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2.  Native and rearranged ALK copy number and rearranged cell count in NSCLC: Implications for ALK inhibitor therapy 
Cancer  2013;119(22):3968-3975.
Background
Anaplastic Lymphoma Kinase positive (ALK+) non-small cell lung cancer (NSCLC) responds to ALK inhibitors. Clinically, ≥ 15% cells showing rearrangements by break-apart FISH classify tumors as positive. Increases in native and rearranged ALK copy number also occur.
Methods
1426 NSCLC clinical specimens (174 ALK+ and 1252 ALK negative), and 24 ALK negative NSCLC cell lines were investigated. ALK copy number and genomic status were assessed by FISH.
Results
Clinical specimens with 0–9%, 10–15%, 16–30%, 31–50% and >50% of ALK+ cells were found in 79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Increased native ALK copy number (≥3 copies/cell in ≥40% cells) was detected in 19% of ALK+ and 62% of ALK negative tumors. In ALK negative tumors, abundant focal amplification of native ALK was rare (0.8%). Other atypical patterns occurred in ~6% of tumors. Mean native ALK copy number ranged from 2.1–6.9 in cell lines and was not correlated with crizotinib sensitivity (IC50s 0.34–2.8 uM) (r=0.279, p=0.1764). Neither native, nor rearranged ALK copy number, nor percentage cells positive correlated with extra-central nervous system progression free survivalin ALK+ patients on crizotinib.
Conclusions
8.5% of cases are below the established positivity threshold by ≤5%. Further investigation of ALK by other diagnostic techniques in such cases may be warranted. Native ALK copy number increases alone are not associated with sensitivity to ALK inhibition in vitro. However, rare complex patterns of increased native ALK in patients should be studied further as atypical rearrangements contained within these may otherwise be missed.
doi:10.1002/cncr.28311
PMCID: PMC3947483  PMID: 24022839
ALK; FISH; copy number; borderline; crizotinib
4.  Treating ALK positive lung cancer: Early successes and coming challenges 
Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur infrequently in non-small cell lung cancer (NSCLC), but provide an important paradigm for oncogene-directed therapy in this disease. Crizotinib, an orally bioavailable inhibitor of ALK, provides significant benefit for patients with ALK positive (ALK+) NSCLC in association with characteristic, mostly mild, toxicities and is now FDA approved in this molecularly defined subgroup of lung cancer. Many new ALK inhibitors are being developed and understanding the challenges of determining and addressing the side-effects that are likely to be ALK specific, maximizing the time of benefit on targeted agents, and understanding the mechanisms that underlie drug resistance will be critical in informing the optimal therapy of ALK+NSCLC in the future.
doi:10.1038/nrclinonc.2012.43
PMCID: PMC4142046  PMID: 22473102
ALK; Lung cancer; crizotinib
5.  A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer 
Investigational new drugs  2010;29(2):340-346.
Summary
Background
2-methoxyestradiol (2ME2) is an estradiol-17β metabolite with antiproliferative and antiangiogenic activities. ENMD-1198 is an analog of 2ME2 which was developed to decrease the metabolism and increase both the bioavailability and antitumor activities of the parent molecule. This first-in-human phase I study evaluated the tolerability, pharmacokinetics and preliminary evidence of activity of ENMD-1198 in advanced cancer patients.
Methods
Eligible patients received ENMD-1198 orally once daily in Part A (standard 3+3 dose escalation design), or in Part B (accelerated dose escalation design). Cycle 1 consisted of 28 days daily dosing followed by a 14-(Part A) or 7-(Part B) day observation period, then continuously in 28 day cycles thereafter.
Results
A total of 29 patients were enrolled in 12 dose cohorts (5 to 550 mg/m2/d). The most common drug-related toxicities were Grade 1/2 fatigue (55%), nausea and vomiting (37%), and constipation (34%). Two DLTs (Grade 4 neutropenia) occurred at 550 mg/m2/day, and 425 mg/m2/d was declared the maximum tolerated dose. ENMD-1198 was absorbed rapidly with a Tmax of 1–2 h. Exposure to ENMD-1198 (Cmax and AUC0–24hr) increased linearly with dose. The mean terminal half-life was 15 h. A 3-fold accumulation was found after multiple doses. Five patients achieved stabilization of disease for at least 2 cycles, three of whom (with neuroendocrine carcinoma of pancreas, prostate cancer and ovarian cancer) demonstrated prolonged stabilization ranging from 8–24.5 cycles.
