An Influx of Data Expands Options, Improves Treatment for Bladder Cancer

OncologyLiveVol. 23/No. 20Volume 23Issue 20

In Partnership With:

The past decade has seen a change in the tide for patients with bladder cancer with the introduction of checkpoint blockade and molecular profiling.

Pedro C. Barata, MD, MSc

The past decade has seen a change in the tide for patients with bladder cancer with the introduction of checkpoint blockade and molecular profiling. These advances have moved beyond the one-size-fits-most approaches of intravesical chemotherapy and BCG instillation, and investigators have ridden the waves of improvements for patients across histologies to address unmet needs in recurrent or residual disease and in cisplatin-ineligible patient populations.1,2

Standard of care still dictates the necessity of maximal transurethral resection of bladder tumor to aid in pathology and staging of disease; however, investigators have also been exploring ways to get patients to therapy faster, rather than waiting and relying on results of tissue analyses.1

“What’s challenging in the field right now is the pace of updates. Every 6 months or so, we’re seeing new, important data in urothelial carcinoma, specifically in the advanced setting, but even in the nonmetastatic setting, which changes the way we think of the disease and changes the way we should treat patients,” Pedro C. Barata, MD, MSc, said in an interview with OncologyLive®. “A challenge that we need to overcome as a community is to make sure we are up to speed with these new data and the importance of novel therapies available for our patients.”

JAVELIN Bladder 100 Shakes Up the Standard of Care

Barata, a genitourinary medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, noted that practice-changing data arrived 2 years ago with the JAVELIN Bladder 100 trial (NCT02603432). Platinumbased chemotherapy is considered the standard of care in advanced disease and is associated with modest survival benefit, with up to 50% of patients experiencing objective response and up to 80% achieving disease control; however, most patients go on to develop treatment resistance.3

Investigators sought to evaluate the effect of maintenance avelumab (Bavencio) in patients with locally advanced or metastatic urothelial cancer following completion of firstline chemotherapy. Patients enrolled on the study received 4 to 6 cycles of gemcitabine plus cisplatin or carboplatin, followed by avelumab (n = 350) or best supportive care (n = 350).

In the overall population, the median overall survival (OS) with avelumab was 23.8 months (95% CI, 19.9-28.8) vs 15.0 months (95% CI, 13.518.2) with best supportive care (BSC; HR, 0.76; 95% CI, 0.63-092; P = .0036). The survival benefit was more pronounced at 30.9 months at data cutoff in the PD-L1–positive cohort who received avelumab (n = 189) vs 18.5 months in the control arm (n = 169; HR, 0.69; 95% CI, 0.52-0.90; P = .0064).3 The 30-month OS rates were 43.7% vs 33.5% in the overall population and 51.3% vs 38.5% in the PD-L1–positive populations with avelumab and BSC, respectively.3

Chemotherapy remains the best treatment option for patients to date, but the results of JAVELIN Bladder 100 have integrated chemoimmunotherapy as a marker of success in the front line, signaling the added importance of testing, according to Guru P. Sonpavde, MD. “Determining PD-L1 status is cheap. It’s a lot cheaper than doing genomic profiling of the tumor [and] takes much less time. It’s very practical and a way to identify patients who may or may not benefit [from a PD-L1 inhibitor],” Sonpavde said in an interview with OncologyLive®. He is the director of genitourinary oncology and the Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute in Orlando, Florida.

Sonpavde added that PD-L1 status, coupled with other factors, will play into treatment decision-making. “For example, a patient who has a very high, unfavorable neutrophil lymphocyte ratio—which is a poor prognostic factor—or a patient with reversible metastasis or low PD-L1 [status], these might not be the patients you want to start with the first-line PD-1 inhibitor,” he said. “This is something to think about it, especially when you have many options in these settings. Should you be giving an immune checkpoint inhibitor, or should you be giving other drugs, such as enfortumab vedotin-ejfv [Padcev], which is available in the second- and third-line settings? I think that this is a model that could be useful in the clinic when you have many options in front of you.”

Shifts in the Sequencing

As advances push chemoimmunotherapy into the front line, a domino effect has triggered changes in the second-line setting as well. However, for patients who are cisplatin ineligible, effective treatment options represent a significant unmet need.

