Assessing Effectiveness and Toxicities in Emerging Therapies in Bladder Cancer

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The expansion of the treatment field for patients with bladder cancer has led to the use of both antibody-drug conjugates (ADC) and tyrosine kinase inhibitors (TKI) for patients with metastatic urothelial cancer (mUC) with proven clinical activity, but challenging toxicities as well. Although the frontline standard of care remains platinum-based chemotherapy, these new targeted agents are expanding treatment beyond the front line and in the maintenance setting.

At the 2023 National Comprehensive Cancer Network (NCCN) Annual conference Arlene O. Siefker-Radtke, MD, discussed these developments highlighting the ongoing use and clinical activity with enfortumab vedotin (Padcev), erdafitinib (Balversa), and sacituzumab govitecan (Trodelvy).¹ These targeted therapies are taking on a new role for patients where previous targeted options in mUC treatment were just the use of atezolizumab (Tecentriq) or pembrolizumab (Keytruda) for patients with a high PD-L1 status or ineligible for platinum-based chemotherapy.² Moreover, these targeted therapies have demonstrated an expanded role in maintenance therapy even as the recommended therapy is avelumab (Bavencio) for patients with a complete/partial response (CR/PR), or stable disease (SD), to platinum based chemotherapy.

“How do we choose a good target? Well, we first need a target that’s easily reproducible. One where anyone would agree that that’s the appropriate target that can achieve CLIA certification,” explained Radtke, professor in the department of genitourinary medical oncology, division of cancer medicine, at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “It can’t be open to interpretation, we all must say this is the right target to hit, and it’s even better to have a target that does not fluctuate or change.”

According to Radtke, this is why these new targeted therapies show so much promise for this patient population because a patient’s PD-L1 status can change depending on their response to chemotherapy and other treatments.

Antibody-Drug Conjugates in mUC

Enfortumab vedotin is the first antibody-drug conjugate (ADC) for patients with mUC and showed an improved progression-free survival (PFS) and overall survival (OS) for patients on the single agent vs preselected chemotherapy in the EV-301 study (NCT03474107).³ In the phase 3 trial, patients were randomized 1:1 to either enfortumab vedotin (n = 301) or preselected chemotherapy (n = 307) after having a prior platinum containing regimen to treat their advanced bladder cancer.

A median OS of 12.88 months (95% CI, 10.58-15.21) was seen in patient on enfortumab vedotin compared with 8.97 months (95% CI, 8.05-10.74) for patients on chemotherapy (HR 0.70; 95% CI, 0.56-0.89, P = 0.001). An improved overall response rate (ORR) was also seen for patients on enfortumab vedotin at 40% vs 18% in the taxane or vinflunine arm and PFS also benefited patients on the ADC vs chemotherapy at a median of 5.5 months vs 3.7 months, respectively.

An update of the trial at 24-months of follow up continued to show the superior OS for patients on enfortumab vedotin vs chemotherapy at a median of 12.91 months (95% CI, 11.01-14.92) vs 8.94 months (95% CI, 8.25-10.25) with a HR of 0.7 (95% CI, 0.58-0.85, P = 0.000015).⁴ These data, according to Radtke, show that the ADC treatment is here to stay for patients with mUC, especially those who had a prior chemotherapy or prior chemotherapy and immune checkpoint inhibitor (ICI). Moreover, results from the EV-201 phase 2 study (NCT03219333) showed that in a cohort of patients given the ADC earlier in the treatment path had an increased PFS at a median of 5.8 months and OS at a median of 14.7 months with an objective response rate (ORR) of 52% among 89 patients.

Yet, results from the EV-201 study highlighted the number of adverse events (AEs) that remain for patients on enfortumab vedotin. In the phase 2 trial treatment-related AEs led to discontinuation in 16% of patients with peripheral neuropathy (4%) being the most common reason and 4 deaths were treatment related due to acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.

Three of these deaths occurred within 30 days of the first dose of enfortumab vedotin for patients with a BMI level of 30 kg/m2 or greater. In comparison, any-grade AEs of note in the EV-301 study included rash (44.9%), severe cutaneous adverse reaction (20.3%), peripheral neuropathy (48%), peripheral neuropathy sensory events (45.6%), and dry eye (16.2%).

“So, why do we see more toxicity [in EV-201]? We see similar activity [between both trials], but a little more toxicity. I think it deals with how we’re clearing enfortumab vedotin,” explained Radtke in her presentation at the conference. “There’s a small proportion of that that is excreted in the urine, but the majority of this compound is cleared in the liver via the biliary tree.”

The second ADC to show promise in treating patients with mUC was sacituzamab govitecan that targets Top-2 expression in a patient’s tumor, which is expressed in approximately 83% of mUC patient samples.⁵ Results from the multicohort, open-label, phase 2 TROPHY-U-01 (NCT03547973) study showed that this therapy was active in the 113 patients on the trial whose disease progressed after platinum chemotherapy and subsequent immunotherapy.

An ORR of 27% was observed (95% CI, 19.5%-36.6%) with 77% of patients having a decrease in their measurable disease.⁶ PFS and OS were not deemed significant, yet the duration of response was 7.2 months (95% CI, 3.5-7.2 months). Neutropenia was the most common grade 3 or higher AE observed in 35% of patients, along with leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%).

