Background: The transcription factor hypoxia-inducible factor (HIF)-2α has been established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC) due to underlying VHL deficiency. Activation of HIF-2α can also promote immunosuppression. In preclinical models, HIF-2α inhibition demonstrated increased efficacy in combination with checkpoint inhibitors (Han et al. AACR 2016). In a Phase 1 dose escalation/expansion trial in heavily pre-treated advanced ccRCC patients, PT2385 monotherapy was associated with variability in drug exposure with higher therapeutic exposure associated with improved anti-tumor activity (Courtney et al. JCO 2018). Methods: In the current Phase 1 expansion cohort, patients with advanced ccRCC who had received 1-3 prior therapies (including at least one VEGF(R)-targeting agent) were treated with PT2385 (800 mg PO BID) in combination with nivolumab (3 mg/kg IV Q2Weeks) to evaluate safety, efficacy, and pharmacokinetics. Results: 50 patients were enrolled. Median age was 62 with 58% ECOG 1 and 42% ECOG 2. Median number of prior therapies was 1; 42% of patients received ≥2 prior lines of therapy. The most common all-grade AEs were anemia (46%), fatigue (46%), nausea (36%), and arthralgia (30%). The most common Grade 3 AE’s were anemia (4%), fatigue (4%), and hypoxia (4%). Two Grade 4 events of elevated ALT and increased lipase/amylase were observed. As of August 31, 2018, ORR = 22% (1 CR, 10 PR). At a median follow up of 12.4 months (m), median PFS was 7.3 m for all patients. Patients who had sub-therapeutic exposures ( < 300 ng/ml) of PT2385 (n = 17) had a median PFS of 4.7 m compared to patients with therapeutic exposures of PT2385 (n = 33), who had a median PFS of 10.0 m. Conclusions: The combination of PT2385 + nivolumab was well tolerated and demonstrated promising anti-tumor activity in advanced ccRCC patients, most notably in patients who achieved therapeutic exposure of PT2385. Single agent and combination studies with PT2977, a second-generation HIF-2α inhibitor with an improved PK profile, are ongoing. Clinical trial information: NCT02293980