Tony Berberabe, MPH

Findings from the single-arm phase 2b Optima II trial shared during the 2022 AUA Annual Meeting showed that health-related quality-of-life (HRQOL) outcomes were maintained with the mitomycin-containing reverse thermal gel UGN-102 in patients with low-grade non–muscle-invasive bladder cancer (NMIBC).

Traditionally, low-grade NMIBC is treated by transurethral resection of the bladder (TURBT), which can lead to worsening health-relate quality of life (HRQOL), according to lead presenter Angela B. Smith, MD, MS, vice chair of academic affairs, director of urologic oncology, and associate professor of urology at the University of North Carolina School of Medicine in Chapel Hill. 

This noninvasive approach evaluated HRQOL through patient-reported questionnaires 3 months after initiation of study medication. Eleven QOL measures were evaluated including questions about urinary symptoms, malaise, future worries, bloating/flatulence, intravesical treatment issues, male sexual problems, sexual intimacy, partner contamination, female sexual problems, sexual function, and sexual enjoyment.

Investigators reported that the gel did not lead to decrements in urinary symptoms, bloating/flatulence, or malaise; further, sexual function mildly worsened. Among patients who completed the questionnaire, 70% (31 of 44) achieved a complete response, defined as having a negative endoscopic examination, cytology, and for-cause biopsy. Demographic and clinical characteristics were not correlated with HRQOL changes, reported the investigators.

Primary outcome measures included complete response rate, and secondary outcome measures included durable complete response, and frequency, seriousness, and severity of adverse events. Area under the curve, concentration, and maximum concentration were also measured.

Eligibility requirements included patients with newly diagnosed or historic low grade NMIBC who are at intermediate risk for progression, defined as having the presence of multiple tumors, recurrence, or a solitary tumor greater than 3 cm. Patients are ineligible if they have received Bacillus Calmette-Guérin treatment for urothelial carcinoma within the past 2 years and a history of neurogenic bladder, active urinary retention, and any condition that would prohibit normal voiding.

A total of 63 patients enrolled in the trial (NCT03558503) and received 6 weekly doses of the mitomycin-containing thermal gel with a sustained release time of up to 8 hours. Forty-four patients were designated for the HRQOL cohort and completed questionnaire. The majority of the HRQOL cohort was comprised of men (61%), patients over 65 years of age (57%), and non-Hispanic Whites (89%). The Sign test was used to measure longitudinal changes, and demographic and clinical characteristics were evaluated using regression testing.

Investigators reported that 10 patients (23%) were interviewed, and transcripts were double-coded using standard methods. In this subcohort, the majority were female (60%), non-Hispanic White (90%), and had a mean age of 65.6 years (8.4%).

During the interview sessions, patients expressed an appreciation of the nonsurgical treatment option and would recommend the gel to other patients, choosing the gel over TURBT. Additionally, patients noted that the gel did not require a long recovery period. Regarding safety, patients recalled minimal adverse events; however, frequent urination, restricted urethra, and blood in the urine were recorded.

The investigators concluded that a phase 3 trial is warranted.

1. Smith AB, Basak R, Mueller D, et al. Longitudinal health-related quality of life outcomes in adults with non-muscle-invasive bladder cancer receiving a chemoablative gel as a primary treatment (Optima II: Phase 2b, single arm, open-label trial). Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP54-06. Accessed May 15, 2022. https://bit.ly/3yEN9v3

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Study shows QoL sustained with mitomycin gel in low-grade NMIBC

Localized upper tract urothelial carcinoma treatment (UTUC) with infigratinib (Truseltiq) was associated with tumor reduction ranging from 25% to 83% in 44% of patients evaluated, researchers report.

