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ALK
ALK ALK(1)
The ALK gene can be oncogenic in two ways: (1) forming a fusion gene with any of several other genes, and (2) mutations of the actual DNA code for the gene itself. The 2;5 chromosomal translocation is associated with approximately 60% ALCLs. The translocation creates a fusion gene consisting of the ALK gene and the nucleophosmin gene: the 3" half of ALK, derived from chromosome 2, is fused to the 5" portion of NPM from chromosome 5. This NPM-ALK fusion gene is oncogenic. The EML4-ALK fusion gene is responsible for approximately 3-5% of NSCLC. ALK lung cancers are found in patients of all ages, although on average these patients may be somewhat younger, and are more common in never or light cigarette smokers.(1)

Drugs/Indications


News
References

1. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA: a cancer journal for clinicians. 2014;64(2):83-103.



News


Wednesday, October 26, 2016 12:34 PM|Denise Brock|GRACE :: Lung Cancer|Labels: ALK
In this eighth video from the webcast series, GRACE presents the lunchtime keynote discussion: The Evolving Landscape of Molecular Testing in Lung Cancer: Who, How and When? featuring Dr. Dara Eisner.
Wednesday, October 26, 2016 7:35 AM|Business Wire Health: Pharmaceutical News|Attachments|Labels: ALK, lung cancer
CAMBRIDGE, Mass.--(BUSINESS WIRE)--ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the publication of preclinical data on brigatinib, its investigational oral tyrosine kinase inhibitor in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC). The design and preclinical characterization of brigatinib are described in an article titled, “The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms o

Wednesday, October 26, 2016 7:10 AM|Hirokazu Taniguchi, Shinji Takeuchi, Koji Fukuda, Takayuki Nakagawa, Sachiko Arai, Shigeki Nanjo, Tadaaki Yamada, Hiroyuki Yamaguchi, Hiroshi Mukae, Seiji Yano|Cancer Science|Labels: ALK, lung cancer
Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer. This article is protected by copyright. All rights reserved.
Tuesday, October 25, 2016 1:51 PM|Christina Kelly|ASCO - FDA|Labels: ALK, lung cancer
October 25, 2016

On October 24, 2016, the U.S. Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.

This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC. 

The FDA approval added the following indications for pembrolizumab: 

  • Patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.
  • Patients with metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal to 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.

Approval was based on results of two randomized, controlled trials that demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy.

In a trial of 305 patients who had no prior treatment for metastatic NSCLC and TPS greater than or equal to 50%, those who received pembrolizumab (200 mg every 3 weeks) had a significant improvement in PFS (HR 0.50 [95% CI: 0.37, 0.68]; p<0.001) with a median PFS of 10.3 months versus 6.0 months for those receiving platinum-based chemotherapy. A pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab as compared with chemotherapy (HR 0.60 [95% CI: 0.41, 0.89]; p<0.005). 

In a three-arm trial of 1033 patients who were previously treated for metastatic NSCLC with a TPS greater than or equal to 1%, those randomized to pembrolizumab 2 mg/kg every 3 weeks (HR 0.71 (95% CI: 0.58, 0.88]; p<0.001) or pembrolizumab 10 mg/kg every 3 weeks (HR 0.61 [95% CI: 0.49, 0.75]; p<0.001) had an improved OS compared with patients receiving docetaxel. The median survival was 10.4 months in the pembrolizumab 2 mg/kg arm, 12.7 months in the pembrolizumab 10 mg/kg arm, and 8.5 months in the docetaxel arm. 

The most common side effects of treatment with pembrolizumab included decreased appetite, fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dose and schedule of pembrolizumab for NSCLC is 200 mg intravenously every three weeks.

FDA granted pembrolizumab breakthrough therapy designation and priority review status, and previously granted accelerated approval. The current approval converts the prior accelerated approval in second-line treatment of metastatic NSCLC patients to regular approval. The application for the first-line indication was approved nearly three months before the PDUFA goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Tuesday, October 25, 2016 10:00 AM|Zhang, S., Anjum, R., Squillace, R., Nadworny, S., Zhou, T., Keats, J., Ning, Y., Wardwell, S. D., Miller, D., Song, Y., Eichinger, L., Moran, L., Huang, W.-S., Liu, S., Zou, D., Wang, Y., Mohemmad, Q., Jang, H. G., Ye, E., Narasimhan, N., Wang, F., Miret, J., Zhu, X., Clackson, T., Dalgarno, D., Shakespeare, W. C., Rivera, V. M.|Clinical Cancer Research Online First Articles|Labels: ALK, lung cancer

Purpose: Non–small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib.

Experimental Design: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib–ALK co-structure was determined.

Results: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.

Conclusion: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 1–12. ©2016 AACR.

Tuesday, October 25, 2016 9:00 AM|Anonymous|American Pharmacists Association - Improving medication use. Advancing patient care.|Comments|Labels: ALK, lung cancer

FDA has approved pembrolizumab (Keytruda—Merck) as a first-line treatment for certain lung cancer patients. The approval is for individuals with metastatic non-small cell lung cancer whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations. The new indication means that pembrolizumab can serve as an initial treatment, rather than chemotherapy for these patients. FDA also approved a pembrolizumab labeling update for second-line treatment for certain patients, following favorable data from the Keynote-010 trial.

Monday, October 24, 2016 6:52 PM|Onclive Lung Cancer Articles|Labels: ALK, lung cancer
The FDA has approved pembrolizumab (Keytruda) for the frontline treatment of patients with metastatic non­–small cell lung cancer whose tumors have ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations. 
 
Monday, October 24, 2016 6:04 PM|Business Wire Health: Pharmaceutical News|Attachments|Labels: ALK, lung cancer
KENILWORTH, N.J.--(BUSINESS WIRE)--$MRK #MRK--FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Metastatic NSCLC for First-Line Treatment of Patients Whose Tumors Have High PD-L1 Expression

Wednesday, October 19, 2016 9:00 AM|Anonymous|American Pharmacists Association - Improving medication use. Advancing patient care.|Comments|Labels: ALK, regulatory

FDA has approved atezolizumab (Tecentriq—Genentech) for the treatment of people with metastatic non-small cell lung cancer who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities. "Tecentriq is a new option to help people with this type of previously treated metastatic lung cancer, regardless of PD-L1 expression, live longer than chemotherapy," said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech.

Tuesday, October 18, 2016 5:22 PM|Christina Kelly|ASCO - FDA|Labels: ALK, EGFR, lung cancer, regulatory
October 18, 2016

On October 18, 2016, FDA approved atezolizumab (TECENTRIQ, Genentech Oncology) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab.

Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody that previously received FDA accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed after platinum-containing chemotherapy.  

This approval was based on two international, randomized, open-label clinical trials (OAK and POPLAR) that demonstrated consistent results in efficacy and safety in a total of 1137 patients with NSCLC. Compared with docetaxel, treatment with atezolizumab in the intended patient population in the two trials resulted in a 4.2 and a 2.9 month improvement in overall survival (OS), respectively. 

The median OS in OAK was 13.8 months (95% confidence interval [CI] 11.8,15.7) in the atezolizumab arm compared to 9.6 months (95% CI 8.6,11.2) in the docetaxel arm (hazard ratio [HR]=0.74 [95% CI 0.63,0.87]; p=0.0004). The median OS in POPLAR was 12.6 months (95% CI 9.7, 16.0) and 9.7 months (95% CI 8.6, 12.0) (HR=0.69 [95% CI 0.52, 0.92]) for the atezolizumab and docetaxel arms, respectively. 

The most common (greater than or equal to 20%) adverse reactions in patients in the primary safety analysis population (POPLAR trial) in patients treated with atezolizumab were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation. The most common (greater than or equal to 2%) grade 3-4 adverse events in patients treated with atezolizumab were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included pneumonitis, hepatitis, colitis, and thyroid disease.

The recommended atezolizumab dose is 1200 mg administered as an intravenous infusion over 60 minutes every three weeks until disease progression or unacceptable toxicity. 

