10Investigating the mechanisms of neoadjuvant olaparib and cediranib in renal cancer: results of arms 1 to 3 of the WIndow of opportunity in REnal cancer (WIRE) clinical trial

Abstract Background New treatments are required for patients with resistance to current renal cell cancer (RCC) therapies. In contrast to the success of immunotherapy and VEGF directed therapies, few treatments have successfully targeted the RCC cell directly. Pre-clinical data suggests that PARP inhibitors have activity against RCC, and PARP inhibitors have been investigated in advanced RCC either alone or combined with VEGF directed therapy. Neoadjuvant window of opportunity studies allow us to understand drug mechanism by comparing the tumour before and after treatment. WIRE (WIndow of opportunity in REnal Cancer) is a phase II, multi-centre, multi-arm, non-randomised, neoadjuvant clinical trial platform (NCT03741426) investigating novel RCC treatments. Here we report updated outcome data for arms 1-3 and ongoing translational analysis. Methods WIRE enrols patients with clear cell RCC, planned to have surgery, stage cT1b+, cN0/1, cM0/1, with no contraindication to IMP. A Bayesian adaptive design with pre-defined stop/go criteria efficiently assigns patients to each arm. Arms 1-3 comprised: 1. cediranib (a VEGF inhibitor), 2. cediranib + olaparib (a PARP inhibitor), 3. olaparib. Patients received 14-28 days of IMP before surgery. The primary endpoint is a ≥ 30% reduction in dynamic contrast enhanced (DCE) MRI assessed vascular permeability (median Ktrans) post-treatment compared to baseline. Secondary endpoints include a ≥ 30% increase in IHC-assessed tumour CD8+ T cell density post-treatment compared to baseline, and percentage change in MRI assessed tumour volume. Extensive tissue and blood samples are taken during the trial for mechanistic analysis. Results 29 patients were recruited (arm 1 = 6, arm 2 = 16, arm 3 = 7), 28/29 were male, median age 61 years (range 48-75 years). 8 patients had M1 disease. Treatment was well tolerated, and importantly all patients had surgery within the planned window. 3 patients were not evaluable for the primary endpoint due to inadequate dose of IMP (<70% compliance rate in total doses of IMP within 7 days prior to presurgical imaging). The numbers of evaluable patients which met the primary endpoint for Ktrans reduction were arm 1 (cediranib): 4/6 (67%), arm 2 (cediranib + olaparib): 4/14 (29%), arm 3 (olaparib): 0/6 (0%). For the secondary endpoint of increase in tumour CD8+ T cell density, the numbers were arm 1: 3/6 (50%), arm 2: 9/14 (64%), arm 3: 1/6 (17%). There were reductions in MRI-assessed tumour volume in arms 1 and 2 compared to arm 3 (median change & [range], arm 1: -9.01% [-43.78% to -4.78%]; arm 2: -11.47% [-37.47% to 10.53%]; arm 3: 8.29% [-5.43% to 13.28%]). In exploratory analysis, there was significant induction of VEGF-A and Placental Growth Factor (PlGF) in plasma prior to surgery compared to baseline in the combination arm 2 (VEGF-A P = .0330, PlGF P = .00071). There were no correlations between degree of angiogenic cytokine induction and MRI assessed change in Ktrans or tumour volume. Conclusions Responses as measured by Ktrans were observed particularly in the cediranib only arm, less so in the combination arm and not at all in the olaparib arm. Within a short duration of therapy, consistent tumour volume reductions occurred in both cediranib containing arms. Greater induction of PlGF and VEGF-A in the combination arm indicates possible synergy between cediranib and olaparib. Ongoing translational work is investigating the relationship between other DCE-MRI metrics assessed during the trial. Transcriptomics and digital pathology will be performed comparing baseline biopsies with multiple regions sampled at nephrectomy. These methods will define tumour environments associated with response or non-response. Machine learning approaches will be used to integrate the multiple data modalities (Figure 1). Arm 4, using volrustomig—a PD-1/CTLA-4 bispecific antibody is actively recruiting.