The interim results from a biomarker-informed preoperative study of infigratinib, an oral inhibitor of FGFR1-3, demonstrated substantial activity and tolerability in patients with localized UTUC, according to findings of a phase 1b trial (NCT04228042).

 mutations were enrolled, with 11 patients deemed evaluable, according to investigators. Nine patients completed therapy and 2 continued on treatment as of the data cutoff; however, 2 patients experienced toxicities that resulted in dose reductions and 2 patients discontinued treatment. One patient discontinued treatment because of fatigue, and one patient discontinued because of liver injury. Four of 9 patients (44%) who completed therapy showed tumor reduction that ranged from 25% to 83%. From a clinical perspective, 2 patients who were scheduled to undergo nephroureterectomy were able to be treated through endoscopic management.

Surena F. Matin, MD, the Monteleone Family Foundation Distinguished Professor with Tenure in the Department of Urology at The University of Texas MD Anderson Cancer Center, Houston, presented findings during the 2022 American Urology Association Annual Meeting.

 Investigators reported that all responders had 

 mutations and that most non-responders had a prior history of bladder cancer, with 1 patient having a 

 fusion. Four patients who were biomarker negative did not have a response.

Patients with low-grade or localized cisplatin ineligible high-grade UTUC who were candidates for either ureteroscopic (URS) management or nephrourectomy/ureterectomy (NU/U) were enrolled from May 2021 to February 2022. Eligibility requirements included having a glomerular filtration rate of 30 or greater, sufficient biopsy tissue that could be used for mutational analysis, and a tumor map for residual tumors after biopsy and ablation. Patients were ineligible if they had a primary malignancy within 3 years, had uncontrolled bladder cancer, or had impaired gastrointestinal function that affects the absorption of oral infigratinib.

Patients received 2 cycles of 125 mg of oral infigratinib for 21 days of a 28-day cycle. After completing the second cycle, patients underwent tumor mapping based on URS or NU/U. The primary end point was tolerability and the secondary end points were objective response based on tumor mapping, circulating cell-free DNA analysis, expression of markers, and FGFR3 alteration type. Targeted sequencing was conducted using a NovaSeq 6000 solid tumor panel accounting for 610 somatic alterations including 33 fusions.

Previously, infigratinib had demonstrated activity in patients with metastatic urothelial cancer (response rate [RR], 25.4%), specifically in patients with metastatic UTUC (RR, 50%).

A phase 2 expansion study that evaluates additional cycles of the agent is underway.

1. Matin S, Adibi M, Shah A, et al. Interim results from a phase 1b clinical trial evaluating tolerability and activity of FGFR inhibition in localized upper tract urothelial carcinoma (UTUC). Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract OBA01-10. Accessed May 15, 2022. 

2. Dizman N, Rosenberg JE, Hoffman-Censits JHH, et al. Infigratinib in upper tract urothelial carcinoma vs urothelial carcinoma of the bladder and association with comprehensive genomic profiling/cell-free DNA results. 

. 2019;37(suppl 15):4510. doi:10.1200/JCO.2019.37.15_suppl.4510

Investigators reported that all responders had FGFR3 mutations and that most non-responders had a prior history of bladder cancer, with 1 patient having a FGFR3-TACC3 fusion. 

Infigratinib associated with tumor reduction in patients with localized upper tract urothelial carcinoma

Investigators reported clinically meaningful activity in patients with advanced renal cell carcinoma who were treated with second-line cabozantinib (Cabometyx, Cometriq) following treatment with first-line standard of care immunotherapy.

The findings came from a data set from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) presented during the 2022 ASCO Genitourinary Cancers Symposium. In addition, investigators evaluated outcomes for patients who received approved third-line treatment after second-line cabozantinib.

Broadly, the median time to treatment failure (TTF) was 7.59 months (95% CI, 6.61-8.98), median overall survival (OS) was 18.12 months (95% CI, 15.42-24.10), the 1-year treatment failure free rate was 34.3%, the 1-year OS was 63.5%, and the overall response rate (ORR) was 26.2%, according to lead author Vishal Navani, MA, MBBS, a medical oncology fellow at the University of Calgary, Tom Baker Cancer Centre, Alberta, Canada.

