Advanced ALK-positive Non-small Cell Lung Research Articles

Real-world data on treatment patterns and survival among ALK+ NSCLC patients in Japan.

e20505 Background: Three ALK inhibitors (ALKi) are approved in Japan for treatment of patients with ALK-positive (ALK+) advanced or metastatic non-small cell lung cancer (NSCLC). However, the optimal sequence of therapy with ALKi is unclear. The objective of this study was to provide real-world data on the treatment patterns and survival among ALK+ NSCLC patients. Methods: ALK+ patients treated with ALKi in our institute were included in this retrospective analysis. Data on the treatment patterns and outcomes were collected from medical records. Results: In total, 60 patients were included. The median age at the diagnosis was 52.5 years, with 60% female and 65% non-smokers. The first treatment was chemotherapy in 67% and ALKi in 33%. The median overall survival (OS) was 186 weeks. We found differences in the OS for Crizotinib use at any line (118 weeks; presence vs. NR; absence) and first-line use of an ALKi (127 weeks; Crizotinib vs. 416 weeks; Alecitinib or Ceritinib, p = 0.0048). Conclusions: The role of Crizotinib in the treatment of ALK+ NSCLC is decreasing. Alectinib followed by Ceritinib seems to be promising. Treatment decision-making based on a re-biopsy is immature at present. The development of sequential therapy with ALKi based on resistance mechanisms is urgently needed. [Table: see text]

Evaluation of efficacy and safety of crizotinib and its prognostic factors in patients with ALK-positive advanced non-small cell lung cancer

Objective To investigate the efficacy and safety of crizotinib in patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and focuse on analysis of its prognostic factors. Methods Fifty patients with advanced (stage ⅢB-Ⅳ) ALK-positive NSCLC confirmed by cytology or histology in Peking Union Medical Collage Hospital from January 2013 to September 2016 were collected. The relevant clinical information and treatment protocols were recorded. The efficacy and safety of crizotinib were followed up, and its prognostic factors were analyzed. Results At the end of follow-up, the median progression free survival (PFS) of progressed patients (n=24) was 9.6 months (95%CI: 8.3-10.9 months), of which five patients died. The median follow-up time of non-progressed patients (n=26) was 10.7 months. The most common adverse event was abnormal liver function (48.0%, 24/50). In the single factor analysis of Kaplan-Meier, younger or equal to 40 years old patients had a longer PFS (P=0.017), and the COX regression analysis (Enter method) also had statistical significance differences (HR=6.1, 95%CI: 1.4-27.5, P=0.018). However, gender (HR=0.8, 95%CI: 0.2-2.6, P=0.697), smoking history (HR=1.5, 95%CI: 0.4-5.6, P=0.524), pathology (HR=1.1, 95%CI: 0.3-4.2, P=0.922), tumor stage (HR=1.7, 95%CI: 0.4-8.4, P=0.502), epidermal growth factor receptor (EGFR) mutant type (HR=0.4, 95%CI: 0.4-4.3, P=0.461), EGFR unknown (HR=1.3, 95%CI: 0.3-6.1, P=0.727), Eastern Cooperative Oncology Group Performance Status (ECOG) PS score (HR=2.0, 95%CI: 0.6-6.8, P=0.290), the status of previous treatment (HR=0.6, 95%CI: 0.2-1.8, P=0.385) and brain metastasis (HR=0.7, 95%CI: 0.1-3.2, P=0.628) were not associated with disease progression. Conclusion Crizotinib has good efficacy and is safe and well-tolerated to advanced ALK-positive NSCLC patients, and age is the independent prognostic factor. Key words: Carcinoma, non-small-cell lung; Prognosis; Anaplastic lymphoma kinase; Crizotinib

Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients.

Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

1291TiP - Phase 1b study of crizotinib in combination with pembrolizumab in patients (pts) with untreated ALK-positive (+) advanced non-small cell lung cancer (NSCLC)