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Tuesday, October 18, 2016 3:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: ALK, EGFR, PD-1/PD-L1, lung cancer, regulatory
The Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) said FDA approved PD-L1 inhibitor Tecentriq atezolizumab to treat non-small cell lung cancer in patients whose disease has progressed following platinum-containing chemotherapy, and with disease progression following treatment with a targeted therapy if their tumors have EGFR or anaplastic lymphoma kinase (ALK) mutations. In September, Genentech said Tecentriq met the co-primary endpoints of the Phase III OAK study to treat NSCLC (see BioCentury Extra, Sept. 1).PD-1 inhibitors Opdivo nivolumab from Bristol-Myers Squibb Co. (NYSE:BMY) and Keytruda pembrolizumab from Merck & Co. Inc. (NYSE:MRK) also have FDA approval in second-line NSCLC. Keytruda is approved only for patients who express PD-L1. Tecentriq also has accelerated approval from FDA to treat urothelial carcinoma.
Friday, October 14, 2016 9:32 AM|Skoulidis, F., Papadimitrakopoulou, V. A.|Clinical Cancer Research Online First Articles|Labels: ALK, lung cancer, regulatory

Over the last 2 years, our therapeutic armamentarium against genomically defined subgroups of non–small cell lung cancer (NSCLC) has extended to patients with acquired resistance to front-line targeted therapy. Alectinib (Alecensa; Roche/Genentech), a second-generation, orally active, potent, and highly selective inhibitor of anaplastic lymphoma kinase (ALK), is indicated for patients with metastatic, ALK rearrangement–positive NSCLC whose disease has worsened after treatment with crizotinib or who became intolerant to the drug. Alectinib received orphan drug designation, breakthrough therapy designation, priority review status, and accelerated approval by the FDA. Clin Cancer Res; 22(21); 1–6. ©2016 AACR.

Friday, October 14, 2016 9:32 AM|Larkins, E., Blumenthal, G. M., Chen, H., He, K., Agarwal, R., Gieser, G., Stephens, O., Zahalka, E., Ringgold, K., Helms, W., Shord, S., Yu, J., Zhao, H., Davis, G., McKee, A. E., Keegan, P., Pazdur, R.|Clinical Cancer Research Online First Articles|Labels: ALK, lung cancer, regulatory

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non–small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28–49] and 44% (95% CI, 36–53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46–74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit–risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 1–6. ©2016 AACR.

Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALK, lymphoma, clinical trial
This partially randomized phase II trial studies how well brentuximab vedotin or crizotinib and combination chemotherapy works in treating patients with newly diagnosed stage II-IV anaplastic large cell lymphoma. Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block cancer growth in different ways by targeting certain cells. Crizotinib and methotrexate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether brentuximab vedotin and combination chemotherapy is more effective than crizotinib and combination chemotherapy in treating anaplastic large cell lymphoma.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALK, lung cancer, clinical trial
This randomized phase III trial studies how well crizotinib works and compares it to placebo in treating patients with stage IB-IIIA non-small cell lung cancer that has been removed by surgery and has a mutation in a protein called ALK. Mutations, or changes, in ALK can make it very active and important for tumor cell growth and progression. Tumors with this mutation may respond to treatments that target the mutation, such as crizotinib. Crizotinib may stop the growth of tumor cells by blocking the ALK protein from working. It is not yet known if crizotinib may be an effective treatment for treating non-small cell lung cancer with an ALK fusion mutation.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALK, FAK, lung cancer, clinical trial, regulatory
This is a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment will be assessed in patients with NSCLC metastatic to the brain and/or to leptomeninges harboring a confirmed ALK rearrangement, assessed at a Novartis designated central laboratory, using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria).
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALK, clinical trial
This is an open-label, multicenter, global Phase 2 basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement. Patients will be assigned to different baskets according to tumor type and gene rearrangement. NSCLC and mCRC will be the main patient populations of interest
Wednesday, October 12, 2016 3:24 PM|Sofia Lampaki, George Lazaridis, Konstantinos Zarogoulidis, Ioannis Kioumis, Antonis Papaiwannou, Katerina Tsirgogianni, Anastasia Karavergou, Theodora Tsiouda, Vasilis Karavasilis, Lonny Yarmus, Kaid Darwiche, Lutz Freitag, Antonios Sakkas, Angeliki Kantzeli, Sofia Baka, Wolfgang Hohenforst-Schmidt, Paul Zarogoulidis|Journal of Cancer (RSS 2.0)|Labels: ALK, BRAF, EGFR, lung cancer, clinical trial

Historical, the non-small cell lung cancer (NSCLC) was as a united disease entity and the chemotherapy to the metastatic cancer had limited results. Recent studies for the metastatic non-small cell lung cancer led to the ascertainment that the NSCLC does not constitute exclusively a disease entity, but different neoplasms guided from different molecular paths, different biological behavior and at extension requires different confrontation. Thus the new direction for the therapeutic approach of NSCLC is henceforth the most individualized approach based on the activated molecular paths of tumor. Distinct subtypes of NSCLC are driven by a specific genetic alteration, like EGFR, ALK, ROS1 or BRAF mutations, and these genetic alterations are sensitized to the inhibition of specific oncogenic pathways. The benefit from the use of tyrosine kinase inhibitors in patients with EGFR mutations it was confirmed by six randomized studies of phase III that investigated the role of gefitinib, erlotinib and afatinib. In these studies the response rates vary in the impressive percentages from 55% to 86% and were connected with a remarkable median progression free survival of approximately 8 to 13 months, and with better quality of life compared to that of chemotherapy. In early stages NSCLC is needed the individualization of systemic treatment in order to reduce toxicity that is observed in the classic chemotherapy and to impact outcome. The role of EGFR TKI's has been evaluated in the adjuvant chemotherapy in early stage resected NSCLC. The data from these studies suggest that adjuvant TKI therapy might not increase the overall survival, but delay the recurrences. Prospective trials restricted to EGFR or ALK driven NSCLC subsets potentially offering the opportunity for a definitive answer in early disease adjuvant setting (ALCHEMIST) or as induction treatment before stage III chemo-radiotherapy (RTOG 1210/Alliance 31101), are ongoing. Ongoing prospective trials may offer the opportunity for a definitive answer of the role of tyrosine kinase inhibitors in induction treatment before chemo-radiotherapy or in early disease adjuvant therapy.

Wednesday, October 12, 2016 3:24 PM|Lara Mussolin, Roberta Burnelli, Marta Pillon, Elisa Carraro, Piero Farruggia, Alessandra Todesco, Maurizio Mascarin, Angelo Rosolen|Journal of Cancer|Labels: ALK, ALL, lymphoma, biomarker diagnostic, HL

Background: Extracellular circulating DNA (cfDNA) can be found in small amounts in plasma of healthy individuals. Increased levels of cfDNA have been reported in patients with cancer of breast, cervix, colon, liver and it was shown that cfDNA can originate from both tumour and non-tumour cells.

Objectives: Levels of cfDNA of a large series of children with lymphoma were evaluated and analyzed in relation with clinical characteristics.

Methods: plasma cfDNA levels obtained at diagnosis in 201 paediatric lymphoma patients [43 Hodgkin lymphomas (HL), 45 anaplastic large cell lymphomas (ALCL), 88 Burkitt lymphomas (BL), 17 lymphoblastic (LBL), 8 diffuse large B cell lymphoma (DLBCL)] and 15 healthy individuals were determined using a quantitative PCR assay for POLR2 gene and, in addition, for NPM-ALK fusion gene in ALCL patients. Wilcoxon rank sum test was used to compare plasma levels among different patient subgroups and controls and to analyze relationship between levels of cfDNA and clinical characteristics.

Results: Levels of cfDNA in lymphoma patients were significantly higher compared with controls (p<0.0001). CfDNA was associated with median age (p=0.01) in HL, and with stage in ALCL (p=0.01). In HL patients high cfDNA levels were correlated with poor prognosis (p=0.03). In ALCL we found that most of the cfDNA (77%) was non-tumor DNA.

Conclusion: level of plasma cfDNA might constitute an important non-invasive tool at diagnosis in lymphoma patients' management; in particular in patients with HL, cfDNA seems to be a promising prognostic biomarker.

Wednesday, October 12, 2016 3:23 PM|Oncology|Labels: ALK, FAK, lung cancer, regulatory
Non–small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.
Wednesday, October 12, 2016 2:58 PM|Onclive Lung Cancer Articles|Labels: ALK, lung cancer
Ranee Mehra, MD, provides an overview of ALK inhibition in non–small cell lung cancer, an observation of the most common treatment-related adverse events, and what impact in-development agents will likely have on the expanding field.
Tuesday, October 11, 2016 3:00 AM|Lung Cancer News From Medical News Today|Labels: ALK, FAK, lung cancer, clinical trial
Ceritinib provides longer progression-free survival than chemotherapy in crizotinib-pre-treated patients with non-small-cell lung cancer harbouring an ALK rearrangement, according to results of the...
Sunday, October 9, 2016 3:41 PM|Onclive Lung Cancer Articles|Labels: ALK, FAK, lung cancer
Progression-free survival was more than 3 times longer with ceritinib (Zykadia) than with chemotherapy, the current second-line standard, in patients with advanced ALK-positive non–small cell lung cancer who progressed after first-line crizotinib.
Thursday, October 6, 2016 8:00 PM|Cancer Research UK|Cancer Research UK News|Labels: ALK, clinical trial

Science blog

Every year in the UK around 1,600 children are diagnosed with cancer, and thanks to research, the number of children surviving their disease has tripled since the 1960s.

But there are still some types of childhood cancer where survival is still simply not good enough.

One of these is neuroblastoma – a disease that affects around 100 children a year in the UK.

