Combinations, Sequencing, and the Contribution of Components: New Frontline Standards for Metastatic Urothelial Carcinoma

Siefker-Radtke, Arlene; Cauley, Diana H.; Alhalabi, Omar

doi:10.1200/jco.23.00987

Cited by 3 publications

(5 citation statements)

References 8 publications

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“…In EV-103 trials, the relatively high incidence of peripheral neuropathy and hyperglycemia in cohorts without uncontrolled DM or severe neuropathy suggest a possible limitation of EVP in patients with these risk factors. Additionally, the FDA prescribing information recommends avoiding the use of EV in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment [ 2 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

“…First, the ability to better predict and monitor side effects would help improve patients’ quality of life and maximize clinical efficacy during EVP treatment. Second, treatment de-escalation might be offered to spare patients long-term accumulating adverse effects such as neuropathy and enable them to receive subsequent cisplatin- or carboplatin-based regimens, known to be neurotoxic but with ancillary clinical utility and survival benefit in mUC [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

“…This list of priorities is not exhaustive, as we will limit our discussion herein to the most prominent goals in both eras. The value of cisplatin or platinum eligibility may still be relevant in limited scenarios in the 1L setting, especially when EV is contraindicated or unavailable [89]. In EV-103 trials, the relatively high incidence of peripheral neuropathy and hyperglycemia in cohorts without uncontrolled DM or severe neuropathy suggest a possible limitation of EVP in patients with these risk factors.…”

Section: The Value Of Biomarkersmentioning

confidence: 99%

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Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

Moussa,

Campbell,

Alhalabi

2024

Biomedicines

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Cisplatin-based chemotherapy has been the standard of care in metastatic urothelial cancer (mUC) for more than two decades. However, many patients with comorbidities cannot receive cisplatin or its alternative, carboplatin. ‘Cisplatin-ineligible’ and ‘platinum-ineligible’ patients lacked effective therapy options. However, the recent combination of enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, with pembrolizumab (P), an antibody targeting the programmed death-1 (PD-1) immune checkpoint, is changing the status quo of frontline mUC treatment, with potential synergy seen in the EV-103 and EV-302 clinical trials. First, we review the working definitions of ‘cisplatin ineligibility’ and ‘platinum ineligibility’ in mUC clinical trials and the standard of care in both categories. Then, we review select clinical trials for frontline treatment of cisplatin- and platinum-ineligible mUC patients on ClinicalTrials.gov. We classify the investigated drugs in these trials by their therapeutic strategies. Alongside chemotherapy combinations, the field is witnessing more immunotherapy combinations with fibroblast growth factor receptor (FGFR) inhibitors, bicycle toxin conjugates, bispecific antibodies, innovative targeted therapies, and many others. Most importantly, we rethink the value of classifying patients by cisplatin or platinum ineligibility in the frontline setting in the post-EVP era. Lastly, we discuss new priority goals to tailor predictive, monitoring, and prognostic biomarkers to these emergent therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Value Of Biomarkersmentioning

confidence: 99%

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Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

Moussa,

Campbell,

Alhalabi

2024

Biomedicines

Self Cite

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“…However, even with these really impressive overall survival and progression-free survival numbers, EV plus pembrolizumab has got toxicity. It’s got a very distinct toxicity profile, which includes things that we don’t normally see in bladder cancer, such as skin reactions, hyperglycemia, and the big thing that we all talk about, which is neuropathy [ 5 – 9 ]. In this patient population, who tend to be older [ 2 , 10 ], they may be vasculopathic; they may have all the risk factors for neuropathy.…”

Section: Key Pointsmentioning

confidence: 99%

“…Even though this is primarily a medical conversation, I think cost is also significant [for EV plus pembrolizumab] [ 9 , 11 ]. These are very expensive drugs, and they work, and so the cost piece is more and more figuring into the conversation.…”

Section: Key Pointsmentioning

confidence: 99%

A Podcast on Platinum Eligibility and Treatment Sequencing in Platinum-Eligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

Gupta,

Moon,

Sridhar

2024

Targ Oncol

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A Podcast on Practical Considerations in Patients with Advanced Urothelial Cancer Receiving First-Line Cisplatin- or Carboplatin-Based Chemotherapy Followed by Avelumab Maintenance in a Changing Therapeutic Landscape

Gong,

Reimers

2024

Adv Ther

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Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-024-02922-w.

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Combinations, Sequencing, and the Contribution of Components: New Frontline Standards for Metastatic Urothelial Carcinoma

Cited by 3 publications

References 8 publications

Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

A Podcast on Platinum Eligibility and Treatment Sequencing in Platinum-Eligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

A Podcast on Practical Considerations in Patients with Advanced Urothelial Cancer Receiving First-Line Cisplatin- or Carboplatin-Based Chemotherapy Followed by Avelumab Maintenance in a Changing Therapeutic Landscape

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