Pfizer Stock Research Articles

Avelumab in Combination with Standard of Care Chemoradiotherapy Versus Chemoradiotherapy Alone in Patients with Locally Advanced Scchn: A Randomised, Double-Blind, Phase 3 Trial

Background: Chemoradiotherapy (CRT) is the current standard of care for unresected locally advanced squamous cell carcinoma of the head of neck (LA SCCHN). We report the results of avelumab (anti–PD-L1) combined with CRT in LA SCCHN (JAVELIN Head and Neck 100). Methods: In this randomised, double-blind, placebo-controlled, multi-centre phase 3 study, patients with histologically confirmed, previously untreated LA SCCHN of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status) and eligible for CRT were randomised 1:1 (stratified by human papillomavirus status, tumour stage, and nodal stage) to receive either avelumab 10 mg/kg intravenously every 2 weeks plus CRT (cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiation therapy with standard fractionation of 70 Gy [35 fractions/7 weeks]), or placebo plus CRT. This was preceded by an avelumab/placebo lead-in dose and followed by avelumab/placebo bi-weekly maintenance therapy for up to 1 year. The primary endpoint was progression-free survival (PFS) by investigator assessment per modified Response Evaluation Criteria in Solid Tumours version 1·1. Findings: Between December 12, 2016 and January 29, 2019, 697 patients were enrolled and randomised to the avelumab plus CRT (n=350) or placebo plus CRT (n=347) arms. The stratified hazard ratio for PFS based on 224 events was 1·21 (95% CI, 0·93-1·57) favouring the placebo arm; one-sided p=0·92. Median PFS was not reached in either arm. Grade ≥3 adverse events were more frequent with avelumab + CRT vs placebo + CRT (305 [88%] vs 281 [82%]). There were 73 deaths (21%) in the avelumab arm and 58 deaths (17%) in the placebo arm. Interpretation: The primary endpoint of prolonging PFS with avelumab plus CRT followed by avelumab maintenance vs placebo plus CRT in patients with LA SCCHN was not met. Trial Registration: This study is registered with ClinicalTrials.gov NCT02952586. Funding Statement: Pfizer and Merck KGaA, Darmstadt, Germany. Declaration of Interests: N Y Lee reports providing a consulting or advisory role for Eli Lilly, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Merck KGaA, Pfizer, Sanofi-Aventis, and UpToDate and has received research funding from AstraZeneca, EMD Serono, and Pfizer. R L Ferris reports providing a consulting or advisory role for Aduro Biotech, AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Iovance Biotherapeutics, MacroGenics, Merck KGaA, Nanobiotix, Novasenta, Numab Therapeutics, Oncorus, Ono Pharmaceutical, Pfizer, PPD (Benetec Immunicum), Regeneron Pharmaceuticals, and Torque Therapeutics; has received research funding from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck KGaA, Novasenta, and Tesaro; has received reimbursement for travel expenses from Ono Pharmaceutical; and owns stock in Novasenta. A Psyrri has received honoraria from Bristol Myers Squibb, EMD Serono, Merck & Co, and Pfizer; has provided a consulting or advisory role for AstraZeneca; has received research funding from AstraZeneca, Bristol Myers Squibb, Kura Oncology, and Roche; and has received reimbursement for travel expenses from Ipsen. R I Haddad has received research funding from Pfizer; and has provided a consulting or advisory role for AstraZeneca, BioNTech, Bristol Myers Squibb, Eisai, Genentech, GlaxoSmithKline, IO Biotech, Kura Oncology, Merck KGaA, Pfizer, and Roche. M Tahara has received honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, EMD Serono, Loxo Oncology, Merck & Co, Novartis, Ono Pharmaceutical, Pfizer, and Rakuten Medical; and has received research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Merck & Co, Novartis, Ono Pharmaceutical, Pfizer, and Rakuten Medical. K Harrington has received honoraria from AstraZeneca, Boehringer Ingelheim, Merck & Co, and Replimune; and has received research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Merck & Co, Pfizer, and Replimune. M A Razaq reports providing speakers services for Merck & Co. J Lovey reports providing speakers services for Danone and Merck & Co. A Rueda reports providing speakers services and a consulting or advisory role for Bristol Myers Squibb, Merck KGaA, Roche, and Takeda. S De Beukelaer reports employment at Pfizer AG, Zurich, Switzerland. D Pavlov reports employment at Pfizer, Inc, La Jolla, CA, USA. H Thurm reports employment at and owns stock in Pfizer, Inc, La Jolla, CA, USA. E Cohen reports providing a consulting or advisory role for ALX Oncology, Ascendis Pharma, Bayer, BioLineRx, Bristol Myers Squibb, Debiopharm, Dynavax Technologies, Merck KGaA, Merck & Co, Regeneron Pharmaceuticals, and Sanofi. All other authors declare no competing interests. Ethics Approval Statement: The trial was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the International Conference on Harmonization Guidelines for Good Clinical Practice, and the Declaration of Helsinki. All patients provided written, informed consent prior to enrolment. The protocol was approved by the institutional review board or independent ethics committee at each participating centre.

O06 Improvements in pain, function and health status with subcutaneous tanezumab compared with placebo in patients with OA: pooled analysis of two randomized controlled trials

Abstract Background Osteoarthritis (OA) causes pain, disability and impaired quality of life. Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the management of OA pain. Two randomised, placebo-controlled studies with a primary aim of assessing the efficacy and safety of subcutaneously administered tanezumab were recently completed as part of a phase 3 OA programme, and the data reported, separately. Here we report pooled analyses of secondary efficacy outcomes from these two trials: Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) treatment response and EuroQol 5 Dimension (EQ-5D-5L) questionnaire. Methods Both studies enrolled patients with moderate-to-severe OA of the hip or knee, for whom standard care was inadequate or unsuitable. In study one (NCT02709486) with primary endpoint at Week 24, patients received three doses of placebo, tanezumab 2.5 mg or tanezumab 5 mg (at baseline/Week 8/Week 16). Study two was a dose-titration study (NCT02697773) with primary endpoint at Week 16, where patients received two doses of: placebo at baseline/Week 8 (pooled with study one placebo group), tanezumab 2.5 mg at baseline/Week 8 (pooled with study one tanezumab 2.5 mg group) or tanezumab 2.5 mg at baseline/tanezumab 5 mg at Week 8 (pooled with study one tanezumab 5 mg group). The current analysis assessed differences between pooled groups in OMERACT-OARSI treatment response, and EQ-5D-5L questionnaire responses and overall utility scores, at Week 16. Results A total of 1,545 patients were evaluated. At Week 16 in the pooled analyses, more patients in the tanezumab 2.5 mg (76.0%, 390/513) or tanezumab 5 mg (77.4%, 400/517) groups than the placebo group (64.7%, 332/513) met the criteria for OMERACT-OARSI response (each p < 0.0001 versus placebo). Patients in the pooled placebo, tanezumab 2.5 mg and 5 mg groups, respectively, recorded their baseline pain/discomfort (EQ-5D-5L) as none (1.8%, 1.0%, 0.6%), slight (7.6%, 9.7%, 8.9%), moderate (52.6%, 50.7%, 50.7%), severe (35.1%, 36.3%, 36.4%) or extreme (2.9%, 2.3%, 3.5%). At Week 16, patients recorded their pain/discomfort as none (12.8%, 15.4%, 15.8%), slight (37.3%, 44.3%, 44.8%), moderate (40.6%, 33.9%, 32.0%), severe (8.8%, 6.4%, 6.4%) or extreme (0.4%, 0.0%, 1.0%). Improvements in mobility, self-care, usual activities and anxiety/depression were also seen. At Week 16, the change from baseline in EQ-5D-5L utility score was greater for the pooled tanezumab 2.5 mg group (difference in least squares means [95% confidence interval], 0.03 [0.01, 0.05], p = 0.0083) or tanezumab 5 mg group (0.04 [0.01, 0.06], p = 0.0015) compared with placebo. Conclusion Together, pooled analyses from these studies show that significant improvements in the composite measure OMERACT-OARSI response are accompanied by significant improvements in overall health status as assessed by the EQ-5D-5L utility score at Week 16 for tanezumab-treated patients compared with placebo. These studies were sponsored by Pfizer and Eli Lilly and Company. Disclosures D. Walsh: Consultancies; consulting fees (non-personal, pecuniary interest) from Pfizer, Lilly, GlaxoSmithKline, AbbVie, Medscape Education, Love Productions. T.J. Schnitzer: Consultancies; TJS has received consulting fees from Pfizer, Lilly, AbbVie, Aptinyx, Genzyme, Regeneron, and Vertex. Grants/research support; TJS has engaged in clinical research for AbbVie, Grünenthal, and Radius. F. Berenbaum: Consultancies; Consulting fees/remuneration from AbbVie, Merck, Regulaxis, 4P Pharma, Bone Therapeutics, Galapagos, Peptinov, Expanscience, Flexion, Janssen, MerckSerono, Novartis, Roche, Gilead, Sanofi, GlaxoSm. S. Howland: Corporate appointments; SH is an employee of Pfizer Ltd. Shareholder/stock ownership; SH holds Pfizer stock options. S. Wilhelm: Corporate appointments; SW is a Lilly employee. Shareholder/stock ownership; SW holds Lilly stock and/or stock options. R. Junor: Corporate appointments; RJ is an employee of Pfizer Ltd. Shareholder/stock ownership; RJ holds Pfizer stock and/or stock options.

