Lenvatinib and pembrolizumab in patients with metastatic papillary renal cell carcinoma: A phase 2 pilot study.

109 Background: Traditionally, metastatic papillary renal cell carcinoma (papillary mRCC) has been treated with tyrosine kinase inhibitors, resulting in a 23% objective response rate and a progression-free survival of 9 months (SWOG 1500 trial). Combinations of immunotargeted therapy have shown improved outcomes in clear-cell mRCC. This prospective pilot study aimed to evaluate the preliminary efficacy of combining lenvatinib with pembrolizumab in patients with papillary mRCC. Methods: At study entry in August 2021, patients with papillary mRCC types 1 or 2, multiple measurable lesions per RECIST 1.1 criteria, and no prior therapy for advanced disease were included. The primary endpoint was the objective response rate. The study employed Simon's two-stage design (Simon, 1989) to test the null hypothesis that the true response rate is 23% against a one-sided alternative. In the first stage, 5 patients were enrolled. If there were 1 or fewer responses among these initial 5 patients, the study would be halted. The null hypothesis would be rejected if 6 or more responses were observed in the entire cohort of 12 patients. This design yields a type I error rate of 0.05 and power of 0.8 when the true response rate is 63%. Results: As planned, 5 patients were enrolled in the stage 1. The median age was 57.4 years. Among them, 4 patients were diagnosed with papillary RCC type 2, and 3 patients had an unresected primary tumor. Additionally, 1 patient presented with brain metastases. The objective response rate was 100%, of which there was 1 complete and 4 partial responses. As of the last follow-up, the status of patients on therapy was as follows: i) three patients remained on therapy for more than 12 months; ii) one patient experienced disease progression after 14.3 months of treatment; iii) one patient who initially had an ongoing response developed grade 3 uncontrolled diarrhea after 5.5 months from the start of therapy. Despite the positive outcomes observed in stage 1 of the study, the enrollment was stopped. This decision was influenced by emerging results from the large phase 2 trial KEYNOTE-B61, as reported by Chung-Han Lee et al. (ASCO 2023). Conclusions: All patients responded to lenvatinib and pembrolizumab therapy. These results suggest promising efficacy of the combination in metastatic papillary RCC. Clinical trial information: KCRB01012021 .