Kristi Rosa

Long-term data for UGN-101 (Jelmyto) showed that the mitomycin-containing reverse thermal gel induced a durable recurrence-free survival benefit in patients with low-grade upper tract urothelial carcinoma (LG-UTUC).

An analysis from the pivotal phase 3 OLYMPUS trial presented during the 2021 AUA Annual Meeting showed that as of March 4, 2021, the median duration of response (DOR) achieved with UGN-101 induction therapy was 28.1 months (95% CI, 14.6-37.1) in 15 evaluable patients. Eighty percent of patients (n = 12) experienced a durable response, defined as having no evidence of recurrence or not having to undergo radical nephroureterectomy.

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

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

“UGN-101 demonstrates long-term durability that exceeds that achieved with kidney-sparing options like laser ablation,” said senior author of the trial Karim Chamie, MD, MSHS, an associate professor of Urology at the University of California, Los Angeles, in a presentation on the data. “With laser ablation therapies, we’ve seen [from] pooled analyses of prior publications the recurrence rates [were] more than 65% at a median follow-up of 43 months.”

LG-UTUC is a rare disease for which limited therapeutic options are available. Despite significant progress made with endoscopic therapies, most patients still need to undergo radical nephroureterectomy, according to Chamie, who added that data from population-level analyses indicate that up to 70% of patients with low-grade, noninvasive disease still undergo more extirpative surgery.

Advances made with endoscopic surgeries have yielded several kidney-sparing benefits. However, results from a pooled analysis of 597 patients, 78% of whom had low- or intermediate-grade disease, demonstrated that 65% of the population experienced disease recurrence following ureteroscopic therapy at a median follow-up of 43 months (range, 24-58).

 “That is quite significant,” Chamie noted.

As such, investigators launched the phase 3 OLYMPUS trial (NCT02793128) to evaluate UGN-101. Earlier results from the study resulted in the April 2020 FDA approval of the mitomycin gel for the treatment of patients with LG-UTUC.

 The previously reported estimated the a durability of response rate of 84% at 12 months in those who achieved a complete response (CR) after UGN-101 induction treatment.

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

Study participants received UGN-101 once a week for the duration of 6 weeks followed by a 4- to 6-week grace period, according to Chamie. In this period, patients were assessed for the primary efficacy end point of CR rate at their primary disease evaluation (PDE) visit. If patients experienced a CR to treatment, they went on to receive the gel monthly for up to 11 additional months.

“Patients were determined to have a CR if ureteroscopy and cytology were entirely normal,” Chamie explained. “If there were any abnormalities, patients underwent a biopsy by which this was determined to be either recurrence or a CR.”

A key secondary end point of the trial was durable response at the 12-month follow-up visit, and other end points included durability of response with UGN-101 at 3, 6, and 9 months following the PDE visit. As part of the long-term follow-up, investigators examined duration of response, disease recurrence, disease progression, and death.

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

Of the 71 patients enrolled to the study (ITT population), 10 discontinued UGN-101 (9 because of adverse effects [AEs] and 1 because of withdrawn consent), and 19 did not achieve a CR by their PDE visit. A total of 42 patients in the ITT population experienced a CR to treatment at the time of their PDE visit, which translated to a CR rate of 59.2% (95% CI, 46.8%-70.7%). Of these patients, 1 withdrew consent, 10 discontinued treatment, and 8 experienced disease recurrence.

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

Limitations of the study included a small sample size and missing data for 8 of 23 patients who had durable responses at 12 months following their PDE visit, Chamie concluded.

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

2. Petros FG, Li R, Matin SF. Endoscopic approaches to upper tract urothelial carcinoma. 

. 2018;45(2):267-286. doi:10.1016/j.ucl.2017.12.009

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

Articles

The mitomycin-containing reverse thermal gel UGN-101 (Jelmyto) produced durable responses in patients with low-grade upper tract urothelial carcinoma.

UGN-101 shows long-term recurrence-free survival benefit in low-grade UTUC

A prognostic factor analysis identified multiple potential biomarkers for over survival (OS) outcomes with lutetium 177 (177Lu) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Specifically, findings presented at the 2021 AUA Annual Meeting showed that both Cancer and Leukemia Group B (CALGB) prognostic risk group and the receipt of subsequent FDA-approved life-prolonging therapies were correlated with OS when 177Lu was administered in this patient population.

The overall median OS observed with 177Lu was 20.7 months in 125 patients with mCRPC who received treatment on sequential prospective clinical trials of the prostate-specific membrane antigen (PSMA)–targeted beta-emitting radionuclide. The median OS in those who received 177Lu-J591 (n = 76) was slightly longer, at 23.3 months. In those who received 177Lu-PSMA-617 (n = 49), the median OS was 16.7 months.

