Chemoimmunotherapy Combo Shows Efficacy in Patients with Advanced Urothelial Cancer

Preliminary results from a single-arm study demonstrated promising progression-free survival (PFS) and a clinically meaningful objective response rate (ORR) with the combination of pembrolizumab (Keytruda) and nab-paclitaxel (Abraxane) as second- or third-line therapy in patients with advanced urothelial carcinoma.

The PEANUT study “is one of the first to report on the results of a chemoimmunotherapy combination in the salvage setting of metastatic urothelial carcinoma. Overall, the median PFS was in line with the results obtained with the most promising therapeutic options in this clinical setting,” explained the lead investigator of the study, Andrea Necchi, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. “The ORR and the [complete response] rate in particular were clinically meaningful and seemingly sustained after a noteworthy duration of follow-up,” Dr Necchi said, as he presented these results during the virtual 2020 American Urological Association Annual Meeting.

Previously, nab-paclitaxel was evaluated as a single agent in the “pre-­immunotherapy” era, and in a Canadian, single-arm, phase 2 study, it was associated with an ORR of 27.7% as second-line treatment in 48 patients treated with platinum-­based therapy, and an encouraging median PFS of 6 months.

“These results led us to hypothesize that chemotherapy with nab-paclitaxel could have enhanced clinical benefit if combined with immune-­oncologic therapy as a salvage therapy regimen,” said Dr Necchi.

In the open-label, single-arm, phase 2 PEANUT clinical trial, 64 patients with urothelial carcinoma of the bladder or the urothelium received 200 mg of pembrolizumab intravenously on day 1 and 125 mg/m2 nab-paclitaxel intravenously on days 1 and 8, and every 3 weeks until disease progression or onset of unacceptable toxicity. Failure of 1 or 2 platinum-based chemotherapy regimens for metastatic disease was a key eligibility criterion.

Genomic profiling was performed on tumor samples using next-generation sequencing. In a subgroup of patients, hybrid-capture–based genomic profiling of circulating tumor DNA (ctDNA) was performed on up to 70 genes.

Median patient age was 67 years and 26% of the study population was female. Some 81% of participants had a pure urothelial carcinoma histology, whereas 11% had urothelial carcinoma and a squamous-cell carcinoma component. The site of the primary tumor was bladder in 84.3% and upper urinary tract in 14.3%. More than one-fourth (28.6%) of patients had liver metastases. In addition, 76% of patients had 1 previous systemic treatment regimen and 24% had 2 previous systemic regimens.

The median PFS was 5 months, and the ORR (per RECIST v1.1) was 38.6%, with 10 (14.3%) complete responses, 17 (24.3%) confirmed partial responses, 8 (11%) unconfirmed partial responses, and 18 (25.7%) with stable disease.

“More than 70% of patients had a reduction in the diameter of target lesions,” despite most of the patients having high-risk features, said Dr Necchi. The duration of response was not reached at a median follow-up of 9 months, and the median time to response was 1.4 months. Median overall survival was not reached.

“Twenty-four patients had maintained response and were receiving treatment, and 5 (7.1%) had ongoing response lasting longer than 1 year,” he said.

Twenty-one patients had complete response/partial response in tissue samples only, 11 in ctDNA analysis only, and 9 in both tissue and ctDNA. Progressive disease was detected in 15 tissue samples only, in 5 patients by ctDNA analysis only, and in 3 patients by both methods.

Grade 3/4 treatment-related adverse events (AEs) occurred in 17 patients (24.3%). Sixteen patients (22.9%) had grade 3/4 nab-paclitaxel–related AEs and 3 (4.3%) had pembrolizumab-related grade 3/4 AEs. Eleven (15.7%) had serious AEs. Four patients (5.7%) discontinued both agents because of AEs, 23 (32.9%) discontinued nab-paclitaxel only because of peripheral neuropathy after a median of 14 doses, and 2 (2.8%) discontinued pembrolizumab only.

Two genes that were frequently altered in responders were PI3KCA and RB1, whereas TSC1 and LRP1B were more frequently altered in the group with progressive disease, Dr Necchi noted.

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