Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.

Abstract

600 Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.