1021. Repeat Infective Endocarditis (rIE) in Persons Who Inject Drugs (PWID)

BackgroundInjection drug use (IDU) is a major risk factor for infective endocarditis (IE). Rates of IE have recently increased in the US concurrent with the opioid crisis. Although IDU-related IE is well described, few data exist on repeat IE (rIE) in persons who inject drugs (PWID).MethodsPatients ≥18 years old seen at Wake Forest Baptist Medical Center from 2004–2017 with an ICD-9 or -10 diagnosis of IE who met Duke criteria for IE and who self-reported IDU in the 3 months prior to admission were identified. The subset of PWID who developed rIE, defined as another episode of IE at least 10 weeks after the diagnosis of the first episode, was then reviewed.ResultsOf the 94 PWID with IE, 22 (23.4%) experienced rIE (19 re-infections, three relapses). All patients were Caucasian, 50% were male, and 68.2% lived in rural areas; the median age was 30. All 22 patients resumed IDU after their first episode of IE. The mean duration from completion of antibiotics for the prior IE episode to admission with rIE was 257.5 days; the episode of rIE occurred within 1 year in 17 patients (77.3%). On repeat admission, those with rIE had a Pitt bacteremia score of 3.0 and an APACHE II score of 13.1. Fever and bacteremia persisted for an average of 5.6 days and 2.6 days, respectively. S. aureus was the cause of rIE in 54.5% of patients and the tricuspid valve (TV) was involved in 77.3% of cases. Valve surgery occurred in 22.7% of patients. Mean length of stay was 25.3 days and mean duration of antibiotic therapy was 32.1 days. Seven patients (31.8%) died during the rIE hospitalization and another died within 12 months after discharge resulting in a 1-year mortality of 36.3%. Compared with their first episode of IE, rIE patients had higher admission Pitt bacteremia (3.0 vs. 1.5, P = 0.07) and APACHE II scores (13.1 vs. 9.5, P = 0.18), fewer S. aureus infections (54.5% vs. 95.4%, P = 0.01), similar TV involvement (77.3% vs. 72.7%, P = 1), and less frequent surgery (22.7% vs. 59.1%, P = 0.06).ConclusionrIE is common in PWID with most episodes occurring within 1 year of the initial episode. Reinfection is more frequent than relapse. The microbiology of rIE is more varied than first episode IE in PWID with S. aureus being less frequently isolated. Illness severity is high, hospitalizations are prolonged, and 1-year mortality is significant. More effective strategies for preventing rIE in PWID are needed.Disclosures J. Peacock, Pfizer: Shareholder, Owns common stock in Pfizer which was inherited and held in a trust.

1085. Enterococcal Cardiac Implantable Electronic Device (CIED) Infections: Clinical Features and Outcomes

BackgroundUnlike enterococcal native and prosthetic valve infective endocarditis (IE), enterococcal CIED infections are not well described.MethodsData from the Multicenter Electrophysiologic Device Infection Collaboration (MEDIC), a prospective, observational, multinational cohort study of CIED infections, were used to provide a descriptive analysis of adult patients with CIED infections due to enterococcal species.ResultsOf 433 patients, 21 (4.8%) were diagnosed with enterococcal CIED infection. Specific data on enterococcal species and antimicrobial susceptibilities were not recorded. The mean age was 70.8 years. No patient had previous CIED infection. Twelve patients (57%) had permanent pacemakers, 5 (24%) had implantable cardioverter defibrillators, and 4 (19%) had biventricular devices. Among the 21 infections, 3 (14%) were categorized as CIED-related bloodstream infections and 18 (86%) as IE; no patient had isolated pocket infection. Of the IE cases, four were valvular IE, eight were lead IE, and six were both. Fourteen cases of IE (78%) were definite by the modified Duke criteria. Median time from last device procedure to infection was 510 days (range 37–2,952 days). The most common presenting symptom was fever (48%); five patients (24%) exhibited local signs of pocket infection. All 21 patients underwent TEE with vegetations demonstrated in 17 (81%). Blood cultures grew enterococci from all patients. The most common antimicrobial regimen was a penicillin plus aminoglycoside (38%); two patients (9.5%) received ampicillin + ceftriaxone. Antibiotics were given for a median of 43 days. Only 14 patients (67%) had complete device removal; the seven patients retaining their device were judged to be at high risk for extraction. There was one death during the index hospital stay with four additional patients dying over the 6 months after therapy (overall mortality 24%); two of the seven patients retaining their CIED died.ConclusionEnterococci caused 4.8% of all CIED infections in our cohort. Most infections appeared to be hematogenous in origin with late onset. IE was the most common infectious syndrome. A penicillin plus aminoglycoside, given for 6 weeks, was the most frequent therapy. Only 67% of patients underwent device removal. At 6 months follow-up, no relapses had occurred but overall mortality was 24%.Disclosures J. E. Peacock Jr., Pfizer, Inc.: Shareholder, Owns common stock in Pfizer which was inherited and held in a trust. M. R. Sohail, TyRx Inc.: Investigator, Research support. Medtronic Inc.: Investigator, Research support. Medtronic Inc.: Consultant, Speaker honorarium. Spectranetics: Consultant, Speaker honorarium. Boston Scientific Corp: Consultant, Speaker honorarium. L. M. Baddour, UpToDate: Collaborator, Royalty payment. J. M. Miro, Abbvie: Consultant and Grant Investigator, Consulting honoraria and Research grant. Bristol-Myers Squibb: Consultant and Grant Investigator, Consulting honoraria and Research grant. Genentech: Consultant and Grant Investigator, Consulting honoraria and Research grant. Medtronic: Consultant and Grant Investigator, Consulting honoraria and Research grant. Novartis: Consultant and Grant Investigator, Consulting honoraria and Research grant. Gilead Sciences: Consultant and Grant Investigator, Consulting honoraria and Research grant. Pfizer: Consultant and Grant Investigator, Consulting honoraria and Research grant. ViiV Healthcare: Consultant and Grant Investigator, Consulting honoraria and Research grant. A. J. Greenspon, Medtronic: Consultant, Speaker honorarium. Boston Scientific: Consultant, Speaker honorarium. St. Jude: Consultant, Speaker honorarium. R. G. Carrillo, St. Jude Medical Group: Speaker’s Bureau, Research support. Spectranetics: Consultant, Speaker honorarium. Sorin Group: Speaker’s Bureau, None. Boston Scientific Corp: Speaker’s Bureau, None. D. Z. Uslan, Medtronic: Investigator, Research support. Boston Scientific: Consultant, Speaker honorarium.

