On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). Approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK-positive advanced NSCLC who had previously received one platinum-containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression-free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no differencein OSbetween treatmentarmsatthe interimanalysis. The most common adverse drug reactions (.25%) in crizotinibtreated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT-interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy. The Oncologist 2014;19:e5-e11Implications for Practice: Prior to identification of activating genetic alternations and their targeted therapies in non-small cell lung cancer (NSCLC), patients with metastatic disease were treated with platinum-doublet chemotherapy and cytotoxic monotherapy regimens in the first-and second-line settings, respectively. However, with the identification of EGFR-mutation-targeted therapies and now ALK-alteration-targeted therapies, standard treatment in patients with NSCLC containing specific genetic alterations is evolving toward more efficacious and less toxic therapies. As more molecular targets are identified and their respective drugs developed, the management of metastatic NSCLC will move away from traditional cytotoxic chemotherapy regimens.

The absence of a universally accepted definition of radiocontrast nephropathy (RCN) has hampered efforts to characterize effectively the incidence and the clinical significance of this condition. The objective of this study was to identify a clinically relevant definition of RCN by assessment of the relationships between increases in serum creatinine (Scr) of varying magnitude after coronary angiography and clinical outcomes. An electronic medical database was used to identify all patients who underwent coronary angiography at the University of Pittsburgh Medical Center during a 12-yr period and abstract Scr levels before and after angiography, as well as demographic characteristics and comorbid conditions. Changes in Scr after angiography were categorized into mutually exclusive categories on the basis of absolute and relative changes from baseline levels, with a separate category denoting "unknown" change. Discrete proportional odds models were used to examine the association between increases in Scr and 30-d in-hospital mortality and length of stay. A total of 27,608 patients who underwent coronary angiography were evaluated. Small absolute (0.25 to 0.5 mg/dl) and relative (25 to 50%) increases in Scr were associated with risk-adjusted odds ratios for in-hospital mortality of 1.83 and 1.39, respectively. Larger increases in Scr generally were associated with greater risks for these clinical outcomes. Small increases in Scr after the administration of intravascular radiocontrast are associated with adverse patient outcomes. This observation will help guide the postprocedure care of patients who undergo coronary angiography and has important implications for future studies that investigate RCN.

On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine-and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDAapproved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, openlabel, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ≥1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2-20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (≥20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. The Oncologist 2018;23:1-7Implications for Practice: This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.