First-line Enfortumab Vedotin Plus Pembrolizumab Has Durable Activity in Urothelial Carcinoma

Responses achieved with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) were found to be rapid and durable in patients with previously untreated locally advanced or metastatic urothelial carcinoma who were cisplatin ineligible, according to updated data from cohort K of the phase 1/2 EV-103/KEYNOTE-869 trial (NCT03288545).¹

Findings presented at the 2023 ASCO Annual Meeting showed that at a median follow-up of 18 months, patients who received the doublet (n = 76) achieved a confirmed objective response rate (cORR) of 64.5% (95% CI, 52.7%-75.1%), which consisted of a 10.5% complete response (CR) rate, a 53.9% partial response (PR) rate, and a 22.4% stable disease (SD) rate; 7.9% of patients experienced progressive disease (PD). Patients given enfortumab vedotin alone (n = 73) experienced an ORR of 45.2% (95% CI, 33.5%-57.3%), which included a 5.5% CR rate, a 39.7% PR rate, a 34.2% SD rate, and a 9.6% PD rate.

Responses were consistent across all prespecified subgroups, with 53.8% of those with liver metastases (n = 13) experiencing a cORR with the combination regimen. Notably, 85.7% of all responses to the combination were achieved at the time of initial assessment, which occurred at week 9. Additionally, the median duration of response (DOR) with the doublet was not yet reached (NR; 95% CI, 10.25-NR) and 13.2 months (95% CI, 6.14-NR) with the monotherapy. Moreover, 65.6% and 59.7% of patients, respectively, had responses that lasted for at least 12 months.

“Enfortumab vedotin plus pembrolizumab continues to show clinical activity in a traditionally poor-prognosis group of patients with locally advanced and metastatic urothelial cancer who are ineligible for cisplatin-based chemotherapy,” lead study author Terence Friedlander, MD, stated in a poster presentation of the data. Friedlander is the chief of Hematology-Oncology, an associate director of Cancer Research at the Zuckerberg San Francisco General, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, and is an associate clinical professor in the Division of Hematology/Oncology at UCSF.

Initial results from cohort K were presented at the 2022 ESMO Congress, and showed that at a data cutoff date of June 10, 2022, the doublet elicited a cORR rate of 64.5% (95% CI, 52.7%-75.1%) with a median DOR that was NR. The cORR reported with enfortumab vedotin alone was 45.2% (95% CI, 33.5%-57.3%), with a median DOR of 13.2 months (95% CI, 6.14-15.97).²

In April 2023, the FDA granted accelerated approval to enfortumab vedotin plus pembrolizumab for this patient population based on combined dose-escalation/cohort A and cohort K of KEYNOTE-869.³

At the 2023 ASCO Annual Meeting, investigators presented an additional 3 months of follow-up from cohort K. The data cutoff for time to ORR and the ORR subgroup analysis June 10, 2022. For all other measures, the data cutoff date was September 16, 2022.

The current analysis included patients with locally advanced or metastatic urothelial cancer who were treatment naïve and cisplatin ineligible. Patients were administered 1.25 mg/kg of enfortumab vedotin on days 1 and 8 with or without 200 mg of pembrolizumab on day 1 of 3-week cycles.

The primary end point was cORR by blinded independent central review (BICR) and RECIST v1.1 criteria. Key secondary end points included investigator-assessed cORR, DOR, disease control rate, progression-free survival (PFS) by both investigator assessment and BICR, overall survival (OS), safety and tolerability, and as well as laboratory abnormalities. Notably, no formal statistical comparisons were performed between treatment arms. 

A total of 151 patients were enrolled in cohort K, including 77 patients in the combination arm and 74 in the monotherapy arm. One patient from each arm did not go on to receive treatment.

“These patients are fairly representative of most patients with metastatic urothelial cancer, with an average age greater than 70 [years] and a slight male predominance,” Friedlander noted in his presentation. “...More than 80% of patients had visceral metastases, including just under 20% of patients who had liver metastases.”

The majority of patients in the combination and monotherapy arms were Caucasian (80.3%; 75.3%) and had their primary tumor located in the lower tract (60.5%; 69.9%). Patients had bone (25%; 28.8%), liver (17.1%; 17.8%), and lung (48.7%; 41.1%) metastases. Regarding ECOG performance status, 43.4%, 43.4%, and 13.2% of patients in the combination arm had a status of 0, 1, or 2, respectively; these percentages were 38.4%, 47.9% and 13.7%, respectively, in the monotherapy arm. 

Patients in the combination arm completed a median number of 12 treatment cycles (range, 1-34), and those in the monotherapy arm completed 8 cycles (range, 1-33).

Additional data showed that the median time to objective response was 2.07 months in the combination (range, 1.1-6.6) and monotherapy (range, 1.9-15.4) groups.