It usually affects children under the age of five, developing from nerve cells and is usually first found in the abdomen.

But once diagnosed, a child’s prospects of a successful recovery can vary considerably. The disease develops as low, intermediate or high risk depending on the aggressiveness of the tumour.

Children with the low risk form, who are often babies, are usually cured with surgery or a small amount of chemotherapy – sometimes the cancer even regresses on its own.

But more than half are diagnosed with the high risk form, where the tumour has already spread in children over the age of 18 months or there are key genetic changes inside the tumour. This type of disease either doesn’t respond to treatment, or more commonly responds initially and then comes back within just a couple of years.

Another 10 per cent of children with neuroblastoma will have the intermediate risk disease, and doctors are still working out how best to treat this type.

This variability can make it difficult for doctors to assess each childs’ needs, and emphasises the importance of research into how different types of neuroblastoma respond to treatment.

And a study published by a team of our scientists this week points to some possible answers.

A complex cancer

The study included data from 189 patients. And it looked at how children with neuroblastoma that has come back – called a relapse – responded to treatment over a 20-year period across four hospitals in the UK.

These four hospitals, The Royal Victoria Infirmary, Newcastle, Leeds Teaching Hospitals NHS Trust, The Royal Manchester Children’s Hospital and The Royal Marsden Hospital, treat around 1 in 3 neuorblastoma patients in the UK.

A relapse occurs when the disease comes back in a new location or the original tumour grows again after initially responding to treatment.

And since the study only looked at children whose neuroblastoma had come back, the vast majority (159 out of 189) of these cases were defined as high risk, while 24 were of intermediate risk.

The researchers found that, despite some improvements in treatment over the last 10-20 years, survival for children with relapsed, high risk neuroblastoma remains very low.

Around the year 2000, high risk patients began being treated more intensively with more different types of treatment, raising the average survival after relapse from 2.9 months to 8.4 months.

But fewer than 1 in 10 of these children survived more than five years.

The researchers found similar survival rates in other countries, demonstrating that getting more effective treatments to high risk relapsing neuroblastoma patients is a truly global problem.

Of the children with a particular type of intermediate risk disease, only 1 in 4 survived after relapse. Even those who had gruelling treatment after their cancer relapsed sadly still lost their lives.

If doctors could be confident which patients in this particular subgroup of intermediate risk neuroblastoma were likely to relapse, then providing more intense treatment upfront could potentially save these children.

Professor Deborah Tweddle, lead author on the study from the Northern Institute for Cancer Research at Newcastle University, thinks it’s essential that doctors and researchers focus their efforts on the underlying biology of the disease to help determine the best treatment for each child.

“For too long outcomes for high-risk relapsed neuroblastoma have been unacceptably poor,” she says. “We must do better.”

“While we have made some progress for these children, it’s only through clinical trials that we can determine which therapies are most effective.

“Once we master the complexity of the disease we can begin to personalise treatment for each child.”

What makes neuroblastoma aggressive?

One of the biggest influences on the likelihood of  neuroblastoma responding to treatment is whether or not the cancer cells contain multiple copies of a gene called MYCN.

The molecule produced by the gene sends a signal telling the cell to grow. But when too much is made – in the case of a cell that carries extra copies of the gene – the cell grows uncontrollably, leading to cancer.

Researchers have known for decades now that too much MYCN leads to a more aggressive form of neuroblastoma. But there hasn’t been an easy way for them to tackle the excess – many believe the molecule produced by the gene is ‘undruggable’.

On top of this, flaws in another molecule, called anaplastic lymphoma kinase (ALK), can also give rise to neuroblastoma tumours in around 10 per cent of cases.

Fortunately, drugs have been developed that directly target cancers with this faulty molecule, but clinical trials are still needed to identify which patients are likely to benefit from these treatments.

Neuroblastoma can also be caused by physical breakages in the organised packages of DNA held within a cell – so-called chromosomal abnormalities. And these can result in the loss of large regions of DNA, causing faults in the cell that can lead to cancer.

Other biological factors that contribute to the aggressiveness of the tumour include how old the child is at diagnosis, whether the disease has already spread and what the tumour looks like under a microscope.

Overall, this complex combination of factors is used to assign a child to a particular risk group. But doctors aren’t yet able to predict who can be cured. Too little treatment for patients in this group and the cancer could come back, while too much treatment risks serious life-long side effects.

So what can be done?

A collective effort

Neuroblastoma is a complex, highly variable cancer, responsible for around 15 per cent of all childhood cancer deaths.

And researchers have a lot of work to do to bring survival up in line with other childhood cancers.

But as scientists understand what is going on ‘beneath the hood’ of the disease, more treatment options are becoming available and clinicians can be more targeted in their approach.

Studies such as the one published this week highlight how patients with relapsed neuroblastoma are being managed today, providing a baseline for which new therapies can be measured.

“I often think of parents of children with cancer sitting in the wards waiting while their children are having treatment,” says Professor Tweddle. “Many of these will have leukaemia, where survival is close to 90 per cent. And the parents of neuroblastoma patients will rightfully be wondering why the outlook for their children’s cancer seem so far behind.”

“The truth is we are getting there. Scientists around the world are combining their knowledge of the disease to unpick which patient’s tumours have weakness we can exploit.”

And the good news is that new therapies are being tested in the lab and in early phase clinical trials.

We’re supporting several trials to develop better treatments for relapsed neuroblastoma.

And new treatments that harness the power of the immune system, target the specific genetic faults driving the disease, or more effective combinations of treatments are all being investigated by researchers.

Finding out which are the most effective and against which types of neuroblastoma is the task ahead.

But with more research and faster, more accurate diagnostics, doctors will be better placed to give the right treatments to the right patients when they need it most.

Alan

Read more
Wednesday, October 5, 2016 6:00 AM|Breaking World Pharma News|Labels: ALK, lung cancer, regulatory
RocheRoche (SIX: RO, ROG; OTCQX: RHHBY) has received a second Breakthrough Therapy Designation (BTD) from the United States Food and Drug Administration (FDA) for its ALK inhibitor, Alecensa (alectinib). The latest BTD was granted for the treatment of adult patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have not received prior treatment with an ALK inhibitor.
Tuesday, October 4, 2016 11:50 AM|Onclive Lung Cancer Articles|Labels: ALK, lung cancer, regulatory
The FDA has granted a breakthrough therapy designation to alectinib (Alecensa) as a frontline treatment for patients with ALK-positive non–small cell lung cancer.
Monday, October 3, 2016 12:05 AM|Gainor, J. F., Dardaei, L., Yoda, S., Friboulet, L., Leshchiner, I., Katayama, R., Dagogo-Jack, I., Gadgeel, S., Schultz, K., Singh, M., Chin, E., Parks, M., Lee, D., DiCecca, R. H., Lockerman, E., Huynh, T., Logan, J., Ritterhouse, L. L., Le, L. P., Muniappan, A., Digumarthy, S., Channick, C., Keyes, C., Getz, G., Dias-Santagata, D., Heist, R. S., Lennerz, J., Sequist, L. V., Benes, C. H., Iafrate, A. J., Mino-Kenudson, M., Engelman, J. A., Shaw, A. T.|Cancer Discovery recent issues|Labels: ALK, FAK, lung cancer

Advanced, anaplastic lymphoma kinase (ALK)–positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118–33. ©2016 AACR.

See related commentary by Qiao and Lovly, p. 1084.

This article is highlighted in the In This Issue feature, p. 1069

Monday, October 3, 2016 12:05 AM|Qiao, H., Lovly, C. M.|Cancer Discovery recent issues|Labels: ALK, lung cancer

Summary: In the setting of recent exciting clinical results and numerous ongoing trials, Gainor and colleagues explored mechanisms of acquired resistance to first- and second-generation ALK inhibitors in ALK-rearranged non–small cell lung cancer and found that an increased frequency and distinct spectrums of resistance mutations emerged with the more potent second-generation inhibitors. Their findings have important and immediate clinical implications as the resistance mutations detected impart differential sensitivities to available ALK inhibitors, thereby highlighting the need for sequential biopsies with molecular testing to determine the most effective treatment strategy upon disease progression. Cancer Discov; 6(10); 1084–6. ©2016 AACR.

See related article by Gainor et al., p. 1118.

