According to results from a phase 2 trial, nab-paclitaxel plus pembrolizumab showed promising efficacy and manageable tolerability for patients with advanced urothelial cancer who are platinum-refractory or cisplatin-ineligible.

The first-line therapy for advanced or metastatic urothelial carcinoma is platinum-based chemotherapy but, as Irene Tsung, MD, and colleagues point out, “Up to 50% of patients are unable to receive cisplatin…” and “outcomes with carboplatin-based regimens are dismal.” In earlier studies, nab-paclitaxel showed activity for patients who with advanced urothelial carcinoma who progressed on platinum-based chemotherapy. There are also studies suggesting the addition of an immune checkpoint inhibitor to nab-paclitaxel could improve efficacy.

In this single-arm, 2-stage trial, 36 patients with urothelial carcinoma who were either cisplatin-ineligible (n = 18) or platinum-refractory (n = 18) were enrolled and were response-evaluable between February 2018 and April 2021. Patients received 200 mg pembrolizumab on day 1 and 125 mg/m² nab-paclitaxel on days 1 and 8, in 21 days cycles. After a planned interim analysis, the starting dose of nab-paclitaxel was reduced to 100 mg/m².  The primary end point of the study was overall response rate. Secondary end points included progression-free survival (PFS), overall survival (OS), complete response, duration of response, duration of therapy, and safety.

At the time of data cut-off, the median treatment duration was 6 cycles of nab-paclitaxel and 7.5 cycles of pembrolizumab and the median follow-up duration was 19.7 months. There were 10 patients still on treatment. The confirmed overall response rate was 50%, including 3 complete responses and 15 partial responses. These results surpassed the primary outcome threshold of an overall response rate of 45%. The median duration of response was 4.4 months. The median PFS was 6.8 months, and the median OS was 18.2 months (confidence interval [CI] 95%, 4.4 to not reached; 10.6 to not reached, respectively). In the cisplatin-ineligible population, the median PFS and OS were not reached.

Of the first 17 patients enrolled, 15 experienced grade 3 adverse events attributed to the first initial dosing of nab-paclitaxel, with 5 patients discontinuing. After the dose reduction of nab paclitaxel, there was only 2 instances of grade 3 adverse events. The most common serious adverse events experienced were 3 thromboembolic events and 2 urinary tract infections.

Grade 3 immune-mediated adverse events that were attributed to pembrolizumab occurred in 10 patients. Overall, 10 patients required 1 dose reduction of nab-paclitaxel and 3 patients required 2 reductions. There were 7 patients who discontinued treatment because of adverse events.

The authors noted the following limitations to their study: a small sample size at a single institution, most patients being men (n = 32), and the inclusion of both upper and lower tract urothelial cancers. Additionally, less than half of the patients had comprehensive tumor genomic profiling data available.

“The combination of nab-paclitaxel and anti-PD-1 therapy offers an efficacious and feasible option for [advanced urothelial cancer] patients who cannot receive cisplatin or are platinum-refractory,” Dr Tsung et al, concluded, adding, “We suggest continued exploration of the role of chemoimmunotherapy to expand the repertoire of therapy options especially in later lines of therapy.”

Source:

Tsung I, Green E, Palmbos P. A phase 2 trial of nab-paclitaxel in combination with anti-PD1 therapy in advanced urothelial cancer. J Urol. Published online: January 1, 2021. doi:10.1097/JU.0000000000002969