AUA 2024: First Line Therapy for Locally Advanced/Metastatic UC in 2024

( The 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX was host to the AUA-IBCG Bladder Cancer Forum. Drs. Chiara Mercinelli, Shilpa Gupta, and Karima Oualla discussed the first line therapy for locally advanced or metastatic urothelial carcinoma in 2024.

Dr. Mercinelli started the debate by sharing the case of a 65-year-old gentleman with hematuria a mass in the left renal pelvis and urinary cytology positive for high-grade urothelial carcinoma (UC). The CT scan showed retroperitoneal and pelvic lymphadenopathy. This hypothetical patient was a diabetic and eligible for cisplatin chemotherapy. She opened a poll for the audience to vote on the first-line therapy for this gentleman. 68% of the audience favored treating the patient with Enfortumab vedotin (EV) + Pembrolizumab, while 32% voted for cisplatinum-based chemotherapy.

Dr. Karima Oualla began the debate by arguing why EV + Pembrolizumab should be the standard of care for advanced bladder cancer. She referenced five phase 3 trials that evaluated checkpoint inhibitor combinations versus platinum-based chemotherapy for metastatic UC. Of these trials, two (IMvigor 1301 and KEYNOTE-3612 had negative read outs, and no benefit of immunotherapy in the first-line setting was observed. However, two recently published trials demonstrated improvement in overall survival for the first-line treatment of metastatic UC patients, both cisplatin eligible and ineligible (CheckMate-9013 and EV-302 (Figure 1).


Patients in the EV-302/KEYNOTE A39 trial were randomized in a 1:1 fashion, stratified by cisplatin eligibility, PD-L1 expression, and presence/absence of liver metastases, to EV + Pembrolizumab (continued until disease progression per blinded independent central review (BICR), clinical progression, unacceptable toxicity, or completion of maximum cycles [35 for pembrolizumab]) versus gemcitabine + cisplatin or carboplatin for a maximum of 6 cycles. The dual primary endpoints were progression free survival (PFS) by BICR and OS. (Figure 2)


The PFS per BICR was significantly improved in the EV + Pembrolizumab arm from a median of 6.3 months to 12.5 months (HR: 0.45, 95% CI: 0.38 – 0.45, p<0.001). The risk of progression or death was reduced by 55% in patients who received the combination.


Dr. Oualla emphasized that the OS was almost double in the EV + Pembrolizumab arm, with median survivals of 31.5 and 16.1 months in the EV +Pembrolizunab and chemotherapy arms, and the risk of death was reduced by 53% in patients who received the combination EV + Pembrolizumab.


Impressively, the subgroup analysis demonstrated consistent OS benefits in favor of EV + Pembrolizumab in all the subgroups analyzed.


Dr. Oualla highlighted that the most common treatment related adverse events (TRAEs) with EV + Pembrolizumab were skin reactions, peripheral neuropathy, ocular disorders, and hyperglycemia. Furthermore, Serious TRAEs occurred in 27.7% of patients in the EV + Pembrolizumab arm, compared to 19.6% in the chemotherapy arm. TRAEs leading to death (per investigator) in 0.9% in the EV+ Pembrolizumab arm vs 0.9% in the chemotherapy arm. The median number of cycles for EV + Pembrolizumab was 12, and 6 cycles for chemotherapy. 


Dr. Oualla compared the EV-302 trial and the CheckMate 901 trial. The latter randomized patients to Nivolumab + Gemcitabine/Cisplatin. In the EV-302 experimental arm, the overall response rate (ORR) was 67.8%, compared to 57.6% in the CheckMate 901 trial. Similarly, the complete response rate was 29.1% in the EV+ pembrolizumab arm of the EV-302 trial, versus 21.7% in the Nivo+ Gem/Cis arm of the CheckMate 901 trial.


Moreover, the median OS for EV +Pembrolizumab was better than for Nivo +Gem/Cis, 31.5 vs 21.7 months respectively. According to Dr. Oualla EV + Pembrolizumab clearly takes first place as the best first line regimen in advanced UC.

Dr. Karima Oualla wrapped up her presentation by delivering strong key take away messages:

  • EV+Pembrolizumab almost doubled the median OS vs chemotherapy (31.5 months), making it the New Standard of Care in the first line setting.
  • EV + Pembrolizumab is also highly effective regardless of:
    • PD-L1 status
    • Liver metastases
    • Cisplatin eligibility
  • Many challenges after EV+Pembrolizumab as a new 1st line standard of care (Financial toxicity, affordability)
  • Questions such as: what is the best strategy in second-line? What if a patient received anti-PD(L)1 in early setting? o dose de-escalation of EV? still need to be answered.

Dr. Shilpa Gupta argued why cisplatinum-based chemotherapy remains relevant as a first-line treatment option for advanced UC. Her reasons are: that it is effective, safety has been proven, there is global access to chemotherapy and it is certainly less costly.

She then went on to discuss how in 2020 the new standard of care after first-line chemotherapy for patients who were responders or had stable disease became maintenance Avelumab. The Javelin Bladder 100 study randomized patients to Avelumab + best standard of care or best-standard of care (observation) alone.4


In the Javelin Bladder 100 trial, Avelumab improved OS and PFS compared to best standard of care with a median OS of 23.8 months.


Dr. Gupta then revisited the results of the CheckMate 901 trial, emphasizing how the combination of Nivo+Gem/Cis improved OS, PFS, and achieved an ORR of 57.6% in patients with advanced UC.

The discussion shifted towards the TRAEs observed in the EV-302 trial, Dr. Gupta highlighted that the study population comprised untreated advanced UC patients eligible for platinum chemotherapy, most of whom were fit individuals. Inclusion of ECOG PS 2 patients was allowed only if they had a hemoglobin ≥10g/dL, GFR ≥50ml/min, and were not classified as NYHA class III for heart failure. 

Dr. Gupta stressed the importance of considering the entire patient and the risks associated with EV+Pembrolizumab, especially in light of TRAEs such as catastrophic diabetes, significant peripheral and motor neuropathy, and life-threatening rash. Furthermore, she discussed the need to factor in the costs of treatment, noting that just one cycle of EV+Pembrolizumab costs approximately 45,000 USD, which exceeds the combined costs of all cycles of Gem/Cis and Avelumab. She urged consideration of the accessibility of EV+Pembro worldwide, highlighting how this has become a global affordability conundrum and how first-line therapy will be dictated by where the patient lives and access and affordability to EV+Pembrolizumab.


Dr. Gupta concluded her talk by emphasizing that:

  • Cisplatinum-based chemotherapy remains relevant and will continue to be so until EV + Pembrolizumab becomes accessible and affordable worldwide.

Presented by:

  • Chiara Mercinelli, MD at Via-Salute San Raffaele University and IRCCS
  • Shilpa Gupta, MD, Director of Genitourinary Medical Oncology at Taussig Cancer Institute – Cleveland Clinic
  • Karima Oualla, MD, MSc, Medical Oncologist at Hassan II University Hospital.

Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Urological Association (AUA) Annual Meeting, San Antonio, TX, May 3rd - 6th, 2024 


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