Patients with previously untreated locally advanced or metastatic urothelial carcinoma experienced favorable progression-free survival (PFS; the time a patient lives without their disease progressing or worsening), overall survival (OS; the time a patient lives after treatment regardless of disease status) and objective response rates (ORRs; patients whose disease responded partially or completely to treatment) when treated with Padcev (enfortumab vedotin-ejfv) and Keytruda (pembrolizumab) versus chemotherapy, according to findings from prespecified subgroup analyses of the phase 3 EV-302/KEYNOTE-A39 trial.
Primary results from the trial were first presented at the 2023 ESMO Congress. During the 2024 Genitourinary Cancers Symposium, lead study author Dr. Michiel S. Van Der Heijden reported new data illustrating the benefit of the combination in previously unpresented subgroups.“
The benefit of (Padcev) plus (Keytruda) in all prespecified subgroups was consistent with the overall patient population. These results further support (Padcev) plus (Keytruda) as a new standard of care in locally advanced or metastatic urothelial carcinoma,” Van Der Heijden, leader of the Michiel Van der Heijden Research Group at the Netherlands Cancer Institute, said in a presentation of the data.
These results showed that the PFS benefit with the combination in patients with visceral metastases (hazard ratio [HR; the chance of something occurring], 0.45) and those with lymph node–only disease (HR, 0.40) was consistent with that of the overall population (HR, 0.45).
Moreover, OS benefit was similar to that of the overall population (HR, 0.47), regardless of the presence (HR, 0.47) or absence (HR, 0.46) of visceral metastases.
In the visceral metastases group, the median OS was 25.6 months with the combination versus 13.6 months with chemotherapy. In the lymph node–only cohort, the median OS was not reached with the combination (meaning more than half of the patients in that cohort were still alive) versus 27.5 months with chemotherapy.
In December 2023, the Food and Drug Administration (FDA) approved the combination for patients with locally advanced or metastatic urothelial cancer. The decision was based on primary results from the EV-302 trial, which enrolled patients with treatment-naive locally advanced or metastatic urothelial cancer with no contraindications to platinum, Padcev or Keytruda. Patients also had to have a glomerular filtration rate at or above 30 mL/min, an ECOG performance status of 0 to 2 (meaning patients are capable of self-care but their ability to carry out daily activities may be limited) and no prior exposure to a checkpoint inhibitor.
Patients were randomly assigned to the combination or up to six cycles of chemotherapy consisting of gemcitabine plus either cisplatin or carboplatin. Treatment in the investigational arm was continued until disease progression, clinical progression, unacceptable toxicity or patients completed 35 cycles of Keytruda. Notably, maintenance therapy was allowed if deemed appropriate by the investigator following the completion and/or discontinuation of platinum-containing therapy.
All patients were stratified by cisplatin eligibility (eligible versus ineligible), PD-L1 expression (low [combined positive score (CPS) of less than 10] versus high [CPS of 10 or greater]), liver metastases (present versus absent), age (younger than 65 versus 65 or older), region (North America vs Europe vs rest of world), sex (female versus male), race (White versus other), ECOG performance status at baseline (0 versus 1 to 2), metastases (visceral versus lymph node only), primary disease site of origin (upper tract versus lower tract) and renal function (normal versus mild versus moderate versus severe).
Previous findings from the primary analysis showed a PFS advantage with the combination in cisplatin-eligible (HR, 0.48) and ineligible (HR, 0.43), as well as PD-L1–high (HR, 0.42) and PD-L1–low (HR, 0.50) subgroups. Similar results were seen in patients with (HR, 0.53) and without (HR, 0.43) liver metastases.
Earlier findings also showed an OS advantage with the combination in cisplatin-eligible (HR, 0.53) and ineligible (HR, 0.43), as well as PD-L1–high (HR, 0.49) and PD-L1–low (HR, 0.44) subgroups. Additionally, the presence of liver metastases did not seem to affect the magnitude of OS benefit seen with the combination (with: HR, 0.47; without: HR, 0.47).
Additional findings from the current analysis showed that consistent with the primary analysis, which showed an ORR of 67.7% with the combination versus 44.4% with chemotherapy, patients in all prespecified subgroups experienced superior response rates with the combination, surpassing at least 60% in all cases.
In cisplatin-eligible patients, the ORR was 70.8% with the combination versus 53% with chemotherapy. In cisplatin-ineligible patients, the ORRs were 63.9% versus 34.9%. In the PD-L1–low subgroup, the ORRs were 63.3% versus 41%. In the PD-L1–high subgroup, the ORRs were 71.1% versus 46.6%. Patients with liver metastases experienced ORRs of 60% versus 41.4%. Patients without liver metastases had ORRs of 70% versus 45.3%. Regarding metastatic disease site, patients with visceral metastases experienced ORRs of 64.1% versus 39.6%. Patients with lymph node–only disease had ORRs of 77.5% versus 53.4%.
The toxicity profile of the doublet was found to be generally manageable. No new safety signals were observed. Grade 3 or greater (moderate to severe) side effects were reported in 55.9% of patients who received Padcev plus Keytruda versus 69.5% of those given chemotherapy.
The most common treatment-related side effects reported in the Padcev/Keytruda arm (440 patients) included peripheral sensory neuropathy (nerve damage; any grade, 50%; grade 3 or higher, 3.6%), pruritus (itching; 39.8%; 1.1%), alopecia (hair loss; 33.2%; 0.5%), maculopapular rash (32.7%; 7.7%), fatigue (29.3%; 3%), diarrhea (27.5%; 3.6%), decreased appetite (26.8%; 1.1%), nausea (20.2%; 1.1%), anemia (low red blood cells; 13.9%; 3.4%), neutropenia (low neutrophils, a type of white blood cell; 9.1%; 4.8%) and thrombocytopenia (low platelets; 3.4%; 0.5%).
In the Padcev/Keytruda arm, four treatment-related side effects led to death: asthenia (fatigue), diarrhea, immune-mediated lung disease and multiple organ dysfunction syndrome. In the chemotherapy arm, four treatment-related side effects resulted in death: febrile neutropenia (fever), myocardial infarction (heart attack), neutropenic sepsis (reaction to an infection) and sepsis.
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