Limited data are available about the activity of cabozantinib in the second line after first-line standard of care immunotherapy: ipilimumab (Yervoy) plus nivolumab (Opdivo) or immune-oncology/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE).

A total of 364 patients were identified who had received cabozantinib in the second line. In the first-line setting, 78 patients had received the ipilimumab plus nivolumab combination, 46 patients received the IOVE combination, and 222 patients received other first-line treatment. ORR, TTF, and OS were key end points. Hazard ratios (HRs) were adjusted for favorable, intermediate, and poor risk groups.

When outcomes for second-line cabozantinib were stratified by frontline therapy, investigators reported that patients who received ipilimumab plus nivolumab had a median TTF of 6.90 (95% CI, 6.05-not evaluable [NE]), a median OS of 21.44 months (95% CI, 12.07-NE), 1-year treatment failure free rate of 34.3%, 1-year OS of 66.6%, and an ORR of 26.4% (14/53 patients).

In patients treated with front-line IOVE, the median TTF was 5.72 months (95% CI, 4.41-NE), median OS was 15.68 months (95% CI, 9.27-NE), 1-year treatment failure free rate of 26.8%, the 1-year OS was 54.3%, and the ORR was 32.5% (13/40 patients).

In patients treated with a first-line therapy other than immunotherapy, the median TTF was 7.96 months (95% CI, 6.81-9.63), median OS was 18.41 months (95% CI, 14.99-25.78), 1-year treatment failure free rate of 35.7%, 1-year OS was 63.5%, and the ORR was 23.9% (43/180 patients).

After adjusting for IMDC risk groups, investigators reported that the HRs for second-line cabozantinib OS and TTF for IOVE vs ipilimumab plus nivolumab were 1.73 (95% CI, 0.83-3.62; 

When patients who received third-line therapy (n = 125) were stratified by second-line cabozantinib, investigators found that the median TTF was 3.22 months (95% CI, 2.76-5.82), the median OS was 10.92 months (95% CI, 9.44-20.02), the 1-year treatment failure free rate was 19.9%, the 1-year OS was 48.4%, and the ORR was 13.3% (12/90 patients).

The investigators concluded that time to event end points and response rates were similar regardless of which first-line immunotherapy was administered. In the third-line setting, post cabozantinib treatment, single-agent VEGF inhibitors also have activity, but as expected, response was diminished compared with earlier lines of therapy, wrote the investigators.

1. Navani V, Wells C, Boyne DJ, et al. CABOSEQ: The efficacy of cabozantinib post up-front immuno-oncology combinations in patients with advanced renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). 

. 2022;40suppl 6; abstr 318). doi: 10.1200/JCO.2022.40.6_suppl.318

The investigators concluded that time to event end points and response rates were similar regardless of which first-line immunotherapy was administered. 

Clinically meaningful activity observed with second-line cabozantinib in advanced renal cell carcinoma

Findings from the phase 1/2 NICARAGUA study shared during the 2022 ASCO Genitourinary Cancers Symposium showed clinical activity with an acceptable safety profile for the combination of the PARP inhibitor niraparib (Zejula) and the multikinase inhibitor cabozantinib (Cabometyx, Cometriq) in patients with metastatic urothelial carcinoma (mUC) or renal cell carcinoma.

Lead author Daniel E. Castellano, MD, of the Hospital Universitario 12 De Octubre in Madrid, Spain, reported zero dose-limiting toxicities (DLTs) for dose level (DL) 1 (n = 5), stomatitis at DL 1.1 (n = 6), and decreased platelet count and anemia, diarrhea, and hepatotoxicity in DL 2 (n = 8). Two patients achieved partial response, both of whom had mUC, and a total of 17 patients had stable disease. The total clinical benefit rate (CBR) was 82.6%. When stratified by dose level, the CBR for DL 1 was 71.4%, DL 1.1 was 100.0%, and DL 2 was 77.8%.