“We’re moving checkpoint inhibitors into the front line with avelumab. That means that second-line therapy used to be checkpoint inhibitors, and now we’re getting other options upon progression,” Barata said, adding that the classic definition for treatment was whether patients were cisplatin eligible or ineligible. “The paradigm is really changing because it’s possible [to administer] checkpoint inhibitors much sooner than we started a few years ago and we can get antibody-drug conjugates that were really not an option for us just 3 or 4 years ago.”

Several trials have added data with strong clinical significance in the past year, highlighting the need to stay on top of presentations and published findings (Table4-8).

Table. New Treatment Options for Patients With Previously Treated Urothelial Carcinoma4-8

EV-103 Trial

Standard criteria for patients who are cisplatin ineligible include those with poor renal function, grade 2 or greater hearing loss, poor ECOG performance status, cardiovascular disease, or peripheral neuropathy.2 The development of antibody-drug conjugates (ADCs) to fill this void in treatment for metastatic urothelial carcinoma led to enfortumab vedotin, which binds to the protein NECTIN4 and has a payload of monomethyl auristatin E.4

The agent demonstrated activity as a single agent in the phase 2 EV-201 trial (NCT03219333) in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who had received prior PD-1/PD-L1 inhibitors. The FDA approved the agent based on the confirmed overall response rate (ORR) of 52% (95% CI, 40.8%-62.4%) among 125 patients. Subgroup analyses demonstrated responses in those with primary tumor sites in the upper tract (ORR, 61%), those with with liver metastasis (ORR, 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR, 48%).4,5

The agent also demonstrated synergy in combination with immunotherapy, specifically pembrolizumab (Keytruda) in cohort K of the phase 1/2 EV-103 trial (NCT03288545) in the first-line setting.9

“Enfortumab vedotin and pembrolizumab as monotherapy have each shown antitumor activity with a survival benefit in pretreated patients with locally advanced or metastatic urothelial cancer,” Jonathan E. Rosenberg, MD, said in an interview with OncologyLive®. “Enfortumab vedotin/pembrolizumab was previously evaluated in the EV-103 dose-escalation cohort A [n = 40], which showed encouraging safety and efficacy activity with a response rate of 73.3%.” Rosenberg is chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, and a professor of medicine at Weill Cornell Medical College in New York, New York.

“The OS in that cohort was an impressive 26.2 months, which is roughly at least double what you might expect with gemcitabine- and carboplatin-based regimens in historical data and probably, I suspect, better than the current treatment paradigm of chemotherapy followed by maintenance avelumab, although there have not been any randomized trials,” Rosenberg added.

A total of 149 patients were included in the study, with 76 treated with enfortumab vedotin plus pembrolizumab and 73 treated with enfortumab vedotin alone. The confirmed ORR for enfortumab vedotin plus pembrolizumab was 64.5%, and the median duration of response (DOR) was not reached. Confirmed ORR for enfortumab vedotin alone was 45.2%, with a median DOR of 13.2 months.9 The study was not powered to compare the arms in cohort K.

Regarding adverse events (AEs), 15.6% of patients receiving enfortumab vedotin plus pembrolizumab and 24.3% of patients receiving enfortumab vedotin alone stopped treatment due to an AE. The most common AEs seen in patients receiving enfortumab vedotin plus pembrolizumab included fatigue, peripheral sensory neuropathy, and alopecia. Three treatment-related AEs leading to death (3.9%) were seen in the combination group and 2 (2.7%) were seen in the monotherapy group.9 Rosenberg reported that skin reactions were more frequent with patients receiving enfortumab vedotin plus pembrolizumab, although none were serious.

Sonpavde noted, “What we’ve seen so far suggests that the enfortumab vedotin/pembrolizumab combination in the first line for cisplatin-ineligible patients is quite active. We believe that this could potentially have a practice impact.” He added that the EV-103 trial also evaluated a cohort of patients who received firstline atezolizumab (Tecentriq) or pembrolizumab, which might be an option in select patients.

TROPHY-U-01 Trial

Sacituzumab govitecan-hziy (Trodelvy) is another ADC with accelerated approval for the treatment of patients with metastatic urothelial carcinoma with disease progression on platinum-based chemotherapy and a checkpoint inhibitor.6 This population represents another group of patients who do not have durable treatment options following standard of care.

