Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the a subunit, which heterodimerizes with HIF1b, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control !4 months was achieved in 42% of patients.Patients and Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n ¼ 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNAsequencing studies.Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2a, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance.Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

Background NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. Methods We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours ( H -score ≥ 200). Results A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m 2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease ( n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours ( P = 0.06). Conclusions ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

Hepatitis C virus (HCV) treatment is rapidly changing but little is known about patients' attitudes and knowledge about HCV. This study used a cross-sectional survey to examine the relationship between HCV knowledge and attitudes towards HCV in patients with HCV mono-infection and HIV/HCV co-infection. Subsequently, an education intervention was developed with an abridged version of the cross-sectional survey administered before and after the education session to assess changes in knowledge and attitudes. 292 people participated in the cross-sectional survey, and 87 people participated in the education intervention. In the cross-sectional survey, the mean knowledge score regarding HCV was low (<50% of the total possible score). Mono-infected and co-infected individuals shared similar knowledge deficits and attitudes towards HCV despite having distinct demographic differences. Attitudes endorsed by patients included the following: 57% feared the consequences of HCV on their life, 37% felt HCV was not fatal, 27% did not believe they needed HCV medication, 21% felt ashamed of having HCV and 16% felt HCV treatment was not important. Attitudes that reflected indifference and shame towards HCV were associated with lower knowledge scores (HCV knowledge score of 15.1 vs. 17.5, P < 0.01 for indifference and 15.3 vs. 17.2 for shame, P = 0.02). The education intervention improved knowledge scores but did not modify the assessed attitudes. Intervention studies are needed to effectively change attitudes towards HCV infection and treatment.

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2517 Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumor types at levels 5- to 200-fold above normal tissue. ARQ761 is a β-lapachone hydroquinone analog that exploits the unique elevation of NQO1 found in solid tumors to cause tumor-specific cell death by eliciting a futile redox cycle generating high levels of reactive oxygen species and ultimately PARP1 hyperactivation-dependent cell death. Methods: 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 as a 1-hr or 2-hr infusion. Eligible patients had refractory advanced solid tumors, ECOG 0-1, adequate organ function, and central venous access. Blood samples were analyzed for ARQ761 levels and NQO1 polymorphisms. Archival tumor tissue was analyzed for NQO1 staining intensity and prevalence. After 18 patients were analyzed, enrollment was restricted to patients with NQO1-positive tumors (defined as Histo-score ≥200). Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. For all schedules, the maximum tolerated dose (MTD) was 390 mg/m2 as a 2-hr infusion. DLT was hemolytic anemia. The most common treatment-related adverse events were anemia (79%), fatigue (45%), hypoxia (33%), hemolysis (17%), nausea (17%) and vomiting (17%). Transient grade 3 hypoxia, due to methemoglobinemia, occurred in 26% of patients. Among 31 evaluable patients, the best response was stable disease (n = 11) and progressive disease (n = 19). For the 18 analyzed cases analyzed prior to NQO1 enrollment biomarker, clinical benefit appeared associated with tissue NQO1 expression: disease control rate was 65% in NQO1-positive tumors and 18% in NQO1-negative tumors ( P=0.06). Analysis of all 31 evaluable patients did not show a significant difference in progression-free survival (PFS) according to NQO1 status ( P=0.26), but 3-mo PFS rate was numerically greater among NQO1-positive cases (40% versus 20%). Conclusions: ARQ 761 has clinical activity in NQO1-positive tumors. Principal toxicities include hemolytic anemia and methemoglobinemia. Combination studies are underway.

Appointment-keeping behavior is an important requisite for HCV linkage and treatment initiation. In this study we examine what impact hepatitis C (HCV) knowledge and attitudes has on appointment-keeping behavior among a cohort of HCV and HCV/HIV patients. Knowledge scores and attitude scales, obtained from a cross-sectional survey, were correlated with proportion of appointments kept 1 year prior to taking the survey. Independent risk factors for missing appointments were examined by multiple regression analysis. 292 HCV patients completed the survey, and 149 (51%) were co-infected with HIV. HCV patients kept 67.5 ± 17.4% of their total appointments and a similar proportion (67 ± 38.2) of Liver Clinic appointments, but they attended a higher proportion (73 ± 24.4) of Primary Care Clinic appointments. However, certain health beliefs, psychiatric illness, and HIV co-infection were independently associated with lower levels of appointment-keeping behavior. HCV knowledge was not associated with appointment-keeping behavior. Health beliefs, psychiatric illness, and HIV co-infection are associated with missing appointments, but no link between knowledge and appointment keeping behavior is apparent. In order to increase engagement into HCV care, HCV care coordination programs need to focus on addressing health beliefs and providing resources to those at highest risk for missing appointments.

<p>Supplementary Tables S2-S9.</p>

<p>Supplementary Figure S4. p53 mutation in Pt27 metastasis progressing on PT2385.</p>