Saturday, October 1, 2016 1:00 AM|Agaram, Narasimhan P.; Zhang, Lei; Sung, Yun-Shao; Chen, Chun-Liang; Chung, Catherine T.; Antonescu, Cristina R.; Fletcher, Christopher DM|The American Journal of Surgical Pathology - Current Issue|Labels: ALK
imageThe family of pediatric fibroblastic and myofibroblastic proliferations encompasses a wide spectrum of pathologic entities with overlapping morphologies and ill-defined genetic abnormalities. Among the superficial lesions, lipofibromatosis (LPF), composed of an admixture of adipose tissue and fibroblastic elements, in the past has been variously classified as infantile fibromatosis or fibrous hamartoma of infancy. In this regard, we have encountered a group of superficial soft tissue tumors occurring in children and young adults, with a notably infiltrative growth pattern reminiscent of LPF, variable cytologic atypia, and a distinct immunoprofile of S100 protein and CD34 reactivity, suggestive of neural differentiation. SOX10 and melanocytic markers were negative in all cases tested. In contrast, a control group of classic LPF displayed bland, monomorphic histology and lacked S100 protein immunoreactivity. To define the pathogenetic abnormalities in these seemingly distinctive groups, we performed RNA sequencing for fusion gene discovery in 2 cases each, followed by screening for any novel alterations identified in a larger cohort representing both entities. The 2 index LPF-like neural tumors (LPF-NT) showed TPR-NTRK1 and TPM3-NTRK1 gene fusions, which were further validated by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction. Subsequent FISH screening of 14 LPF-NT identified recurrent NTRK1 gene rearrangements in 10 (71%) cases. Of the NTRK1-negative LPF-NT cases, 1 case each showed ROS1 and ALK gene rearrangements. In contrast, none of the 25 classic LPFs showed NTRK1 gene rearrangements, although regional abnormalities were noted in the 1q21-22 region by FISH in a majority of cases. Furthermore, NTRK1 immunostaining was positive only in NTRK1-rearranged S100-positive LPF-NT but negative in classic LPF. These results suggest that NTRK1 oncogenic activation through gene fusion defines a novel and distinct subset of soft tissue tumors resembling LPF, but displaying cytologic atypia and a neural immunophenotype, provisionally named LPF-like neural tumors.
Saturday, October 1, 2016 1:00 AM|Zito Marino, Federica; Morabito, Alessandro; Gridelli, Cesare; Rocco, Gaetano; Liguori, Giuseppina; De Rosa, Nicla; Botti, Gerardo; Franco, Renato|Applied Immunohistochemistry & Molecular Morphology - Current Issue|Labels: ALK, lung cancer
imageAnaplastic lymphoma kinase (ALK) rearrangement is a therapeutic target in non–small cell lung cancer. To date, few reports have been provided related to ALK-rearranged late recurrence and sensitivity to the treatment with specific ALK inhibitors. We report a case of a 35-year-old man who underwent a right lower lobe lobectomy for lung adenocarcinoma, and treated with the platinum-based chemotherapy regimen. After 10 healthy years, he developed a lung nodule in the same site as the previous. Cytopathologic diagnosis was lung adenocarcinoma. Furthermore, the pulmonary nodule was considered a late recurrence in relation to the lymph node involvement, the same histotype and the site, ALK fluorescence in situ hybridization test and epidermal growth factor receptor analysis were performed on the formalin-fixed paraffin-embedded specimens of the previous resected tumor, because of inadequacity cytologic sample. Being positive for ALK rearrangement, the patient was treated with crizotinib with a good response. To the best of our knowledge, it is the first case of a late relapse of ALK-positive lung adenocarcinoma sensitive to crizotinib in the literature.
Thursday, September 15, 2016 9:42 AM|Gainor, J. F., Shaw, A. T., Sequist, L. V., Fu, X., Azzoli, C. G., Piotrowska, Z., Huynh, T. G., Zhao, L., Fulton, L., Schultz, K. R., Howe, E., Farago, A. F., Sullivan, R. J., Stone, J. R., Digumarthy, S., Moran, T., Hata, A. N., Yagi, Y., Yeap, B. Y., Engelman, J. A., Mino-Kenudson, M.|Clinical Cancer Research recent issues|Labels: ALK, EGFR, PD-1/PD-L1, lung cancer

Purpose: PD-1 inhibitors are established agents in the management of non–small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients.

Experimental Design: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TIL) were evaluated by IHC.

Results: Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre–tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI–resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8+ TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens.

Conclusions: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585–93. ©2016 AACR.

See related commentary by Gettinger and Politi, p. 4539

Thursday, September 15, 2016 9:42 AM|Gettinger, S., Politi, K.|Clinical Cancer Research recent issues|Labels: ALK, EGFR, PD-1/PD-L1, lung cancer

Programmed death axis 1 (PD-1) inhibitors have ushered in a new error of cancer immunotherapeutics for advanced smoking-associated non–small cell lung cancer. Their role in treating EGFR-mutant and ALK-rearranged lung cancer has yet to be determined. Clin Cancer Res; 22(18); 4539–41. ©2016 AACR.

See related article by Gainor et al., p. 4585

Thursday, September 1, 2016 2:33 AM|PBR - Regulatory Affairs News|Labels: ALK, lung cancer, regulatory
Pfizer has secured approval from the European Commission (EC) for Xalkori (crizotinib) to treat adults with ROS1-positive advanced non-small cell lung cancer (NSCLC).
Thursday, September 1, 2016 12:05 AM|Evageliou, N. F., Haber, M., Vu, A., Laetsch, T. W., Murray, J., Gamble, L. D., Cheng, N. C., Liu, K., Reese, M., Corrigan, K. A., Ziegler, D. S., Webber, H., Hayes, C. S., Pawel, B., Marshall, G. M., Zhao, H., Gilmour, S. K., Norris, M. D., Hogarty, M. D.|Clinical Cancer Research recent issues|Labels: ALK

Purpose: Deregulated MYC drives oncogenesis in many tissues yet direct pharmacologic inhibition has proven difficult. MYC coordinately regulates polyamine homeostasis as these essential cations support MYC functions, and drugs that antagonize polyamine sufficiency have synthetic-lethal interactions with MYC. Neuroblastoma is a lethal tumor in which the MYC homologue MYCN, and ODC1, the rate-limiting enzyme in polyamine synthesis, are frequently deregulated so we tested optimized polyamine depletion regimens for activity against neuroblastoma.

Experimental Design: We used complementary transgenic and xenograft-bearing neuroblastoma models to assess polyamine antagonists. We investigated difluoromethylornithine (DFMO; an inhibitor of Odc, the rate-limiting enzyme in polyamine synthesis), SAM486 (an inhibitor of Amd1, the second rate-limiting enzyme), and celecoxib (an inducer of Sat1 and polyamine catabolism) in both the preemptive setting and in the treatment of established tumors. In vitro assays were performed to identify mechanisms of activity.

Results: An optimized polyamine antagonist regimen using DFMO and SAM486 to inhibit both rate-limiting enzymes in polyamine synthesis potently blocked neuroblastoma initiation in transgenic mice, underscoring the requirement for polyamines in MYC-driven oncogenesis. Furthermore, the combination of DFMO with celecoxib was found to be highly active, alone, and combined with numerous chemotherapy regimens, in regressing established tumors in both models, including tumors harboring highest risk genetic lesions such as MYCN amplification, ALK mutation, and TP53 mutation with multidrug resistance.

Conclusions: Given the broad preclinical activity demonstrated by polyamine antagonist regimens across diverse in vivo models, clinical investigation of such approaches in neuroblastoma and potentially other MYC-driven tumors is warranted. Clin Cancer Res; 22(17); 4391–404. ©2016 AACR.

Thursday, September 1, 2016 12:05 AM|Pietrantonio, F., Oddo, D., Gloghini, A., Valtorta, E., Berenato, R., Barault, L., Caporale, M., Busico, A., Morano, F., Gualeni, A. V., Alessi, A., Siravegna, G., Perrone, F., Di Bartolomeo, M., Bardelli, A., de Braud, F., Di Nicolantonio, F.|Cancer Discovery recent issues|Labels: ALK, BRAF, EGFR, CRC

A patient with metastatic BRAF-mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Pre-existing cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplification in the rebiopsy taken at progression. In BRAF-mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK–MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical efficacy of anticancer agents, the identification of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefit.

Significance: MET amplification is here identified—clinically and preclinically—as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF-mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefit after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9); 963–71. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 932

Thursday, September 1, 2016 12:05 AM|Unknown Author|Cancer Discovery recent issues|Labels: ALK, FAK, lung cancer

Ceritinib produces durable responses in heavily pretreated patients who progressed on crizotinib.

Wednesday, August 31, 2016 7:00 AM|Unknown Author|Press Release|Labels: ALK, lung cancer, biomarker diagnostic, regulatory
Dateline City:
NEW YORK

XALKORI is the first and only approved biomarker-driven therapy for ROS1-positive advanced NSCLC in the EU

NEW YORK--(BUSINESS WIRE)--Pfizer Inc. (NYSE:PFE) today announced that the European Commission has approved XALKORI® (crizotinib) for the treatment of adults with ROS1-positive advanced non-small cell lung cancer (NSCLC). In the European Union (EU), XALKORI is also indicated for treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced NSCLC. In March of this year, XALKORI was approved by the United States (U.S.) Food and Drug Administration for patients with metastatic NSCLC whose tumors are ROS1-positive.

