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Gemcitabine, split-dose cisplatin and pembrolizumab as neoadjuvant therapy before a radical cystectomy in muscle-invasive bladder cancer patients

Early phase studies have demonstrated the efficacy of immune checkpoint inhibition in the neoadjuvant treatment of muscle-invasive bladder cancer (MIBC) patients. Phase II results presented at ASCO GU 2021 show that neoadjuvant gemcitabine, split-dose cisplatin plus pembrolizumab results in pathological downstaging in 56% of patients. This downstaging rate was similar in patients with and without PD-L1 expression. The regimen proved to be tolerable which supports its further evaluation in the ongoing phase III Keynote-866 trial.


Neoadjuvant cisplatin-based combination chemotherapy, followed by radical cystectomy (RC) is the current standard-of-care (SoC) for patients with muscle-invasive bladder cancer (MIBC). However, with this regimen outcomes in MIBC remain sub-optimal. In recent years, immune checkpoint inhibitors proved to be active in patients with metastatic disease and early phase studies also demonstrated clinical activity of these agents in the neoadjuvant setting. ASCO GU 2021 featured the presentation of a phase II LCCC1520 trial evaluating the efficacy and safety of gemcitabine and split-dose cisplatin (GC) in combination with pembrolizumab as a neoadjuvant therapy prior to RC in patients win MIBC.

The study at hand enrolled a total of 39 MIBC patients with cT2-T4aN0M0 disease, who were eligible for RC, to receive pembrolizumab (200 mg on day 1) plus gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (35 mg/m2 days 1 and 8), every 3 weeks for 4 cycles, followed by RC within 4-8 weeks. The first 6 patients of this study received full-dose cisplatin (70 mg/m2 on day 1) and a lead-in pembrolizumab dose, although this protocol was discontinued due to excess toxicity. The primary objectives of the study was to estimate the rate of pathological downstaging <pT2, with secondary objectives including estimations of the complete pathological response rate (pT0N0M0), the event-free survival and the overall survival.

Pathological downstaging in more than half of the patients

The median age of patients in the study was 66 years and 82% of them was male. Furthermore, 85% of patients had a current or former smoking history and 72% presented with T2 disease. Finally, 72% of patients in this study had pure urothelial carcinoma histology, and 54% were found to be PD-L1 positive. At time of analysis, 56% patients had a pathologic downstaging <pT2N0M0, including a complete pathologic response in 36%. The pathologic response rate was comparable in both PD-L1 positive and negative subgroups (67% vs. 47%, respectively, P= 0.25).

Grade ≥3 treatment-related adverse events (TRAEs) occurred in 74% of patients, with the most common presentations being thrombocytopenia (33%), neutropenia (41%) and febrile neutropenia (13%). 51% of patients had an increase in creatinine and 8% (N= 3) had a thromboembolic event. 1 grade ≥3 event of diabetic ketoacidosis was reported, attributed to pembrolizumab.


This study found that for patients with MIBC who were eligible for RC, that neoadjuvant gemcitabine, split-dose cisplatin plus pembrolizumab resulted in a pathological downstaging rate of 56%, which is comparable to other studies. Furthermore, this downstaging rate was observed regardless of PD-L1 status. Combined with a manageable safety profile, the results of this phase II study support the investigation of this neoadjuvant combination in the ongoing phase III Keynote-866 trial.


Rose TL et al., Phase II study of gemcitabine and split-dose cisplatin plus pembrolizumab as neoadjuvant therapy prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC). Presented at ASCO GU 2021; Abstract 396.

Speaker Tracy L Rose

Tracy L Rose

Tracy L Rose, MD, UNC School of Medicine, Chapel Hill, North Carolina, United States


See: Keyslides

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