Crizotinib is approved internationally for the treatment of ALK+ advanced NSCLC. However, disease progression ultimately occurs in the vast majority of pts, often due to the development of secondary crizotinib-resistant ALK mutations or signal transduction bypass pathways. The immune checkpoint programmed cell death 1 (PD-1) pathway can be exploited by tumors to limit T cell activity, allowing tumors to evade immune detection. ALK+ NSCLC is associated with high PD ligand 1 (PD-L1) expression, and data from a preclinical model has suggested that combining PD-1- and ALK-targeted therapies may be beneficial (Ota et al, Clin Cancer Res 2015; Voena et al, Cancer Immunol Res 2015). The anti–PD-1 antibody, pembrolizumab is approved in the US for the treatment of advanced PD-L1+ NSCLC after progression on a platinum-based chemotherapy and an approved tyrosine kinase inhibitor for those with an EGFR or ALK genomic aberration. Trial design: The primary objectives of this ongoing multicenter study (NCT02511184) are to determine the maximum tolerated dose (MTD) of crizotinib combined with pembrolizumab (dose-finding; part 1) and the recommended phase 2 dose (dose expansion; part 2), with secondary objectives to evaluate the safety profile and antitumor activity of the combination, the pharmacokinetics of both drugs, and PD-L1 expression as a predictor of antitumor activity. Part 1 uses a modified toxicity probability interval method to determine the MTD, with a starting crizotinib dose of 250 mg twice daily on a continuous schedule and intravenous pembrolizumab 200 mg on day 1 of each 21-day cycle. Seventy patients are expected to be enrolled, with 30 dose-limiting toxicity-evaluable patients expected in part 1, including a target of 10 treated at the MTD who will also contribute to the planned 50 required for part 2. Key eligibility criteria include ALK+ advanced NSCLC, no prior systemic therapy for metastatic disease, measurable disease (RECIST v1.1), available archival tumor tissue, and ECOG performance status 0/1 (part 1) or 0–2 (part 2). Pts with stable treated brain metastases are eligible. Enrollment in part 1 began in Oct 2015, with 5 pts currently enrolled. Clinical trial identification: Clinical Trials Registration number: NCT02511184 Legal entity responsible for the study: N/A

P14.08 Neurological complications of emerging targeted therapies

AbstractIntroduction:The development of new biological and immunotherapeutic agents to treat cancer associates unknown neurological toxicities. Crizotinib (Cri), an anaplastic lymphoma kinase and c-ros oncogene 1 hepatocyte growth factor receptor tyrosine-kinase inhibitor, has been approved for the treatment of advanced ALK-positive non-small cell lung cancer. Ipilimumab (Ipi), an anticytotoxic T-lymphocyte antigen-4 antibody, was the first agent to demonstrate improved survival in patients with metastatic melanoma. This report describes a patient treated with Ipi showing a not previously reported neurological adverse event; and a patient treated with Cri showing atypical brain metastases.Patients and methods:Patient 1(P1): 66-year-old male with a history of irresectable nasal melanoma, started on Ipi plus concomitant radiotherapy on September/2015, obtaining a radiological partial response. Two months later he developed progressive cognitive impairment, urinary incontinence and gait difficulties. A neuroaxis MRI revealed multiple acute and subacute subcentimeter ischemic lesions with contrast enhancement and restricted diffusion with diffuse FLAIR signal changes. CSF reported protein elevation, normal glucose and mild lymphocytic pleocytosis without neoplastic cells. Microbiological cultures and PCRs were negative. Echocardiography was normal. Patient 2(P2): 54-year-old non-smoker female with lung adenocarcinoma (EGFR wild-type and ALK translocation) and spinal metastatic disease at diagnosis, started on Cri after failure of first-line treatment with cisplatin plus pemetrexed. After 16 cycles, an increase in carcinoembryonic antigen was noted without progression of ganglio-pulmonary disease. Although asymptomatic, CNS progression was suspected and follow-up brain MRI reported multiple bilateral supra and infratentorial large cystic lesions with perilesional edema and no contrast enhancement.Results:P1: primary angiitis of the CNS was suspected, although arteriography was unremarkable. He received high-dose metilprednisolone followed by cyclophosphamide bolus. The inflammatory component of CSF and neurological symptoms presented partial improvement but brain MRI showed a dissociate response. P2: PET scan revealed irregular distribution of the radiotracer and hypometabolic lesions. Follow-up brain MRI revealed stabilization with a perfusion-weighted sequence reporting an increase in the relative cerebral blood volume of the bigger cystic lesion. These features led us to the diagnostic of indolent brain metastases.Conclusions:Early recognition of new neurological patterns of toxicity may lead to drug discontinuation or dose adjustment preventing further neurological deterioration. A better knowledge of these toxicities will help differentiate treatment-related complications from metastatic progression.

The renal effects of ALK inhibitors.

Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is associated with development of peripheral edema and rare electrolyte disorders. This review focuses on the adverse renal effects of Crizotinib in clinical practice.

Real-world evidence on treatment patterns and survival among ALK+ NSCLC patients in Canada who discontinue crizotinib treatment.

e20610Background: Crizotinib is indicated for treatment of patients with ALK-positive (ALK+) advanced or metastatic non-small cell lung cancer (NSCLC), yet patients eventually progress or develop d...

174P: Comparison of cardiovascular effects of crizotinib and chemotherapy in patients (pts) with ALK-positive (+) advanced non-small cell lung cancer (NSCLC)

174P: Comparison of cardiovascular effects of crizotinib and chemotherapy in patients (pts) with ALK-positive (+) advanced non-small cell lung cancer (NSCLC)

177P: Renal effects of crizotinib in patients (pts) with ALK-positive (+) advanced non-small cell lung cancer (NSCLC)

177P: Renal effects of crizotinib in patients (pts) with ALK-positive (+) advanced non-small cell lung cancer (NSCLC)

Efficacy of crizotinib for 28 cases of advanced ALK-positive non-small cell lung cancer

This study aims to evaluate the efficacy and safety of crizotinib for advanced ALK-positive non-small cell lung cancer (NSCLC) patients. Twenty-eight patients with advanced ALK-positive NSCLC were given orally crizotinib 250 mg b. i.d., and were followed up to evaluate the therapeutic efficacy and safety. Among the 28 patients, the objective response rate (ORR) was 71.4% (20/28) and disease control rate (DCR) was 92.9% (26/28). Three patients achieved complete response. Seventeen patients had partial response. The most common drug-related adverse events were mild flickering vision and gastrointestinal reaction. Eleven patients experienced flickering vision. Nine patients had nausea and vomiting. Eight patients had diarrhea. They were all reversible and of grade I or II. Only one patient had grade III myelosuppression. Among the 28 patients, 16 cases were disease-free and 12 cases had progressive disease, with a progression-free survival of 8.2 months. Crizotinib is effective and tolerable in the treatment of advanced ALK-positive NSLCC. However, its long-term treatment efficacy requires to be further studied.

Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer: Results of a multicenter analysis

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed. We collected the data of 69 advanced ALK-positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded. Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments (P=0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression (P=0.89). Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome.

Crizotinib as first line therapy for advanced ALK-positive non-small cell lung cancers.

The field of targeted therapeutic development has been propelled forward by remarkable advances in the understanding of driver mutations, particularly in non-small cell lung cancer (NSCLC). Our initial understanding of the importance of driver mutations developed from the discovery of somatic oncogenic epidermal growth factor receptor (EGFR) mutations, which sensitize tumors to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib (1), erlotinib (2), and afatinib (3). Anaplastic lymphoma kinase (ALK) gene rearrangements act as a distinct oncogenic driver in about 4% of NSCLC tumors (4). Testing of metastatic NSCLC adenocarcinomas to determine if they are “ALK-positive” has become the standard of care, because these tumors respond well to ALK inhibitors such as crizotinib, an orally available TKI. Crizotinib induced remarkable responses in patients with ALK positive NSCLCs in phase I and II trials (5), and appeared to improve survival of these patients in a retrospective analysis (6). A second line phase III study subsequently showed that crizotinib was superior to both pemetrexed and docetaxel as standard chemotherapy (7).

Future options for ALK-positive non-small cell lung cancer.

Recent advances in the understanding of non-small cell lung cancer (NSCLC) biology have revealed a number of 'targetable' genetic alterations that underlie cancer growth and survival in specific patients subgroups. The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a population of NSCLCs in whom dysregulation of ALK-tyrosine kinase (-TK) leads to uncontrolled proliferation of cancer cells, thus providing the basis for the therapeutic use of ALK-TK inhibitors (-TKIs) in ALK-rearranged (-positive) disease. Crizotinib was the first ALK-TKI to undergo clinical development in ALK-positive advanced NSCLC, in which it has been shown to greatly outperform the best available chemotherapy regimen in either second- or first-line setting. More recently, the novel second-generation ALK-TKI ceritinib has been shown to be highly active in either crizotinib-pretreated or -naïve population. Nevertheless, as mechanisms of resistance to crizotinib and ALK-TKIs in general are being progressively elucidated, the treatment landscape of ALK-positive NSCLC is expected to evolve rapidly. In the present review we will briefly discuss the current knowledge of ALK-positive advanced non-small cell lung cancer. Also, we will touch upon new developments on drugs/combination regimens aimed at inhibiting the ALK-TK, in an attempt to delineate how treatment of ALK-positive disease may change in the next future.