Factors linked with longer OS included CALGB prognostic score (28.1 months vs 16.9 months; 

<.0001), circulating tumor cell (CTC) decline (24.9 months vs 19.2 months; 

= .046), and receipt of subsequent therapy (28.1 months vs 14.8 months; 

Moreover, higher PSMA PET standardized uptake value (SUV; imaging score 4 vs 0 to 3) was linked with prolonged OS (18 months vs 10 months; 

= .015), and higher administered activity (22.1 months vs 18.6 months; 

= .074) and DNA damage repair (DDR) alterations (33.9 months vs 20.6 months; 

= .24) tended to be associated with longer OS.

“DDR mutations, higher administered radioactivity, higher PSMA PET SUV, and posttreatment [circulating tumor cell] count decline are promising biomarkers worthy of further exploration,” Scott Tagawa, MD, MS, FACP, study author, professor of medicine and urology at Weill Cornell Medicine, and an attending physician at NewYork-Presbyterian–Weill Cornell Medical Center, said in a poster presentation on the data.

PSMA-targeted radionuclide therapy represents a promising treatment for patients with advanced prostate cancer, Tagawa said. PSMA can be targeted using antibodies, such as J591, or small molecule ligands, like PSMA-617, labeled with 177Lu. However, optimal selection and effective biomarkers still need to be defined and established, Tagawa added.

To conduct the combined prognostic analysis presented during the meeting, investigators collected data from a total of 125 patients who received treatment with 177Lu on prospective PSMA-TRT clinical trials at a single institution between 2003 and 2020. To be included in the analysis, patients had to have completed treatment with the radionuclide therapy at least 1 year before the analysis.

Variables of interest included type of PSMA targeting, dose administered, comorbidities, CALGB prognostic risk group, PSMA imaging, CTC counts, known DDR alterations, and receipt of subsequent therapies. PSMA imaging was scored based on the maximum tumor uptake relative to the mean liver uptake on a scale that ranged from 0 to 4. Investigators utilized Cox regression analysis and the Kaplan-Meier method to examine the link between the variables and survival. The data cutoff for the combined analysis was March 2021.

Among the 125 patients included, the median PSA was 50.14 ng/dL (range, 0.66-2222.4) and the median age at treatment was 72 years (range, 48-93). Regarding Halabi risk category, 57.6% of patients had high risk, 37.6% had intermediate risk, and 4.8% had low risk. Additionally, 49.6% previously received taxane chemotherapy and 47.2% previously received abiraterone acetate (Zytiga)/enzalutamide (Erleada). Eighty percent of patients had metastasis in the lymph node, 24.8% in the liver, 24.8% in the lung, and 97.6% in the bone.

The median number of subsequent therapies received was 1 (range, 0-10), and these included abiraterone/enzalutamide (26.4%), docetaxel (32.8%), cabazitaxel (Jevtana; 18.4%), platinum chemotherapy (17.6%), radium-223 dichloride (Xofigo; 7.2%), sipuleucel-T (Provenge; 4.8%), and additional PSMA-TRT (11.2%).

Additional data from a multivariable analysis indicated that high Halabi risk group (HR, 1.78; 95% CI, 1.16-2.73; 

= .009) and total number of subsequent therapies (HR, 0.79; 95% CI, 0.71-0.89; 

<.001) retained their prognostic significance. Moreover, a trend for DDR mutations holding prognostic significance was observed (HR, 0.68; 95% CI, 0.34-1.36; 

1. Sun M, Thomas C, Ho B, et al. Long-term follow-up and prognostic factor analysis in men with metastatic castration-resistant prostate cancer (mCRPC) who receive prostate-specific membrane antigen (PSMA)-targeted lutetium-177 (177Lu). Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-05.

The prognostic factor analysis included patients who received either 177Lu-PSMA-617 or 177Lu-J591.

Study highlights prognostic factors for Lutetium 177 in mCRPC

While there are multiple frontline options in renal cell carcinoma (RCC), new data suggest that for patients with the rare non–clear cell histology, upfront immune checkpoint inhibitor therapy could improve overall survival (OS).

Findings shared during the 2021 Genitourinary Cancers Symposium showed that in a population of 1181 patients with non–clear cell metastatic RCC, the median OS was 28.6 months in patients receiving an immune checkpoint inhibitor–based regimen compared with 19.2 months and 12.6 month, respectively, in patients being treated with a VEGF inhibitor and an mTOR inhibitor.

The median time-to-treatment failure (TTF) in those who received an immunotherapy-based regimen was also longer at 6.9 months (95% CI, 2.8-14.0) versus 5.1 months with a VEGF inhibitor (95% CI, 4.6-5.7) and 3.9 months (95% CI, 3.0-5.1) with an mTOR inhibitor.

