ESMO 2018: Neoadjuvant Therapy with Pembrolizumab Alone or in Combination with Cisplatin plus Gemcitabine for Locally Advanced Urothelial Cancer, A Phase Ib/2 Study

Munich, Germany ( Treatment of muscle-invasive urothelial cancer can involve a combination of systemic therapies, radiation, and surgery. When muscle-invasive urothelial cancer (UC) is treated with surgery alone, almost half of patients will develop metastatic disease within two years, and 5-year survival overall survival for patients who receive only cystectomy or radiation range from 27% - 88%1. The current standard of care chemotherapies includes MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), GC (gemcitabine plus cisplatin), and CMV (cisplatin, methotrexate, and vinblastine). However, many patients are not candidates for platinum-based chemotherapy regimens, either due to poor performance status or underlying kidney disease. Thus, there is an unmet need in the space of neoadjuvant therapy for muscle-invasive UC.

Pembrolizumab has demonstrated disease activity in both neoadjuvant therapy as well as second-line therapy for metastatic UC. For metastatic UC, KEYNOTE-045 randomized 542 patients with advanced UC that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab or investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine2. KEYNOTE-045 demonstrated that pembrolizumab improved median overall survival compared with chemotherapy amongst patients with a PD-L1 combined score of 10% or more (8.0 months vs 5.2 months, hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005).

In the neoadjuvant space, pembrolizumab was given in an open label single arm phase 2 study, where patients were enrolled regardless of cisplatin eligibility. Patients received 3 cycles of pembrolizumab (200 mg) every 3 weeks before radical cystectomy and the primary endpoint was a pathologic complete response (pT0). Of all 43 treated patients, a pT0 was obtained in 39.5% of patients, which is similar to the pT0 of neoadjuvant MVAC (38%)3,4. The mean PD-L1 combined positive score (CPS, Dako 22C3 assay) was 44.8% for the pT0 patients compared with 17.4% non-pT0 patients. Patients with RB1 and PBRM1 alterations were enriched for complete pathologic responses. This study seeks to add further evidence for neoadjuvant therapy with combination immune checkpoint inhibitor plus chemotherapy.

This phase I/II study examines both neoadjuvant therapy with pembrolizumab alone (Cohort II – cis ineligible) as well as combination pembrolizumab + cisplatin + gemcitabine in a cis eligible cohort. This abstract describes the outcome of patients from cohort 1.

ESMO 2018 data from cohort I

40 patients received Pembro + Gem/Cis. Median age was 65 and predominantly men (78%). Most patients had an ECOG performance status of 0 (31/40) and the majority had baseline stage of cT2 (invades muscularis propria – 51%) or cT3 (invades perivesical tissue – 44%).

The median time to surgery was 18.8 weeks from the onset of chemotherapy, with a median time of 5.7 weeks from the end of chemo to surgery. In terms of response, 40% of patients had a complete response (P0), which is similar to MVAC and 61% of patients had a ypT1N0 or lower.

ESMO 2018 pathologic response in RC population

Most patients received cystectomy (36/40). 4 patients did not receive cystectomy – 3 were due to patient preference, and one was due to grade 4 thrombocytopenic purpura (which is a known adverse effect of gemcitabine). One patient had a Grade 3 acute coronary syndrome on cycle 4 day 13. One patient died due to mesenteric ischemia after radical cystectomy. In terms of survival follow up at 18 months, investigators reported 81% overall survival and disease-specific survival of 90% at 18 months.

ESMO 2018 Adverse Events

This study demonstrates that the combination of gem/cis with pembrolizumab is feasible and results in pathologic downstaging (61%) in the majority of patients with a completely pathologic response in 40% of patients. Limitations of this study include the lack of a randomized comparator arm and there still exists some uncertainty regarding the surrogacy of the primary endpoint for overall survival. A number of studies are examining the role of neoadjuvant pembrolizumab. PECULIAR is an open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab in combination with epacadostat (EudraCT number 2017-002379-24)5. PURE-01 is an open-label, single-arm, phase 2 study where patients will receive 3 cycles of pembrolizumab prior to cystectomy (NCT02736266)4. Ultimately, the goal is to improve not only the survival of patients but also their quality of life, and perhaps one day save our patients from cystectomy in the future with combination therapies.

Presented By: Christopher J. Hoimes, DO, Department of Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio

Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany


1. Raghavan D, Shipley WU, Garnick MB, Russell PJ, Richie JP. Biology and management of bladder cancer. New England Journal of Medicine 1990;322:1129-38.
2. Bellmunt J, De Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. New England Journal of Medicine 2017;376:1015-26.
3. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. New England Journal of Medicine 2003;349:859-66.
4. Necchi A, Briganti A, Bianchi M, et al. Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. American Society of Clinical Oncology; 2018.
5. Necchi A, Briganti A, Bianchi M, et al. PECULIAR: An open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab (PEM) and epacadostat (EPA), preceding radical cystectomy (Cy), for patients (pts) with muscle-invasive urothelial bladder cancer (MIUBC). American Society of Clinical Oncology; 2018.
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