Data from the TROPHY-U-01 trial (NCT03547973) showed that the Trop-2–directed ADC had a confirmed ORR of 27.7% (31 of 113; 95% CI, 19.6%-36.9%), including a 5.4% complete response rate with a median DOR of 7.2 months. The median progression-free survival (PFS) with sacituzumab govitecan was 5.4 months (95% CI, 3.5-6.9), and the median OS was 10.5 months (95% CI, 8.2-12.3).6 Confirmatory data are being generated in the phase 3 TROPiCS-04 trial (NCT04527991).

COSMIC-021 Trial

Tyrosine kinase inhibitors (TKIs) may also influence the treatment landscape for patients who are cisplatin ineligible or experience disease progression on an immune checkpoint inhibitor, as demonstrated in findings from the multicenter, phase 1b COSMIC-021 trial (NCT03170960), in which participants received cabozantinib (Cabometyx) plus atezolizumab.10

Three cohorts were evaluated: those who had received no prior therapy and were ineligible for cisplatin-based chemotherapy (n = 30), those who had received no prior therapy and were eligible for cisplatin-based chemotherapy (n = 30), and those who had received 1 prior immune checkpoint inhibitor and no prior VEGFR TKI therapy (n = 31).10

The ORR was 20%, 30%, and 10%, respectively, with disease-control rates of 80%, 63%, and 61%, respectively. The median PFS and OS for each of the 3 cohorts were 5.6 and 14.3 months, 7.8 and 13.5 months, and 3.0 and 8.2 months, respectively. Investigators concluded that the combination demonstrated encouraging clinical activity in these cohorts.10

Biomarkers Leave a Trail for Investigators

The rapid uptake of molecular testing is starting to signal even more nuances in the treatment of bladder cancer, with retroactive and prospective analyses revealing actionable targets in the space.

FGFR3

FGFR3 is an attractive therapeutic target in bladder cancer given the 10% to 30% prevalence of FGFR3 aberrations (activating mutations or aberrant gene fusions) in these tumors and their preclinical sensitivity to FGFR-targeted therapy.11 Further, FGFR3 aberrations lead to oncogenic signaling through the MAPK and PI3K pathways. Activating mutations in FGFR3 occur in 10% to 20% of muscle-invasive bladder cancers.11

The FGFR TKI erdafitinib (Balversa) was FDA approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer with susceptible FGFR3 or FGFR2 genetic alterations who have progressed on platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.12 The decision was based on data from the phase 2 BLC2001 trial (NCT02365597).

Longer-term data from BLC2001 published in The Lancet showed that at a median follow-up of 24.0 months (range, 22.7-26.6) with a median treatment duration of 5.4 months (range, 2.8-9.0), patients treated with the erdafitinib regimen achieved an objective response rate of 40% (95% CI, 30%-49%; n = 40/101). Further, 36% of the 40 responding patients experienced a partial response, and 4% achieved a complete response. Forty-one percent of responders had a best response of stable disease for at least 36 days, which translated to an overall disease control rate of 80% (95% CI, 72%-88%).7

The median PFS with erdafitinib was 5.5 months (95% CI, 4.3-6.0), and the 12-month PFS rate was 21% (95% CI, 13%-29%). The median OS was 11.3 months (95% CI, 9.7-15.2), and the 12-month and 24-month OS rates were 49% (95% CI, 39%-59%) and 31% (95% CI, 22%-40%), respectively.7

The most common treatment-emergent AEs of any grade included hyperphosphatemia (grade 1 or 2, 76%; grade 3, 2%), stomatitis (21% and 14%, respectively), diarrhea (50% and 4%), and dry mouth (45% and 1%).

The proportion of patients with central serous retinopathy, which is a known class effect of FGFR inhibitors and a treatment-emergent AE of special interest, was 27% and 85% of instances were grade 1 or 2. The median time to first onset of central serous retinopathy was 53 days (range, 32-100) for any grade and 94 days (range, 72-154) for grade 3 effects.7

POU2F2

The absence of POU2F2 may be predictive of response to maintenance avelumab in patients with advanced or metastatic urothelial carcinoma, according to findings from an analysis of peripheral blood samples taken in the JAVELIN Bladder 100 trial.13 POU2F2, a transcription factor with known roles in B-cell maturation and participation in T-cell dependent humoral immunity, was strongly associated with the T-effector signature.13

“In the peripheral blood, the chromatin signature was looked at in the peripheral blood cells, the white blood cells, and what was found was the lack of a signature, called the POU2F2, in peripheral blood, and this is derived from the chromatin signature within the nuclei of these white blood cells,” Sonpavde said. “The absence of the signature in peripheral blood correlated with increased gene expression, immune gene expression in tumor tissue, and correlated with better outcomes with maintenance avelumab.”

