Background: The combination of ipilimumab and nivolumab (Ipi/Nivo) is approved for patients (pts) with treatment-naïve, intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of re-induction at progression is unknown. A phase II trial of intermittent Ipi/Nivo with re-induction at progression was conducted (NCT03126331). Methods: Patients with treatment-naïve mRCC were treated with induction Ipi/Nivo followed by up to 24 weeks (+/- 8 weeks) of maintenance Nivo. Pts who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Pts were restaged every 12 weeks. Pts with no disease progression (PD) remained off therapy. Upon PD, pts were re-challenged with 2 doses of Ipi/Nivo every 3 weeks, with 1 or 2 more doses at physician discretion. The study objectives were to estimate success rate of observation in pts who achieve a CR/PR (defined by 50% of CR/PR pts sustaining a treatment-free interval of at least 9 months), and to assess toxicity in pts undergoing re-induction. The study was closed early given poor accrual in the rapidly changing mRCC treatment landscape. Results: Nine pts were included; 89% male, median age 57, 78% prior nephrectomy, 67% clear-cell histology, all had KPS ≥ 80%, and 78% were intermediate-risk by IMDC criteria. All pts had 4 doses of induction Ipi/Nivo. Response to Ipi/Nivo and Nivo maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) pts patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). The success rate of 0.78 (95% CI: 0.40-0.97) exceeded the pre-specified threshold of 50%. Two pts had PD off therapy (3 and 8 months after therapy cessation; both with best initial response of PR). Both received 2 cycles of re-induction Ipi/Nivo. No grade 3 or greater toxicities occurred with re-induction, but both pts developed PD at their first scans after re-induction. Conclusions: This pilot prospective study demonstrates that patients with a radiographic response to Ipi/Nivo can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. Correlative investigations for this trial are ongoing. Clinical trial information: NCT03126331.