Phase II trial of lurbinectedin combined with avelumab as maintenance therapy for metastatic urothelial carcinoma with stable or responding disease following platinum-based chemotherapy.

Abstract

TPS590 Background: Maintenance avelumab following stable/responding disease after 4-6 cycles of platinum-based chemotherapy is a conventional first-line therapy for metastatic urothelial carcinoma (mUC). Given the attrition of patients between lines of systemic therapy, there is a role for extending the benefits of maintenance avelumab by combinations with tolerable and active agents. Lurbinectedin (Lurbi) is an alkylating agent and selective inhibitor of oncogenic transcription. Lurbi is approved by the US FDA for treating small cell lung cancer with progression on platinum-based chemotherapy with typical dosing as 3.2 mg/m2 intravenously (IV) every 3 weeks. The activity of lurbi in the presence of DNA damage repair (DDR) alterations, multiple transcriptomic drivers and preclinical synergism with and feasibility of co-administration with immune checkpoint inhibitors (ICI) suggests potential activity of combination lurbi and ICI in mUC. Patients with stable or responding disease following platinum-based chemotherapy are phenotypically selected for deficiencies in DDR. Lurbi may be tolerable in this setting given mostly reversible myelosuppression and no serious non-hematologic toxicities especially neurotoxicity. Thus, the combination of lurbi with maintenance avelumab may warrant evaluation in mUC. Methods: A non-randomized multicenter (Advent Health Cancer Institute, Moffitt Cancer Center) phase II trial (n=36) is designed to evaluate combination avelumab (800 mg IV every 2 weeks) and lurbi (3·2 mg/m2 IV as a 1-h infusion every 4 weeks) for those with stable or responding disease following 4-6 cycles of platinum-based first-line platinum-based chemotherapy for mUC. Therapy is continued till progression of disease, intolerable toxicities or patient decision. Patients are seen for a clinical examination every 4 weeks (1 cycle) with laboratory evaluation every 2 weeks. Radiographic imaging is performed every 8 weeks for 6 months and then every 12 weeks thereafter to assess disease. Premedication for lurbi includes corticosteroids (dexamethasone 8 mg or equivalent) and serotonin antagonists. Mandatory granulocyte-colony stimulating factor (G-CSF) prophylaxis will be administered to all patients. Baseline archival tumor tissue and periodic blood is collected for correlative studies (tumor genomics/PD-L1 expression, circulating tumor DNA and immune markers). Given a median progression-free survival (PFS) with avelumab alone of 3.7 months, an alternative median PFS of 6 months is of interest warranting further development. We will enroll 33 evaluable patients to achieve 90% power at a 1-sided alpha level 0.1 to detect hazard ratio of 0.62. Given ~10% of enrolled patients may be inevaluable, we may enroll up to 36 patients. Clinical trial ID: NCT05574504. Clinical trial information: NCT05574504 .