Impact of Crizotinib on Patient-Reported Symptoms and Global Quality of Life (Qol) Compared with Platinum Based Chemotherapy in Phase III Study of Treatment Naïve Advanced Alk-Positive Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Aim: The main objective of our analysis was to compare patient-reported symptom and global QOL improvement and worsening rates between crizotinib and platinum based chemotherapy in treatment naive patients with advanced ALK-positive NSCLC in PROFILE 1014 study (Pfizer; NCT01154140). Methods: Patients in the ongoing PROFILE 1014 study were randomized to crizotinib (250 mg PO bid; n= 172) or chemotherapy (pemetrexed 500 mg/m2 + either cisplatin 75 mg/m2 or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n= 171). Patient-reported outcomes were assessed at baseline, day 7 and day 15 of cycle 1, day 1 of subsequent 3-week cycles and end of treatment using EORTC QLQ-C30 and lung can¬cer module QLQ-LC13. Higher scores (range 0 - 100) indicated higher symptom severity or better functioning/QOL. A clinically meaningful change was defined as a ≥10-point change from baseline. The percentage of patients classified as having improved (≥10-point increase for functioning/QOL scales / ≥ 10-point reduction for symptoms in average of change from baseline scores across cycles for a patient) or worsened (≥10-point reduction for functioning / ≥ 10-point increase for symptoms in average of change from baseline scores across cycles) was examined and compared between treatment groups using chi-square tests. Results: Completion rates at baseline were ≥95% in each group and scores were balanced. A significantly (p Conclusions: Treatment with crizotinib led to higher improvement rates in global QOL, physical functioning and key lung cancer symptoms compared with chemotherapy. Disclosure: F. Blackhall: Advisory boards: Pfizer; E. Felip: Advisory boards: Boehringer-Ingelheim, Novartis, Roche, BMS, Lilly; F. Cappuzzo: Advisory boards: Pfizer; D.W. Kim: Advisory boards: Pfizer, Novartis; Y. Wu: Other substantive relationships (Honoraria): Roche, AstraZeneca, Eli Lilly; B. Solomon: Advisory boards: Pfizer, Novartis, Roche, Clovis Oncology, AstraZeneca, Merck, BMS, Lilly; T. Mekhail: Advisory boards: Pfizer, Genentech, Eli Lilly, Celgene; Corporate-spnsored research: Pfizer, Genentech, Lilly, Celgene, BMS, AstraZeneca; Other substantive relationships (Speakers' Bureau): Pfizer, Genentech, Eli Lilly, Celgene; J. Paolini: Employment and stock ownership: Pfizer; T. Usari: Employment and stock ownership: Pfizer; S. Iyer: Employment, stock ownership and corporate-sponsored research: Pfizer; A. Reisman: Employment and stock ownership: Pfizer; K. Wilner: Employment, stock ownership, advisory board and corporate-sponsored research: Pfizer; J. Tursi: Employment and stock ownership: Pfizer; T. Mok: Advisory boards: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer-Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin; Board of directors: IASLC; Corporate-sponsored research: AstraZeneca. All other authors have declared no conflicts of interest.

Overall and Intracranial (Ic) Efficacy Results and Time to Symptom Deterioration in Profile 1014: 1St-Line Crizotinib Vs Pemetrexed - Platinum Chemotherapy (Ppc) in Patients (Pts) with Advanced Alk-Positive Non-Squamous Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Aim: Clinical outcomes (overall and IC efficacy, lung cancer symptoms) with crizotinib (criz) vs standard chemotherapy as 1st-line treatment for advanced ALK-positive NSCLC were compared in the ongoing randomized open-label phase III study PROFILE 1014 in the whole pt population and in pt subgroups. Methods: Pts with previously untreated advanced non-squamous ALK-positive NSCLC (N = 343) were randomized 1:1 to criz 250 mg PO BID (n = 172) or PPC (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n = 171). Continuation of/crossover to criz after PD (per independent radiology review [IRR]) was allowed for pts randomized to criz or PPC, respectively. The primary endpoint was PFS per IRR. Secondary endpoints included OS, IC TTP, time to deterioration in symptoms of chest pain, dyspnea, or cough (TTDS), and safety. Results: 171 pts received criz, 91 pem - cis, 78 pem-carbo, and 3 no treatment. The study met its primary objective: criz was superior to PPC in prolonging PFS (median 10.9 vs 7.0 mo; HR: 0.45; 95% CI: 0.35 - 0.60; P Conclusions: Crizotinib treatment showed significant improvements in PFS and TTDS vs PPC, a numerical improvement in IC TTP, and an acceptable safety profile, establishing crizotinib as the standard of care for pts with treatment-naive advanced ALK-positive non-squamous NSCLC. Disclosure: B. Solomon: Advisory boards: Pfizer, Novartis, Roche, Clovis Oncology, AstraZeneca, Merck, BMS, Lilly; E. Felip: Advisory boards: Boehringer-Ingelheim, Novartis, Roche, BMS, Lilly; F.H. Blackhall: Advisory boards: Pfizer; T.S.K. Mok: Ad boards: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer-Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin Pharm; Board of directors: IASLC; Corp-sponsored research: AstraZeneca; D. Kim: Advisory boards: Pfizer, Novartis; Y. Wu: Other substantive relationships (Honoraria): Roche, AstraZeneca, Eli Lilly; T. Mekhail: Advisory boards: Pfizer, Genentech, Eli Lilly, Celgene; Corporate-spnsored research: Pfizer, Genentech, Lilly, Celgene, BMS, AstraZeneca; Other substantive relationships (Speakers' Bureau): Pfizer, Genentech, Eli Lilly, Celgene; J. Paolini: Employment and stock ownership: Pfizer; T. Usari: Employment and stock ownership: Pfizer; S. Iyer: Employment, stock ownership and corporate-sponsored research: Pfizer; A. Reisman: Employment and stock ownership: Pfizer; K. Wilner: Employment, stock ownership, advisory board and corporate-sponsored research: Pfizer; J. Tursi: Employment and stock ownership: Pfizer; F. Cappuzzo: Advisory boards: Pfizer. All other authors have declared no conflicts of interest.

Crizotinib in advanced ALK-positive non-small cell lung cancer: Results of a retrospective cohort in Complejo Hospitalario de Navarra, Spain.

e19158 Background: Crizotinib is an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and has been approved in several countries for treatment of advanced ALK-positive no...

PCN38 - Estimating the Budget Impact of Crizotinib for Alk-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) in Argentina

PCN38 - Estimating the Budget Impact of Crizotinib for Alk-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) in Argentina

Abstract 1618: Combination of axitinib and crizotinib in renal cell carcinoma models.

Abstract Background: The vascular endothelium growth factor (VEGF) pathway plays a pivotal role in angiogenesis. Axitinib (AG-013736), a potent small molecule receptor tyrosine kinase inhibitor highly selective for VEGF receptor 1, 2 and 3, is currently being tested in Phase II/III clinical trials for the treatment of solid tumors and has been approved as a second-line treatment for renal cell carcinoma (RCC). The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) pathway has also been shown to play an important role in tumor vascularization, as well as epithelial to mesenchymal transition (EMT), metastatization, and acquired resistance. Crizotinib (PF-02341066), a potent and selective inhibitor of anaplastic lymphoma kinase (ALK) and c-Met kinase, has been approved for the treatment of advanced ALK-positive non-small cell lung cancer. The aim of this study was to assess the combinational effect of axitinib and crizotinib in two models of RCC with differing degrees of c-Met expression and sensitivity to anti-angiogenic agents. We hypothesized that the combination would provide greater anti-tumor and anti-angiogenesis efficacy compared to single-agents. Methods: Human high c-Met expressing 786-O and low c-Met expressing RP-01 (developed from a skin metastasis of a patient with sporadic clear cell RCC) xenografts were inoculated into SCID mice (8/group). After approximately 6 weeks of tumor growth, mice were treated with vehicle, axitinib (36 mg/kg, 2x/day, oral gavage), crizotinib (25 mg/kg, 1x/day, oral gavage), or axitinib plus crizotinib. Once tumor volume of vehicle mice reached 200 mm2, mice were sacrificed and tumor tissue was excised and analyzed. A sunitinib-resistant RP-01 model was also developed through continued in vivo exposure to sunitinib (60 mg/kg, 1x/day, oral gavage) to further test the different responses to treatments and to evaluate the possible role of c-Met in sunitinib resistance. Compounds were kindly provided by Pfizer. Results: We observed that single-agent crizotinib anti-tumoral activity was strongly related to c-Met expression, inhibiting 786-O tumor growth in vivo, but not RP-01. More interestingly, significant synergistic effects were found with crizotinib and axitinib, whereby enhanced inhibition of 786-O xenograft tumor growth was found (from 17%, axitinib, to 76% combination, p <0.05 of combination vs. both single agents). No overt signs of toxicity were observed in any of the experimental groups. Vessel density, pericyte coverage (CD31 and NG2), and EMT markers are being evaluated with immunohistochemistry. Results from combination treatment in the sunitinib-resistant model will be presented. Summary: Overall, the data demonstrate that this combination therapy resulted in significant anti-tumor activity in a high c-Met expressing RCC model, highlighting the potential therapeutic application of combined VEGF and c-Met blockade in the treatment of RCC. Citation Format: Eric S. Ciamporcero, Kiersten M. Miles, Remi Adelaiye, Stefania Pizzimenti, Giuseppina Barrera, Roberto Pili. Combination of axitinib and crizotinib in renal cell carcinoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2013-1618