Patients with UC whose tumors overexpress c-Met may benefit from this unique combination, thus investigators sought to evaluate the maximum tolerated dose (MTD) of the combination in patients with advanced kidney/UC, as well was preliminary efficacy in advanced UC.

Overall, the NICARAGUA trial (NCT03424201) followed a traditional 3 + 3 dose escalation design that measured safety, tolerability, DLT, and MTD. The primary objective of phase 1 was to determine the MTD of niraparib and cabozantinib in patients with advanced UC or renal cell carcinoma. Secondary objectives for phase 1 were to determine the safety profile for the combination at administered dose levels. Phase 2 measured the efficacy of the combination in patients with advanced UC. Phase 2 objectives were to determine the safety profile of the combination at selected dose levels and efficacy based on objective response rate, disease control rate, duration of response, and overall survival.

The planned dose levels for phase 1 were DL 1 niraparib 100 mg and cabozantinib 20 mg; DL 1.1 niraparib 100 mg and cabozantinib 40 mg; DL2 niraparib 200 mg and cabozantinib 20 mg; DL3 niraparib 200 mg and cabozantinib 40 mg; and DL 4 niraparib 200 mg and cabozantinib 60 mg. In phase 2, patients received niraparib and cabozantinib, once daily each, in 28-day cycles at doses recommended in the phase 1 portion. Patients continued with the dose escalation portion of the study until disease progression, a serious life-threatening adverse event, consent withdrawal, or severe noncompliance to the protocol.

Patients were accrued to each dose level in cohorts of 6 until the MTD was achieved, which was defined as the highest dose at which 1 out of 6 patients experience a DLT. DLT was evaluated during the first 2 cycles of treatment.

Patients were eligible for enrollment if they had advanced or metastatic disease not amenable to curative surgery or radiation, UC of the urinary tract that was confirmed by histology (for phase 1 and 2) or renal cell carcinoma (for phase 1), ECOG performance status of 0 or 1, and no prior therapy with PARP or c-MET inhibitors. Twenty-three patients were included in phase 1. Of those, 19 were deemed evaluable for DLT.

Although DLTs were observed in 2 of 6 patients in DL 2, the sponsor and coordinating investigators agreed to include 3 additional patients at this dose level to provide a greater sample size for risk/benefit assessment and to select the most suitable dose for the second phase of the trial.

Regarding safety, the most common toxicities observed were hypertension (31.8%), constipation (31.8%), and asthenia (31.8%), followed by palmar-plantar erythrodysesthesia (27.3%) and platelet count decrease (22.7%). One patient each reported anemia, diarrhea, hepatotoxicity, platelet count decrease, and palmar-plantar erythrodysesthesia, of grade 3 toxicity. No grade 4 or 5 toxicities were reported.

Based on the dose escalation portion of the study, investigators recommended the phase 2 dose as niraparib 100 mg/day plus cabozantinib 40 mg/day. The second phase of the study is now recruiting patients with metastatic UC.

1. Castellano DE, Duran I, Mellado B, et al. Phase I-II study to evaluate safety and efficacy of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial): Preliminary data of phase I study. 

. 2022;40(suppl 6; abstr 490). doi 10.1200/JCO.2022.40.6_suppl.490

The combo of the PARP inhibitor niraparib and the multikinase inhibitor cabozantinib showed positive early efficacy and safety signals in patients with metastatic urothelial carcinoma or renal cell carcinoma.

Tony Berberabe, MPH

Articles

Study shows QoL sustained with mitomycin gel in low-grade NMIBC

Infigratinib associated with tumor reduction in patients with localized upper tract urothelial carcinoma

Clinically meaningful activity observed with second-line cabozantinib in advanced renal cell carcinoma

Niraparib/Cabozantinib combo shows promise in bladder and kidney cancers