Supporting Resource-Stratified Metastatic Breast Cancer Policy Development: A Global Policy Analysis

Purpose Patients with metastatic breast cancer (mBC) have significant unmet needs that current policies do not fully address. Methods A comprehensive analysis of national cancer control programs and breast cancer (BC) policies and programs was conducted across 16 countries representing diverse geographies, socioeconomic status, and health care systems. Key policy components were identified, aligned with the journey of a patient with BC, and evaluated using standardized criteria that measured the adoption and implementation of national cancer control program goals and mBC-specific programs. The identified gaps for patients with mBC were aligned with promising practices implemented or spearheaded by civil society that demonstrated success at filling the gaps with the objective of creating an information resource that other organizations in the field can use as practice-based evidence. Results Despite considerable BC policy development and implementation, important gaps for patients with mBC persist across all areas of the patient journey and vary between countries studied. Inadequate public awareness, lack of trained specialists, inefficient coordination of care delivery, and limited access to innovative mBC treatments are barriers to effective care in select regions in high-income countries and overall in low- and middle-income countries. In addition, the provision of palliative care remains in its infancy in low- and middle-income countries, although this is an area of increasing policy development in high-income countries. Promising practices that evaluate patient advocacy efforts have revealed that adaptable models can support policy adoption and target specific gaps through an approach that can be tailored to countries’ resource contexts. For example, advocacy efforts identified in sub-Saharan Africa used a range of tools, in collaboration with key hospitals, to address barriers at the diagnosis stage and facilitate access to care. In the United States, a Clinical Trial Helpline launched in partnership with local patient groups aims to connect patients with mBC with innovative treatment options through clinical trials. Conclusion The 70th United Nations World Health Assembly’s cancer resolution discussed the need to leverage efforts and collaborative initiatives among stakeholders. This research exemplifies successful multistakeholder engagement solutions, which are tailored to the country context, and offer targeted ideas to further policy development. Phased BC control implementation strategies must ensure that the policies and programs address the needs of both patients with early BC and of those with advanced BC. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc . Anna Cabanes Research Funding: Pfizer, Genentech, Merk (Inst) Travel, Accommodations, Expenses: Pfizer, AstraZeneca Fatima Carodso Consulting or Advisory Role: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genetech, GlaxoSmithKline, Macrogenics, Merk-Sharp, Merus BV, Mylan Mundipharma, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Samsung Bioepis, Teva Expert Testimony: Pfizer, Roche Maia Thrift-Perry Employment: Pfizer Stock or Other Ownership: Pfizer

Positive Medication Changes Resulting from Comprehensive and Noncomprehensive Medication Reviews in a Medicare Part D Population.

Health care organizations face the challenge of reducing costs while improving health outcomes. Currently, more than 39 million seniors are enrolled in a Medicare Part D prescription benefit plan, many of whom also qualify for medication therapy management (MTM) services. MTM programs provide valuable services designed to prevent or resolve medication-related problems (MRPs). Two core components of all MTM programs include comprehensive medication reviews (CMRs) with followup interventions and focused non-CMR interventions. Currently, there is limited research comparing the rate of MRPs resolved by CMR and non-CMR interventions. To determine whether CMRs versus non-CMR interventions resulted in more pharmacist-initiated intervention recommendations and positive medication changes. This retrospective, cross-sectional quality improvement project evaluated outcomes for individuals who received interventions following a CMR compared with those who received non-CMR interventions as part of a comprehensive MTM program. For this project, eligible individuals qualified for an MTM program. A positive medication change was defined as the addition of an appropriate medication or the removal of an inappropriate medication within 120 days of a pharmacist recommendation. Differences between the groups were calculated using the Wilcoxon rank sum test. During the 2-year period (2012 and 2013), 788,756 beneficiaries were enrolled in the MTM program and evaluated for potential MRPs. In both years, pharmacists recommended more medication changes per member for those receiving a CMR (0.81 in 2012 and 0.82 in 2013) compared with the non-CMR group (0.68 in 2012 and 0.61 in 2013; P value < 0.001 for both years). However, recommendations made via non-CMR interventions (representing the vast majority of all medication reviews) were more likely to result in a positive medication change (OR = 1.24, 95% CI = 1.21-1.28 for 2012; OR = 1.26, 95% CI = 1.22-1.30 for 2013). These quality improvement project results suggest that Medicare Part D beneficiaries participating in a university-based MTM program who received non-CMR interventions had a higher likelihood of having positive medication changes than those receiving CMRs. These results are enlightening and may provide initial evidence to support inclusion of a non-CMR performance metric for the Centers for Medicare & Medicaid Service's star ratings for MTM programs. No outside funding supported this study. The University of Arizona Medication Management Center (UAMMC)/SinfoniaRx provides grant funding to the University of Arizona for research. Augustine reports support from the UAMMC and ownership of Pfizer stock and was a graduate student at the University of Arizona College of Pharmacy at the time of this study. The authors report no other potential conflicts of interest. Buhl and Augustine contributed study concept and design, collected the data, and wrote the manuscript. Data interpretation was performed by all the authors. Taylor, Warholak, Augustine, and Martin revised the manuscript.

Real-World Treatment Patterns, Time to Next Treatment, and Economic Outcomes in Relapsed or Refractory Multiple Myeloma Patients Treated with Pomalidomide or Carfilzomib.

Negligible real-world evidence exists for later line treatment of multiple myeloma (MM) to assist treatment decisions or reimbursement models, such as episode-based payments. To describe the treatment patterns and clinical/economic outcomes when pomalidomide or carfilzomib is used for relapsed/refractory MM. A U.S. claims database was used to identify MM patients with an initial pomalidomide or carfilzomib claim (index date) between February 1, 2013, and February 28, 2015, which was assumed to be relapse therapy. Treatment regimens were defined as all MM chemotherapy observed within 60 days of index. Patients receiving pomalidomide and carfilzomib within 60 days of index were excluded. Time to next treatment (TTNT), a progression proxy, was defined as the addition of a new agent > 60 days from index or as treatment restart following a > 90-day therapy gap. Cost estimations used plan-allowed amounts. Descriptive statistics were used to compare outcomes between treatment groups, and regression models were used to adjust for baseline patient characteristics. There were 454 patients initiating treatment with pomalidomide (n = 264) or carfilzomib (n = 190) during the index period. The most frequent initial regimens for pomalidomide patients included pomalidomide + dexamethasone (47.0%) and pomalidomide alone (33.0%); the most frequent regimens for carfilzomib patients were carfilzomib alone (45.3%) and carfilzomib + dexamethasone (14.7%). The most frequent next line treatment for pomalidomide patients who progressed was the addition of (14.0%) or switch to (15.0%) carfilzomib ± dexamethasone and for carfilzomib patients, the most frequent next line treatment was pomalidomide + dexamethasone (9.3%) and carfilzomib alone or carfilzomib + dexamethasone + cyclophosphamide (6.7% each). The median (95% CI) TTNT for pomalidomide patients was 11.9 (10.7-14.8) compared with 9.4 (7.7-10.0) months for carfilzomib (P = 0.060). For patients followed to progression (pomalidomide: n = 100, 37.9%; carfilzomib: n = 75, 39.5%), mean TTNT was longer for patients initiating therapy with pomalidomide (6.9 months) versus carfilzomib (5.3 months, P = 0.016). When adjusted for baseline confounders, pomalidomide patients had a nonsignificant longer time to a subsequent treatment line. Inpatient encounters observed during the index line were very low (mean = 1) for both groups; outpatient encounters were fewer in pomalidomide patients. Adjusted analyses revealed inpatient encounters were higher (P = 0.005), while outpatient use was lower in pomalidomide patients (P = 0.006). Unadjusted median costs incurred during the initial line were similar between the 2 groups (pomalidomide: $102,805; carfilzomib: $127,203; P = 0.110) but significantly lower in pomalidomide patients after adjusting for baseline characteristics (P = 0.013). Unadjusted per patient per month (PPPM) costs incurred over the entire follow-up period were lower in pomalidomide-initiated patients ($18,298 vs. $24,734, P = 0.001) but not statistically significant in adjusted analyses (P = 0.230). A longer time to a subsequent line of therapy was observed in pomalidomide patients compared with carfilzomib patients, although the difference lost significance in adjusted analyses. Compared with carfilzomib, pomalidomide patients were observed to have lower unadjusted median PPPM costs over the entire post-index period and lower adjusted mean monthly costs during initial therapy. Funding for this study was provided by Celgene. Chen, McGuiness, and Wade are employees of QuintilesIMS, which was contracted by Celgene to undertake this research. McGuiness also owns stock in Pfizer. Parikh, Abouzaid, Purnomo, and Hussein are employees of Celgene and participated fully in the development and approval of the manuscript. Portions of the results of this research were previously presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting; June 3-7, 2016; Chicago, Illinois. Study concept and design were contributed by Chen, Parikh, Abouzaid, McGuiness, and Wade. Chen and McGuiness took the lead in data collection, along with Wade, and data interpretation was performed by Hussein and Wade, with assistance from the other authors. The manuscript was written by McGuiness, Chen, and Wade, with assistance from Parikh and Abouzaid, and revised by McGuiness and Hussein, along with the other authors.

Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency.

Frequent molecular monitoring (qPCR tests), as recommended by evidence-based monitoring guidelines, is associated with higher adherence to tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML); both factors have been associated with better clinical and economic outcomes. To (a) estimate the effect of more frequent qPCR tests on health care resource utilization (HRU) and associated costs, including direct (effect of qPCR test frequency on HRU) and indirect (through TKI adherence) effects, and (b) develop an economic model applicable to multiple clinical practice scenarios. Adult patients newly diagnosed with CML who started TKI firstline therapy were identified from U.S. administrative claims data (2010-2015). TKI adherence (medication possession ratio [MPR]), number of inpatient days, emergency room (ER) visits, outpatient service days, and mean costs per HRU event were measured during the first year of CML treatment. Direct and indirect effects of qPCR test frequency were estimated using multivariate regression models. Subsequently, an economic model was developed to assess the overall effect of varying qPCR test frequency on HRU and associated costs during the first year of CML treatment under different clinical practice scenarios; the scenario reported is the increase from 1 to 2 qPCR tests. Of the 1,431 patients included, 36% had no qPCR tests, the average qPCR test frequency was 1.6, and the average MPR was 0.86 during the first year of CML treatment. The direct effect of increasing qPCR test frequency by 1 was associated with 13.0% fewer inpatient days (adjusted incidence rate ratio [adjusted IRR] = 0.87; P = 0.010); 8.3% fewer ER visits (adjusted IRR = 0.92; P = 0.043); and 3.0% more outpatient service days (adjusted IRR = 1.03; P = 0.002). Each increase of 1 test was associated with an increase in TKI adherence by 2.2 percentage points (adjusted MPR difference = 0.022; P < 0.001). When considering the indirect effect of qPCR test frequency through TKI adherence, an increase of 1 qPCR test combined with an increase in TKI adherence by 2.2 percentage points was associated with a greater reduction of inpatient days from 13.0% to 15.2%, ER visits from 8.3% to 8.6%, and a smaller increase of outpatient service days from 3.0% to 2.6%. Based on the economic model, an increase from 1 to 2 qPCR tests, considering the increase in TKI adherence, was associated with a reduction of 0.87 (95% CI = -1.49, -0.18) inpatient days and 0.06 (95% CI = -0.12, 0.05) ER visits, an increase of 0.98 (95% CI = 0.25, 1.60) outpatient service days and a cost savings of $2,918 (95% CI = -5,213, -349) per patient per year. Closer alignment with the monitoring guidelines' recommended qPCR test frequency and better adherence to TKIs were associated with lower HRU and medical service costs. Managed care initiatives to increase qPCR test frequency and TKI adherence might benefit from an enhanced reduction because of the interaction between both factors. This study was funded by Novartis Pharmaceuticals, which was involved in all stages of the study and in the decision to submit the report for publication. Latremouille-Viau, Guerin, Gagnon-Sanschagrin, and Dea are employees of Analysis Group, which received consulting fees from Novartis Pharmaceuticals for work on this study. Joseph is an employee of Novartis Pharmaceuticals and owns stock in Amgen and Pfizer. Cohen was an employee of Novartis Pharmaceuticals at the time of this study. Portions of this study were presented online (beginning May 20, 2016) as part of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, on June 3-7, 2016, and as a poster at the American Society of Hematology (ASH) Annual Meeting in San Diego, California, on December 3-6, 2016. Study concept and design were contributed by Latremouille-Viau and Guerin, along with the other authors. Gagnon-Sanschagrin and Dea took the lead in data collection, assisted by the other authors, and data interpretation was performed by Cohen and Joseph, along with the other authors. The manuscript was written by Latremouille-Viau, along with the other authors, and revised by Joseph, along with the other authors.

Real-World Axitinib Use in the United States: A Retrospective Study Using Linked Datasets.

Axitinib is approved by the FDA for the treatment of advanced renal cell carcinoma (RCC) after failure of 1 previous systemic therapy and is distributed primarily through specialty pharmacies. Although the efficacy and safety of axitinib have been established in clinical trials, information from real-world populations will help to elucidate patients' clinical profiles and utilization patterns. Prescription records alone provide limited information on patient characteristics and other treatment experiences. Expansion of these data with information from medical claims databases should yield observational real-world data that may help to optimize therapy for patients with advanced RCC. To link information from a specialty pharmacy database with information from medical and pharmacy claims databases to characterize real-world treatment patterns of axitinib as subsequent systemic therapy in patients with RCC in the United States. This retrospective, observational, cohort study linked de-identified patient-level data from 22 specialty pharmacies that dispense axitinib with databases of longitudinal medical and pharmacy claims. Eligible patients had a diagnosis of RCC (> 1 claim for RCC defined as ICD-9-CM code 189.0), previously received > 1 systemic therapy, had the first prescription for axitinib dispensed between May 2012 and April 2013 (index), and had consistent claims reporting by pharmacies and physicians. All treatment data were used to calculate cycle, line of therapy, and duration of therapy; prescription data were used to determine axitinib dose modifications. Multivariate and logistic regression analyses were conducted to assess the effect of patient/prescriber characteristics on duration of axitinib therapy and dose modifications, respectively. In all, 1,175 patients met the study inclusion criteria and had data present in specialty pharmacy and claims databases. Most patients (74%) were male, and 68% were aged 55-74 years. Mean (SD) Charlson Comorbidity Index score was 2.7 (± 1.1); the most common comorbidity was hypertension (in 199 patients, 17%). Based on Rx-Risk-V, the most frequent concomitant conditions were pain (40%) and ischemic heart disease/hypertension (30%); the most frequent concomitant medications were antihypertensive medications (46%) and opiates (40%). Most prescribers (63%) were affiliated with an academic center, and all U.S. geographic regions were represented. In all, 847 patients (72%) had commercial insurance. Axitinib was prescribed as second-line therapy in 659 patients (56%), as third-line therapy in 326 patients (28%), and as fourth-line or later therapy in 190 patients (16%). In the overall population, mean (SD) duration of axitinib therapy was 168.6 (± 148.4) days. Axitinib treatment duration was 21 days longer in males than females (P = 0.013); 28 days longer in patients in the Northeast than in the Midwest or West (P = 0.010 and P = 0.016, respectively); and 26 days longer in patients receiving baseline hypothyroidism treatment (P = 0.004). In patients receiving second-line axitinib, the most common first-line therapy was sunitinib (56%), followed by pazopanib (16%) and everolimus (12%). Mean (SD) duration of second-line axitinib treatment was 172.3 (± 150.6) days and ranged from 127 days in patients who previously received temsirolimus to 196 days in those who previously received sorafenib. Of 1,025 patients who initiated axitinib at the standard 5 mg twice daily starting dose, 70% remained at this dose throughout treatment, whereas 10% had a dose increase. Younger age and gender (male) were associated with dose increases (OR = 0.958, 95% CI = 0.941-0.975 and OR = 0.573, 95% CI = 0.364-0.903, respectively). Baseline hypothyroidism treatment was associated with dose decreases and increases (OR = 1.662, 95% CI = 1.088-2.539 and OR = 2.149, 95% CI = 1.353-3.413, respectively). This analysis demonstrates the feasibility and utility of linking specialty pharmacy data to other longitudinal databases to better understand patient, provider, and reimbursement characteristics. These data provide insight into routine clinical use of axitinib as subsequent RCC therapy in the United States in the period following FDA approval, as well as additional information on sequencing of targeted agents in patients with advanced RCC. This study was sponsored by Pfizer. MacLean and Cisar are employees of and hold stock in Pfizer. At the time of this analysis, Mehle, Eremina, and Quigley were employees of IMS Health who were paid consultants to Pfizer during the conduct of this study and in connection with the development of this manuscript. MacLean and Cisar contributed to study design and manuscript development. Mehle, Eremina, and Quigley contributed to study design, analysis, and manuscript development.