Language:
English
Contact:

Pfizer Inc.
Media:
Lisa O’Neill, +44 1737 331536
or
Investors:
Ryan Crowe, 212-733-8160

Ticker Slug:
Ticker:
PFE
Exchange:
NYSE
ISIN:
US7170811035

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Friday, August 26, 2016 11:45 PM|Toyoaki Hida, Kazuhiko Nakagawa, Takashi Seto, Miyako Satouchi, Makoto Nishio, Katsuyuki Hotta, Toshiaki Takahashi, Yuichiro Ohe, Koji Takeda, Masahiro Tatsuno, Takashi Asakawa, Tadashi Shimada, Tomohiro Tanaka, Tomohide Tamura|Cancer Science|Labels: ALK, lung cancer
We report pharmacokinetics, efficacy, and safety data for a new 150 mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naïve and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40 mg and 150 mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg versus 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1−15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast ± standard deviation 3230 ± 914 h•ng/mL versus 3710 ± 1040 h•ng/mL, respectively, for 150 mg versus 20/40 mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1−2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), overall response rate was 70.0% (95% CI 50.6−85.3) and 65.0% (95% CI 40.8−84.6), and median progression-free survival was 13.9 months (95% CI 11.1−not reached) and 12.9 months (95% CI 3.9−not reached), respectively. The 150 mg capsule had a similar exposure profile to 20/40 mg capsules. Alectinib demonstrated promising efficacy and was well tolerated. This article is protected by copyright. All rights reserved.
Monday, August 15, 2016 12:05 AM|Shaver, T. M., Lehmann, B. D., Beeler, J. S., Li, C.-I., Li, Z., Jin, H., Stricker, T. P., Shyr, Y., Pietenpol, J. A.|Cancer Research recent issues|Labels: ALK, breast cancer
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency “driver” alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3–TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1. The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850–60. ©2016 AACR.
Monday, August 15, 2016 12:05 AM|Jen, J., Mansfield, A., Eiken, P. W., Stoddard, S., Pierson, K., Hou, X., Ren, H. Z., Molina, J., Yi, J., Yang, P.|Clinical Cancer Research recent issues|Labels: ALK, EGFR, FAK, lung cancer, biomarker diagnostic

Mutations in the EGFR gene or transcript fusion involving EML4-ALK result in oncogenic activation of these oncogenes driving lung adenocarcinoma growth in tumors carrying such an alteration. For lung adenocarcinoma with these genetic changes, small-molecule tyrosine kinase inhibitors have been highly effective at reducing tumor burden and improve the outcome of the patients. Unfortunately, drug resistance eventually develops in these tumors and challenges remain in controlling lung cancer recurrence after targeted therapy.

To overcome recurrence, we initiated a prove-of-principle study to evaluate the feasibility of an integrated strategy utilizing genomic profiles of the tumor and patient-specific tumor xenografts derived (PDX) from biopsies for ex vivo evaluation of antitumor drugs to help guide personalized treatment of lung cancer in patients who have developed resistance to targeted therapy drugs. Our study has three main objectives. 1) Use tumor biopsies obtained at the time of recurrence for oncogene mutation and RNAseq analyses to identify molecular changes in oncogenes and gene pathways that can be potentially targeted. 2) Evaluate drug efficacy and optimize personalized therapy for each patient using PDX models. 3) Assess clinical feasibility and our experience using integrated approaches for lung cancer patients who failed targeted therapy.

This study was approved by the Mayo Clinic Institutional Review Board (IRB) and utilizes both clinical and research biopsies. A dedicated nurse study coordinator reviews clinical patient list and history on weekly basis and informs the study team of each potential candidate patient. A total of 30 patients having ALK positive lung cancers have been identified and followed up from nearly 500 potentially ALK positive cases between April 2014 to Sept. 2015. Most patients were never smokers but six were former smokers and two were current smokers. Age at diagnoses ranged from 27-78 years (median = 61). Seven patients (23%) were 45 years or younger at the time of diagnosis. A total of 22 patients are currently being treated with crizotinib while eight are on ceritinib or alectinib. For each biopsy, tumor tissues are obtained using a 20 gauge needle, transferred on ice in preserving media and implanted within one hour into 6-8 week old NOD/SCID mice. Many patients have been on treatment for 2-3 years with stable disease so they do not require biopsy. Using a similar strategy, we also obtained biopsies from patients with EGFR gene mutations in their tumors and have progressed while on targeted therapy.

A total of seven cases have been implanted. We will report our experiences in patient selection, clinical follow up, patient consent, PDX development, time from biopsy to tumor establishment, and the results of molecular analyses. Our study enabled us to gain new insights regarding the molecular changes associated with recurring tumors after they have failed targeted therapy as well as clinical experiences on how to utilize state-of-the art approaches and comprehensive genomic information to further improve cancer patient care upon disease progression.

Acknowledgements: This work is supported in part by the Hillsberg Award from the National Foundation for Cancer Research and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine.

Citation Format: Jin Jen, Aaron Mansfield, Patrick W. Eiken, Shawn Stoddard, Karlyn Pierson, Xiaonan Hou, Hong Zheng Ren, Julian Molina, Joanne Yi, Ping Yang. Integrated Approaches to Treating Lung Adenocarcinoma Resistant to Targeted Therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B34.

Monday, August 15, 2016 12:05 AM|Houghton, P. J., Kurmasheva, R. T.|Clinical Cancer Research recent issues|Labels: ALK, aurora, BRAF, FLT, PLK, biomarker diagnostic

The Pediatric Preclinical Testing Program (PPTP) has evaluated almost 97 single agents and several combinations over the last 10 years. A total of 89 xenograft models that encompass solid tumors, brain tumors, and acute leukemias have been used as a screen to identify novel agents that could be accelerated for clinical trial. With few exceptions, all models were directly established in mice from patient biopsies, and approximately half of the models were established from patients who were refractory or had relapsed.

Expression analysis showed that tumor models clustered with their appropriate clinical histotype, and exome sequencing showed mutation frequency and identity to be similar to published genomic data for patient cancers. The models accurately identified known active agents that are used as standard of care therapy for solid tumors and leukemias, thus validating the models.

Criteria for assessing response similar to clinical criteria were developed. Of the 97 agents tested, twenty-four signaling inhibitors (ligand or receptor binding antibodies, kinase inhibitors etc.) were evaluated. With the exception of inhibitors of Aurora kinase A, and Polo-like kinase 1, the overall objective response rate (ORR) was <2%. The low response rate is probably an accurate reflection of likely ORR in clinical trials, as the models identified selumetinib in an astrocytoma with BRAF (V600E) mutation, dasatinib in a Ph+ ALL, sorafenib in a Flt3 mutant ALL, and crizotinib in an ALK mutant neuroblastoma.

The models identified several cytotoxic agents as having broad-spectrum antitumor activity (eribulin, alisertib, PR-104), with small molecule and antibody conjugated antimitotic agents showing high-level activity in many models (eribulin in sarcoma and ALL, glembatumab in osteosarcoma). The major issue is that the models overpredict drug activity due to tolerance of the host (mouse) compared to patients. Thus, it is imperative to adjust dose/schedule to accurately reproduce clinical exposures.

Another issue to be addressed is whether the models adequately encompass genomic and epigenomic heterogeneity. With increasing evidence of molecular subtypes within histotypes previously considered as relatively homogeneous, it is clear that additional models need to be established. We have analyzed 2134 tumor/drug studies undertaken as part of the PPTP to determine whether alternative experimental designs can be used that would allow an increased genomic diversity to be interrogated using current resources.

Citation Format: Peter J. Houghton, Raushan T. Kurmasheva. Promise and challenges of pediatric cancer PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA15.

Tuesday, August 2, 2016 12:05 AM|Unknown Author|Cancer Discovery recent issues|Labels: ALK, lung cancer, clinical trial

Data from a phase I study indicate that the investigational ALK inhibitor lorlatinib is active in patients with ALK- or ROS1-positive non–small cell lung cancer, including those with brain metastases. Objective responses were seen among patients with known ALK resistance mutations who had relapsed following treatment with other tyrosine kinase inhibitors.

Monday, July 11, 2016 3:55 PM|Facchinetti, F., Loriot, Y., Cassin-Kuo, M.-S., Mahjoubi, L., Lacroix, L., Planchard, D., Besse, B., Auger, N., Farace, F., Remon, J., Scoazec, J.-Y., Andre, F., Soria, J.-C., Friboulet, L.|Clinical Cancer Research Online First Articles|Labels: ALK, EGFR, FAK, lung cancer

Background: The identification of molecular mechanisms conferring resistance to Tyrosine Kinase Inhibitor (TKIs) is a key-step to improve therapeutic results for patients with oncogene-addiction. Several alterations leading to Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far. Methods: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (Whole exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations. Results: Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations. Conclusions: Clinical evidence, in vitro validation and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib.

