“We are getting closer to [optimizing a] targeted, personalized therapy for our patients with bladder cancer,” commented Arlene O. Siefker-Radtke, MD, Professor of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, and a member of the NCCN Bladder Cancer Guidelines Panel. At the NCCN 2023 Annual Conference, she discussed the safety and efficacy of emerging targeted therapies, which, when combined with immunotherapeutic agents, may outperform platinum-based chemotherapy and transform standard of care in this clinical context.
Frontline Standards of Care for Metastatic Urothelial Cancer
“The first-line standard of care [for the treatment of metastatic urothelial cancer] has changed a little bit,” Dr. Siefker-Radtke remarked. “Yet, platinum remains the backbone of the frontline standard.”
Per the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer, for patients with cisplatin-eligible disease, there is category 1 evidence supporting both DDMVAC (dose-dense methotrexate/vinblastine/doxorubicin/cisplatin) and gemcitabine/cisplatin as preferred regimens. Gemcitabine/carboplatin is recommended for those with cisplatin-ineligible disease. Those who cannot tolerate systemic therapy may be administered single-agent pembrolizumab; the NCCN Guidelines were updated to include atezolizumab as an alternative in this clinical context.1
Furthermore, maintenance therapy with avelumab may now be considered for patients who have achieved stable disease or better after undergoing frontline platinum-based chemotherapy. This recent category 1 recommendation provides clinicians with more options to improve long-term outcomes in the setting of metastatic urothelial cancer.
Targeted Therapy
Enfortumab Vedotin
“Following this frontline standard, we now have multiple targeted agents,” commented Dr. Siefker-Radtke. She began by discussing enfortumab vedotin, which was the first antibody–drug conjugate to be approved for the treatment of metastatic urothelial carcinoma. Its target, Nectin-4, is expressed in 83% of patient samples; thus, testing for this transmembrane protein is not required prior to treatment.2
The phase III EV-301 trial demonstrated improved median overall survival (OS; 12.9 vs 9.0 months) and progression-free survival (PFS; 5.5 vs 3.7 months) outcomes with enfortumab vedotin versus investigator’s choice in patients who received a prior platinum-containing chemotherapy regimen and had experienced disease progression during or after PD-1/PD-L1 inhibition; the objective response rates (ORRs) were 40% and 18%, respectively.3 After a longer duration of follow-up, this Nectin-4–directed antibody–drug conjugate continued to show an OS benefit.4
“This is certainly a treatment that is here to stay,” Dr. Siefker-Radtke stated. “However, there is toxicity [with enfortumab vedotin].” Rash, peripheral neuropathy, vision problems, and hyperglycemia were among the most frequently reported adverse events with enfortumab vedotin in this trial.4 Of note, the prescribing information carries a black box warning for Stevens-Johnson syndrome.5
Compared with the aforementioned data, primary findings from cohort 2 of the multicenter phase II EV-201 trial revealed similar OS (14.7 months) and PFS (5.8 months) outcomes in patients with cisplatin-ineligible bladder cancer compared with enfortumab vedotin.6 However, this population was found to experience more treatment-related adverse events (55%), including deaths (n=4), than patients with cisplatin-eligible disease.
“I think [the reason we see more toxicity in this population] deals with how we are clearing enfortumab vedotin; the majority of this compound is cleared in the liver,” Dr. Siefker-Radtke commented. “We should use caution when using this in platinum-ineligible patients, [especially in] those with cirrhotic livers.”
Erdafitinib
Erdafitinib was the first biomarker-directed therapy to be approved for metastatic urothelial carcinoma. The efficacy and safety of this FGFR inhibitor were evaluated in the phase II BLC2001 trial of patients with FGFR-altered disease; based on the results of an interim analysis, the starting dose was established as 8 mg per day, with potential uptitration to 9 mg per day, in a continuous regimen. The ORR was 40%, and 77% of the study population experienced a reduction in the sum of target-lesion diameters.7
“We saw similar activity with this agent regardless of whether there were node-only metastases or liver metastases,” Dr. Siefker-Radtke remarked. “Erdafitinib is a good cytoreducer.”
With a longer duration of follow-up, treatment with the selected regimen of erdafitinib continued to demonstrate antitumor activity.8 Median rates of PFS and OS were 5.5 and 11.3 months, respectively.
“We do not yet have a truly nontoxic therapy,” Dr. Siefker-Radke commented. She noted that hyperphosphatemia, nail changes (onycholysis and paronychia), palmar–plantar erythrodysesthesia, and central serous retinopathy were frequently reported in this population. Clinicians should be informed about how to prevent and treat these conditions, which may include dose modifications, over-the-counter and prescription medications, lifestyle adjustments, and, when necessary, referral to a specialist for further evaluation and management.
“Keep in mind [that] most people do need to hold erdafitinib after approximately 2.0 to 2.5 months of treatment, but are then able to resume therapy” Dr. Siefker-Radtke stated.