The analysis showed that POU2F2 expression in the tumor was linked to a survival benefit with maintenance avelumab. The benefit was highest in patients who had POU2F2 expression and a tumor mutation burden above the median threshold of 7.66 nonsynonymous single- nucleotide variants per Mb (HR, 0.69; 95% CI, 0.51-0.93). Moreover, the absence of the POU2F2 loop in the blood samples was also associated with a better survival benefit with maintenance avelumab (HR, 0.62; 95% CI, 0.36-1.08).13

The median survival probability for the 22 patients who received avelumab and did not have POU2F2 expression but did have a low tumor mutation burden was 36.99 months vs 13.6 months for the 18 patients who only received BSC.13

HER2

Another agent making a move in the treatment of patients with metastatic urothelial carcinoma is disitamab vedotin (RC48-ADC), a humanized anti-HER2 ADC.8 Under investigation in 2 studies, the agent is for patients with HER2-positive disease documented as immunohistochemistry (IHC) 2+ or 3+.

The 2 single-arm phase 2 studies (RC48-C005 [NCT03507166] and RC48-C009 [NCT03809013]) enrolled 107 patients with metastatic urothelial carcinoma, with 64.5% having received at least 2 lines of systemic chemotherapy. Patients received disitamab vedotin at 2 mg/kg intravenously every 2 weeks. The confirmed ORR with the ADC per blinded independent review committee was 50.5%.8

In a subgroup analysis, the confirmed ORR was 52.1% for patients with liver metastasis (n = 48) and 55.6% for patients who had received prior PD-1/L1 treatment (n = 27). In terms of HER2 expression stratification, the confirmed ORR was 62.2% for those with HER2 IHC 2+ and fluorescence in situ hybridization (FISH)+ or with IHC 3+ (n = 45); 55.6% for HER2 IHC 2+ and FISHunknown status (n = 9); and 39.6% for HER2 IHC 2+ and FISH-negative status (n = 53). The disease control rate was 82.2%.8

References

  1. Pardo JC, de Porras VR, Plaja A, et al. Moving towards personalized medicine in muscle-invasive bladder cancer: where are we now and where are we going? Int J Mol Sci. 2020;21(17):6271. doi:10.3390/ijms21176271
  2. Tran L, Xio JF, Agarwal N, Duex JE, Theodorescu D. Advances in bladder cancer biology and therapy. Nat Rev Cancer. 2021;21(2):104-121. doi:10.1038/s41568-020-00313-1
  3. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487
  4. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6):394. doi:10.1200/JCO.2021.39.6_suppl.394
  5. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Ann Oncol. 2022;33(suppl 7):S1441. doi:10.1016/j.annonc.2022.08.079
  6. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2472-2485. doi:10.1200/JCO.20.03489
  7. Pal SK, Agarwal N, Singh P, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): results from cohorts 3, 4, 5 of the COSMIC-021 study. J Clin Oncol. 2022;40(suppl 16):4504. doi:10.1200/JCO.2022.40.16_suppl.4504
  8. Balversa. Prescribing information. Janssen Pharmaceutical Companies; 2022. Accessed October 4, 2022. bit.ly/3CEVYa3
  9. Siefker-Radtke AO, Necchi A, Park SH, et al; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol.2022;23(2):248-258. doi:10.1016/S1470-2045(21)00660-4
  10. Powles TB, Sridhar S, Bellmunt J, et al. Genomic biomarkers in peripheral blood (PB) from patients (pts) enrolled in the JAVELIN Bladder 100 trial of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (aUC). Ann Oncol. 2022;33(suppl 7):S1442. doi:10.1016/j.annonc.2022.08.080
  11. Sheng X, He Z, Shi Y, et al. RC48-ADC for metastatic urothelial carcinoma with HER2-positive: combined analysis of RC48-C005 and RC48-C009 trials. J Clin Oncol. 2022;40(suppl 16):4520. doi:10.1200/JCO.2022.40.16_suppl.4520
Related Videos
View All
Related Content