Adjuvant Pembrolizumab Prolongs DFS Regardless of PD-L1 or Nodal Status in High-Risk MIBC

Andrea B. Apolo, MD

Treatment with adjuvant pembrolizumab (Keytruda) produced a statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs observation regardless of PD-L1 expression or lymph node status in patients with high-risk muscle-invasive bladder cancer (MIBC) who underwent radical surgery, according to follow-up data from the phase 3 AMBASSADOR trial (NCT03244384) presented at the 2024 ESMO Congress.¹

“In this setting, pembrolizumab doubled the median DFS at 29.6 months compared with 14.2 months in the observation arm,” Andrea B. Apolo, MD, a senior investigator in the Genitourinary Malignancies Branch of the National Cancer Institute, Bethesda, Maryland, said during a presentation of the data in the intention-to-treat population (HR, 0.73; 95% CI, 0.59-0.90; P = .0027) that was published in The New England Journal of Medicine.^1,2

A total of 702 enrolled patients were randomly assigned to receive 200 mg of pembrolizumab every 3 weeks (n = 354) vs observation (n = 348) with dual primary end points of DFS and overall survival (OS). Across both cohorts, the median age was 68.0 years, and the majority of patients were men (74.6%) and White (90.2%).

In the pembrolizumab arm, 57.3% of patients were PD-L1 positive (combined positive score ≥ 10) compared with 57.8% of patients in the observation arm. In the pembrolizumab arm, the primary tumor sites were bladder (75.4%), upper tract (22.9%), and urethra (1.7%) compared with the observation arm: 75.6%, 21.0%, and 3.4%, respectively.

When evaluating subgroups, Apolo noted that DFS in patients who were PD-L1 positive showed a benefit in terms of prognosis. “The marker was prognostic, but not predictive because both arms, PD-L1–positive and –negative, benefited from adjuvant pembrolizumab,” Apolo added.

Turning to DFS for primary tumor sites in the upper and lower tract, investigators reported small numbers, “so it is hard to draw conclusions from these cohorts,” Apolo said. Exploratory DFS subgroups were also evaluated and included an evaluation of lymph node status, upper tract neoadjuvant therapy, ECOG performance status, and histologic variants.

“Focusing on the lymph node status, we observed that the higher the lymph node stage, the worse the patient did,” Apolo said. In all patients with N0 stage disease, the HR for DFS was 0.53 (95% CI, 0.34-0.79). In N1, the HR was 0.81 (95% CI, 0.54-1.22), and for patients with N2/N3 stage disease, the HR was 0.71 (95% CI, 0.52-0.98). “This was prognostic, but adjuvant pembrolizumab benefited all groups including N0 and N1, and N2 and N3,” she continued.

Evaluation of lymph node stage by lower tract vs upper tract demonstrated that “patients with disease present in the lower tract, which were predominantly bladder patients, showed benefit from adjuvant pembrolizumab, regardless of N0 or N-plus status,” Apolo said. “Looking at patients with upper tract disease, we noted that the [DFS] numbers are very small and the data are inconclusive,” Apolo continued.

The investigators reported that the most common sites of metastatic disease occurrence (n = 702) were abdominal lymph nodes (40%), pelvic lymph nodes (30%), bone (22%), chest/neck lymph nodes (20%), and liver (18%). Apolo noted that these recurrence sites were “interesting and hypothesis-generating.”

In the primary analysis of the AMBASSADOR study,³ pembrolizumab showed a significant improvement in DFS vs observation after a 22-month follow-up. The trial closed early due to the FDA approval of nivolumab (Opdivo) in high-risk MIUC after surgery.⁴ At that point, 34% of patients in the observation arm and 20% of patients in the pembrolizumab arm had received a non-protocol checkpoint inhibitor or withdrew consent. “The interim OS had been presented although the final analysis of OS had not been performed because only 8% of events had been reached,” Apolo said.

Apolo concluded the presentation noting that subgroup analysis showed a DFS benefit with pembrolizumab vs observation regardless of PD-L1 expression and lymph node status.

“Based on the doubling of the median DFS and the previously presented manageable toxicity, this trial supports adjuvant pembrolizumab as a therapeutic option in patients with high-risk MIUC,” Apolo said.

References

1. Apolo AB. Alliance A031401: AMBASSADOR study of adjuvant pembrolizumab in muscle-invasive urothelial carcinoma vs observation: extended follow-up results and metastatic disease recurrence distribution. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1964MO.
2. Apolo AB, Ballman KV, Sonpavde GP, et al. Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma. N Eng J Med. 2024. Published September 14, 2024. doi:10.1056/NEJMoa2401726
3. Apolo AB, Ballman KV, Sonpavde GP, et al. AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. J Clin Oncol. 2024;42(suppl 4):LBA531. doi:10.1200/JCO.2024.42.4_suppl.LBA531
4. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. FDA. Accessed September 15, 2024. https://tinyurl.com/ytnm4urp