Conclusion
ENMD-1198 is well-tolerated with a pharmacokinetic exposure profile compatible with once daily dosing. The recommended phase II dose of ENMD-1198 is 425 mg/m2/d. Early evidence of prolonged disease stabilization in pre-treated patients suggests ENMD-1198 is worthy of additional investigation.
doi:10.1007/s10637-009-9383-9
PMCID: PMC4331064  PMID: 20084425
ENMD-1198; Phase I; Pharmacokinetics
6.  Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study 
The lancet oncology  2012;13(10):1011-1019.
Summary
Background
ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study.
Methods
In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195.
Findings
Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6).
Interpretation
Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.
Funding
Pfizer.
doi:10.1016/S1470-2045(12)70344-3
PMCID: PMC3936578  PMID: 22954507
7.  Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs 
IMPORTANCE
Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
OBJECTIVES
To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
DESIGN, SETTING, AND PARTICIPANTS
From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
INTERVENTIONS
Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
MAIN OUTCOMES AND MEASURES
Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
RESULTS
From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).
CONCLUSIONS AND RELEVANCE
Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
doi:10.1001/jama.2014.3741
PMCID: PMC4163053  PMID: 24846037
8.  Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR-Mutant Lung Cancer With and Without T790M Mutations 
Cancer discovery  2014;4(9):1036-1045.
EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post-acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4); median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib/cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation.
doi:10.1158/2159-8290.CD-14-0326
PMCID: PMC4155006  PMID: 25074459
afatinib; cetuximab; acquired resistance
9.  Correlations between the percentage of tumor cells showing an ALK gene rearrangement, ALK signal copy number and response to crizotinib therapy in ALK FISH positive non-small cell lung cancer 
Cancer  2012;118(18):4486-4494.
Background
FISH, using break-apart red (3’) and green (5’) ALK probes, consistently shows rearrangements in < 100% of tumor cells in ALK+ NSCLC. Increased copy numbers of fused and rearranged signals also occur. Here we explore correlations between the percentage of ALK positive cells and signal copy number and their association with response to ALK inhibition.
Methods
Ninety ALK + NSCLC cases were evaluated. The percentage of positive cells, pattern of positivity (split, single red, or both) and copy number of fused, isolated red and green signals were recorded. Thirty patients had received crizotinib.
Results
Increased isolated red signal copy number (contributing to both single red and split patterns of positivity) correlated with a higher percentage of ALK+ cells (r = 0.743, p = <0.0001). Mean fused copy number was negatively associated with isolated red signal copy number (r = −0.409, p = <0.0001). Neither percentage cells positive (r = 0.192, p = 0.3), nor copy number of isolated red (r = 0.274, p = 0.195) correlated with maximal tumor shrinkage with crizotinib.
Conclusions
The strong association between increased copy number of of key ALK signals and percentage positive cells suggests that the <100% rate of cellular positivity in ALK+ tumors is due to technical factors not biology. In ALK+ tumors, neither percentage cells positive, nor signal copy number appear to be informative variables for predicting benefit from ALK inhibition. The inverse relationship between fused and isolated red copy number suggests ALK+ may be a distinct ‘near diploid’ subtype of NSCLC developing before significant chromosomal aneusomy occurs.
doi:10.1002/cncr.27411
PMCID: PMC3342464  PMID: 22282074
ALK; FISH; copy number; crizotinib
10.  Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer 
The New England journal of medicine  2014;370(13):1189-1197.
BACKGROUND
Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.
METHODS
In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.
RESULTS
A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).
CONCLUSIONS
Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.)
doi:10.1056/NEJMoa1311107
PMCID: PMC4079055  PMID: 24670165
11.  Stereotactic Radiotherapy Can Safely and Durably Control Sites of Extra-CNS Oligoprogressive Disease in ALK-Positive Lung Cancer Patients on Crizotinib 
Purpose
A preliminary analysis demonstrated that local ablative therapy (LAT) can provide short-term control of extra-CNS (eCNS) lesion progression in tyrosine-kinase addicted non-small cell lung cancer (NSCLC) patients. However, little is known about the long-term efficacy and safety of single and multiple courses of radiotherapy when used to treat these sites of progressive disease. This study analyzes the durability and toxicity of radiotherapeutic LAT applied to eCNS disease progression in ALK+ NSCLC patients.
Materials and Methods
ALK+ NSCLC patients receiving crizotinib manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT.
