Promising Responses Observed in Preliminary Data of Pembrolizumab Plus Nab-Paclitaxel in Advanced Urothelial Carcinoma

Andrea Necchi, MD

The combination of checkpoint inhibitor pembrolizumab (Keytruda) plus nab-paclitaxel (Abraxane) induced a clinically meaningful objective response rate (ORR) as salvage therapy for patients with advanced urothelial carcinoma in the second- and third-line settings, according to interim results from the phase II PEANUT study presented through the American Urological Association’s (AUA) Virtual Experience platform for the 2020 AUA Annual Meeting.¹

The median progression-free survival (PFS) was also considered promising at 5 months (95% CI, 4-not reached [NR]).

“This study is 1 of the first [to report on a] chemoimmunotherapy combination in the second- and third-line setting of metastatic urothelial carcinoma,” lead author Andrea Necchi, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori Milan, said during his presentation. “The response rate and CR [complete response] rate, in particular, were very promising, and the safety profile was very favorable.”

The median ORR per RECIST v1.1 criteria was 38.6% (95% CI, 27.2%-51%), with a CR observed in 10 patients and a partial response (PR) in 8 patients. The CR and PR rates observed were 14.3% (95% CI, 7.1%-24.7%) and 24.3%, respectively. There were also 8 unconfirmed PRs, and 18 patients had stable disease. Seventeen patients had progressive disease (PD).

According to an analysis of PET/CT response, 12 patients had an absence of residual pathologic fluorodeoxyglucose (FDG) uptake (17.1%) and 18 had a decrease in FDG uptake (25.7%). Thirty-five patients had no response or increased FDG uptake (50%).

The median follow-up was 9 months, and the median time to response was 1.4 months. The duration of response (DOR) was NR. Overall, 24 patients had maintained their response and continued to receive treatment as of the data cutoff for the interim analysis. Additionally, 5 patients (7.1%) had ongoing responses lasting more than 12 months.

Any-grade adverse events (AEs) of all causes were observed in 61 patients (87.1%). Grade 3/4 AEs of all causes were experienced by 23 patients (32.9%), and 1 patient experienced a grade 5 all-cause AE (1.4%). Treatment-related AEs (TRAEs) were experienced by 57 patients (81.4%) of any grade and TRAEs of grade 3/4 severity were observed in 17 patients (24.3%).

Investigators also noted that 59 patients experienced AEs related to nab-paclitaxel (84.3%) and 25 experienced AEs related to pembrolizumab (35.7%) of any grade. Nab-paclitaxel- and pembrolizumab-related AEs of grade 3/4 occurred in 16 (22.9%) and 3 patients (4.3%), respectively. Serious AEs of any grade occurred in 11 patients (15.7%), of grade 3/4 in 7 patients (10%), and of grade 5 in 1 patient (1.4%).

Treatment discontinuation was caused by any grade AE in 2 patients (2.9%), grade 3/4 AEs in 1 patient (1.4%), and grade 5 AEs in 1 patient (1.4%). Nab-paclitaxel was discontinued in 17 patients (24.3%) due to peripheral neuropathy of any grade and in 6 patients due to grade 3/4 peripheral neuropathy (8.6%). Pembrolizumab was discontinued due to any-grade or grade 3/4 AEs in 1 patient each (1.4% each).

Investigators also noted that PI3KCA and RB1 genes were more frequently altered among patients who responded to therapy, whereas TSC1 and LRP1B genes were altered more frequently among patients who had PD.

Pembrolizumab is approved by the FDA and European Medicines Agency for the treatment of locally advanced metastatic urothelial carcinoma after failure on platinum-based chemotherapy. A single-arm phase II clinical trial of nab-paclitaxel in Canada previously demonstrated an ORR of 27.7% in patients who had previously been treated with platinum chemotherapy (n = 48), and the study also led to an encouraging median PFS of 6 months.² These data ultimately led to the hypothesis for the current trial that nab-paclitaxel could have enhanced benefit in combination with an immunotherapeutic agent as salvage therapy.

To be eligible for the PEANUT study, patients had to have an ECOG performance status of 0 or 1 and have failed 1 to 2 prior lines of cisplatin-based conventional chemotherapy for treatment of metastatic disease. Patients with prior treatment with neoadjuvant/adjuvant regimens were also eligible if they had relapsed within 6 months of their last cycle of chemotherapy.

The median age of the 64 patients in the study was 67 years (range, 60-73), and the population was primarily men, whereas women made up 26% of the population. Overall, 48 patients (69%) had an ECOG status of 0 and 22 (31%) had a status of 1.

Visceral disease was observed in 41 patients (58.6%), including lung metastases in 16 patients (22.9%), liver metastases in 20 (28.6%), and bone metastases in 20 (28.6%). Twenty-three patients (32.9%) had lymph node–only disease, and 9 patients had a hemoglobin level <10 gr/dL (13%). The Bellmunt score was 0 in 35 patients (50%), 1 in 20 (29%), 2 in 14 (20%), and 3 in 1 (1%).

Fifty-three patients had received 1 prior line of systemic therapy (76%) while 17 patients had received 2 prior lines (24%).

Previous treatment with either neoadjuvant or adjuvant chemotherapy was observed in 27 patients (39%), and 48 patients had radical removal of their primary tumor (69%). Twenty patients had a history of non–muscle invasive urothelial carcinoma (29%), and 13 had received prior Bacillus Calmette-Guerin intravesical instillations (19%).

Pembrolizumab was administered intravenously on day 1 at 200 mg and nab-paclitaxel was given at a dose of 125 mg/m2 intravenously on days 1 and 8 every 3 weeks. Patients were treated until clinical benefit was lost or they had unacceptable toxicity, withdrew their consent, or died. The primary end point was PFS, and secondary end points included safety and tolerability, ORR, DOR, and OS.

Overall, the ORR and CR rate were considered clinically meaningful and appeared sustained after significant follow-up. The safety profile demonstrated that chemotherapy could be viable option in combination with an immunotherapy backbone. The genomic alterations discovered in the circulating tumor DNA were not negligible, confirming the need for re-assessment of tumors with liquid biopsies prior to the initiation of later lines of therapy in this patient population.

_References

1. _{Necchi A, Raggi D, Bandini M, et al. Pembrolizumab and nab-paclitaxel as salvage therapy for platinum-treated, locally advanced or metastatic urothelial carcinoma: results of the open-label, single-arm, phase 2 PEANUT study. J Urol. 2020; 203(suppl 4):PD51-01. doi:10.1097/JU.0000000000000953.01}
2. _{Ko YJ, Canil CM, Mukherjee SD, et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013;14(8):769-776. doi 10.1016/S1470-2045(13)70162-1}