ASCO 2019: Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab versus Placebo after First-Line Chemotherapy in Patients with Metastatic Urothelial Cancer: HCRN GU14-182 - Medical Oncologist Perspective

Chicago, IL ( The standard of care for cisplatin eligible patients with metastatic urothelial carcinoma (mUC) is a cisplatin-based chemotherapy regimen, most frequently combination gemcitabine/cisplatin or MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin).1,2 Unfortunately, disease progression invariably occurs after stopping chemotherapy, and chemotherapy cannot be given indefinitely due to toxicity. Thus, there is an unmet need for maintenance therapy for patients with mUC. One prior study evaluated sunitinib, as angiogenesis is thought to contribute to the progression of UC and sunitinib is a multi-kinase inhibitor including VEGF receptors.3 However, maintenance therapy with sunitinib in that study did not improve the 6-month progression rate. Another study evaluated lapatinib as maintenance therapy in HER1/HER2 positive UC.4 Unfortunately, this was also a negative study and showed no significant benefit in progression-free survival or overall survival.4 A third study evaluating maintenance vinflunine showed that maintenance therapy reduced the risk of progression by 44% but survival data has not yet been reported.5 In this study, the use of pembrolizumab as maintenance therapy after chemotherapy is described for patients with mUC.

This abstract provides data on 107 patients who were randomly assigned to maintenance placebo or pembrolizumab after receiving platinum-based chemotherapy for mUC. Baseline characteristics are shown below.
The majority of patients had visceral metastases (62% in placebo, 71% in pembro) and most patients had an objective response to chemotherapy (69% placebo, 73% pembro). Cisplatin-based chemotherapy was more commonly given than carboplatin-based chemotherapy. The primary objective was to determine the progression-free survival (PFS) per immune RECIST criteria. Patients progressing on placebo were allowed to cross over to pembrolizumab (which is frequently the next standard of care therapy). After a median follow up of 14.7 months, 41 patients had died and half of the patients randomized to placebo had crossed over the pembrolizumab. PFS was significantly longer for patients randomized to pembrolizumab and the mean PFS was 5.4 months with pembrolizumab and 3.2 months with placebo (HR 0.64, p=0.038).
The authors also used a novel statistical method to calculate a restricted mean PFS (rmPFS) time. At 18 months, the rmPFS was 8.1 months with pembrolizumab and 2.6 months with placebo.

Adverse events were consistent with prior studies of pembrolizumab but this is one of the first studies to show pembrolizumab compared with placebo, both as single agents. There was numerically increased Grade 3/Grade 4 toxicity with pembrolizumab, in particular, fatigue and elevated transaminases. 35% of patients on pembrolizumab had grade 1-2 diarrhea compared with 19% of patients on placebo.
Following platinum-based chemotherapy, patients receiving maintenance pembrolizumab had longer progression-free survival compared to those who received placebo, followed by pembrolizumab. Overall survival data has not been reported yet. This data looks promising for a switch therapy strategy, however, the author and panel members were asked if this should be the new standard of care starting today and all authors stated that additional data is necessary before starting this strategy in clinic today.

Presented by: Matt D. Galsky, MD, FASCO, Mount Sinai Hospital, New York, NY 

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

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