ASCO GU 2023: Patient-Reported Outcomes in Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer Treated with Enfortumab Vedotin Alone or in Combination with Pembrolizumab in the Phase 1b/2 EV-103 Cohort K

(UroToday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16^th and 18^th was host to a supportive care of patients with urothelial carcinoma session. Dr. Matthew Milowsky presented patient-reported outcomes from the phase 1b/2 EV-103 Cohort K study of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma treated with enfortumab vedotin alone or in combination with pembrolizumab.

Patients with locally advanced or metastatic urothelial carcinoma are known to have a poor prognosis with 5-year survival rates of ~7.7%.¹ The associated high symptom burden/pain negatively impacts quality of life and functioning.² 1^st line therapeutic options remain an unmet need for patients with cisplatin ineligible for locally advanced/metastatic urothelial carcinoma. Furthermore, there are limited PRO data available for 1^st line therapies in the cisplatin-ineligible patient population. This analysis aimed to describe the impact of 1^st line enfortumab vedotin (EV) plus pembrolizumab or EV monotherapy on QoL, functioning, and symptoms from the patient's perspective.

EV-103 Cohort K was part of an open-label, multiple cohorts, phase 1b/2 study in patients with locally advanced or metastatic urothelial carcinoma who were cisplatin ineligible. All patients received dose escalation with EV + pembro (n=5), followed by expansion to a cohort of 40 patients. Subsequently, 151 patients in cohort K were randomized 1:1 to either EV + pembro or EV monotherapy. The primary endpoint was confirmed ORR by RECIST v1.1 per blinded independent central review. Key secondary endpoints included:

• Confirmed ORR per RECIST v1.1 by the investigator
• Duration of response
• Disease control rate
• Progression-free survival
• Overall survival
• Safety/tolerability
• Lab abnormalities

Exploratory endpoints included:

• Pharmacokinetics
• Biomarkers
• PFS2
• PROs (EORTC QLQ-C30, BPI-SF, EQ-5D-5L, HRU)

No formal statistical comparisons between the two treatment arms were performed.

This analysis included 149 evaluable patients. Renal impairment was the main reason for cisplatin-ineligibility, as demonstrated below. The median patient age was 71 – 74 years. Approximately 83% of patients had known visceral metastases.

From an oncologic efficacy standpoint, the combination of EV and pembrolizumab demonstrated a confirmed objective response rate of 64.5% (95% CI: 52.7 – 75.1%) compared to 45.2% (95% CI: 33.5 – 57.3%) in the EV monotherapy arm. The median time to ORR was 2.07 months, and the median number of treatment cycles was 11.0 in the EV + pembro arm versus 8.0 cycles in the EV mono arm. 85.7% of responses in the EV + pembro arm were observed at the first assessment (week 9 +/- 1 week). The most common AEs were fatigue, peripheral sensory neuropathy, alopecia, and maculopapular rash.

In this analysis of PROs, the EORTC QLQ-C30 and BPI-SF were used. These instruments were administered at:

• Baseline (day 1, pre-dose, and post-randomization)
• Weekly for cycles 1-3
• Every cycle until end of treatment

Weeks 8-12, 24, and 51 were prespecified time points of interest. The authors utilized descriptive analyses to evaluate changes from baseline, measured using a Mixed Model for Repeated Measures and time to sustained improvement.

65/76 and 61/73 patients treated with EV + pembrolizumab or EV monotherapy completed the questionnaire at baseline, respectively. The quality of completion rates was ≥84% through Week 24.

At baseline, the EORTC Quality of Life Questionnaire (QLQ)-C30 demonstrate that fatigue, sleep disturbances and pain were the most burdensome symptoms. These were typical of those reported for patients with locally advanced/metastatic urothelial cancer.³ 

The combination of EV + pembrolizumab was associated with preservation or improvement in QoL and functioning scale scores:

• Emotional functioning demonstrated a consistent pattern of mild/moderate improvement (range 5-10 points)
• Mild to moderate transient worsening in QoL, role, and social functioning were observed at week 3, then returned to baseline where they were maintained 

With respect to symptom scales measured via the EORTC QLQ-C30, the following trends were seen:

• Pain: Clinically meaningful improvements in pain were seen at Week 12 (-14.41 [3.14]) versus baseline and persisted through Week 24 (-14.99 [3.56]).
• Insomnia and constipation demonstrated a consistent pattern of mild to moderate improvement (range: 5 – 10 points) versus baseline
• Diarrhea worsened at week 3 but returned to baseline levels at weeks 8 and 24 

With regards to pain scores at baseline measured via the Brief Pain Inventory Short Form (BPI-SF), more than 1/3 of patients had moderate to severe pain at baseline: 45.2% and 36.2% of patients in the EV+ pembrolizumab and EV alone arms, respectively, had moderate to severe worst pain at baseline.

Serial BPI-SF score measurements demonstrated improvements in the worst pain score in the EV + pembrolizumab arm:

• A clinically meaningful improvement in worst pain was observed at Week 24 (-2.07 [0.37])
• Worst pain, average pain, pain interference, and pain severity consistently showed improved scores from Week 4 to 24.

45% of patients experienced sustained pain improvements. The median time to sustained improvements was 1.1 (0.5 – 1.2) months.

In the EV monotherapy arm, improvements in QoL, functioning, and pain scores were similar to those seen in the EV + pembrolizumab arm:

• QoL, functioning, and symptom scale scores were directionally similar to those in the EV + pembro arm
  • Clinically meaningful improvements in pain were observed at Week 24 (-12.55)
  • Clinically meaningful improvements in insomnia were observed at Week 24 (-14.5)
• BPI-SF pain scores
  • Consistent small to moderate improvements in the BPI worst pain, average pain, and pain severity were observed
• BPI-SF time to improvement
  • 36.2% of patients had moderate to severe worst pain at baseline
    • 62% experienced sustained improvement
    • Median time to sustained improvement of worst pain was 1.4 months

Dr. Milowsky concluded his presentation as follows:

• Overall, PRO data showed that EV + pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma was associated with preservation or improvement of QoL, functioning, and symptoms:
  • Transient worsening in some symptoms was observed at Week 3 that returned to baseline within 1-2 weeks
• In both treatment arms, similar trends in rapid improvement of pain were demonstrated
• EV + pembrolizumab is the first regimen in the 1^st line setting to show clinically meaningful improvements in pain in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma
• PRO results for EV monotherapy were directionally similar to those of EV + pembrolizumab
• These PRO data complement the encouraging efficacy and safety profile of EV + pembrolizumab in 1^st line cisplatin-ineligible patients with locally advanced/metastatic urothelial carcinoma
• A confirmatory randomized phase 3 study (EV-302) is ongoing to assess efficacy, safety, and evaluate PROs in patients with previously untreated locally advanced or metastatic urothelial carcinoma treated with 1^st line EV + pembrolizumab or cisplatin/carboplatin-based regimens (NCT04223856)

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, February 16th – February 18th, 2023

 References:

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Bladder Cancer. National Institute of Health. 2021.
2. Mamtani R, et al. J Clin Oncol. 2021;39(suppl 15):4539.
3. O’Donnell PH, et al. Cancer. 2020;126(2):432-443.