The combination of pembrolizumab plus nab-paclitaxel demonstrated clinically meaningful and sustainable responses, along with prolonged progression-free survival when administered as salvage therapy to patients with metastatic urothelial carcinoma.
The combination of pembrolizumab (Keytruda) plus nab-paclitaxel demonstrated clinically meaningful and sustainable responses, along with prolonged progression-free survival (PFS) when administered as salvage therapy to patients with metastatic urothelial carcinoma (mUC), according to results from the phase 2 PEANUT study.
Preliminary research showed an objective response rate (ORR) of 27.7% with nab-paclitaxel given as monotherapy in the second-line setting to patients with mUC. Since pembrolizumab has become the standard of care for patients with mUC after prior chemotherapy failure, there was rationale to combine the agents as treatment of this patient population.
PFS per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was the primary end point of the study. The secondary end points explored were safety/tolerability, duration of response (DOR), and overall survival (OS). The study was 90% powered to detect a minimum 3.0-month improvement in PFS up to a 5.0-month improvement.
The median PFS was 5.9 months (95% CI, 3.1-11.5), meeting the primary end point of the study. Pembrolizumab plus nab-paclitaxel also led to an ORR of 38.6% (95% CI, 27.2%-51.0%). Complete responses were observed in 10 patients (14.3%; 95% CI, 7.1%-24.7%), partial responses (PRs) were observed in 17 patients (24.3%), and unconfirmed PRs were noted in 8 patients (11.4%). Eighteen patients (25.7%) in the study had stable disease from the combination treatment, and progressive disease was seen in 17 patients (24.3%).
The median DOR was not reached (NR) in the study (95% CI, 11.5-NR). According to PET/CT scans, responses included the absence of residual pathologic of FDG-uptake in 17.1% of patients, a decrease in FDG-uptake in 25.7%, and no response or increase in FDG-uptake in 50% of patients.
The median OS was also NR in the study (95% CI, 9.5-NR).
Patients in the study were followed for a median of 9.8 months. The median time to response was 1.4 months. Notably, responses were maintained in 24 patients who received the combination regimen, and of those patients, ongoing responses lasting more than 12 months were observed in 5 patients.
In the first 12 patients in the study, no serious adverse events (AEs) or grade 3/4 AEs were observed. In the overall study population, AEs of any grade occurred in 87.1%, treatment-related AEs occurred in 84.3%, and of that, 81.4% were related to treatment with nab-paclitaxel and 35.7% were related to pembrolizumab. Serious AEs of any grade occurred in 15.7% of the overall population.
Overall, 11 patients discontinued treatment, 2.9% due to both therapies, 24.3% to nab-paclitaxel, and 1.4% due to pembrolizumab.
The study findings led to a question during the 35th Annual European Association of Urology Congress of whether the combination of pembrolizumab and nab-paclitaxel could be switch maintenance after frontline chemotherapy in this patient population. Andrew Neechi, MD, the presenter of the PEANUT data, noted that it is a possibility.
The PEANUT study was an open-label, single-arm clinical trial (NCT03464734). Intravenous (IV) pembrolizumab 200 mg was administered to patients on day 1 of treatment and IV nab-paclitaxel 125 mg/m2 was administered on days 1 and 8, every 3 weeks. Treatment in the study was continued until loss of benefit, unacceptable toxicity, or investigator decision or withdrawal by the patient.
Eligible patients were those with histologically confirmed UC of the bladder or the urothelium, measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1. Patients must have failed 1 or 2 cisplatin-based conventional chemotherapy regimens for metastatic disease. Prior chemotherapy could include neoadjuvant or adjuvant regimens if the patient relapsed within 6 months of the last cycle of chemotherapy.
According to baseline screening, the median age of patients in the study was 67 years (range, 60-73). Female patients made up 26% of the population. The ECOG performance status was calculated as 0 in 69% of patients and 1 in 31% of patients. In terms of histology at baseline, 81% of patients had pure UC, 11% had UC and squamous cell carcinoma, 4% were diagnosed with UC and glandular component, and 3% had other variants of the disease. Most of the study participants were former smokers (59%), but 27% never smoked while 14 were current smokers. The site of the primary tumor in the study was most commonly the bladder (84.3%), followed by the urinary tract (14.3%) and the urethra (1.4%).
Baseline disease characteristics showed visceral disease in 58.6% of patients, along with lung metastases in 22.9%, liver metastases in 28.6%, and bone metastases in 28.6%. In addition, 32.9% of patients had lymph node-only disease. Hemoglobin level of <10 gr/dL was observed in 13% of patients. The Bellmunt prognostic risk factors score varied in patients, but most patients (50%) had a score of 0, followed by 1 in 29% of the population, 2 in 20% of patients, and 3 in 1%.
The number of prior therapies was 1 for 76% of patients and 2 for the remaining 24%. Prior treatment included neoadjuvant or adjuvant chemotherapy in 39% of patients and radical removal of the primary tumor in 69%.
Twenty-nine percent of patients had a history of previous non-muscle-invasive UC, and 19% had previous Bacillus Calmette-Guerin instillations.
Neechi A, Raggi D, Bandini M, et al. Interim results of PEANUT: An open-label, single-arm, phase 2 study evaluating pembrolizumab plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC). Presented at: 35th Annual European Association of Urology Congress; July 20-26, 2020; Virtual. Poster 1056.