Both median PFS (95% CI, 8.31-NR) per BICR and median OS (95% CI, 21.39-NR) were NR with the combination. Enfortumab vedotin monotherapy resulted in a median PFS of 8.2 months (95% CI, 6.05-15.28) and a median OS of 21.7 months (95% CI, 15.47-NR). Twelve-month PFS rates were 54.5% and 40.3% with the combination and monotherapy, respectively. At a median follow-up of 17.6 months for the combination, the 12-month OS rate was 81.5%; with the monotherapy, this rate was 69.7% at a median follow-up of 18.2 months.

“Importantly, the median DOR, PFS, and OS have not yet been reached for the combination arm. We expect these data to mature with more time,” Friedlander noted.

Investigators noted that the clinical activity of enfortumab vedotin monotherapy was consistent with what has previously been reported with this approach in the second-line treatment of patients with locally advanced or metastatic urothelial cancer.

At the time of data cutoff, most patients in both arms remain on study. Specifically, 24.7% and 8.1% of patients in the combination and monotherapy arms, respectively, remain on treatment. For the 74% and 90.5% of patients in each arm, respectively, who are no longer on treatment, reasons for discontinuation included progressive disease (45.5%; 54.1%), adverse effects (AEs; 16.9%; 27%), patient decision (5.2%; 4.1%), and the physician decision (3.9%; 4.1%).

Patients discontinued the study due to death (29.9%; 40.5%), patient withdrawal of consent (2.6%; 2.7%), or other unspecified reasons (1.3%; 1.4%).

In his presentation, Friedlander stated that there was no meaningful change in the safety profile of enfortumab vedotin plus pembrolizumab with additional follow-up.

The AE profile of the combination was manageable and consistent with previous data. All patients in the combination arm experienced an any-grade treatment-related AE (TRAEs) vs 93.2% of those in the monotherapy arm. The most common any-grade TRAEs experienced in at least 20% of patients in the combination arm were fatigue (56.6%), peripheral sensory neuropathy (53.9%), maculopapular rash (47.4%), and alopecia (46.1%). 

Serious TRAEs occurred in 25% of patients given enfortumab vedotin and pembrolizumab vs 15.1% of those who received enfortumab vedotin alone. As per investigator assessment, 3.9% of patients in the combination arm experienced TRAEs that resulted in death; these included pneumonitis, respiratory failure, and sepsis. In the monotherapy arm, the TRAEs that led to death in 2.7% of patients were multiple organ dysfunction and respiratory failure.

Grade 3 or higher TRAEs of special interest in the combination and monotherapy arms, respectively, included skin reactions (21.1%; 6.8%), peripheral neuropathy (2.6%; 2.7%), and hyperglycemia (6.6%; 9.6%). The remaining events were grade 1/2. The most frequent any-grade TRAEs of specific interest included skin reactions (67.1%; 45.2%), peripheral neuropathy (63.2%; 54.8%), ocular disorders (26.3%; 28.8%), hyperglycemia (14.5%; 11.0%), and infusion-related reactions (3.9%; 5.5%). Notably, the most prevalent reason for treatment discontinuation was peripheral neuropathy.

The incidence of treatment-emergent AEs (TEAEs) of special interest related to pembrolizumab was generally consistent with that of pembrolizumab monotherapy, except for severe skin reactions (any grade, 27.6%; grade 3 or higher, 19.7%).

The combination of enfortumab vedotin and pembrolizumab is being compared with chemotherapy alone in the frontline setting in cisplatin-eligible and -ineligible patients with untreated locally advanced or metastatic urothelial cancer as part of the ongoing phase 3 EV-302 trial (NCT04223856).

Disclosures: Dr Friedlander reported serving as a consultant or in an advisory role for AADi, Astellas Pharma, Basilea, Dava Oncology, EMD Serono, Foundation Medicine, Merck, Seagen, and Taiho Oncology; he reports recieving institutional research funding from Bristol-Myers Squibb, Neon Therapeutics, Roche/Genentech, and Seagen; Astellas Pharma; Astellas Scientific and Medical Affairs Inc; AstraZeneca/MedImmune; and EMD Serono; he has a leadership role with Med BioGene; he received monetary support for travel and accommodations from Astellas Pharma; AstraZeneca/MedImmune, Genentech/Roche, and Jounce Therapeutics.

References

1. Friedlander T, Milowsky M, O’Donnel P, et al. Enfortumab vedotin (EV) with or without pembrolizumab (P) in patients (pts) who are cisplatin-ineligible with previously untreated locally advanced or metastatic urothelial cancer (la/mUC): additional 3-month follow-up on cohort K data. J Clin Oncol. 2023;41(suppl 16):4568. doi:10.1200/JCO.2023.41.16_suppl.4568
2. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Ann Oncol. 2022;33(suppl 7):LBA73. doi:10.1016/annonc/annonc1089
3. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed April 6, 2023. https://www.fda.gov/drugs/resources