Ability and Use of Comparative Effectiveness Research by P&T Committee Members and Support Staff: A 1-Year Follow-up.

In recent years, comparative effectiveness tools and methods have evolved to assist health care decision makers in identifying optimal therapies. In-person training programs on comparative effectiveness research may be helpful in understanding and applying this information. To provide a follow-up assessment of the use of comparative effectiveness research (CER) in the pharmacy and therapeutics (P&T) committee decision-making process, using information collected from participants 1 year after attending a live continuing education program, in which participants were taught about CER designs and how to access available CER resources through the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care (EHC) Program. A retrospective, cross-sectional questionnaire was developed and mailed to 2 groups of individuals: CER workshop attendees and interested nonattendees (expressing an interest in attending a workshop but did not attend for unknown reasons). The questionnaire asked respondents to indicate personal and organizational use of CER in the decision-making process. Participants were asked to indicate whether their knowledge, ability, and use of CER studies increased since participating in the program. Data were analyzed using nonparametric tests to compare the responses of attendees and nonattendees, as well as overall reliability of the instrument. A total of 164 respondents completed the questionnaire (63 attendees and 101 nonattendees; overall response rate = 44%). The majority of respondents were pharmacists (n = 157, 95.7%) and were affiliated with a hospital (n = 106, 64.6%). Proportions of attendees and nonattendees differed significantly in the use of EHC research reviews/reports (45% and 28%, respectively; P = 0.02) and EHC executive summaries of research reviews/reports (48% and 29%, respectively; P = 0.01). At 1-year follow-up, the majority of attendees reported an increase ("somewhat" or "very much") in knowledge of CER (91.5%), ability to use CER (83.0%), and use of CER studies (58.7%). Health professionals attending a continuing education CER program reported higher use of EHC CER materials compared with nonattendees. Additionally, attendees reported increased use of CER in clinical decision making. A continuing education program such as this may provide an effective avenue for introducing CER methods and resources to the P&T committee and clinical decision-making processes. This project was supported by grant number R18HS019220 from the Agency of Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency of Healthcare Research and Quality. Augustine has stock in Pfizer. The authors declared no other potential conflicts of interest associated with this study. Study concept and design were primarily contributed by Malone, along with Warholak, Hines, Brown, Hurwitz, and Taylor. Warholak, Hines, Brown, Hurwitz, and Taylor collected the data, assisted by Malone, Brixner, Cobaugh, and Schlaifer. Data interpretation was performed by Malone and Augustine, with assistance from the other authors. The manuscript was written primarily by Augustine, with assistance from Malone, Sun, Warholak, Hines, Brown, Hurwitz, and Taylor. Malone revised the manuscript, assisted by Warholak, Hines, Brown, Hurwitz, Taylor, Brixner, Cobaugh, and Schlaifer.

843P - Long-Term Safety with Axitinib in Advanced Renal Cell Carcinoma

ABSTRACT Aim: Axitinib is approved globally in patients with advanced renal cell carcinoma (RCC) who failed one prior therapy. Although tyrosine kinase inhibitors have been available to treat RCC since 2005, long-term safety data are limited. Here we report long-term safety results with single-agent axitinib in advanced RCC, using pooled data from 14 clinical trials conducted from Apr 2002 to Oct 2013. Methods: In the 14 studies included, starting dose of oral axitinib was 5 mg twice daily continuously. Dose interruptions and modifications were allowed per protocols. Common, long-term, treatment-emergent adverse events (AEs) were identified in patients who received axitinib ≥2 yr; these AEs were then evaluated in all patients. Analyses conducted were 1) interval analysis of AEs over successive treatment periods (0– Results: As of Oct 2013, 1304 patients with solid tumours, including 672 with advanced RCC, received single-agent axitinib in phase I-III studies. Among patients with RCC, 108 (16%) received axitinib ≥2 yr. In these patients, common AEs were most frequently reported within the first 6 mo of treatment, with rates stable or decreasing over time (Table). Rates of proteinuria, peripheral oedema, and elevated blood creatinine increased over time. Similarly, by cumulative analysis, most AEs analysed were reported within the first 6 mo–1 yr of treatment, with few new cases reported thereafter. Based on interval analysis, rates of common grade ≥3 AEs decreased over time with the exception of increased amylase and myocardial infarction. Table. Interval analysis of the most common AEs in patients with advanced RCC treated with axitinib ≥2 yr (n = 108). AE 0– 6 mo– 1– ≥2 yr Diarrhoea 53% 53% 45% 32% Fatigue 38% 15% 19% 13% Proteinuria 11% 10% 19% 11% Decreased appetite 27% 16% 16% 9% Hypertension 58% 16% 19% 9% Weight loss 28% 27% 25% 9% Conclusions: In patients with RCC, rates of most AEs were stable or declined after prolonged axitinib treatment. Results did not indicate that sustained exposure to axitinib is associated with unanticipated or more severe AEs. Disclosure: S. Hariharan, W.G. Roberts and Z. Askerova, J. Tarazi and B. Rosbrook: is an employee of and owns stock in Pfizer Inc.; B. Escudier has served as an advisor for Bayer, Pfizer, and Novartis, and has received honoraria from Bayer, Roche, Pfizer, Genentech, Novartis, and AVEO; R.J. Motzer: has served as an advisor for Pfizer, Genentech, and AVEO, received research funding from Pfizer, Novartis, and GlaxoSmithKline, and provided paid expert testimony for Pfizer; B.I. Rini: has served as an advisor for and received research funding from Pfizer.

Randomised Study of Axitinib (Axi) Plus Best Supportive Care (Bsc) Versus Placebo (Pbo) Plus Bsc in Patients with Advanced Hepatocellular Carcinoma (Hcc) Following Prior Antiangiogenic Therapy

