Enfortumab Vedotin/Pembrolizumab Does Not Negatively Impact QOL in Metastatic Urothelial Cancer

EV plus pembrolizumab in mUC - bladder cancer: © Sebastian Kaulitzki - stock.adobe.com

The combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) improved survival outcomes vs platinum-based chemotherapy with no detriment to global health status (GHS)/quality of life (QOL), pain, or functioning in patients with previously untreated, locally advanced or metastatic urothelial cancer, according to findings from a study assessing patient-reported outcomes (PROs) from the phase 3 EV-302 trial (NCT04223856).¹

Data presented at the 2024 ASCO Breakthrough Conference, showed that the median time to pain progression (TTPP) was 14.2 months (95% CI, 6.6-not reached [NR]) in the enfortumab vedotin plus pembrolizumab arm (n = 376) vs 10.0 months (95% CI, 5.9-NR) in the chemotherapy arm (n = 355; HR, 0.92; 95% CI, 0.72-1.2; 2-sided P = .48). The median time to confirmed deterioration (TTCD) was 5.9 months in the enfortumab vedotin plus pembrolizumab arm vs 3.2 months in the chemotherapy arm (HR, 0.98; 95% CI, 0.79-1.2).

“PRO data presented here complement the published clinical efficacy and safety data, add the patient perspective, and support the use of enfortumab vedotin plus pembrolizumab for patients with locally advanced, metastatic urothelial cancer,” lead study author Eiji Kikuchi, PhD, of the St. Marianna University School of Medicine in Kawasaki City, Kanagawa, Japan, stated in the presentation.

Previously, EV-302 showed that patients who received enfortumab vedotin plus pembrolizumab achieved a median progression-free survival of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .001).²

Furthermore, at a median follow-up of 17.2 months, the combination yielded a median overall survival of 31.5 months (95% CI, 25.4-NR) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy (HR, 0.47; 95% CI, 0.38-0.58; P < .001). Investigators deemed the safety profile of enfortumab vedotin plus pembrolizumab to be generally manageable and consistent with previous studies of the agents.

Based on these findings, the FDA approved enfortumab vedotin plus pembrolizumab in 2023 for the treatment of patients with locally advanced or metastatic urothelial cancer.³ The combination is now considered the frontline standard of care for this population.¹

Investigators collected PRO data from EV-302 at baseline, including on day 1, prior to patients’ first dose, and post-randomization; weekly for 12 weeks; and every 3 weeks beyond the end of treatment and progression through survival follow-up. Patients completed the EORTC Core Quality of Life questionnaire (EORTC-QLQ-C30), which has a score range of 0 to 100. A higher score represents greater symptom burden, higher functioning, and greater QOL. The EORTC-QLQ-C30 assesses cancer-related symptoms, such as constipation, appetite loss, dyspnea, diarrhea, insomnia, fatigue, pain, nausea, and vomiting; physical, cognitive, emotional, role, and social function outcomes; and QOL/GHS. Patients also completed the Brief Pain Inventory—Short Form (BPI-SF) questionnaire, which has a score range of 0 to 10, with a higher score representing more pain. The BPI-SF assessed pain categories including worst pain, average pain, least pain, pain right now, pain interference, and location of pain.

“One notable aspect of the present study is that it collected PRO data beyond the end of treatment and beyond stage progression,” Kikuchi emphasized.

Prespecified study end points that were included in the hierarchical statistical testing plan included TTPP and mean change from baseline in worst pain at week 26. Prespecified descriptive analyses included data on change from baseline and TTCD. Patients with moderate or severe pain at baseline (enfortumab vedotin plus pembrolizumab arm, n = 128; chemotherapy arm, n = 128) were prespecified as a subgroup of interest.

In the enfortumab vedotin plus pembrolizumab arm, patients’ mean worst pain level per BPI-SF was 3.1 (standard deviation [SD], 2.8). This level was 3.3 (SD, 3.0) in the chemotherapy arm.

