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Neoadjuvant pembrolizumab regimen impresses in locally advanced urothelial cancer


Neoadjuvant pembrolizumab plus chemotherapy achieved a high rate of pathologic downstaging to noninvasive disease and was associated with a high radical cystectomy rate in cisplatin-eligible patients with urothelial cancer.

A neoadjuvant regimen of pembrolizumab (Keytruda) plus chemotherapy was shown to be safe and effective in patients with locally advanced urothelial cancer, according to the final results from the cisplatin-eligible cohort of the phase 1/2b GU14-188 trial.1

Data shared during the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that in patients treated with pembrolizumab plus gemcitabine/cisplatin, the radical cystectomy (RC) rate was 87.8% (36 of 41 evaluable patients) and the median time from the end of treatment to RC was 5.7 weeks. Regarding downstaging, the pathologic non-muscle invasive rate (PaIR; (≤ypT1N0), was 61.1% (n = 22), with a 44.4% (n = 16) pT0 rate.

These rates compare favorably to historic pathologic downstaging rates with cisplatin-containing regimens: 44% for PaIR and 30% for ypT0. Further, P0 response per baseline stage showed a 47% rate for baseline cT2 and a 58% rate for baseline cT3/T4.

“The study met its primary end point by achieving a pathologic downstaging to noninvasive disease (≤ypT1N0) rate of 61%. Neoadjuvant gemcitabine/cisplatin plus pembrolizumab is a regimen that is tolerable, associated with a high radical cystectomy rate, and achieves better pathologic response rates and longer survival than historical controls,” said Christopher J. Hoimes, medical oncology, Case Western Reserve University School of Medicine/University Hospitals Seidman Cancer Center, Cleveland, Ohio.

“Patients with bladder cancer who are cisplatin eligible are now encouraged to enroll in the phase 3 KEYNOTE-866 perioperative trial of gemcitabine/cisplatin plus pembrolizumab,” added Hoimes.

The safety run-in component of the phase Ib GU14-188 trial accrued patients with muscle-invasive cT2-4aN0M0 urothelial cancer eligible for cisplatin and radical cystectomy. In the phase 2 component, patients received the recommended phase 2 doses of neoadjuvant pembrolizumab at 200 mg/m2 intravenously every 3 weeks for 5 doses, starting on day 8 of cycle 1 of neoadjuvant chemotherapy, which comprised 4 twenty-one day cycles of gemcitabine plus cisplatin administered according to standard dosing.

The cohort included 43 patients with cisplatin-eligible advanced urothelial cancer. The median patient age was 65 years (range, 42-77), 26% of patients were female, 83.7% were non-Hispanic White, and the ECOG performance status was 0 for 77% of patients. Among 36 patients whose disease stage was known at screening, 17 had cT2 disease and 19 had cT3/T4 disease. PD-L1 expression was measured by combined positive score (CPS). Among the 40 patients whose PD-L1 status was known, 20 had CPS ≥10 and 20 had CPS <10.

At a median follow-up of 34.2 months, the 2-year relapse-free survival rate was 66% among 42 evaluable patients. The 4-year disease-specific survival (DSS) rate was 86.4% and the 4-year overall survival (OS) rate was 82%.

“It’s unclear if pathologic downstaging is an appropriate surrogate for OS when using chemoimmunotherapy. The full benefit of chemoimmunotherapy may not be realized at the time of cystectomy and may have ongoing effects that impact DSS and OS beyond what would be predicted with pathologic downstaging alone. Biomarkers and/or tumor microenvironment immune features may need to be integrated with pathology to establish an OS surrogate for chemoimmunotherapy,” said Hoimes.

The safety analysis included all 43 patients. Forty (95%) patients experienced at least 1 treatment-related adverse event (TRAE) of any grade. Grade 3/4 hematologic TRAEs occurred in 60% of patients. These included neutropenia (n = 11), anemia (n = 9), thrombocytopenia (n = 4), and lymphopenia (n = 1).

Grade 3/4 nonhematologic TRAEs occurred in 30% of patients. These included 2 patients each with thromboembolism, neutropenia fever, hyponatremia, and elevated creatinine. There was 1 patient each with acute coronary syndrome, thrombocytopenic purpura, dehydration, emesis, and infection.

“Of note, there were no dose-limiting toxicities (DLTs) during the phase Ib DLT period, which spanned from cycle 1, day 8, to cycle 2, day 14,” said Hoimes.

One patients died on day 9 following RC. The death was due to mesenteric ischemia and was not considered to be related to study treatment. Five patients were withheld from radical cystectomy, 2 due to TRAEs, 1 due to disease progression, and 2 due to patient choice. The TRAEs leading to the withholding of RC were grade 4 thrombocytopenic purpura in a patient who remained relapse-free at 44 months, and grade 3 venous thromboembolism in a patient who remained relapse-free at 25 months.

The double-blind phase 3 KEYNOTE-866 trial (NCT03924856) is randomizing cisplatin-eligible patients with muscle-invasive bladder cancer to neoadjuvant chemotherapy combined with either perioperative pembrolizumab or placebo.2 The study has 4 primary endpoints: overall pathologic complete response (pCR), pCR in patients with CPS ≥10, overall event-free survival (EFS), and EFS in patients with CPS ≥10. Secondary outcome measures included OS, disease-free survival, and pathologic downstaging rate. The targeted enrollment is 790 patients, and the estimated primary completion date is January 15, 2025.


1. Hoimes CJ, Adra N, Fleming MT, et al. Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)- eligible cohort of HCRN GU14-188. J Clin Oncol 38: 2020 (suppl; abstr 5047). doi: 10.1200/JCO.2020.38.15_suppl.5047

2. Perioperative Pembrolizumab (MK-3475) Plus Neoadjuvant Chemotherapy Versus Perioperative Placebo Plus Neoadjuvant Chemotherapy for Cisplatin-eligible Muscle-invasive Bladder Cancer (MIBC) (MK-3475-866/KEYNOTE-866) (KEYNOTE-866). NIH US National Library of Medicine. Last updated June 11, 2020. https://clinicaltrials.gov/ct2/show/NCT03924856. Accessed June 16, 2020.

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