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Keytruda Improves Disease-Free Survival in Advanced Bladder Cancer

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Postsurgical Keytruda improved disease-free survival — but not overall survival — in patients with locally advanced, muscle-invasive bladder cancer.

Postsurgical Keytruda (pembrolizumab) tended to lengthen the time patients lived without relapse or complications from their cancer — a statistic known as “disease-free survival” (DFS) — compared to observation in patients with locally advanced urothelial carcinoma (bladder cancer), according to data from the phase 3 AMBASSADOR Alliance A031501 trial.

Study highlights:

  • Keytruda showed promise in extending disease-free survival for patients with locally advanced urothelial carcinoma (bladder cancer) after surgery, compared to observation alone.
  • The positive effects of Keytruda were observed irrespective of the PD-L1 status, a pathway in cancer cells that Keytruda targets to enhance the immune system's ability to combat cancer.
  • While the trial met its main goal, the overall survival endpoint — which is the time patients live before death of any cause — did not show a significant difference, potentially influenced by patients in the observation group later receiving a checkpoint inhibitor.
  • The AMBASSADOR trial, which compared Keytruda to observation, closed early due to the FDA approval of adjuvant Opdivo for high-risk urothelial carcinoma in August 2021.
  • Keytruda demonstrated benefits across various patient subgroups, except for those with a primary tumor site in the upper tract, which requires further investigation.

Keytruda’s benefit was observed regardless of PD-L1 status, according to findings presented at the 2024 ASCO Genitourinary Cancers Symposium. PD-L1 is part of the PD-1 pathway found on cancer cells that Keytruda inhibits. In doing so, the immune system is better able to find and fight cancer.

At a median follow-up of 22.3 months, the median DFS with Keytruda in the intention-to-treat population was 29 months versus 14 months with.

However, at a median follow-up of 36.9 months, the median overall survival (OS; time patients live before death of any cause) was 50.9 months with Keytruda versus 55.8 months with observation.

“The trial met its efficacy end point and is a positive trial,” Dr. Andrea B. Apolo, of the National Institutes of Health in Bethesda, Maryland, stated in a presentation of the data. “The OS end point was not met at interim analysis. It may have been impacted by the high number of patients in the observation arm receiving a checkpoint inhibitor.”

Although the standard of care for patients with muscle-invasive urothelial carcinoma (MIUC) is radical surgery with or without postsurgical cisplatin-based chemotherapy, many patients are not eligible for cisplatin or have persistent muscle-invasive disease after neoadjuvant chemotherapy and surgery. Furthermore, cisplatin-based therapy in the adjuvant setting is not recommended for patients who have received neoadjuvant chemotherapy and is associated with side effects and administration difficulties post-radical surgery in patients not treated with neoadjuvant chemotherapy.

About the AMBASSADOR Trial

The AMBASSADOR trial assessed the PD-1 checkpoint inhibitor Keytruda versus observation in patients with high-risk MIUC, including cancers of the bladder, renal pelvis, urethra and ureter.Patients must have received radical surgery, including cystectomy, nephrectomy, nephroureterectomy or ureterectomy, more than four but no more than 16 weeks before trial initiation

AMBASSADOR closed early because of the August 2021 FDA approval of adjuvant Opdivo (nivolumab) for patients with high-risk urothelial carcinoma.

Patients in AMBASSADOR were randomly assigned to either Keytruda (354 patients) every three weeks for one year (18 cycles) or observation (348 patients).

DFS and OS served as the main areas assessed by researchers. Other areas of interest included DFS and OS by PD-L1 status and safety. Researchers also assessed DFS and OS by circulating tumor DNA (ctDNA) status; DFS and OS by immune gene signatures; DFS and OS by tumor molecular subtype; DFS and OS by T-cell receptor clonality; and quality of life.

A total of 131 and 126 OS events occurred in the Keytruda and observation arms, respectively. Patients in the Keytruda arm received a mean of 11 treatment cycles. All patients enrolled in the trial are currently not receiving study treatment.