Sacituzumab Govitecan
The highly specific antibody–drug conjugate sacituzumab govitecan is designed to target Trop-2; this transmembrane glycoprotein has been found to be expressed in approximately 83% of metastatic urothelial cancers, rendering testing unnecessary before treatment.9 Sacituzumab govitecan employs a hydrolysable linker to facilitate targeted delivery in malignant cells.
“[This] probably accounts for more of the toxicity,” commented Dr. Siefker-Radtke. “There is more hydrolysis in the circulation, resulting in systemic absorption and systemic release.”
Based on the primary results from cohort 1 of the phase II TROPHY-U-01 trial, sacituzumab govitecan demonstrated an ORR of 27% in patients who experienced disease progression after undergoing platinum-based combination chemotherapy and checkpoint inhibition.10 The median durations of PFS and OS were 5.4 and 10.9 months, respectively. “Some of these patients had been heavily pretreated, including [with] prior enfortumab vedotin,” Dr. Siefker-Radtke remarked. “I think we need more data to see where the ORR settles out in comparison to some of the other targeted strategies.”
Despite the aforementioned positive outcomes, it is important to note that patients treated with sacituzumab govitecan may experience side effects. Neutropenia, including febrile neutropenia, and diarrhea, nausea, and vomiting were among the most frequently reported treatment-related adverse events in the study population.10
“Patients with bladder cancer, in general, are [older and] may have had prior chemotherapy regimens, so there could be reasons why their bone marrow is a bit more fragile in the treatment setting compared with a patient population with breast cancer,” commented Dr. Siefker-Radtke. “I personally am using growth factor support in all of my patients in [the setting of] sacituzumab govitecan because of neutropenia and neutropenic fever.”
Combining Targeted Therapy With Immunotherapy
“We are seeing a lot of excitement for [targeted therapy and immunotherapy] combinations,” Dr. Siefker-Radtke remarked. In patients with treatment-naïve, cisplatin-ineligible disease, enfortumab vedotin + pembrolizumab has demonstrated an ORR of approximately 73%.11 [Editor’s Note: Combination enfortumab vedotin + pembrolizumab was granted FDA accelerated approval on April 2, 2023, for use in frontline treatment metastatic, surgically unresectable cisplatin-ineligible bladder cancer.]
“There is a lot of hope that this combination may change the frontline standard for cisplatin-ineligible patients with bladder cancer,” she commented. “I hope that maybe we now have a strategy that can beat platinum in general and result in less toxic therapy for our patients.”
However, despite the aforementioned clinical benefits, patients treated with enfortumab vedotin + pembrolizumab may still experience toxicities. Neuropathy, fatigue, and alopecia, as well as enfortumab vedotin–associated side effects, such as Stevens-Johnson syndrome, peeling of the skin, diabetic ketoacidosis, and diarrhea, have been reported.11
Combination erdafitinib + cetrelimab has also demonstrated antitumor activity in metastatic urothelial cancer.12 Early results of the phase II NORSE trial have revealed ORRs of 68% and 33% with and without the addition of cetrelimab, respectively, in treatment-naïve, cisplatin-ineligible patients with FGFR-altered tumors. “This [combination] is based on the idea that the [FGFR-altered] tumors tend to be ‘immunologically cold,’” Dr. Siefker-Radtke remarked. “They don’t have a lot of immune cells and, if you profile their genes, the immune response genes seem to be dysregulated or ‘turned off’ in these tumors.”
Of note, compared with the aforementioned combinations, data from cohort 3 the TROPHY-U-01 trial revealed a lower ORR with sacituzumab govitecan + pembrolizumab (34%).13 “It is possible that sacituzumab govitecan, being more myelosuppressive, induces more lymphopenia,” Dr. Siefker-Radtke explained. “Perhaps eradication of lymphocytes is resulting in the lack of additive to synergistic benefit.”
References
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Flaig TW, Spiess PE, Abern M, et al. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 1.2023. Accessed April 15, 2023. To view the most recent version, visit https://www.nccn.org
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Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody–drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76:3003–3013.
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Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384:1125–1135.
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Rosenberg JE, Powles T, Sonpavde GP, 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;40(Suppl):Abstract 4516.
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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):Abstract 394.
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Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381:338–348.
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Siefker-Radtke AO, Necchi A, Park SH, et al. 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;23:248–258.
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Zaman S, Jadid H, Denson AC, et al. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther 2019;12:1781–1790.
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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;39:2474–2485.
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Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol 2023;41:22–31.
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Powles TB, Chistyakov V, Beliakouski V, et al. Erdafitinib (ERDA) or ERDA plus cetrelimab for patients with metastatic or locally advanced urothelial carcinoma and fibroblast growth factor receptor alterations: first phase II results from the NORSE study. Ann Oncol 2021;32(Suppl_5):S1303. Abstract LBA27.
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Grivas P, Pouessel D, Park CH, et al. TROPHY-U-01 cohort 3: sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. J Clin Oncol 2022;40(Suppl):Abstract 434.