Results
33 of 38 patients progressed on crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1–3 courses of LAT with radiotherapy. The 6 and 12 month actuarial local lesion control rates (LC) with radiotherapy was 100 and 86%, respectively. The 12 month LC with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% vs. 60% (p = 0.01). No acute or late grade >2 radiotherapy-related toxicities were observed. Median overall time on crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 and 10.1 months, respectively. Patients remaining on crizotinib for >12 months vs ≤12 months had a 2 year OS of 72% vs 12%, respectively (p < 0.0001).
Conclusions
LAT safely and durably eradicated sites of individual lesion progression in ALK+ NSCLC patients receiving crizotinib. A dose-response relationship for LC was observed. The suppression of OPD on crizotinib by LAT allowed an extended duration of exposure to crizotinib, which was associated with longer OS.
doi:10.1016/j.ijrobp.2013.11.010
PMCID: PMC4160890  PMID: 24462383
13.  Clinical Benefit From Pemetrexed Before and After Crizotinib Exposure and From Crizotinib Before and After Pemetrexed Exposure in Patients With Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer 
Clinical lung cancer  2013;14(6):636-643.
Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib-naive anaplastic lymphoma kinase-positive (ALK+) non–small-cell lung cancer (NSCLC). We report the results of a retrospective analysis of ALK+ patients exposed to crizotinib and pemetrexed to determine if any clinical cross-resistance exists. Progression-free survival (PFS) results for ALK+ patients administered pemetrexed followed by crizotinib (PEM-CRIZ) and ALK+ patients first treated with crizotinib and then pemetrexed (CRIZ-PEM) are reported.
Background
Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated.
Patients and Methods
Patients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared.
Results
Objective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ-PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM-CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100–6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727–3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed.
Conclusion
Crizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes.
doi:10.1016/j.cllc.2013.06.005
PMCID: PMC4126227  PMID: 23931899
ALK; Crizotinib; Lung cancer; NSCLC; Pemetrexed
14.  Anaplastic Lymphoma Kinase Gene Rearrangements in Non-small Cell Lung Cancer are Associated with Prolonged Progression-Free Survival on Pemetrexed 
Hypothesis
To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer.
Methods
In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively.
Results
Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1–9), KRAS mutant (7 months; 1.5–10), ALK positive (9 months; 3–12), and triple negative (4 months; 3–5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17– 0.73], p = 0.0051).
Conclusions
In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.
doi:10.1097/JTO.0b013e31820cf053
PMCID: PMC3626562  PMID: 21336183
Anaplastic lymphoma kinase; Non-small cell lung cancer; Epidermal growth factor receptor; KRAS; Pemetrexed
15.  Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non-Small Cell Lung Cancer 
Cancer discovery  2013;3(4):430-443.
EML4-ALK gene rearrangements define a unique subset of non-small cell lung cancer (NSCLC) patients and the clinical success of the ALK inhibitor crizotinib in this population has become a paradigm for molecularly-targeted therapy. Here we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, resulting in greater in vitro potency, superior antitumor efficacy and prolonged animal survival compared to crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a NSCLC patient with crizotinib-resistant disease. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinases were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.
doi:10.1158/2159-8290.CD-12-0440
PMCID: PMC4086149  PMID: 23533265
Hsp90 inhibition; non-small cell lung cancer; anaplastic lymphoma kinase; ganetespib; crizotinib resistance
16.  Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients 
Cancer  2013;119(13):2383-2390.
Background
Crizotinib is a tyrosine kinase inhibitor active against ALK, MET and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.
Methods
Male cancer patients treated with crizotinib had total testosterone levels measured, and results compared to non-crizotinib treated patients. Albumin, sex-hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement.
Results
Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib treated patients (27/32 patients below LLN, 84%) compared to +29% above LLN in 19 non-crizotinib treated patients (6/19 below LLN, 32%), p=0.0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19/25 patients below LLN, 76%). 84% (16/19) with low free levels and 79% (19/24) with low total levels had symptoms of androgen deficiency. 5/9 (55%) patients with low testosterone given testosterone supplementation had an improvement in symptoms, coincident with increases in testosterone above LLN.
Conclusion
Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.
doi:10.1002/cncr.28089
PMCID: PMC3686910  PMID: 23585220
Crizotinib; NSCLC; Testosterone; ALK gene rearrangements; hypogonadism
18.  A Randomized, Phase II, Biomarker-Selected Study Comparing Erlotinib to Erlotinib Intercalated With Chemotherapy in First-Line Therapy for Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2011;29(26):3567-3573.
