Committee met on September 9, 2024 to discuss the submitted new drug application (NDA) for sulopenem etzadroxil/probenecid (oral sulopenem) for the proposed indication of adult patients with uncomplicated urinary tract infection (uUTI) caused by designated susceptible bacteria.

During the discussion, the Committee discussed “a) antimicrobial stewardship issues raised by potential approval and subsequent use of what would be the first oral penem in the US; and b) the most appropriate target patient population(s) for treatment of uUTI with sulopenem etzadroxil/probenecid.”

 Dr. A. Lenore Ackerman on antibiotic stewardship in managing UTIs

A. Lenore Ackerman, MD, PhD, discusses the problem of antimicrobial resistance 

Dr. A. Lenore Ackerman on antibiotic stewardship in managing UTIs

While the committee did not vote on the application, the discussion is anticipated to influence the final FDA decision on the company’s NDA, which has a target action date of October 25, 2024.

Overall, the committee determined that, if approved, oral sulopenem would provide substantial benefit to a subset of patients; there is a risk for off-label use as well as a risk to the community and individuals in the spread of antimicrobial resistance; a plan regarding post-marketing analysis is essential; and observation of changes to the rates of antimicrobial resistance may be necessary.

Below is a live report of the FDA Advisory Committee meeting as covered by 

Following a presentation of all the data, the following 2 questions were posed to the Antimicrobial Drugs Advisory Committee for discussion.

Is the overall benefit-risk assessment favorable for the use of sulopenem etzadroxil/probenecid for this indication?

Considering the totality of the evidence in this application, what are the considerations that would be important to convey to medical providers to ensure appropriate use of sulopenem etzadroxil/probenecid?

On the first point, the proposed indication was again stated as adult women 18 years of age or older who have uncomplicated urinary tract infection caused by designated susceptible microorganisms. Dr. John Farley, director of the Office of Infectious Diseases, FDA, noted that the next step in the application process for oral sulopenem is labeling negotiation between Iterum and the FDA. Farley asked that any opinions regarding wording for the proposed indication be shared.

A definition for “designated susceptible microorganisms” was first discussed. A committee member indicated that their interpretation of the phase was microorganisms susceptible to the proposed agent. If this is the true definition, they suggested they would not support a favorable risk/benefit assessment.

They noted, “In my mind, a positive risk/benefit ratio would require wording that restricts the use to a population at substantially higher risk of treatment failure with currently available first-line oral agents.”

Ideally, they added that this would include patients who had a culture demonstrating resistance to accepted first-line agents. They also brought up the idea of identifying a population of women who are at very high risk for treatment failure with first-line agents, which may be based on demographic features or prior microbiologic results.

A member agreed that the wording was too broad. They also noted that an oral agent may be tremendously beneficial to a subset of patients, but the question remains on how to minimize the risk to society as a whole. The ideal audience, another member reiterated, would be patients with a resistant organism and/or someone who has failed a first-line therapy.

Another question was then posed: Should antimicrobial testing be a requirement? One suggestion was to change the wording of the indication to reflect patients with microorganisms that are resistant to other oral agents. However, it was noted that this still could allow off-label use of the drug. The idea of a requiring a culture also brought up a concern for equity, as some patients may have insurance that doesn’t cover obtaining a culture.

The panel then moved on to the second question regarding considerations for appropriate use.

A committee member questioned about the options available to the FDA if the drug is approved and is then shown, in a post-market setting, to be inappropriately used or to be driving resistance. The agency responded by saying that in the first scenario, the FDA could fall back on labeling, in collaboration with the sponsor, to make changes in the wording of the indication. In the second scenario, there would be more options available to the FDA given that this is considered a safety concern of the drug.

Another committee member suggested that there is also a risk to the individual due to the drug potentially changing their flora, or contributing to "microbiome injury". This, another member added, should be assessed in antimicrobial trials moving forward.

On the issue of labeling, some proposed solutions were to invoke a limitations of use statement indicating this drug for patients with a resistant organism and/or someone who has failed a first-line therapy as well as a possible warning regarding the risk in off-label use of the drug. These actions, in combination with post-marketing assessments of its use in clinical practice as well as assessments of changes to rates of antimicrobial resistance, may support a more favorable risk/benefit ratio for oral solupenem, one panel member concluded.  

Follow Urology Times' coverage of the full-day FDA advisory committee meeting regarding Iterum Therapeutics' new drug application for oral sulopenem for uncomplicated urinary tract infection.

Leslie M. Rickey, MD, MPH

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