ABSTRACT Aim: The efficacy and safety of Axi, a potent and selective inhibitor of VEGF receptors 1-3, was evaluated in a global, randomised, double-blind phase II clinical trial in patients (pts) with locally advanced or metastatic HCC. Methods: Eligible pts progressed on or were intolerant to 1 prior antiangiogenic therapy and had ECOG performance status 0 or 1. Pts were randomised 2:1 to receive Axi + BSC or Pbo + BSC at a starting dose of 5 mg twice daily and stratified by tumour invasion (presence vs absence of extrahepatic spread and/or vascular invasion) and geographic region (Asia vs non-Asia). Primary end point was OS and secondary end points included ORR, PFS and safety. The study had 80% power to detect an improvement in median OS (mOS) from 5.0 to 8.3 mo with Axi + BSC, corresponding to a HR 0.60 (1-sided a = 0.025). Results: Two hundred two pts (134 Axi vs 68 Pbo), predominantly of Asian origin (63 vs 62%), were randomised. Baseline pt characteristics and stratification factors were well balanced between the Axi vs Pbo arms. All pts were in Child-Pugh A category and 76% of pts in both arms had tumour invasion. mOS with Axi was 12.7 mo (95% CI: 10.2, 14.9) vs 9.7 mo (95% CI: 5.9, 11.8) with Pbo and was not statistically significant (HR 0.870; 95% CI: 0.620, 1.222; 1-sided stratified P = 0.211). Investigator-assessed median PFS (mPFS) with Axi was 3.6 mo vs 1.9 mo with Pbo and was statistically significant (HR 0.618; 95% CI: 0.438, 0.871; P = 0.004). ORR was 9.7% with Axi vs 2.9% with Pbo (P = 0.083). More pts discontinued due to AE with Axi vs Pbo (23 vs 13%). Most common all causality AEs (Axi vs Pbo, % of pts) were diarrhoea (54 vs 12%), hypertension (54 vs 13%), decreased appetite (47 vs 21%), fatigue (35 vs 26%), abdominal pain (34 vs 21%), hand-foot syndrome (34 vs 6%), weight decrease (27 vs 3%), nausea (26 vs 10%), dysphonia and hypothyroidism (25 vs 0% each). Conclusions: Axi + BSC did not demonstrate statistically significant improvement in mOS but improved mPFS compared to Pbo + BSC in pts with advanced HCC who received prior antiangiogenic therapy. Safety profile with Axi was consistent with earlier clinical trials and no new safety signal was detected. Disclosure: Y. Kang: I have been a consultant for Pfizer Inc and Bayer Healthcare Pharmaceuticals; J. Park: I am (was) a member of Consultancy/Advisory Board of Taiho Pharmaceutical, Bayer Healthcare Pharmaceuticals, and Roche, and received honorarium from Taiho Pharmaceutical and research funding from Bayer Healthcare Pharmaceuticals; S.L. Chan: I received research funding from Pfizer Inc.; J. Tang and O. Valota: I am employed by and own stock in Pfizer; D. Chakrabarti: is an employee of and owns stock in Pfizer.All other authors have declared no conflicts of interest.

Anaplastic Lymphoma Kinase (Alk) Positivity in Non Small Cell Lung Cancer (Nsclc) Has Similar or Worse Prognosis for Clinical Outcome As Alk Wild Type: a Systematic Review of Published Literature

ABSTRACT Aim: Anaplastic lymphoma kinase (ALK) positive NSCLC identifies a unique subset of patients who respond to treatment with crizotinib (Pfizer Inc, NY), an ALK receptor tyrosine kinase inhibitor. However, it is not well established whether ALK status is predictive of a better or a worse outcome for those who do not receive crizotinib. We performed a systematic review of recent literature on ALK positive NSCLC to answer this question. Methods: Ovid Medline and Embase databases were searched for publications on ALK-positive NSCLC until December 2013. Studies were included if outcomes for crizotinib naive patients were presented for either Progression-Free Survival (PFS) or Overall Survival (OS). For each study identified, 2 investigators independently extracted and tabulated relevant findings. Demographics, ALK status, type of diagnostic test, treatment received and response to treatment were noted. To determine if ALK status was prognostic, efficacy outcomes (PFS and / or OS) for ALK-positive patients were compared to ALK wild type (WT) patients. Results: Twenty one studies published between 2009 to 2013, with nearly 8000 screened NSCLC patients and 700 ALK-positive patients, met the selection criteria. All publications were retrospective in nature, majority reported single institution experiences, with a mix of completely resected early stage NSCLC and recurrent or advanced disease. The number of ALK-positive patients in studies determined by Fluorescent In Situ Hybridisation (FISH) ranged from 7 to 121 (mean = 32) and the number of ALK-positive patients in studies determined by non-FISH methods ranged from 3 - 39 (mean = 18). Enrichment strategies were commonly employed with predominantly adenocarcinomas being selected for ALK testing. PFS and / or OS for ALK-positive NSCLC patients did not demonstrate a favourable outcome and was similar or worse compared to EGFR WT/ ALK WT patients. Conclusions: This analysis of published retrospective studies in ALK-positive NSCLC, suggest that ALK-positivity is not a positive prognostic factor and does not confer a favourable outcome in absence of crizotinib therapy. Disclosure: J. Binko: Employee of Pfizer Oncology and holder of Pfizer stock; P. Delahoy: Employee of Pfizer Oncology and holder of Pfizer stock. M. Alam: Employee of Pfizer Oncology and holder of Pfizer stock.

409TiP - Phase III Study of Palbociclib in Combination with Exemestane Vs. Capecitabine, in Hormonal Receptor (Hr) Positive/Her2 Negative Metastatic Breast Cancer (Mbc) Patients with Resistance to Non-Steroidal Aromatase Inhibitors (Nsai): Pearl Study (Geicam/2013-02_Cecog/Bc.1.3.006)

ABSTRACT Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer (BC) patients. AIs have become the treatment of choice in postmenopausal patients. The high response rates with ET in these patients are partially undermined by the resistance developed by most of them over time. On early disease recurrence/progression to AIs, the treatment options include other AI, estrogen-receptor antagonists or chemotherapy (being capecitabine one of the best options). Preclinical data suggest that ER + /HER2- BC are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in delaying/reverting endocrine resistance. Palbociclib is an oral novel CDK4/6 inhibitor that seems to be synergistic with ET in preclinical and clinical studies. Trial design: This is an international (6 countries) randomized phase III study. Patients are randomized 1:1 to exemestane (25 mg daily) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR + /HER2 MBC are eligible if resistant to previous NSAI (letrozole or anastrozole) defined as: recurrence while on or within 12 months after the end of adjuvant treatment or progression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or lytic bone lesions in the absence of measurable disease. The primary objective is Progression-Free Survival (PFS); secondary objectives are overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarker's defined changes. The study will recruit 348 patients to detect a difference of 2.75 months in the median PFS (from 6 to 8.75 months; hazard ratio= 0.686), with a power of 80% and a 5% two sided significance level. The study started recruitment in March 2014 and 10 patients have been included so far (ClinTrials.gov reference NCT02028507). Disclosure: C.H. Bartlett: Employee of Pfizer and hold Pfizer stock; M. Koehler: Employee of Pfizer and hold Pfizer stock; C. Zielinski: Honoraria and Advisory Boards from Roche. All other authors have declared no conflicts of interest.

462P - A Population Pharmacokinetic (Pk) Analysis of Palbociclib (Pd-0332991) in Patients (Pts) with Advanced Solid Tumors

ABSTRACT Aim: Palbociclib, a selective oral inhibitor of cyclin-dependent kinases 4 and 6, is in phase 2 and 3 clinical trials across multiple oncology indications. Objectives of this analysis were to describe the population PK of palbociclib in cancer pts, identify significant covariates, and provide individual PK predictions. Methods: This analysis was based on pooled data from 183 pts treated with palbociclib isethionate salt capsules in 3 studies. Compartmental PK models were tested with food effect in the base model. Graphic inspection and stepwise covariate modeling were used to assess covariates of interest based on the metabolic mechanism, including demographic factors, laboratory test variables, and concomitant medications. The significant covariates included in the final model were evaluated for clinical importance by calculating the magnitude of effects on PK parameters. Diagnostic plots, visual predictive check (VPC), and standardized VPC were used for model evaluation. Results: Palbociclib PK was best described by a 2-compartment model with 1st order absorption. Population typical values were estimated to be 60.2 L/h for apparent oral clearance (CL/F) and 2710 L for volume of central compartment (V2/F) (inter-patient variability: CL/F, 36.2%; V2/F, 30.2%); the absorption rate constant and absorption lag time were estimated to be 0.367 1/h and 0.658 h, respectively. The relative bioavailability and absorption lag time of palbociclib were increased by 16.0% and 28.8%, respectively, when taken with a high-fat meal versus fasted conditions. Baseline body weight (BWT) and age were significant covariates on CL/F; BWT was a significant covariate on V2/F. However, they were not considered clinically important. Other tested covariates (liver enzymes, creatinine clearance, co-administration of acid-reducing agents) were not significant covariates on relevant PK parameters of palbociclib. Model evaluation showed no bias in model predictions. Conclusions: The population PK model of palbociclib was well defined. Results support the recommendation that no dose adjustment is necessary for age, BWT, sex, pts with mild or moderate renal impairment, or pts with mild hepatic impairment. Disclosure: W. Sun: Employment: Pfizer; D.D. Wang: Employment: Pfizer Stock ownership: Pfizer.