Friday, July 1, 2016 9:56 AM|Chong, C. R., Bahcall, M., Capelletti, M., Kosaka, T., Ercan, D., Sim, T., Sholl, L. M., Nishino, M., Johnson, B. E., Gray, N. S., Janne, P. A.|Clinical Cancer Research Online First Articles|Labels: ALK, MET, VEGF, lung cancer, regulatory

Purpose: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1- and ROS1-rearrangements, are complicated by the cost and protracted timeline of drug discovery. Experimental design: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes. Results: This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nM, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nM, respectively), entrectinib (IC50 = 6/2,200 /3,500 nM), and PF-06463922 (IC50 = 1/270/2 nM). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924, potently inhibited CD74-NTRK1 transformed compared to parental Ba/F3 cells (IC50 = 19 nM vs. > 470 nM). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response. Conclusions: While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance, and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib.

Monday, June 27, 2016 12:52 PM|TASAKI, T., FUJITA, M., OKUDA, T., YONESHIGE, A., NAKATA, S., YAMASHITA, K., YOSHIOKA, H., IZUMOTO, S., KATO, A.|Anticancer Research recent issues|Labels: ALK, brain cancer

Background: Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the proto-oncogene mesenchymal–epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM. Patients and Methods: To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo. Results: Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs. Conclusion: Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.

Wednesday, June 8, 2016 12:24 PM|Wang, E., Nickens, D. J., Bello, A., Khosravan, R., Amantea, M., Wilner, K., Parivar, K., Tan, W.|Clinical Cancer Research Online First Articles|Labels: ALK, lung cancer

Purpose:We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area-under-the-curve at steady state (AUCss) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer. Experimental Design:A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P{less than or equal to}0.001) by evaluating their effects on CL/F and V2/F and estimated their magnitudes. Results:Age, Eastern Cooperative Oncology Group performance status, aspartate aminotransferase (AST) levels, albumin levels, and smoking status had no effect on CL/F or V2/F. Statistically significant covariates were Asian race and female sex for CL/F and V2/F and body weight, creatinine clearance (CLcr), and total bilirubin for CL/F only. The model predicted that CL/F would be 9% lower or higher in a 40-kg or a 100-kg patient, respectively; 16% lower in patients with CLcr 30 mL/min; 23% lower in Asians; and 11% lower in females than the reference patient (65-kg non-Asian male; baseline CLcr, 91.6 mL/min; total bilirubin, 0.41 mg/dL). The effect of total bilirubin on CL/F was small. V2/F was 23% lower in Asians than non-Asians and females than males. Effects of all significant covariates on AUCss were not predicted to be clinically relevant. Conclusions:Crizotinib at a 250-mg twice-daily starting dose appears to be appropriate for all patients irrespective of age, sex, race, body weight, mild or moderate renal impairment, or hepatic function (in the range evaluated: bilirubin {less than or equal to}2.1 mg/dL or AST {less than or equal to}124 U/L).

Monday, March 21, 2016 12:47 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3-15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0-2 cells/1.88 mL of blood). The latter range was validated as the 'false positive' cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential C...
Saturday, March 19, 2016 11:00 PM|Chinese Journal of Lung Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Conclusion The clinical features, efficacy, and adverse events of crizotinib in the treatment of the 40 patients with ALK/ROS1-positive NSCLC are similar to the data from the previous reports. The most common site of progression was brain metastases. The treatment of crizotinib-resistant patients using 2nd/3rd generation ALK-TKI could delay progression. DOI: 10.3779/j.issn.1009-3419.2016.03.07 (Source: Chinese Journal of Lung Cancer)
Saturday, March 19, 2016 12:51 PM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, lung cancer
CONCLUSION: Fifty eight percent of patients wild type by standard testing for EGFR/KRAS/ALK have GAs identifiable by CGP that suggest benefit from target therapy. CGP used when standard molecular testing for NSCLC is negative can reveal additional avenues of benefit from targeted therapy. PMID: 26992220 [PubMed - as supplied by publisher] (Source: Oncotarget)
Saturday, March 19, 2016 12:51 PM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, lung cancer
CONCLUSIONS: This is the largest three gene molecular epidemiology study in East Asian NSCLC patients. Each genetic alteration was associated with distinct clinicopathologic characteristics. Furthermore, different age and sex are associated with different subtypes of EGFR and KRAS mutations. PMID: 26992209 [PubMed - as supplied by publisher] (Source: Oncotarget)
Friday, March 18, 2016 7:00 PM|Medicine|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, FAK, lung cancer
Lung cancer is a heterogeneous group of diseases at both the histopathological and molecular levels. Individual treatment plans should be based on the histological and molecular characteristics of the tumour as well as the stage of disease at diagnosis, performance status and co-morbidities. Surgery, chemotherapy including maintenance therapies, targeted therapies, radiotherapy and palliative care all have a role in the management of patients with lung cancer, depending on stage. Recent advances in non-small cell lung cancer (NSCLC) include the use of stereotactic radiotherapy for patients with medically inoperable stage 1 NSCLC, routine anaplastic lymphoma kinase testing and licensing for crizotinib and ceritinib, and licensing of nivolumab immunotherapy. (Source: Medicine)
Friday, March 18, 2016 9:21 AM|Pneumologie|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Authors: von Laffert M, Schirmacher P, Warth A, Weichert W, Büttner R, Huber RM, Wolf J, Griesinger F, Dietel M, Grohé C Abstract The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as tyrosine kinase inhibitors directed against the EML4-ALK signalling pathway lead to improved progression free and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify the patients in time. While FISH techniques have been implemented to characterize this translocation for some time, the implementation of this testing is hampered by its broad use of r...
Monday, March 14, 2016 7:00 PM|Pharmaceutical Technology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, regulatory
Pfizer has received approval from the US Food and Drug Administration (FDA) for a supplemental new drug application (sNDA) for Xalkori (crizotinib) to treat patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC). (Source: Pharmaceutical Technology)
Monday, March 14, 2016 2:13 PM|American Cancer Society :: News and Features|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, regulatory
By Stacy SimonThe US Food and Drug Administration (FDA) has approved the first treatment for people with advanced, ROS1-positive non-small cell lung cancer. These tumors have a mutation in the ROS1 gene that affects only about 1% of people with non-small cell lung cancer. Many people with this type of lung cancer tend to be younger than the average lung cancer patient and are less likely to have been smokers.The drug, Xalkori (crizotinib), was previously approved for patients with advanced non-small cell lung cancer that has a mutation in a gene called ALK. It’s a targeted therapy that works by blocking the changes in the lung cancer cells that help them grow.The FDA based its latest approval of Xalkori on a study of 50 people with ROS1-positive non-small cell lung cancer that had sp...
Sunday, March 13, 2016 7:00 PM|Thorax|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, regulatory
Introduction Lung cancer is a disease with a heterogeneous complement of mutations.1 Although point mutations and deletions are among the most common types of mutations in lung cancer, translocations in the ALK gene, which occur in approximately 5% of lung adenocarcinomas, exist predominantly in non-smokers. ALK translocations gained notoriety recently because they are targets for the kinase inhibitor crizotinib (Xalkori).1 Crizotinib has exhibited profound efficacy and has obtained FDA (United States Food and Drug Administration) approval for use in patients with non-small cell lung cancer (NSCLC) with ALK translocation, as determined by a break-apart fluorescent in situ hybridisation (FISH) assay.2 Here we report a case where a patient with a complicated ALK genotype, including an EML4-A...
Sunday, March 13, 2016 7:00 PM|Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Crizotinib is the standard of care for advanced non–small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased acti...