Purpose
Erlotinib prolongs survival in patients with advanced non–small-cell lung cancer (NSCLC). We report the results of a randomized, phase II study of erlotinib alone or intercalated with chemotherapy (CT + erlotinib) in chemotherapy-naïve patients with advanced NSCLC who were positive for epidermal growth factor receptor (EGFR) protein expression and/or with high EGFR gene copy number.
Patients and Methods
A total of 143 patients were randomly assigned to either erlotinib 150 mg daily orally until disease progression (PD) occurred or to chemotherapy with paclitaxel 200 mg/m2 intravenously (IV) and carboplatin dosed by creatinine clearance (AUC 6) IV on day 1 intercalated with erlotinib 150 mg orally on days 2 through 15 every 3 weeks for four cycles followed by erlotinib 150 mg orally until PD occurred (CT + erlotinib). The primary end point was 6-month progression-free survival (PFS); secondary end points included response rate, PFS, and survival. EGFR, KRAS mutation, EGFR fluorescent in situ hybridization and immunohistochemistry, and E-cadherin and vimentin protein levels were also assessed.
Results
Six-month PFS rates were 26% and 31% for the two arms (CT + erlotinib and erlotinib alone, respectively). Both were less than the historical control of 45% (P = .001 and P = .011, respectively). Median PFS times were 4.57 and 2.69 months, respectively. Patients with tumors harboring EGFR activating mutations fared better on erlotinib alone (median PFS, 18.2 months v 4.9 months for CT + erlotinib).
Conclusion
The feasibility of a multicenter biomarker-driven study was demonstrated, but neither treatment arms exceeded historical controls. This study does not support combined chemotherapy and erlotinib in first-line treatment of EGFR-selected advanced NSCLC, and the patients with tumors harboring EGFR mutations had a better outcome on erlotinib alone.
doi:10.1200/JCO.2010.34.4929
PMCID: PMC3179254  PMID: 21825259
19.  Optimizing the Detection of Lung Cancer Patients Harboring Anaplastic Lymphoma Kinase (ALK) Gene Rearrangements Potentially Suitable for ALK Inhibitor Treatment 
Clinical Cancer Research  2010;16(22):5581-5590.
Purpose
Anaplastic lymphoma kinase (ALK) rearrangements, associated with sensitivity to an experimental ALK/MET inhibitor, occur in 3% to 5% of non-small cell lung cancers. Intratumoral fluorescence in situ hybridization (FISH) heterogeneity has been reported. We explored the heterogeneity basis, the requirements for accurately determining ALK FISH positivity, and the effect of enriching the tested population using clinical and molecular factors.
Experimental Design
Lung cancer patients were screened by ALK and MET FISH and for EGFR and KRAS mutations.
Results
Thirteen ALK-positive cases were identified from 73 screened patients. Gene copy number increases occurred together with classic rearrangements. All positive cases were adenocarcinomas, 12 were EGFR/KRAS wild-type, and 1 had a coexistent EGFR exon 20 mutation. No association with MET amplification occurred. ALK positivity was associated with <10-pack-year smoking status (P = 0.0004). Among adenocarcinomas, without KRAS or EGFR mutations, with <10-pack-year history, 44.8% of cases were ALK positive. ALK FISH positivity was heterogeneous, but mean values in tumor areas from ALK-positive patients (54% of cells; range, 22-87%) were significantly higher than in adjacent normal tissue or tumor/ normal areas from ALK-negative patients (mean, 5-7%). Contiguous sliding field analyses showed diffuse heterogeneity without evidence of focal ALK rearrangements. One hundred percent sensitivity and specificity occurred when four or more fields (~60 cells) were counted.
Conclusions
Intratumoral ALK FISH heterogeneity reflects technique, not biology. The clinical activity of ALK/MET inhibitors in ALK-positive patients probably reflects ALK, but not MET, activity. Prescreening by histology, EGFR/KRAS mutations, and smoking status dramatically increases the ALK-positive hit rate compared with unselected series.
doi:10.1158/1078-0432.CCR-10-0851
PMCID: PMC3395226  PMID: 21062932
20.  Diagnostic Assays for Identification of Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer 
Cancer  2012;119(8):1467-1477.