Regarding EORTC-QLQ-C30 outcomes, patients in the enfortumab vedotin plus pembrolizumab arm had a mean GHS/QOL score of 62.4 (SD, 22.5). The mean cognitive, social, emotional, physical, and role functioning scale scores in this arm were 84.3 (SD, 19.6), 77.3 (SD, 27.4), 75.5 (SD, 20.7), 76.5 (SD, 22.7), and 75.8 (SD, 28.3), respectively. In the chemotherapy arm, patients had a mean GHS/QOL score of 60.3 (SD, 25.4). The mean cognitive, social, emotional, physical, and role functioning scale scores in this arm were 83.9 (SD, 19.9), 76.3 (SD, 26.3), 74.6 (SD, 22.0), 72.8 (SD, 24.3), and 73.2 (SD, 29.4), respectively.

Predefined clinically meaningful thresholds for change in worst pain per the BPI-SF were not met in either arm (mean least square [LS], –0.58; 95% CI, –1.05 to –0.11; 2-sided P = .015). However, patients in the enfortumab vedotin plus pembrolizumab arm reported improved pain compared with baseline, and larger improvements in pain were observed in the enfortumab vedotin plus pembrolizumab arm vs the chemotherapy arm.

In both arms, patients with moderate or severe pain at baseline had clinically meaningful improvements in worst pain (mean LS, –0.5; 95% CI, –1.0 to –0.02; P = .04). Greater improvements in pain were observed in the enfortumab vedotin plus pembrolizumab arm vs the chemotherapy arm in this subgroup.

Patients in the enfortumab vedotin plus pembrolizumab arm had a transient worsening in GHS/QOL score at week 3, and scores returned to baseline at week 4. Patients in the chemotherapy arm had a worsening of GHS/QOL score from week 1 through week 17, and scores retuned to baseline from week 20. The mean LS was 2.5 (95% CI, 0.4-4.7; P = .020).

Patients in the enfortumab vedotin plus pembrolizumab arm had improvements across all functioning domains compared with patients in the chemotherapy arm based on changes from baseline within the first 26 weeks. The respective mean LS for role, physical, social, cognitive, and emotional functioning between the enfortumab vedotin plus pembrolizumab and chemotherapy arms were 4.13 (95% CI, 1.47-6.79; P = .0024), 3.62 (95% CI, 1.54-5.70; P = .0007), 2.57 (95% CI, –0.07 to 5.22; P = .0561), 2.15 (95% CI, 0.10-4.20; P = .0040); and 1.89 (95% CI, –0.19 to 3.97; P = .0750).

“Data collected across the entire patient journey was a notable approach and was associated with differences in compliance between the 2 arms,” Kikuchi concluded.

The study authors noted that findings from this study may inform the design of future trials.

Disclosures: Dr Kikuchi reports consulting or advisory roles with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb-Ono Pharmaceutical, Chugai Pharma, Janssen, Merck/Pfizer, and MSD; Speakers’ Bureau participation with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb-Ono Pharmaceutical, Chugai Pharma, Ferring; Janssen, Kissei Pharmaceutical, Kyorin, Kyowa Kirin International, Merck, MSD, Nippon Kayaku, Nippon Shinyaku, Pfizer, Sanofi, Taiho Pharmaceutical, and Takeda; and research funding from Chugai Pharma (Inst), Kissei Pharmaceutical (Inst), Kyorin (Inst), Kyowa Kirin International (Inst), Nihonkayaku (Inst), Nippon Shinyaku (Inst), Otsuka (Inst), Sanofi (Inst), Taiho Pharmaceutical (Inst), and Takeda (Inst).

References

1. Kikuchi E, Loriot Y, Van der Heijden M, et al. Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC). J Clin Oncol. 2024;42(suppl 23):108. doi:10.1200/JCO.2024.42.23_suppl.108
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed August 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer