A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma: evaluation of safety and clinical and immunologic response

Abstract

BackgroundCurrent first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates.MethodsThe phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon’s two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment.DiscussionThe progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564).Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1251-3) contains supplementary material, which is available to authorized users.

Improved outcomes with pembrolizumab treatment in two cases of double cancer including non-small-cell lung cancer

“…Bronchoscopic lung biopsy was performed and he was diagnosed with stage IIIA squamous cell carcinoma As the examined lung tissue was 70% positive for PD-L1 expression, pembrolizumab was selected as a third-line therapy. Interestingly, there is also evidence suggesting that pembrolizumab may be effective for urological cancer [7]. After pembrolizumab treatment, the macroscopic hematuria was almost fully resolved.…”

Radiotherapy for the treatment of distant nodes metastases from oligometastatic urothelial cancer: A retrospective case series

“…Recently, immunotherapy has proven to be effective for the treatment of locally advanced or metastatic bladder cancer, both in the first‐line and in second‐line setting for platinum‐refractory tumors; to date, five checkpoint inhibitors (atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab) received FDA approval for the treatment of advanced urothelial carcinoma, opening a new landscape for disease management. Furthermore, a phase I study of anti‐PD1 pembrolizumab plus RT for the treatment of advanced platinum‐refractory urothelial carcinoma will evaluate the potential role of combination regimen . Nivolumab and atezolizumab are also currently being investigated in combination with RT for metastatic disease .…”

“…Furthermore, a phase I study of anti-PD1 pembrolizumab plus RT for the treatment of advanced platinum-refractory urothelial carcinoma will evaluate the potential role of combination regimen. 31 Nivolumab and atezolizumab are also currently being investigated in combination with RT for metastatic disease. 32 On the basis of preclinical evidence and clinical reports of the RT-induced abscopal effect, a future role of RT in combination with immunotherapy for metastatic disease seems appealing and, in our opinion, should be considered for future research in the metastatic setting.…”

Immune checkpoint inhibitors for metastatic bladder cancer

“…Several phase I/II clinical trials are exploring the association between Pembrolizumab and radiation therapy with (NCT02662062, NCT02621151) or without (NCT02560636) chemotherapy in different stage of the disease. Among them, a phase I-II study led by Sundahl et al is exploring the efficacy and safety of fixed-dose stereotactic body radiotherapy with sequential or concurrent Pembrolizumab in patients with metastatic UC [48]. On the other hand, the association between Durvalumab and radiation therapy is under investigation as adjuvant treatment in a phase I/II trial (NCT02643303).…”