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Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT ( = 760) and CONCUR ( = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.

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: Level I evidence indicates that neoadjuvant cisplatin-based chemotherapy, in combination with radical cystectomy (RC), is associated with a significant survival advantage for patients with muscle-invasive bladder cancer. Despite this, neoadjuvant chemotherapy is not uniformly used. Our objective was to determine the patterns of utilization of neoadjuvant chemotherapy in patients undergoing RC for muscle invasive bladder cancer in a contemporary cohort in a tertiary care center. METHODS: A retrospective review was performed of patients with bladder cancer who underwent RC between 2003 and 2008 at our institution. Clinical stage, pathologic stage, renal function, and perioperative chemotherapy treatments were tabulated. Primary outcome measures were the type and use of neoadjuvant chemotherapy among eligible patients. Secondary measures were the utilization patterns of adjuvant chemotherapy, renal function, pathologic outcomes, and disease specific and overall survival. Reasons for nonutilization of chemotherapy were also examined. RESULTS: Among 238 patients who underwent RC for bladder cancer, 145 had a preoperative clinical stage !T2. Only 17% (25 of 145) of these patients received cisplatin-based neoadjuvant chemotherapy. The renal function was adequate (CrCl > 60 ml/min) in 97 (67%) of these patients. Patients who received neoadjuvant chemotherapy had higher p0 rates (29% vs 8%) than patients who did not receive neoadjuvant therapy. Advanced patient age, comorbidities, concerns over toxicity of chemotherapy, and the modest nature of benefit from neoadjuvant chemotherapy may explain why this treatment is not often used. CONCLUSIONS: Despite level I evidence, neoadjuvant cisplatin-based chemotherapies continue to be underutilized in the management of bladder cancer, even at a high-volume tertiary center. A prospective evaluation of management choices, including the patient and physician factors involved in the use of perioperative cisplatin-based chemotherapy in bladder cancer, is indicated. Cancer 2011;117:276-82.

OBJECTIVE To compare the outcomes of patients treated for upper tract urothelial carcinoma with either immediate nephroureterectomy (NU) or initial endoscopic management. PATIENTS AND METHODS The treatments of 108 patients (120 renal units) at the authors’ institution were retrospectively reviewed and divided into two groups, i.e. those who received immediate NU and those who had conservative initial therapy, which included renal units solely treated with endoscopy with or without delayed NU. Overall and disease‐specific survival (DSS) were compared between the treatment groups. RESULTS There were 48 low‐grade tumours, of which 27 (56%) were managed conservatively and 21 (44%) by immediate NU. Seven patients treated conservatively had stage or grade progression and had delayed NU. The mean (sd) DSS at 5 years in patients with low‐grade disease was equally good for conservative treatment and immediate NU, at 86.2 (9.1)% vs 87.4 (8.4)% (P = 0.909). There were 68 high‐grade tumours, of which 12 (18%) patients had conservative management and 56 (82%) had immediate NU. Among the former, seven of 12 had a solitary kidney and three had bilateral disease. In patients managed endoscopically, four of 30 (13%) required delayed NU. The DSS for the conservative and immediate NU groups were 68.6 (18.6)% vs 75.0 (8.1)% (P = 0.528). CONCLUSION Management with a conservative approach in selected patients provides comparable outcomes to immediate NU in patients with low‐grade disease.