All prespecified patient subgroups benefitted from Keytruda versus observation, except for those with a primary tumor site of the upper tract.

“The upper tract subgroup I think needs further investigation, and the magnitude of benefit is unclear,” Apolo noted.

In patients with PD-L1–positive disease, defined as those with a PD-L1 combined positive score (CPS) of at least 10%, the median DFS was 32.8 months with Keytruda versus 20.7 with placebo. In patients with PD-L­1–negative disease, the median DFS was 22.1 months with Keytruda vs 9.1 months with placebo. Regarding OS differences between prespecified patient subgroups, the HR in the subgroup whose primary site was in the upper tract was 1.45.

The median OS in patients with PD-L1–positive disease was not reached (meaning that researchers could not analyze this outcome because more than half of patients were alive) with Keytruda versus 56.1 months with observation. The median OS in patients with PD-L1–negative disease was 43.8 months with Keytruda versus 36.7 months with observation.

“PD-L1 positivity using the CPS was associated with a better prognosis but was not predictive for treatment efficacy,” Apolo emphasized. “PD-L1 status should not be used to select patients for treatment.”

Among the patients in the Keytruda arm who did not withdraw consent, 99 received alternative systemic therapy. Patients were permitted to report multiple alternative treatments. In the post-DFS setting, 82 patients received alternative systemic therapy, including a checkpoint inhibitor (19 patients), chemotherapy (38 patients), antibody-drug conjugates (ADCs; 45 patients), and other therapy (four patients). In the pre-DFS setting, 17 patients received alternative systemic therapy, including a checkpoint inhibitor (six patients), chemotherapy (four patients) and ADCs (three patients).

Among the patients in the observation arm who did not withdraw consent, 123 received alternative systemic therapy. In the post-DFS setting, 104 patients received alternative systemic therapy, including a checkpoint inhibitor (76 patients), chemotherapy (34 patients), ADCs (21 patients) and other therapy (three patients). In the pre-DFS setting, 19 patients received alternative systemic therapy, including a checkpoint inhibitor (18 patients), chemotherapy (six patients) and ADCs (one patient).

Study Side Effects

In the Keytruda arm, 48.4% of patients experienced side effects of grade 3 or higher, meaning that they were moderate to severe. In total, 38.6%, 4.9% and 4.9% of patients had grade 3 (moderate), 4 (severe) and 5 (fatal) side effects, respectively. Grade 3 and 4 blood-related side effects were observed in 5.5% and 0.9% of patients, respectively. Among the non-hematologic side effects observed, 37.7%, 4.6% and 4.9% were grade 3, 4 and 5, respectively.

MORE:Keytruda Side Effects: ‘If Something Doesn’t Feel Right … Call’

In the observation arm, 31.8% of patients experienced side effects of grade 3 or higher. In total, 23.3%, 3.8% and 4.7% of patients had grade 3, 4 and 5 side effects, respectively. Grade 3 blood-related side effects were observed in 2.6% of patients, and no grade 4/5 blood-related side effects were reported. Among the non-hematologic side effects observed, 22.7%, 3.8% and 4.7% were grade 3, 4 and 5, respectively.

Among the patients who received Keytruda, the most common treatment-related side effects were fatigue (any-grade, 47%; grade 3, 2%); itching (22%; 1%); diarrhea (21%; 3%); hypothyroidism (20%; 0%); maculo-papular rash (17%; 2%); increased creatine (15%; 1%); anorexia (15%; 1%); anemia (14%; 2%); increased lipase, which can indicate pancreatic issues (13%; 3%); difficulty breathing (11%; 0%); increased serum amylase, which can also indicate pancreatic issues (9%, 2%); hyperthyroidism (8%; 0%); and increased alanine aminotransferase (6%; 1%). Additionally, 1% of patients experienced grade 4 lipase increase.

“These results support adjuvant (Keytruda) as a new therapeutic option for patients MIUC at high risk of recurrence,” Apolo concluded.

Follow-up is ongoing for the final DFS/OS analysis of AMBASSADOR, as well as the ctDNA analyses and additional correlative analyses.


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