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Saturday, March 12, 2016 4:48 PM|Lung Cancer|Labels: ALK, lung cancer, regulatory
The US Food and Drug Administration (FDA) approved Xalkori (crizotinib) to treat patients with advanced non-small cell lung cancer (NSCLC) who have tumors with an ROS-1 gene alteration.
Friday, March 11, 2016 10:09 PM|WSJ.com: Health|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, biomarker diagnostic, regulatory
The U.S. Food and Drug Administration approved Pfizer Inc.’s Xalkori for treatment of a rare form of advanced non-small-cell lung cancer, making it the first biomarker-driven therapy for the condition. (Source: WSJ.com: Health)
Friday, March 11, 2016 4:30 PM|Medscape Hematology-Oncology Headlines|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, regulatory
The FDA has approved crizotinib for the treatment for patients with ROS-1-positive non-small cell lung cancer. FDA Approvals (Source: Medscape Hematology-Oncology Headlines)
Friday, March 11, 2016 3:32 PM|Health News - UPI.com|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
HealthDay News Xalkori has been approved by the U.S. Food and Drug Administration to treat advanced non-small cell lung cancer with tumors that have a rare gene mutation. (Source: Health News - UPI.com)
Friday, March 11, 2016 2:03 PM|Drugs.com - New Drug Approvals|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, regulatory
March 11, 2016 -- The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration. Xalkori is the first and only FDA... (Source: Drugs.com - New Drug Approvals)
Friday, March 11, 2016 10:28 AM|Food and Drug Administration|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, regulatory
The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration. Xalkori is the first and only FDA approved treatment for patients with ROS-1 positive NSCLC. (Source: Food and Drug Administration)
Thursday, March 10, 2016 6:00 PM|Therapeutic Advances in Respiratory Disease|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, lung cancer
Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents. In addition, mutations leading to resis...
Monday, March 7, 2016 6:00 PM|Journal of Hematology and Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications fo... (Source: Journal of Hematology and Oncology)
Sunday, March 6, 2016 6:00 PM|Bioorganic and Medicinal Chemistry Letters|Bioorganic and Medicinal Chemistry Letters via MedWorm.com|Comments|Labels: ALK
Authors: Zhang P, Dong J, Zhong B, Zhang D, Yuan H, Jin C, Xu X, Li H, Zhou Y, Liang Z, Ji M, Xu T, Song G, Zhang L, Chen G, Meng X, Sun D, Shih J, Zhang R, Hou G, Wang C, Jin Y, Yang Q Abstract Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate. PMID: 26979157 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Saturday, March 5, 2016 2:48 PM|Expert Review of Anticancer Therapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, biomarker diagnostic
Authors: Zito Marino F, Rocco G, Morabito A, Mignogna C, Intartaglia M, Liguori G, Botti G, Franco R Abstract To date, ALK-rearrangement is a molecular target in several cancers, i.e. NSCLC. The dramatic benefits of crizotinib have prompted research into identifying other possible patients carrying ALK gene alterations with possible clinical significance. The ALK gene is involved not only in several rearrangements but also in other alterations such as amplification. ALK-amplification (ALK-A) is a common genetic event in several cancers, generally associated with poor outcome and more aggressive behaviour. Here we review the role of ALK-A in cancer as a prognostic and predictive biomarker. Furthermore, several critical issues regarding ALK-A in relation to; methods of detection, acq...
Saturday, March 5, 2016 6:00 AM|Internal Medicine|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Authors: Matsuo N, Sekine A, Kato T, Hosoda C, Ito H, Baba T, Umeda S, Iwasawa T, Okudela K, Ogura T Abstract Crizotinib is highly effective for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether crizotinib has a beneficial effect on elderly patients with ALK-positive NSCLC with a poor performance status (PS). We herein present the case of an 85-year-old man with stage IV ALK-positive NSCLC, whose PS score was 4 due to pericardial and pleural effusions. After initiating crizotinib therapy, a drastic response was observed and the PS score improved to 0. Adverse effects were manageable. Our results indicate that crizotinib could be an important choice when treating elderly patients with ALK-positive NSCLC with poor PS. ...

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Monday, February 29, 2016 6:00 PM|Neoplasia|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, FAK, lung cancer
Authors: Dong X, Fernandez-Salas E, Li E, Wang S Abstract Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. P...

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Thursday, February 25, 2016 6:00 PM|Critical Reviews in Oncology Hematology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, lung cancer
The low survival rates observed in Non-Small cell lung cancer (NSCLC) patients occurs due to a dangerous association of late detection and limited efficacy of the available treatments (Jemal et al., 2009). The discovery of common oncogene drivers, such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase fusion (EML-ALK) and proto-oncogene tyrosine-protein kinase ROS1 rearrangements, has led to the development of new accurate and efficient targeted therapies, radically improving the clinical outcomes of patients that harbor these mutations, opening the new era of targeted therapy in lung cancer (Solomon et al., 2014; Rosell et al., 2012). (Source: Critical Reviews in Oncology Hematology)
Sunday, February 21, 2016 6:00 PM|Journal of Clinical Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, clinical trial
Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases. (Source: Journal of Clinical Oncology)
Wednesday, February 17, 2016 11:44 AM|Expert Opinion on Emerging Drugs|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, lung cancer
This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK. EXPERT OPINION: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the...
Wednesday, February 17, 2016 9:36 AM|Expert Review of Anticancer Therapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, FAK, lung cancer
Authors: Muller IB, De Langen AJ, Honeywell RJ, Giovannetti E, Peters GJ Abstract In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second-generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are curre...
Wednesday, February 17, 2016 9:36 AM|Expert Review of Anticancer Therapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, fibrosarcoma, lung cancer
Authors: Khanal N, Ganti AK Abstract Lung cancer is the leading cause of cancer-related deaths in United States, accounting for more than one-fourth of the deaths annually. Although comparatively rare and relatively less studied, genetic abnormalities other than epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and Kirsten rat sarcoma (KRAS) mutations account for significant proportion of the driver mutations identified thus far. The targeted agents against B-rapidly accelerated fibrosarcoma (BRAF) V600E mutation, MNNG-HOS transforming gene (MET) pathway, ROS1 rearrangement, rearranged during transfection (RET) rearrangement, and HER2 pathways offer promising therapeutic options. Recruiting patients with these rarer mutations to wel...
Tuesday, February 16, 2016 6:00 PM|Tumor Biology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, lung cancer
Abstract We used immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) to evaluate anaplastic lymphoma kinase (ALK) protein expression and gene rearrangements, respectively, in 283 cases of wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer biopsy specimens. Immunohistochemistry was positive for ALK in 52 cases (18.4 %), and there was no significant difference in staining between various monoclonal antibodies (Roche ALK test kit, D5F3, p-ALK, and EML4-ALK). On RT-PCR, 36 cases (12.7 %) were positive for ALK. Immunohistochemistry and RT-PCR were both positive in 35 cases and both negative in 230 cases, and both have a high consistency (265/283, 93.6 %). Including 17 cases, immunohistochemistry was positive but RT-PCR was nega...
Sunday, February 14, 2016 8:15 AM|Expert Review of Clinical Pharmacology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, FAK, lung cancer
Authors: Landi L, Cappuzzo F Abstract Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop ...

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Sunday, February 14, 2016 8:09 AM|Expert Opinion on Investigational Drugs|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, Trk
Authors: Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L Abstract INTRODUCTION: Receptor tyrosine kinases (RTKs) and their signaling pathways, control normal cellular processes; however, their deregulation play important roles in malignant transformation. In advanced non-small cell lung cancer (NSCLC), the recognition of oncogenic activation of specific RTKs, has led to the development of molecularly targeted agents that only benefit roughly 20% of patients. Entrectinib is a pan-TRK, ROS1 and ALK inhibitor that has shown potent anti-neoplastic activity and tolerability in various neoplastic conditions, particularly NSCLC. AREAS COVERED: This review outlines the pharmacokinetics, pharmacodynamics, mechanism of action, safety, t...
Thursday, February 4, 2016 6:00 PM|Cancer Chemotherapy and Pharmacology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Conclusion These results indicated that alectinib has potent antitumor activity against NSCLC cells harboring the crizotinib-resistant mutation ALK G1269A. It is expected that alectinib would provide a valuable therapeutic option for patients with NSCLC having not only native ALK but also crizotinib-resistant ALK mutations. (Source: Cancer Chemotherapy and Pharmacology)