“This antibody uses a hydrolysable linker, so it probably accounts for more of the toxicity [as] there’s more hydrolysis in the circulation, resulting in systemic absorption and systemic release,” said Radtke, explaining that the makeup of this compound accounts for AEs like diarrhea and neutropenia, but that in the study these AEs were ultimately manageable.

Managing AEs in Biomarker Therapy

Erdafitinib marks the first biomarker targeted therapy for patients with mUC as a pan-FGFR inhibitor. This therapy has shown its effectiveness in the open-label, non-comparator, phase 2 BLC2001 study (NCT02365597) for patients who had 1 to 3 lines or more of a prior therapy with 77% of patients on the study having a present visceral metastasis.⁷

For the 101 patients treated with selected erdafitinib at 8 mg a day, at a median follow up of 24-months investigators observed an objective response rate of 40% (95% CI, 30-49) and a median PFS and OS of 5.5 months and 11.3 months, respectively. This has warranted further follow up with this therapy, but according to Radtke there are several AEs that need to be managed with lifestyle related changes.

While the study showed that the majority of AE were grade 1 to 2 and all grade 4 and 5 AEs were unrelated to the drug, Radtke noted that hyperphosphatemia peaked at 6 weeks after initialization of treatment with normalization occurring at cycle 5. Prevention of this includes the patient taking on a low phosphorous diet that maxes out at 600 to 800 mg of phosphorous a day, so patients need to avoid food items like cola beverages, cheese and dairy, and processed foods. According to Radtke, phosphorous levels may be a surrogate for inhibition of FGFR-3 and if patients are not achieving the target phosphate levels then increased levels of sevelamer given can be.

Other AEs to look out for on this therapy include nail changes like onycholysis and paronychia that can be treated with a break in therapy, when warranted, and wearing gloves when having to wash the dishes or do work. Of note, 27 patients in the BLC2001 study developed central serous retinopathy where patients will present with blurred vision or wavy lines in their eyesight. Recommendations suggest withholding treatment and resume upon improvement checking on the patient’s status every 2 weeks, however, Radtke notes that it’s important to ask patients to blink a few times and determine if they are experiencing eye dryness or continued central serous retinopathy.

Combination Therapy and The Future of Treating Bladder Cancer

With 3 targeted therapies available for treating patients with mUC, the growth of the field has been impressive, but more therapies are on the horizon as investigators prove the usefulness of combining these drugs with immunotherapy.

In the case of enfortumab vedotin, the FDA granted approval to the combination of the ADC with pembrolizumab for patients with locally advanced or mUC who are not eligible to receive cisplatin-containing chemotherapy.⁸ This approval was based on the phase 1b/2 EV-103 trial (NCT03288545; KEYNOTE-869) that evaluated the combination showing a confirmed ORR of 64.5%, and in enfortumab vedotin alone the confirmed ORR was 45.2%, with a median DOR of 13.2 months, however, a median DOR was not reached on the combination.⁹ The most common TRAEs included glucose increased (74%), aspartate aminotransferase increased (73%), and rash (71%).

Other ongoing trials have begun to show promise in smaller subsets of patients, including the early results of the phase 2 NORSE trial (NCT03473743) that looked at erdafitinib alone or combined with cetrelimab for patients with mUC and FGFR alterations in their tumor.¹⁰ Responses were seen with patients who had FGFR mutations or alterations, whereas patients with a low PD-L1 status had a 71% response rate compared with 50% for those on erdafitinib alone.

“We really are getting closer to that targeted, personalized strategy for our [patients with] bladder cancer. And with time, we hope to build better combinations, and maybe even better sequences of treating, knowing which patients should receive erdafitinib or enfortumab vedotin first to hopefully benefit our patients, improve the toxicity of the therapies they receive, but also improve their overall survival, which I am seeing being extended now compared to the typical 1 year that we had historically,” concluded Radtke.

References

1. Siefker-Radtke A. Emerging Therapies in the Treatment of Bladder Cancer. Presented at: National Comprehensive Cancer Network 2023 Annual Conference; March 31-April 3, 2023; Orlando, Florida.

2. National Comprehensive Cancer Network. Bladder Cancer (Version 1.2023). https://bit.ly/3KzQShJ. Accessed April 12, 2023.

3. Powles T, Rosenberg J, Sonpavde G, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. doi: 10.1056/NEJMoa2035807

4. Rosenberg J, Powles T, Sonpavde G, et al. Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. J Clin Oncol. 2022 June 1;40(16):42516-42516. doi: 10.1200/JCO.2022.40.16_suppl.4516

5. Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019 Mar 1;12:1781-1790. doi: 10.2147/OTT.S162447

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 Aug 1;39(22):2474-2485. doi: 10.1200/JCO.20.03489

7. Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882. doi: 10.1016/S1470-2045(21)00094-2

8. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA.gov. Accessed April 14, 2023. https://bit.ly/4062b7b

9. 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):LBA73. doi:10.1016/annonc/annonc1089

10. Powles T, Carroll D, Chowdhury S, et al. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med. 2021 May;27(5):793-801.