Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) led to better overall survival (OS; time from treatment until death of any cause) compared with chemotherapy in patients with previously untreated locally advanced or metastatic (spread to other parts of the body) urothelial carcinoma, a type of bladder cancer, according to findings from the phase 3 EV-302 clinical trial.
Findings, which were presented at the 2023 ESMO Congress, showed that at a median follow-up of 17.2 months, treatment with Padcev plus Keytruda — a regimen the researchers referred to as “EVP” — reduced the risk of disease progression or death by 53% versus chemotherapy.
The median OS was 31.5 months in the EVP arm compared with 16.1 in the chemotherapy arm. The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin and was not impacted by PD-L1 status or existence of visceral metastases.
Treatment with the combination also led to a significant improved in progression-free survival (PFS; time from treatment until disease gets worse or patients die) versus chemotherapy. The median PFS was 12.5 months with EVP compared with 6.3 months with chemotherapy, translating to a 55% reduction in the risk of disease progression or death. The PFS benefit was sustained across all pre-specified subgroups, such as those defined by cisplatin eligibility, PD-L1 status and visceral metastases.
“This is the first time (in urothelial carcinoma) we’ve managed to beat chemotherapy in the first-line setting for overall survival, despite multiple previous attempts. (Padcev) and (Keytruda) showed significant decrease in the risk of death and a decrease in the risk of progression compared to chemotherapy. These results support (Padcev) plus (Keytruda) as a standard of care in this setting,” said lead study author Dr. Thomas B. Powles, director, Barts Cancer Centre at St. Bartholomew’s Hospital in London.
The open-label EV-302 trial included 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma with an ECOG performance status of 2 or lower, indicating that they can perform most of their daily tasks with minimal help, who were eligible for cisplatin- or carboplatin-containing chemotherapy. The median age in both arms was 69 years and about three-fourths of patients were male. The majority of patients in the trial were White, making up 69.7% and 65.3% of the EVP and control arms, respectively. About 97% of patients in both arms had an ECOG performance status of 0 or 1.
In the EVP arm, the primary tumor location was upper tract for 30.5% of patients and lower tract for 69.0%. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and 72% had visceral metastases. Regarding PD-L1 status, 58% of in each arm had high expression (combined positive score [CPS] ≥10), with the remaining 42% having low expression (CPS <10).
Patients were randomly assigned to receive standard of care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (444 patients) or Padcev on days 1 and 8 and Keytruda on day 1 of 3-week cycles (442 patients). The maximum number of Keytruda cycles allowed was 35 and there was no maximum number of cycles for Padcev. The co-primary end points were OS and PFS.
The confirmed objective response rate (ORR; percentage of patients whose disease responded to treatment) was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP group consisted of a complete response (CR; meaning that there were no tracible signs of cancer after treatment) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%.
The median number of cycles received was 12 (range, 1-46) for EVP and six (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Side effect-related discontinuations occurred in 21.9% and 14.0% of the two arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/L1 inhibitor and 30% of patients received maintenance Bavencio (avelumab).
“The safety profile of EVP was generally manageable, with no new safety signals observed,” said Powles. “Hematological toxicity was more prominent with chemotherapy, while peripheral neuropathy, rash, and hyperglycemia are adverse events of special interest with EVP.”
The safety data showed that 56% of patients receiving EVP and 70% of patients in the chemotherapy arm experienced grade 3 or higher treatment-related side effects. Serious side effects occurred in 27.7% vs 19.6% of the two arms, respectively.
In April 2023, the FDA granted an accelerated approval to Keytruda plus Padcev for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.
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