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Wednesday, February 3, 2016 6:00 PM|Current Respiratory Care Reports|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Abstract ROS1 is a membrane tyrosine kinase receptor of which encoding gene has recently been found rearranged in non-small cell lung cancer (NSCLC), leading to constitutive activation of the ROS1 kinase activity. The ROS1 gene rearrangement has been described in roughly 1 % of patients with NSCLC and such rearrangement needs to be assessed by a FISH break-apart assay (CD74-ROS1) with ROS1 immunohistochemistry as a screening tool in tumor histological samples. The clinical and histological features of patients with ROS1-rearranged NCSCL include adenocarcinoma histology with TTF-1 expression, predominantly young women patients, and never-smokers. Targeting ROS1 fusion proteins with a kinase inhibitor of ROS1 kinase domain, such as crizotinib, seems to be promising. Indeed, this po...
Tuesday, February 2, 2016 6:00 PM|Cancer Chemotherapy and Pharmacology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, lung cancer, biomarker diagnostic
Conclusion Combined analysis of these commonly studied genes may promote the individual treatment in NSCLC. RRM1 may be a prognostic and predictive biomarker for PFS in patients with NSCLC who received platinum-based adjuvant chemotherapy, and combining EGFR mutation and RRM1 expression or combining ERCC1 and RRM1 expression can enhance prognostic and predictive power for PFS. (Source: Cancer Chemotherapy and Pharmacology)
Monday, January 25, 2016 2:39 PM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: ALK, lung cancer
Authors: Ye M, Zhang X, Li N, Zhang Y, Jing P, Chang N, Wu J, Ren X, Zhang J Abstract During the past decade, more than 10 targetable oncogenic driver genes have been validated in non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) and ROS1 kinase are two new driver genes implicated in ALK- and ROS1-rearranged NSCLC. Inhibition of ALK and ROS1 by crizotinib has been reported to be highly effective and well tolerated in these patients. However, resistance to crizotinib emerges years after treatment, and increasing efforts have been made to overcome this issue. Here, we review the biology of ALK and ROS1 and their roles in cancer progression. We also summarize the ongoing and completed clinical trials validating ALK and ROS1 as targets for cancer treatment. In the la...
Sunday, January 24, 2016 6:00 PM|Critical Reviews in Oncology Hematology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, STAT, lung cancer
Targeted treatment of advanced non-small cell lung cancer patients with afatinib in EGFR mutation or crizotinib in ALK break positive patients results in profound tumor responses but inevitably induces resistance. In this review we present currently known resistance mechanisms for afatinib and crizotinib two recently approved drugs.Resistance mechanisms identified for afatinib include c-MET amplification and the V843I EGFR mutation. Expression of FGFR1, increased IL6R/JAK/STAT signaling, enhanced interference with aerobic glycolysis and autophagy are associated with resistance to afatinib. (Source: Critical Reviews in Oncology Hematology)
Saturday, January 23, 2016 6:00 PM|Journal of Genetics and Genomics|MedWorm: Cancer Therapy|Comments|Labels: ALK, BRAF, EGFR, lung cancer
Publication date: Available online 15 September 2015 Source:Journal of Genetics and Genomics Author(s): Jingwu Xie, Xiaoli Zhang There is high expectation for significant improvements in cancer patient care after completion of the human genome project in 2003. Through pains-taking analyses of genomic profiles in cancer patients, a number of targetable gene alterations have been discovered, with some leading to novel therapies, such as activating mutations of EGFR, BRAF and ALK gene fusions. As a result, clinical management of cancer through targeted therapy has finally become a reality for a subset of cancers, such as lung adenocarcinomas and melanomas. In this review, we summarize how gene mutation discovery leads to new treatment strategies using non-small cell lung cancer (NSCLC) as...
Thursday, January 21, 2016 6:00 PM|Nature Reviews Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
Nature Reviews Cancer 16, 69 (2016). doi:10.1038/nrc.2016.6 Author: Lydia Shipman A new study reports how tracking the evolution of resistance in serial biopsies revealed the molecular mechanisms by which a patient with metastatic non-small-cell lung cancer became resensitized to crizotinib. (Source: Nature Reviews Cancer)
Thursday, January 21, 2016 12:49 PM|Oncology Letters|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, lung cancer
Authors: Ren W, Zhang BO, Ma J, Li W, Lan J, Men H, Zhang Q Abstract Non-small-cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation is resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, but responds to the ALK-TKI crizotinib. Characterization of EML4-ALK translocation may provide invaluable information to facilitate disease diagnosis and improve the outcome of customized treatment. Although the occurrence of EML4-ALK translocation is likely to be affected by the smoking habits and gender of patients, the translocation has not been characterized extensively in female never-smokers with NSCLC. Therefore, 280 female never-smokers that we...
Thursday, January 21, 2016 6:52 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, lung cancer
Authors: Li W, Zhang Z, Guo L, Qiu T, Ling Y, Cao J, Guo H, Zhao H, Li L, Ying J Abstract To investigate the use of molecular testing on cytological specimens in selecting advanced non-small cell lung cancer (NSCLC) patients who are adequate for targeted treatment, a total of 137 NSCLC cases were analyzed by fluorescence in situ hybridization (FISH) for anaplastic lymphoma kinase (ALK) rearrangements, and Epidermal growth factor receptor (EGFR), kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were evaluated by quantitative real-time PCR (qRT-PCR) platform combining amplification refractory mutation system (ARMS) primers and TaqMan probes. Cytological specimens included 91 fine-needle aspirates, 5 fibreoptic bronchoscopic derived samples and 41 pleural effusions. Among 1...
Thursday, January 14, 2016 6:00 PM|The Lancet|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, lung cancer
This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). T...
Wednesday, January 13, 2016 6:00 PM|Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: AKT, ALK, EGFR, mTOR, lung cancer
Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT–mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT–mTOR pathway promotes immune escape by driving expression of PD-L1, which was conf...
Monday, January 11, 2016 6:00 PM|Frontiers in Bioscience - Elite|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK
Authors: Farina F, Gambacorti-Passerini C Abstract Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase protein implicated in a variety of tumors, both solid and hematological. Few years ago crizotinib, an inhibitor of the receptor tyrosine kinases c-Met and ALK, demonstrated its activity in ALK positive non-small-cell lung cancer and other tumors with excellent toxicity profile. Subsequently several ALK inhibitors have been developed, offering new personalized treatment options. This review addresses some clinical considerations on the use of ALK inhibitors in ALK positive tumors and on the development of resistance to them. PMID: 26709645 [PubMed - in process] (Source: Frontiers in Bioscience - Elite)
Sunday, January 10, 2016 6:00 PM|Cellular and Molecular Life Sciences : CMLS|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK
Authors: Bayliss R, Choi J, Fennell DA, Fry AM, Richards MW Abstract A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechan...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, FAK, MET
In this study, we explored ceritinib-resistant mechanisms using ceritinib-resistant, echinoderm microtubule-associated protein-like 4-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. Genetic alteration was examined by sequencing of cancer related genes. Protein expression related to ceritinib was examined by receptor-tyrosine kinase (RTK) array, immunoblotting and IHC. To overcome the identified resistance, single or combination treatment of the kinase inhibitors was testes in vitro and in vivo.We identified three novel ceritinib resistance mechanisms: a resistance mutation (L1198F), fibroblast growth factor receptor 3 (FGFR3) activation, and cMET gene amplification. L1198F-mutated ALK was the most sensitive to crizotinib. Molecular dynamic structure simulation succe...

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Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, TGF, lung cancer
Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non–small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosph...

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Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, skin cancer
Conclusions: ALK and ROS-1 rearrangement was found in 4.1% and 2.7% of NSCLC, respectively, in keeping with literature data. In other solid tumors, the percentage of rearrangements is exceedingly low, but melanoma, neuroendocrine tumors, pancreatic and colon cancer may show significant CNV. We speculate that such aberrations of ALK and ROS-1 could act as potential therapy targets, but additional investigation by immunohistochemistry and next generation sequencing is clinically warranted.Citation Format: Maria Silvia Cona, matteo Duca, Adele Testi, Sara Cresta, Katia Fiorella Dotti, Alice Indini, Diego Signorelli, Giuseppe Pelosi, Filippo Guglielmo de Braud, Silvia Damian. ALK and ROS-1 status: A retrospective analysis in solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC Inter...

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Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, biomarker diagnostic
Conclusions: The SRM assay showed superior sensitivity in poorly fixed specimens and can inform therapeutic decision-making in NCSLC patients with ALK screening discordances.Citation Format: TAE-JUNG KIM, HIDEKI TERAI. Utility of multiplexed biomarker analysis in non-small-cell lung cancer patients with discrepancies between FISH and immunohistochemical results of ALK testing. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A33. (Source: Molecular Cancer Therapeutics)

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Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK
In this study, we describe a comprehensive survey of gene fusions in 7428 cancer samples from 27 different cancer types, using paired-end RNA-seq data created by the TCGA project. At least one fusion gene was identified in 3801/7428 samples, with over 9000 genes taking part in a total of ~11000 fusion gene events. The number of gene fusions per tumor is highly variable, with the largest number of fusions typically identified in tumors with high level amplifications. This suggests many of the fusion genes identified here may arise as byproducts of amplicon formation, making them likely passenger events.Several potentially targetable genes take part in gene fusions across different cancer types. For instance, we identified a total of 12 gene fusions involving ALK in 5 different cancer types....
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer, biomarker diagnostic
Conclusions. Induced crizotinib resistance in ALK-fusion lung PDX can be useful to investigate crizotinib resistant mechanism and future drugs overcoming the resistance.References1. Koivunen, J.P., et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 4275-4283 (2008).2. Kwak, E.L., et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363, 1693-1703 (2010).3. Takeuchi, K., et al. RET, ROS1 and ALK fusions in lung cancer. Nature medicine 18, 378-381 (2012).4. Katayama, R., et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Science translational medicine 4, 120ra117 (2012).5. Katayama, R., et al. ...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, lung cancer
In this study we have extended the capability of this technology to plasma samples from donors previously diagnosed with NSCLC. Data generated during the development of this test involved extraction of RNA from cell lines and donor plasma, processing to cDNA, adaptor ligation and two-step anchored PCR with specificity for human ALK, RET and ROS1. Amplicons were sequenced on a MiSeq (v2 chemistry) and reads were mapped to the human genome and a fusion specific database in order to identify the specific fusion partner(s). Test turn-around time from RNA extraction to results averaged 72 hours. With this test system we evaluated known variant-positive cell lines for EML4-ALK, SLC34A2-ROS1 and CCDC6-RET, as well as remnant prospectively-collected plasma from NSCLC donors (females of less than 6...