In the entire population of patients included in the analysis, the objective response rate (ORR) achieved in those who received an immunotherapy-based regimen was 25%; it was 17.8% in those who received VEGF targeted therapy and 5.8% in those who received mTOR-targeted treatment (

“Immune checkpoint inhibitor–based frontline therapy appears to be associated with improved OS compared to VEGF and mTOR targeted therapy in treatment-naïve metastatic non–clear cell RCC, even after adjustment for International Metastatic RCC Database Consortium [IMDC] risk, histology, and age,” lead study author Jeffrey Graham, MD, of the University of Manitoba, and colleagues, wrote in a poster on the data.

Immunotherapy options have induced impressive activity in patients with metastatic clear-cell RCC; as such, these options have become part of standard frontline treatment. Although non–clear cell RCC represents about 15% of all kidney cancers, findings supporting the efficacy of immune checkpoint inhibitors up front has remained largely limited.

To address this need, investigators launched a study to detail the real-world effectiveness of frontline approaches containing immune checkpoint inhibitors in patients with metastatic non–clear cell RCC.

To perform a retrospective analysis of the IMDC, investigators included all patients who had non–clear cell histology. Patients were categorized into 3 groups based on first-line treatment: single-agent VEGF therapy, single-agent or combination immunotherapy, and single-agent mTOR therapy. For the analysis, investigators looked at outcomes, such as ORR, TTF, and OS.

The median age of the entire patient population was 60.6 years, 65.4% were male, 76.4% had undergone nephrectomy, and 16.6% had sarcomatoid features. The most common histologic subtype across the groups was papillary disease (54.2%), and most patients fell into the intermediate IMDC risk group (55.1%). Across the groups, 25.1% of patients had liver metastases, 34.2% had bone metastases, and 3.6% had brain metastases.

Of the 1181 patients included in the analysis, 78.2% had received VEGF treatment (n = 924), which included sunitinib (Sutent; n = 632; 68.4%), pazopanib (Votrient; n = 171; 18.5%), sorafenib (Nexavar; n = 72; 7.8%), cabozantinib (Cabometyx; n = 12; 1.3%), or other (n = 37; 4%). Moreover, 15.8% had received mTOR inhibitors (n = 186) in the frontline setting, such as temsirolimus (Torisel; n = 141; 75.8%) or everolimus (Afinitor; n = 45; 24.2%).

The remaining 5.5% had received immune checkpoint inhibitor–based therapy (n = 65), which could include nivolumab (Opdivo) and ipilimumab (Yervoy; n = 20; 30.8%), atezolizumab (Tecentriq) plus bevacizumab (Avastin; n = 14; 21.5%), nivolumab (n = 13; 20.0%), pembrolizumab (Keytruda; n = 13; 20.0%), or other (n = 5; 7.7%).

Investigators performed a multivariable Cox regression analysis to adjust for imbalances in prespecified prognostic covariates, such as IMDC risk, histologic subtype, and age. Results revealed that the hazard ratio (HR) for OS between immune checkpoint inhibitor–based therapy and VEGF treatment was 0.58 (95% CI, 0.35-0.94; 

= .03), while it was 0.48 (95% CI, 0.29-0.80; 

= .005) for immunotherapy-based treatment versus mTOR therapy.

Additionally, the HR for TTF with immunotherapy-based treatment versus VEGF therapy was 0.72 (95% CI, 0.72; 95% CI, 0.51-1.0; 

= .06) and it was 0.54 (95% CI, 0.37-0.78; 

= .001) for immunotherapy-based treatment versus mTOR treatment.

When looking at ORR per histologic subgroup, those with papillary disease who received VEGF treatment experienced an ORR of 13.0% versus 3.7% with mTOR therapy and 31.6% with immunotherapy-based treatment (

= .002). In patients with the chromophobe subtype, the ORRs were 20.6% versus 13.6% versus 9.1% in those who received VEGF therapy, mTOR therapy, and an immunotherapy-based regimen, respectively (

= .527). Those with an unclassified disease subtype experienced ORRs of 15.2%, 0%, and 33.3%, respectively (

“The ORR of 25% in the entire population is consistent with the existing literature of immune checkpoint inhibitor therapy in non–clear cell RCC, with lower responses seen in the chromophobe subgroup and higher responses seen in the papillary subgroup,” the authors of the poster wrote. “The study population was predominantly papillary RCC, and the effectiveness of immune checkpoint inhibitor–based therapy in other less common histologic subtypes remains inconclusive.”

The results yielded from the analysis must be confirmed in prospective, randomized clinical trials, the authors concluded.

