ASCO GU 2024: Advanced Urothelial Carcinoma Discussant

The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25^th and 27^th was host to a urothelial carcinoma oral abstract session. Dr. Parminder Singh delivered the discussant session for the two previously presented abstracts:

• Enfortumab vedotin (EV) in combination with pembrolizumab versus chemotherapy in previously untreated locally advanced/metastatic urothelial carcinoma: Subgroup analyses results from EV-302, a phase 3 global study
• Cabozantinib plus pembrolizumab as first-line therapy for cisplatin-ineligible advanced urothelial carcinoma (PemCab)

PemCab is a phase II trial that evaluated the activity and safety of 1^st line combination of cabozantinib and pembrolizumab in (cisplatin-ineligible/PD-L1 positive) and cisplatin-refusing or platinum ineligible locally advanced/metastatic urothelial carcinoma. The PemCab study design is illustrated below. Eligible patients were administered pembrolizumab 200 mg IV every 3 weeks plus cabozantinib 40 mg orally once daily. The primary endpoint was objective response rate (ORR), per RECIST v1.1.
This trial enrolled 36 patients. An ORR was observed in 16 patients (46%), of whom 4 (14%) had a complete response. On radiographic evaluation, 80% of patients demonstrated evidence of tumor shrinkage. While notable, these were not ‘groundbreaking’ results, per Dr. Singh. Furthermore, many patients experienced fatigue (64%), diarrhea (58%), pruritis (39%), and anorexia (33%), among other side effects. As such, he argued that the risk-profile for such a combination is unclear. He noted that this trial adds to the litany of negative TKI/IO or VEGF/chemotherapy phase 2/3 trials in urothelial carcinoma. As such, should this spell the end for such combinations in urothelial carcinoma, or should they be explored in alternate settings?
Based on these results, Dr. Singh concluded that the PemCab combination shows modest activity as 1^st line novel combination. Given the evolving paradigm of 1^st line therapy, it is unlikely that this combination will have a future role in 1^st line therapy for advanced urothelial carcinoma. 

With regards to potential future directions in this space and for such combinations, new multi-kinase inhibitors like XL092 (similar to cabozantinib) with better tolerability/therapeutic indices could be used:

• In combination with pembrolizumab in the maintenance setting in patients who are responding/stable to enfortumab vedotin + pembrolizumab (to avoid cumulative neuropathy from enfortumab vedotin)
• Cabozantinib + nivolumab could reinvigorate immune responses in IO-refractory patients. Newer multi-kinase inhibitors can similarly be explored.
• May be investigated as salvage monotherapy, potentially informed by predictive biomarkers (lack of neurotoxicity could be advantageous)

Next, Dr. Singh discussed the subgroup analyses of EV-302 presented by Dr. van der Heijden. He noted that cisplatin eligibility has long defined treatment in this disease space. The seminal paper by Dr. Galsky in 2011 has long defined cisplatin eligibility for these patients and has shaped clinical trial design since.¹
This had shaped the pre-EV-302 treatment paradigm of advanced urothelial carcinoma. Cisplatin eligible patients would receive gem/cis or ddMVAC, those who were cisplatin ineligible would receive enfortumab vedotin, Gem/Carbo, or Gem/Paclitaxel, and those who were chemo ineligible would receive pembrolizumab.
What was its impact in the clinic? Real world data of patients from the Flatiron database between 2016 and 2020 demonstrated that ~25% of patients did not receive 1^st line therapy, and half of patients did not receive 2^nd line therapy. Among those who were cisplatin eligible, only 40% received cisplatin combination chemotherapy, and 25% received immunotherapy. Conversely, among those who were cisplatin ineligible, 50% received immunotherapy.
He noted that EV-302 challenges this paradigm. EV-302 is a phase 3 global trial of enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma. There was no maximum number of treatment cycles for enfortumab vedotin and up to 35 cycles of pembrolizumab were allowed. All included patients were platinum and immunotherapy eligible.
The objective response rates were ≥60% for enfortumab vedotin + pembrolizumab across all evaluable subgroups.
He noted that these ORR results correlate strongly with those observed in the earlier, smaller phase studies of this combination:
He noted that with the impressive results of EV-302, the combination of enfortumab vedotin + pembrolizumab is likely to be used much more commonly in the 1^st line setting. As such, we need to be familiar with the safety/adverse event profile of this combination and learn how to manage them, including skin reactions, peripheral neuropathy, ocular disorders, and hyperglycemia.
In light of these ‘novel’ side effects, he suggested the following toxicity management ‘pearls’:

• Early dose reduction of enfortumab vedotin for neuropathy – 1 mg/kg or 0.75 mg/kg
• Growth factor support for cytopenia
• Topical steroids and dose reduction for skin rash - use lotion, not ointment
• Strict diabetes management
• Ocular toxicity
• And treatment interruptions in exceptional responders - need to be investigated 

Dr. Singh noted that EV-302 has made it ‘simple for the community oncologist’, whereby this combination is safe for advanced urothelial carcinoma patients meeting the following criteria:

• Cisplatin eligibility (safe up to 30 ml/min GFR)
• ECOG <2
• High-risk group like liver metastases 0 median time to response in the 1^st two months
• No risk of cardiac overload
• No need to think about PD-L1 score
• No need to wait for next generation sequencing or any specialized testing

His concluding takeaways from the EV-302 trial were as follows:

• Enfortumab vedotin + pembrolizumab is the new standard of care for locally advanced/metastatic urothelial carcinoma patients.
• There were consistent benefits across various subgroups including cisplatin eligible/ineligible, visceral metastasis (present/absent), and irrespective of PD-L1 status
• It is unclear if enfortumab vedotin + pembrolizumab is curative for some patients.
  • Need data on durability of CRs and longer follow-up
• Gemcitabine/Cisplatin + nivolumab (awaiting FDA review) may play a role in selected cisplatin-eligible patients who are predicted to have a CR
• The JAVELIN paradigm and pembrolizumab monotherapy may continue to play a role in select frail or poor performance status patients with significant comorbidities

Presented by: Parminder Singh, MD, Assistant Professor of Hematology and Oncology, Mayo Clinic, Phoenix, AZ

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25^th – January 27^th, 2024

1. Galsky MD, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432-8.