463P - Effect of Food on the Bioavailability of Palbociclib 125 Mg Capsules in Healthy Volunteers

ABSTRACT Aim: Palbociclib (P), a selective oral cyclin-dependent kinase 4/6 inhibitor that blocks G1/S cell cycle progression, is in phase 2 and 3 clinical trials across multiple oncology indications. P has low solubility and high permeability. This completed phase 1 study estimated the effect of food on P bioavailability. Methods: This randomized, open-label, 4-sequence, 4-period crossover study (NCT01904747) in 28 healthy adult volunteers estimated the relative bioavailability of single-dose P 125 mg (free base capsule) administered 30 min after a high fat/calorie meal, 30 min after a low fat/calorie meal, or between 2 moderate fat/standard calorie meals (1 h after/2 h before) versus after fasting ≥10 h overnight (washout: ≥10 d between study periods). No food was allowed ≥4 h postdose (all conditions except moderate fat meal). Pharmacokinetic (PK) samples were collected predose and serially up to 144 h postdose; P concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. PK data were analyzed using a non-compartmental approach based on a mixed effects model. Results: Time to maximum P concentration (Tmax) and terminal plasma half-life (t1/2) values were similar across fed and fasted conditions (median Tmax: 8 h, all; mean t1/2: 22.03–23.90 h). Relative to the fasted condition, ratios of adjusted geometric means for high fat, low fat, and moderate fat conditions were 121%, 112%, and 113%, respectively, for AUCinf and 138%, 127%, and 124%, respectively, for Cmax; the slight increase in exposure in the fed versus fasted conditions was driven mainly by a subgroup of subjects (n = 3) with significantly lower exposure in the fasted condition. PK variability (% coefficient of variation) was reduced in the fed (AUCinf, 23%–27%; Cmax, 21%–24%) versus fasted (AUCinf, 39%; Cmax, 73%) conditions. In a supplemental analysis excluding the 3 subjects with significantly lower exposure in the fasted condition, food intake did not affect P exposure, and PK variability was similar across fed and fasted conditions. Conclusions: Overall, P exposure was marginally affected, but PK variability was greatly reduced, in the fed versus the fasted condition. Thus, P should be administered with food. Disclosure: A. Ruiz-Garcia: Employment: Pfizer Inc Stock ownership: Pfizer Inc.; A. Plotka: Employment: Pfizer Stock ownership: Pfizer; S. Pawlak: Speakers’ bureau: Pfizer Employment: Pfizer Stock ownership: Pfizer; M. O'Gorman, S. Nidadavolu and S. Phillips: Employment: Pfizer; M. Kosa: Employment: Contractor at Pfizer (Clinical Assay Group) through Atrium Services. D.D. Wang: Employment: Pfizer Stock ownership: Pfizer.

793PD - Axitinib vs Sorafenib for Advanced Renal Cell Carcinoma: Phase III Overall Survival Results and Analysis of Prognostic Factors

ABSTRACT Purpose In the phase III AXIS trial, axitinib prolonged progression-free survival (PFS) compared with sorafenib as 2nd-line therapy for metastatic renal cell carcinoma (mRCC) (Lancet 2011;378:1931). Mature overall survival (OS) data (as of Nov 1, 2011) are reported. Methods 723 patients (pts) with clear cell mRCC, progressive disease after 1 systemic therapy, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 were stratified by ECOG PS and prior therapy and randomised 1:1 to axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. OS was analysed as a secondary endpoint based on 425 events and compared using a 1-sided log-rank test stratified by ECOG PS and prior therapy. Pretreatment prognostic factors were studied by multivariate analyses. Pts were grouped by diastolic blood pressure (dBP) on therapy (≥1 dBP measurement ≥90 vs dBP Results Median OS (mOS) was 20.1 mo (95% confidence interval [CI]16.7, 23.4) in the axitinib arm and 19.2 mo (95% CI 17.5, 22.3) in the sorafenib arm; hazard ratio (HR) 0.969 (95% CI 0.800, 1.174); P = 0.3744. In prior therapy subsets, mOS with axitinib vs sorafenib was: prior cytokine, 29.4 vs 27.8 mo (HR 0.813; 95% CI 0.555, 1.191); prior sunitinib, 15.2 vs 16.5 mo (HR 0.997; 95% CI 0.782, 1.270); prior bevacizumab plus interferon-α, 14.7 vs 19.8 mo (HR 1.825; 95% CI 0.942, 3.535); and prior temsirolimus, 14.0 vs 8.5 mo (HR 0.459; 95% CI 0.165, 1.278). Prognostic factors for longer OS with 2nd-line therapy (P Conclusions Axitinib resulted in prolonged PFS and similar OS compared with sorafenib for 2nd-line mRCC. OS results and prognostic factors may be used in clinical trial design for novel agents in 2nd-line therapy. Disclosure R.J. Motzer: Pfizer Consultant. Research Funding from Pfizer. B. Escudier: Advisory role for Novartis, Bayer, Pfizer, Aveo, GSK. S. Negrier: Ad Board : Pfizer Honoraria: Novartis Research grants: GSK, Roche. M.E. Gore: Speaker bureau and advisory boards: Roche, GSK, Novartis, Bayer, Pfizer, Schering Plough, Bristol Myers Squibb, Aveo, AstraZeneca, Astellas. J. Tarazi: Employee of and own stock in Pfizer. S. Hariharan: Employee of and own stock in Pfizer. B. Rosbrook: Employee of and own stock in Pfizer. S. Kim: Employee of and own stock in Pfizer. B.I. Rini: Consulting and research funding from Pfizer. All other authors have declared no conflicts of interest.

811P - Clinic and Home Blood Pressure Measurements are Reliable for Guiding Therapy in Patients with Metastatic Renal Cell Carcinoma Receiving Axitinib as First-Line Therapy

ABSTRACT Background Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is approved in the US in patients (pts) with metastatic renal cell carcinoma (mRCC) who failed 1 prior systemic therapy. Blood pressure (BP) increases are commonly observed with axitinib. BP measurements are subject to error and can vary by method employed, eg, home measurements by pts, ambulatory monitoring, and in-clinic assessments. As part of a phase II study evaluating safety and efficacy of axitinib for treatment-naive mRCC, we prospectively characterised and compared BP measurements from clinic, home, and 24-hr ambulatory BP monitoring (ABPM). Methods Clinic BP was obtained at baseline, Days 1 and 15 of the first 2 treatment cycles, and Day 1 of subsequent 28-day cycles. Home BP was obtained by pts twice daily during the treatment period. In a subset of pts, 24-hr ABPM was performed at baseline and Days 4 and 15. Results 213 pts enrolled. Mean age was 61 years; 67% were men. Pooled median progression-free survival was 14.5 months. No pts had uncontrolled hypertension (HTN) at study entry. All-grade HTN occurred in 63% and grade 3 in 29%, with no grade 4 HTN. By 24-hr ABPM, median increases from baseline in systolic BP/diastolic BP (sBP/dBP) were 10/8 mmHg by Day 4, with modest incremental increases by Day 15 and stabilisation thereafter; changes in BP were generally consistent at all clock times of day. dBP outcomes were highly consistent between clinic and home measurements (mean 83 ± 9 vs 83 ± 9 mmHg on Cycle 1 Day 15, n = 200; 84 ± 11 vs 84 ± 10 mmHg on Cycle 3 Day 1, n = 171). Similarly, dBP measurements were consistent between clinic and 24-hr ABPM (mean 84 ± 10 vs 84 ± 9 mmHg on Cycle 1 Day 15, n = 63). Consistent sBP outcomes were also observed across various time points and measurement modalities. Conclusions BP increased early with axitinib and was generally well-managed. 24-hr ABPM suggests there is no best time of day to measure BP; rather, measuring at a consistent time of day in individual pts would provide the most useful data. Results from clinic and home monitoring appear consistent and both could be reliable in measuring BP and guiding axitinib therapy. Disclosure V. Grunwald: Advisory and honoraria: GSK, Pfizer, Roche, Novartis, Bayer. Research grant: Pfizer. M.N. Fishman: Dr Fishman has received research funding, participated in compensated advisory board and promotional presentations from the manufacturer of the study drug. M. Carducci: Pfizer DSMB for unrelated product (compensated). JHU received research funding for conduct of the trial. A. Bair: Employee of and own stock in Pfizer. Y. Chen: Employee of and own stock in Pfizer. S. Kim: Employee of and own stock in Pfizer. B.I. Rini: Consulting and research funding from Pfizer.

