Padcev Improves Outcomes for Cisplatin-Ineligible Bladder Cancer

Neoadjuvant (presurgical) Padcev (enfortumab vedotin) had promising treatment outcomes in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC), according to updated findings from the EV-103 trial presented at the 2024 American Society of Clinical Oncology Annual Meeting.

“Importantly, from a safety standpoint, all patients in this trial who received neoadjuvant treatment proceeded to undergo cystectomy and there were no [Padcev]-related [side effects] that caused delay in surgery for any patients,” study author Dr. Peter H. O’Donnell said in a presentation of the data.

O’Donnell is an associate professor of medicine at the University of Chicago Medicine and specializes in genitourinary malignancies including prostate, kidney, testicular and bladder cancers.

In cohort H of the EV-103 phase 1b/2 study, Padcev was administered as a monotherapy treatment to 22 patients with MIBC who were cisplatin ineligible, meaning that they were not able to receive cisplatin chemotherapy treatments. The achieved event-free survival (EFS; time patients live without cancer signs and symptoms) rate was 62% at two years. In the overall population, however, the median EFS was not reached (NR), meaning that not enough patients experienced a cancer-related event for the researchers to calculate an average.

Of the evaluated patients, eight patients (36.4%) achieved a pathological complete response (pCR; disappearance of cancer) following neoadjuvant Padcev, and six patients remain disease-free at the data cut-off of Nov. 20, 2023, according to investigators. Also at the data cut-off, 15 patients continued long-term follow-up.

The median EFS for patients with a pCR was NR compared with patients without a pCR, which was 18.8 months.

Among patients, 86.4% successfully completed all three cycles of Padcev and the median duration of treatment was 2.1 months. The pCR rate was 36.4% and the pathological downstaging (pDS; decrease in the disease’s staging) rate reached 50%.

Patients included in the trial had either stage cT2 (tumor that grew into the muscular layer of the bladder wall; 68.2%), cT3 (cancer that has grown through the bladder wall into surrounding tissue; 27.3%) or cT4 (cancer that has grown extensively through the bladder wall into other organs; 4.5%) disease, 68.2% had urothelial carcinoma and 31.8% had a mixed histology. Of the patients evaluated (22 patients), the median age was 74.5 years. All patients were White (100%), 20 were male (90.9%) and 21 (95.5%) were current or former smokers.

Patients had an ECOG performance score of 2 or less, indicating that they could perform all or most of their daily tasks independently, and were eligible for surgical removal of the entire bladder and pelvic lymph node dissection.

Subsequent cancer-related therapy was administered to 36.4% of patients and included adjuvant therapy of Keytruda (pembrolizumab; two patients), carboplatin-based therapy (one patient), and Balversa (erdafitinib; one patient). One patient received systemic therapy for progressive disease, and three patients received other therapy.

The primary end point (main result measured at the end of a study) was pCR rate, and the secondary end points were pDS safety and EFS as determined by investigator assessment. This encompassed radiographic progression before radical cystectomy (RC), failure to undergo RC, gross residual disease at time of RC, recurrence or death.

“The safety profile for enfortumab vedotin was generally manageable and consistent with known prior [side effects] for this drug,” O’Donnell explained.

The prevalent treatment-emergent side effects associated with Padcev were fatigue (45.5%), changes in taste (36.4%) and hair loss (31.8%). There were 18.2% of patients who experienced moderate (grade 3) or greater Padcev-related side effects and the most common were dehydration, drug-induced skin disorder and high blood sugar (hyperglycemia) levels occurring in one patient each. Any-grade surgery-related side effects affected 68.2% of patients, with procedural pain (18.2%), anemia (13.6%) and constipation (13.6%) being the most common.

Most side effects were grade 1 or 2 (mild or serious) and those experiencing skin-related side effects and hyperglycemia side effects were resolved at 100%. Those experiencing peripheral neuropathy (pain or numbness in the hands and feet) were resolved at 44%.

There were three patients who died because of side effects not related to Padcev treatment, according to investigators. These deaths were acute kidney injury, cardiac arrest and pulmonary embolism, and each occurred less than 30 days after the last dose of Padcev.

Currently, there are no established neoadjuvant treatment options proven to enhance survival for patients diagnosed with MIBC who are ineligible for cisplatin and are undergoing radical cystectomy with pelvic lymph node dissection.

Padcev is an antibody-drug conjugate, which is a type of drug that binds to a target on immune cells and another on cancer cells, bringing the two together. The agent targets Nectin-4, a protein highly expressed in urothelial cancer. Both alone and in combination with Keytruda, Padcev improves overall survival (time patients live before death of any cause) compared with chemotherapy in patients with previously treated and untreated locally advanced or metastatic urothelial cancer.

“These follow-up data continue to show the efficacy of [Padcev] as a monotherapy treatment in the neoadjuvant setting for patients who are cisplatin-ineligible and have MIBC. These results also support the ongoing phase 2 and 3 trials that are evaluating [Padcev] alone and in combination with [Keytruda] for patients with MIBC,” O’Donnell concluded.

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