Crizotinib: a guide to its use in previously treated advanced anaplastic lymphoma kinase-positive non-small cell lung cancer in the EU

Crizotinib (Xalkori®), an oral anaplastic lymphoma kinase (ALK) fusion protein inhibitor, was recently approved in the EU for the treatment of adults with previously treated ALK-positive advanced non-small cell lung cancer. In clinical trials in this patient population, crizotinib has shown benefits with regard to response and progression-free survival, and was associated with a generally manageable tolerability profile.

1231PD - Impact of Crizotinib Treatment on Patient-Reported Symptoms and Quality of Life (QOL) in Advanced Alk-Positive Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background Crizotinib is a potent, selective, ATP-competitive ALK inhibitor demonstrating a high response rate in advanced ALK-positive NSCLC. The effect of crizotinib on patient-reported symptoms, functioning and QOL from PROFILE 1005 is presented. Methods PROFILE 1005 is an ongoing global, multicenter, open-label, single-arm, phase II study evaluating the safety and efficacy of crizotinib (250 mg BID in 3-week cycles) in previously treated patients with advanced ALK-positive NSCLC. Patient-reported outcomes (PROs) were assessed as secondary endpoints using the European Organisation for Research and Treatment of Cancer questionnaire (EORTC-QLQ-C30) and lung cancer module (QLQ-LC13) at baseline, Day 1 of each cycle and at end of treatment. Functioning, symptoms and global QOL were assessed and scored on scales of 0–100. Higher scores indicate higher symptom severity or higher functioning/QOL. Change from baseline was assessed for statistical and clinical significance (defined as ≥10-point change from baseline). Results As of Jan 2012, 901 patients were evaluable for safety and 797 (88%) of these patients had completed the entire questionnaire at baseline. The majority of patients was female (57%), never smokers (66%), and had adenocarcinoma (92%), with a median age of 52 years. A clinically meaningful (≥10-point) improvement from baseline was observed early and maintained in patient-reported symptoms of cough (Cycle 2 onwards), pain (Cycles 2 to 19), dyspnea from QLQ–C30 (Cycles 3 to 19), pain in chest (Cycles 3 to 20 except for Cycle 18), pain in arm and shoulder (Cycles 3 to 16) and fatigue (Cycles 4 to 21). Clinically significant deterioration was observed for constipation (Cycles 2 and 3) and diarrhea (Cycle 2 to 6, 9 and 10). Clinically meaningful improvements were observed for physical functioning (Cycle 8 and 9), role functioning (Cycles 9 and 10), social functioning (Cycles 4 to 15, except Cycle 12) and global QOL (Cycles 3 to 15, except Cycle 11). Conclusion Treatment with crizotinib in pretreated patients with advanced ALK-positive NSCLC showed an overall positive impact on patient-reported lung cancer symptoms and global QOL. Disclosure F.H. Blackhall: Advisory relationship with Pfizer. Honoraraia, research funding and other remuneration received from Pfizer. D. Moro-Sibilot: Honoraria received from Pfizer. K. Wilner: Employed by Pfizer as a Senior Director and has stock ownership with Pfizer. A. Reisman: Employed by Pfizer and has stock ownership with Pfizer. S. Iyer: Employed as a Director (Global Outcomes Research) by Pfizer. All other authors have declared no conflicts of interest.