820P - Sunitinib Global Expanded-Access Trial in Metastatic Renal Cell Carcinoma (MRCC) – Final Results

ABSTRACT Background Sunitinib had a manageable safety profile and encouraging efficacy in a global expanded-access mRCC study (ClinicalTrials.gov, NCT00130897; Pfizer) initiated prior to regulatory approval, in patients (pts) ineligible for other trials (Gore et al, 2009). Here we report final results. Methods Pts aged ≥18 yrs with treatment-naive or previously treated mRCC received oral sunitinib on the approved 50 mg/day 4-wk-on/2-wk-off schedule. Safety was assessed regularly and tumor measurements were done as per local standard practice using RECIST-defined response. Analyses included all pts who received ≥1 dose of sunitinib. Results 4,577 pts were enrolled. From July 2005 to November 2011, 4,543 pts received treatment, including poor prognosis pts with brain metastases (7%), Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 (14%), non-clear cell RCC (12%) and age ≥65 yrs (33%). Median treatment duration was 7.5 mths and median follow-up was 13.6 mths. 4,298 pts (95%) discontinued; reasons included lack of efficacy (37%), death (20%) and adverse events (AEs; 15%). The most common treatment-related AEs of any grade were diarrhea (47%), fatigue (40%), nausea (36%), decreased appetite (31%), mucosal inflammation (29%), stomatitis and vomiting (both 28%), hand–foot syndrome (HFS; 27%), dysgeusia (25%), hypertension (24%), thrombocytopenia (23%) and asthenia (22%). The most common treatment-related grade 3/4 AEs were fatigue (9%), thrombocytopenia (8%), HFS and asthenia (both 7%), hypertension and neutropenia (both 6%) and diarrhea (5%). In 4,219 evaluable pts, the objective response rate (ORR) was 16% (n = 660) with subgroup ORR as follows: baseline brain metastases (30/324 [9%]), ECOG PS ≥2 (32/587 [5%]), non-clear cell RCC (42/505 [8%]), and age ≥65 yrs (195/1,386 [14%]). Overall median progression-free survival was 9.4 mths (95% CI: 8.8, 10.0) and overall survival was 18.7 mths (95% CI: 17.5, 19.5). Conclusions Results from this global expanded-access mRCC trial confirm the safety and efficacy of sunitinib in >4,500 pts with wide-ranging disease states in a real-world setting. The sunitinib AE profile in this broad population was manageable and consistent with prior trial results. Disclosure M.E. Gore: Advisory relationships with Roche, Pfizer, Bristol Myers, Novartis, GSK, Aveo\\Astellas, Bayer. Honoraria to disclose from Roche, Pfizer, Bristol Myers, Novartis. C. Porta: Advisory relationship Pfizer Bayer-Schering Hoffman La Roche GSK Novartis Astellas Boehringer Recordati. Honoraria: Pfizer Bayer-Schering Hoffman La Roche GSK Novartis Astellas Boehringer Recordati Research funding Bayer-Schering Novartis. S. Bracarda: Advisory relationship with Novartis Bayer Schering Pfizer GSK Aveo/Astellas Boheringer-Ingelheim. Honoraria to disclose from Novartis and Pfizer. G.A. Bjarnason: Advisory relationship with Pfizer. Honoraria to disclose from Pfizer. Research funding to disclose from Pfizer.. S. Oudard: Advisory relationships: Pfizer, Bayer-Schering, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis Honoraria: Pfizer, Bayer-Schering, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. S. Lee: Advisory relationships with Pfizer, Novartis, Bayer. Honoraria to disclose from Pfizer, Novartis, Bayer. K. Fly: Employed by Pfizer Inc. as an Oncology Clinician. Hold Pfizer stock as does an immediate family member. C. Szczylik: Advisory relationship with Pfizer, GSK, Bayer. Honoraria from Pfizer, GSK, Bayer. All other authors have declared no conflicts of interest.

LBA1_PR - Phase III Study of Crizotinib Versus Pemetrexed or Docetaxel Chemotherapy in Patients with Advanced Alk-Positive Non-Small Cell Lung Cancer (NSCLC) (Profile 1007)

ABSTRACT Background Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) are associated with marked clinical responses to crizotinib, an orally available tyrosine kinase inhibitor targeting ALK. This global randomized phase III study compared the efficacy and safety of crizotinib (C) with standard chemotherapy (pemetrexed or docetaxel [P/D]) as 2nd-line therapy for patients (pts) with advanced ALK+ NSCLC. Methods Between Feb 2010 and Feb 2012, 347 pts with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive C 250 mg PO BID (n = 173) or either P 500 mg/m2 or D 75 mg/m2 IV q3w (n = 174; 58% P, 42% D). ALK was detected by FISH in a central lab. Pts with progressive disease on P/D were offered C on PROFILE 1005. The primary endpoint was progression-free survival (PFS) per independent radiologic review; secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. Results The study met its primary objective by demonstrating the superiority of C over P/D in prolonging PFS (median 7.7 vs 3.0 mo; HR 0.49; 95% CI 0.37–0.64; P Conclusions C showed significant improvement in PFS and ORR compared with P/D and had an acceptable safety profile. These findings establish C as the standard of care for pts with previously treated advanced ALK+ NSCLC. Disclosure A.T. Shaw: Advisory relationship with Pfizer, Ariad, Chugai, Novartis and Daiichi-Sankyo. Research funding from AstraZeneca and Novartis. D.W. Kim: Advisory relationship with Pfizer. Honoraria from Pfizer. K. Nakagawa: Honoraria from Pfizer and Eli Lilly. B. Besse: Research funding from Pfizer. B. Solomon: Advisory relationship with Pfizer. Research funding from Pfizer. F.H. Blackhall: Advisory relationship with Pfizer. Honoraria from Pfizer. Research funding from Pfizer. Expert testimony for UK NICE scoping for crizotinib. Y. Wu: Honoraria from Pfizer, Roche, AstraZeneca, Eli Lilly, and Sanof-Aventis. Research funding from Pfizer, Roche, and AstraZeneca. M. Thomas: Advisory relationship with Pfizer. K.J. O'Byrne: Adivsory relationships with and honoraria, research funding, travel-cost remuneration from Pfizer and Eli Lilly. D. Moro-Sibilot: Honoraria from Pfizer. R. Camidge: Advisory relationship with Pfizer. Honoraria from Pfizer. V. Hirsh: Advisory relationship with Pfizer. Honoraria from Pfizer. T.S.K. Mok: Advisory relationships with and honoraria from Pfizer, AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Taiho, GSK, and Boehringer Ingelheim. Research funding from AstraZeneca. V. Tassell: Employed by Pfizer. Holds Pfizer stock. A. Polli: Employed by Pfizer. Holds Pfizer stock. P. Janne: Advisory relationships with Pfizer, Boehringer Ingelheim, Roche, Genentech, Abbott, AstraZeneca, Sanofi, and Teva. Renumeration from LabCorp. All other authors have declared no conflicts of interest.