1. Graham J, Wells C, Dudani S, et al. Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma. 

. 2021;39(suppl 6):316. doi:10.1200/JCO.2021.39.6_suppl.316

Determining the optimal treatment approach for patients with non–clear cell renal cell carcinoma has long been an unmet medical need in the field. 

Study suggests immunotherapy may be optimal frontline choice in non–clear cell RCC

The antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) induced an overall response rate (ORR) of 27% in heavily pretreated patients with metastatic urothelial carcinoma following the failure of both platinum-based chemotherapy and checkpoint inhibition, according to the final data from cohort 1 of the phase 2 TROPHY-U-01 trial presented during the 2020 ESMO Congress.

There were 31 responders, including 6 (5%) complete responses (CRs) and 25 (22%) partial responses (PRs). The median response duration with the ADC was 5.9 months. 

"The final results from TROPHY-U-01 cohort 1 confirmed the interim findings and the results from the prior phase 1 study, and showed that sacituzumab govitecan is generally well tolerated and has significant anticancer activity in heavily pretreated [patients with] metastatic urothelial cancer who have progressed on both platinum-based chemotherapy and checkpoint inhibitors,” Yohann Loriot, MD, PhD, lead author of the study and a medical oncologist at the Institut de Cancèrologie Gustave Roussy, in Villejuif, France, said in a presentation during the congress.

The open-label, global phase 2 TROPHY-U-01 trial evaluated sacituzumab govitecan in 3 cohorts: patients with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy and checkpoint inhibition (cohort 1); those who were ineligible for platinum-based chemotherapy and progressed following checkpoint inhibition (cohort 2); and those who never received checkpoint inhibitors but had progressed on platinum-based therapy (cohort 3).

The findings shared at ESMO were from cohort 1, which patients received 10 mg/kg of the ADC on days 1 and 8, every 21 days and continued treatment until loss of clinical benefit or intolerable toxicity. The primary end point of this analysis was ORR per central review.

Among the evaluated patients, the median age was 66 years, with 23% of patients 75 years of age or older and 78% male. Moreover, the majority of patients were white, at 74%. Twenty-eight percent of patients had an ECOG performance status of 0, while 72% had a status of 1. Overall, 62% of patients had visceral metastases; 40% had lung metastases, 28% had liver metastases, and 12% had other.

The median number of prior anticancer regimens received was 3. “Therefore, this is a heavily pretreated patient population, and sacituzumab govitecan was the fourth line of therapy,” noted Loriot.

Sixteen (14%) of 113 evaluable patients continued to receive treatment with sacituzumab govitecan at the time of the analysis. The majority of patients who discontinued treatment did so because of disease progression (66%; n = 75). Only 7% (n = 8) of patients discontinued the ADC because of toxicity. Three percent of patients (n = 3) discontinued because of withdrawn consent and 3% (n = 3) died. The median time on treatment was 3.7 months, according to Loriot, and the maximum time on treatment is 16 months thus far. Fifty-percent of patients (n = 56) are in follow-up for survival.

The median time to onset of response was 1.6 months. The ORR, median DOR, and median time to response reported were consistent with investigator assessments.

“There was a reduction in target lesion size in three-quarters of patients,” noted Loriot. Moreover, 27 of 31 responders were alive with 8 of these patients still experiencing a response and receiving the treatment at the time of the data cutoff.

Regarding safety, diarrhea was the most commonly experienced treatment-related adverse effect, occurring in two-thirds of patients (all grade, 65%); this is consistent with what has been reported in prior studies with the ADC. However, most of these effects were grade 1/2, noted Loriot.

Grade 3 diarrhea occurred in 9% of patients, with only 1% experiencing grade 4. Forty-six percent of patients experienced neutropenia, with 22% having a grade 3 effect and 12% reporting a grade 4 effect. “However, neutropenia was manageable with dose reductions and granulocyte colony-stimulating factor; it was reversible,” said Loriot. “Thirty-percent of patients received GCSF either as primary prophylaxis or in response to neutropenia.”

Moreover, 1 treatment-related death was reported, with a patient presenting with sepsis due to febrile neutropenia.

The phase 3 TROPiCs-04 trial (NCT04527991) is being launched to confirm these promising phase 2 results.

“Sacituzumab govitecan received fast track designation [from the FDA] for this indication and may have the potential to change practice in this setting,” Loriot concluded.

1. Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based regimens and checkpoint inhibitors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA24.

Pivotal phase 3 trial launched to confirm promising results in metastatic urothelial carcinoma.

Kristi Rosa

Articles

UGN-101 shows long-term recurrence-free survival benefit in low-grade UTUC

Study highlights prognostic factors for Lutetium 177 in mCRPC

Study suggests immunotherapy may be optimal frontline choice in non–clear cell RCC

Sacituzumab Govitecan sustains strong activity in heavily pretreated bladder cancer