L. Tye

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.

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.

Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer

Background:Sunitinib malate (SUTENT) has promising single-agent activity given on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) in advanced non-small cell lung cancer (NSCLC).Methods:We examined the activity of sunitinib on a continuous daily dosing (CDD) schedule in an open-label, multicentre phase II study in patients with previously treated, advanced NSCLC. Patients ⩾18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy, received sunitinib 37.5 mg per day. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), 1-year survival rate, and safety.Results:Of 47 patients receiving sunitinib, one patient achieved a confirmed partial response (ORR 2.1% (95% confidence interval (CI) 0.1, 11.3)) and 11 (23.4%) had stable disease (SD) ⩾8 weeks. Five patients had SD>6 months. Median PFS was 11.9 weeks (95% CI 8.6, 14.1) and median OS was 37.1 weeks (95% CI 31.1, 69.7). The 1-year survival probability was 38.4% (95% CI 24.2, 52.5). Treatment was generally well tolerated.Conclusions:The safety profile and time-to-event analyses, albeit relatively low response rate of 2%, suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced, refractory NSCLC.

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.

A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC)

BACKGROUND Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review. RESULTS One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%). CONCLUSIONS The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours.

Background:Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study.Methods:Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed.Results:Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4.Conclusions:Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.

Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study

Background:This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours.Methods:Two schedules with sunitinib (25–50 mg per day) and IV gemcitabine (750–1250 mg m−2) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability.Results:Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug–drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ⩾6 weeks.Conclusion:Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug–drug interactions.

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.

1299PCLINICAL ACTIVITY OF CRIZOTINIB IN ROS1-REARRANGED NON-SMALL CELL LUNG CANCER

ABSTRACT Aim: Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a distinct molecular subset of non-small cell lung cancer (NSCLC), which may be susceptible to therapeutic ROS1 inhibition. Crizotinib is a small molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1 and c-MET. Methods: Fifty patients with advanced NSCLC harboring a ROS1 rearrangement were enrolled into an expansion cohort of the global phase 1 study of crizotinib. Local ROS1 testing was used, including break-apart fluorescence in situ hybridization (FISH) in 47 of 50 cases. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily, and assessed for safety and response to therapy. The primary endpoint was objective response rate (ORR). Duration of response (DR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. ROS1 fusion partners (if tissue was available) were identified using next generation sequencing (NGS) or reverse-transcriptase-polymerase-chain reaction (RT-PCR) assays. Results: At the time of data cutoff, median follow-up of the 50 ROS1 patients was 16.1 months. The majority of patients (86%) had received at least one prior line of standard therapy for advanced NSCLC. The ORR was 70% (95% CI, 55%, 82%), with 3 complete responses and 32 partial responses. Median DR was 75.9 weeks (95% CI, 61.6, NR). Median PFS was 19.2 months (95% CI, 14.6, NR), with 24 patients (48%) still in follow-up for PFS. Median OS has not been reached; 1-year OS was 85% (95% CI, 71%, 93%). Among 24 tumors tested (21 with NGS and 3 with RT-PCR), 7 different ROS1 fusion partners were identified, including 5 known and 2 novel partner genes. No correlation was observed between type of ROS1 rearrangement and clinical response to crizotinib. The safety profile of crizotinib in ROS1 patients was similar to that seen in patients with ALK-rearranged NSCLC. Conclusions: Crizotinib exhibits robust antitumor activity in patients with advanced ROS1-rearranged NSCLC, with an ORR of 70% and a median PFS of 19.2 months. Responses were durable with a median DR of 75.9 weeks. In this trial ROS1 defines an additional distinct population of NSCLC patients for whom crizotinib is highly effective. Disclosure: A. Shaw: Consultant/SAB: Pfizer, Novartis, Ariad, Chugai, Genentech, Ignyta; S.I. Ou: Advisory boards: Pfizer; Corporate-sponsored research: Pfizer; Y. Bang: Advisory boards: Pfizer; Corporate-sponsored research: Pfizer; B. Solomon: Advisory boards: Pfizer, Novartis, Roche, Clovis Oncology, AstraZeneca, Merck, BMS, Lilly; G.J. Riely: Advisory boards: Ariad, Celgene, Mersana; Corporate-sponsored research: Novartis, Pfizer, Millennium, Roche, GSK, Merck; M. Varella-Garcia: Advisory board: Exelixis; Corporate-sponsored research: Abbott Molecular; Other substantive relationships (Speaker engagement in educational seminars): Abbott Molecular; D. Costa: Other substantive relationships (Consultancy): Pfizer; R. Doebele: Advisory board: Pfizer, Boehringer-Ingelheim; Corporate-sponsored research: Pfizer, Mirati Therapeutics; L.P. Le: Stock ownership: Enzymatics; Other substantive relationships (Consulting with compensation): Enzymatics; Z. Zheng: Stock ownership: Enzymatics; P. Stephenson: Other substantive relationships (Consultancy): Pfizer; S.M. Shreeve: Stock ownership: Johnson and Johnson, Pfizer; Other substantive relationships (Employment): Janssen Pharmaceutical Companies of Johnson and Johnson; L. Tye: Employment and stock ownership: Pfizer; J. Christensen: Stock ownership: Pfizer; K. Wilner: Employment, stock ownership, advisory board and corporate-sponsored research: Pfizer; A. Iafrate: Advisory boards: Chugai, Constellation, Enzymatics; Stock ownership: Enzymatics. All other authors have declared no conflicts of interest.