Crizotinib in ROS1-rearranged non-small-cell lung cancer.

BACKGROUND: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. RESULTS: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Sunitinib plus erlotinib for the treatment of advanced/metastatic non-small-cell lung cancer: a lead-in study.

BACKGROUND: This randomized, double-blind, multicenter study evaluated sunitinib plus erlotinib versus placebo plus erlotinib. Subjects with advanced non-small-cell lung cancer had received prior treatment with a platinum-based regimen. Here, we report safety, pharmacokinetics, and antitumor activity of the combination of sunitinib and erlotinib. METHODS: Lead-in subjects in this phase II study received sunitinib 37.5 mg/d and erlotinib 150 mg/d. Safety, including dose-limiting toxicities (DLTs, cohort 1 only), pharmacokinetic profiles, and antitumor activity were investigated (cohorts 1 and 2). RESULTS: Thirty patients were evaluated. The combination of sunitinib and erlotinib was tolerable. Diarrhea (76.9%), fatigue (61.5%), and decreased appetite (53.8%) were the most frequent adverse events in cohort 1; and diarrhea (52.9%) and rash (41.2%) were the most frequent adverse events in cohort 2. DLTs were observed (fatigue, n = 2 and paronychial inflammation, n = 1) in three of 13 patients evaluated for DLTs. Geometric mean ratios for the maximum plasma concentration (Cmax) and area under plasma concentration-time profile from time 0 to 24 hours of erlotinib with and without sunitinib were 1.05 and 1.03, respectively. Corresponding values for sunitinib with and without erlotinib were 0.62 and 0.62 for sunitinib, 2.13 and 2.07 for SU12662; and 0.81 and 0.79 for total drug. Three patients experienced partial response as per response evaluation criteria in solid tumor. CONCLUSION: A dosage of sunitinib 37.5 mg/d concurrently with erlotinib 150 mg/d was tolerable and established the recommended combinatorial dose in subjects with platinum-refractory non-small-cell lung cancer. Coadministration of sunitinib with erlotinib does not affect the pharmacokinetics of erlotinib, but may result in decreased exposure to sunitinib.

Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial.

PURPOSE: Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC. PATIENTS AND METHODS: Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm. CONCLUSION: In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.

A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors.

PURPOSE: This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors. PATIENTS AND METHODS: Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m(2)) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts. RESULTS: Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m(2) twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m(2) twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1). CONCLUSION: The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.

Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study.

PURPOSE: Sunitinib in combination with docetaxel enhances antitumor activity in xenograft models of human breast and non-small cell lung cancer. We assessed the maximum tolerated doses (MTDs), safety, pharmacokinetic profiles, and preliminary efficacy of sunitinib plus docetaxel in patients with advanced solid tumors. METHODS: In this phase I study, successive patient cohorts received sunitinib 25, 37.5, or 50 mg/day for 4 weeks of a 6-week cycle (Schedule 4/2, 4 weeks on, 2 weeks off) or for 2 weeks of a 3-week cycle (Schedule 2/1, 2 weeks on, 1 week off) with docetaxel 60 or 75 mg/m(2) IV q21d to determine the MTDs of this treatment combination. RESULTS: Fifty patients enrolled: 10 on Schedule 4/2 and 40 on Schedule 2/1. MTDs were established as sunitinib 25 mg on Schedule 4/2 with docetaxel 60 mg/m(2) q21d, and as sunitinib 37.5 mg on Schedule 2/1 with docetaxel 75 mg/m(2) q21d. On Schedule 2/1, the most frequent dose-limiting toxicity was neutropenia (+/-fever; grade [G]3/4, n = 5) and the most common G3/4 non-hematologic adverse event (AE) was fatigue (G3, n = 8). Hematologic AEs were managed with growth factor support in 11 of 23 (48%) patients treated at Schedule 2/1 MTD. Three patients achieved a partial response at the Schedule 2/1 MTD. There were no pharmacokinetic drug-drug interactions with either schedule. CONCLUSIONS: Oral sunitinib 37.5 mg/day on Schedule 2/1 with docetaxel 75 mg/m(2) IV q21d is a clinically feasible regimen with a manageable safety profile, no pharmacokinetic drug-drug interactions, and shows antitumor activity in patients with advanced solid tumors.

Activity of sunitinib in patients with advanced neuroendocrine tumors.

PURPOSE: Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients. PATIENTS AND METHODS: Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed. RESULTS: Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment. CONCLUSION: Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.

Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer.

PURPOSE: Aberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signaling have been shown to play a role in non-small-cell lung cancer (NSCLC) pathogenesis and are associated with decreased survival. We evaluated the clinical activity and tolerability of sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor that blocks the activity of receptors for VEGF and PDGF, as well as related tyrosine kinases in patients with previously treated, advanced NSCLC. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC for whom platinum-based chemotherapy had failed received 50 mg/d of sunitinib for 4 weeks followed by 2 weeks of no treatment in 6-week treatment cycles. The primary end point was objective response rate (ORR); secondary end points included progression-free survival, overall survival, and safety. RESULTS: Of the 63 patients treated with sunitinib, seven patients had confirmed partial responses, yielding an ORR of 11.1% (95% CI, 4.6% to 21.6%). An additional 18 patients (28.6%) experienced stable disease of at least 8 weeks in duration. Median progression-free survival was 12.0 weeks (95% CI, 10.0 to 16.1 weeks), and median overall survival was 23.4 weeks (95% CI, 17.0 to 28.3 weeks). Therapy was generally well tolerated. CONCLUSION: Sunitinib has promising single-agent activity in patients with recurrent NSCLC, with an ORR similar to that of currently approved agents and an acceptable safety profile. Further evaluation in combination with other targeted agents and chemotherapy in patients with NSCLC is warranted.