In series dominated by adenocarcinoma histology, approximately 5% of non–small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression-free survival in ALK-positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK-positive NSCLC using an FDA-approved diagnostic test. Currently, only break-apart fluorescence in situ hybridization testing is FDA approved as a companion diagnostic for crizotinib; however, many other assays are available or in development. In the current review, the authors summarize the diagnostic tests available, or likely to become available, that could be used to identify patients with ALK-positive NSCLC, highlighting the pros and cons of each.
doi:10.1002/cncr.27913
PMCID: PMC3935240  PMID: 23280244
crizotinib; non-small cell lung cancer; anaplastic lymphoma kinase (ALK) gene rearrangements; fluorescence in situ hybridization
21.  First-in-Human Phase I Trial of Two Schedules of OSI-930, a Novel Multikinase Inhibitor, Incorporating Translational Proof-of-Mechanism Studies 
Purpose
OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors.
Experimental Design
OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted.
Results
Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n =8). Dose-limiting toxicities were observed at 600 mg twice a day (n =3): G3 rash (n =2) and G4 γ-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1–2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients.
Conclusions
OSI-930 is safe and well tolerated, with pharmacokinetic–pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.
doi:10.1158/1078-0432.CCR-12-2258
PMCID: PMC3880798  PMID: 23403628
22.  Resistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer 
PLoS ONE  2013;8(12):e82236.
The targeting of oncogenic ‘driver’ kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.
doi:10.1371/journal.pone.0082236
PMCID: PMC3862576  PMID: 24349229
23.  Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene addicted non-small cell lung cancer 
Introduction
Many patients with oncogene driven non-small cell lung cancer treated with TKIs experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to CNS and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.
Materials and Methods
Patients with metastatic ALK+ NSCLC treated with crizotinib (n=38) and EGFR-MT NSCLC treated with erlotinib (n=27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression free survival (PFS1) and site of first progression were recorded. A subset of patients with either non-leptomeningeal CNS and/or ≤4 sites of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same TKI. The subsequent median progression free survival from the time of first progression (PFS2) and pattern of progression were recorded.
Results
PFS1 in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. 25 of 51 (49%) patients who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, 1 with surgery, and continuation of the same targeted therapy. Post LAT, 19/25 patients progressed again, with median PFS2 of 6.2 months
Discussion
Oncogene addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with >6 months of additional disease control.
doi:10.1097/JTO.0b013e3182745948
PMCID: PMC3506112  PMID: 23154552
24.  Characteristics of Lung Cancers Harboring NRAS Mutations 
Purpose
We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS mutant lung cancer cells.
Patients and Methods
We reviewed clinical data from patients whose lung cancers were identified at 6 institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. 6 NRAS mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e. EGFR, ALK, MET, IGF-1R, BRAF, PI3K and MEK).
Results
Among 4562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45% to 0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS mutated lung tumors compared to KRAS-mutant NSCLCs (NRAS: 13% (4/30), KRAS: 66% (1772/2733), p<0.00000001). 5 of 6 NRAS mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.
Conclusion
NRAS mutations define a distinct subset of lung cancers (~1%) with potential sensitivity to MEK inhibitors. While NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.
doi:10.1158/1078-0432.CCR-12-3173
PMCID: PMC3643999  PMID: 23515407
NRAS mutation; EGFR mutation; KRAS mutation; lung cancer; non-small cell lung cancer; driver mutation; MEK inhibitor; erlotinib; gefitinib; crizotinib
25.  Oncogene Status Predicts Patterns of Metastatic Spread in Treatment-Naïve Non-Small Cell Lung Cancer 
Cancer  2012;118(18):4502-4511.
Background
The discovery of distinct subsets of non-small cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly impacted personalized therapy. We hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis.
Methods
209 consecutive patients with stage IV non-squamous NSCLC with an EGFR mutation (N=39), KRAS mutation (N=49), ALK gene rearrangement (N=41), or wild-type for all three (triple negative, N=80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort.
Results
ALK gene rearrangement was significantly associated with pericardial disease (OR=4.61, 95% CI 1.30, 16.37, p=0.02) and pleural disease (OR=4.80, 95% CI 2.10, 10.97, p<0.001). Patients with ALK gene rearrangements (OR=5.50, 95% CI 1.76, 17.18, p= 0.003) and patients with EGFR mutations (OR=5.17, 95% CI 1.63, 16.43, p= 0.006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than the triple negative cohort (mean = 3.6 sites vs. 2.5 sites, p<0.0001).
Conclusion
The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis.
doi:10.1002/cncr.27409
PMCID: PMC3370097  PMID: 22282022
metastasis; Non-Small Cell Lung Cancer; EGFR; ALK tyrosine kinase receptor; KRAS

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