Publications by authors named "Sai-Hong I Ou"

31 Publications

Continuation of Lorlatinib in ALK-positive NSCLC Beyond Progressive Disease.

J Thorac Oncol 2022 Jan 10. Epub 2022 Jan 10.

Medical Oncology, National Institute for Cancer Research CRO-IRCCS, Aviano, Italy.

Introduction: Lorlatinib, a potent, selective third-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK TKI), showed overall and intracranial anti-tumor activity in patients with ALK-positive non-small cell lung cancer (NSCLC).

Methods: Retrospective analyses in the ongoing phase II trial (NCT01970865) investigated clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with prior crizotinib as the only ALK TKI were Group A (n = 28); those with ≥1 prior second-generation ALK TKIs were Group B (n = 74). LBPD was defined as >3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with a best overall response of complete or partial response or stable disease were included.

Results: There were no major differences in baseline characteristics between groups. Median duration of treatment for LBPD patients was 32.4 months (Group A) and 16.4 months (Group B) versus 12.5 months (Group A) and 7.7 months (Group B) for non-LBPD patients. Median overall survival (OS) in Group A was not reached (NR) in LBPD patients versus 24.4 months (95% confidence interval [CI] 12.1-NR); Group B median was 26.5 months (95% CI 18.7-35.5) in LBPD patients versus 14.7 months (95% CI 9.3-38.5) in non-LBPD patients. Median OS post-progression for Groups A and B was NR (95% CI 21.4-NR) and 14.6 months (95% CI 11.2-19.2) in LBPD patients, and 8.0 months (95% CI 1.5-NR) versus 5.3 months (95% CI 2.8-14.3) in non-LBPD patients.

Conclusions: Continuing LBPD is a viable treatment option for select patients with ALK-positive NSCLC who progressed on lorlatinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.12.011DOI Listing
January 2022

Response to Immune Checkpoint Inhibition as Monotherapy or in Combination With Chemotherapy in Metastatic -Rearranged Lung Cancers.

JTO Clin Res Rep 2021 Jul 18;2(7):100187. Epub 2021 May 18.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: fusions are oncogenic drivers in 1% to 3% of NSCLCs. The activity of immune checkpoint inhibitor (ICI) monotherapy or in combination with chemotherapy (chemotherapy with ICI [chemo-ICI]) in these tumors and their immunophenotype have not been systematically described.

Methods: In this multi-institutional retrospective study, tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) were evaluated in patients with rearranged NSCLC. Time-to-treatment discontinuation (TTD) and objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) were calculated for patients treated with ICI or chemo-ICI in the metastatic setting.

Results: A total of 184 patients were identified. Among 146 assessable cases, PD-L1 expression was less than 1% in 60 (41%), 1% to 49% in 35 (24%), and greater than or equal to 50% in 51 tumors (35%). Of 100 (92%) TMB-assessable tumors, 92 had less than 10 mutations per megabase. TMB was significantly lower for rearranged tumors (n = 97) compared with tumors with (n = 1250) or alterations (n = 1653) and all other NSCLC tumors (n = 2753) evaluated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (median TMB = 2.6 versus 3.5, 7.0, and 6.1 mutations per megabase, < 0.001). Among patients treated with ICI, median TTD was 2.1 months (95% confidence interval [CI]: 1.0-4.2 mo; n = 28) and ORR 13% (2 of 16 RECIST-assessable; 95% CI: 2%-38%). Among patients treated with chemo-ICI, median TTD was 10 months (95% CI: 4.7-14.1 mo; n = 11) and ORR 83% (5 of 6 RECIST-assessable; 95% CI: 36%-100%). There was no difference in PD-L1 expression ( = 0.91) or TMB ( = 0.83) between responders and nonresponders.

Conclusions: Most rearranged NSCLCs have low PD-L1 expression and TMB. The activity of ICI in these tumors is modest. In contrast, chemo-ICI can achieve meaningful activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtocrr.2021.100187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474494PMC
July 2021

Acquired Resistance to KRAS Inhibition in Cancer.

N Engl J Med 2021 06;384(25):2382-2393

From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).

Background: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS). The mechanisms of acquired resistance to these therapies are currently unknown.

Methods: Among patients with -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS inhibitors.

Results: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the allele. Acquired bypass mechanisms of resistance included amplification; activating mutations in , , , and ; oncogenic fusions involving , , , , and ; and loss-of-function mutations in and . In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of mutations that confer resistance to KRAS inhibitors.

Conclusions: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2105281DOI Listing
June 2021

A Phase II Study of the Multikinase Inhibitor Ponatinib in Patients With Advanced, -Rearranged NSCLC.

JTO Clin Res Rep 2020 Sep 24;1(3):100045. Epub 2020 Apr 24.

Department of Medicine, Center for Thoracic Cancers, Massachusetts General Hospital, Boston, Massachusetts.

Introduction: rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of -rearranged NSCLC.

Methods: In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, -rearranged NSCLC (NCT01813734). rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate.

Results: Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49-73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1-5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83-5.30) and 17.47 months (95% CI: 6.57-19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity.

Conclusions: Ponatinib has limited clinical activity in patients with -rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtocrr.2020.100045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474450PMC
September 2020

Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC.

J Thorac Oncol 2019 10 20;14(10):1794-1806. Epub 2019 Jun 20.

Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC.

Introduction: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562).

Methods: Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (v4.03).

Results: Of 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis.

Conclusions: Durvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.06.010DOI Listing
October 2019

Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis.

Lung Cancer 2019 07 11;133:96-102. Epub 2019 May 11.

Massachusetts General Hospital Cancer Center, Boston, USA.

Objectives: Although dramatic responses to MET inhibitors have been reported in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC), the impact of these treatments on overall survival in this population is unknown.

Methods: We conducted a multicenter retrospective analysis of patients with METex14 NSCLC to determine if treatment with MET inhibitors impacts median overall survival (mOS). Event-time distributions were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios.

Results: We identified 148 patients with METex14 NSCLC; the median age was 72; 57% were women and 39% were never smokers. Of the 34 metastatic patients who never received a MET inhibitor, the mOS was 8.1 months; those in this group with concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P =  0.06). Of the 27 metastatic patients who received at least one MET inhibitor the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P =  0.04) compared to patients who did not receive any MET inhibitor. Among 22 patients treated with crizotinib, the median progression-free survival was 7.4 months.

Discussion: For patients with METex14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2019.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135929PMC
July 2019

Safety and efficacy of durvalumab in patients with head and neck squamous cell carcinoma: results from a phase I/II expansion cohort.

Eur J Cancer 2019 03 4;109:154-161. Epub 2019 Feb 4.

Tumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Introduction: Durvalumab selectively blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1. Encouraging clinical activity and manageable safety were reported in urothelial carcinoma, non-small-cell lung cancer (NSCLC), hepatocellular carcinoma (HC) and small-cell lung cancer (SCLC) in a multicenter phase I/II study. Safety and clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) were evaluated in the expansion phase.

Methods: Patients received 10 mg/kg of durvalumab intravenously every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. The primary objective was safety; clinical activity was a secondary objective.

Results: Sixty-two patients were enrolled and evaluable (received first dose ≥24 weeks before data cutoff). Median age was 57 years; 40.3% were human papillomavirus (HPV)-positive; 32.3% had tumour cell PD-L1 expression ≥25%, and 62.9% were current/former smokers. They had a median of 2 prior systemic treatments (range, 1-13). All-causality adverse events (AEs) occurred in 98.4%; drug-related AEs occurred in 59.7% and were grade III-IV in 9.7%. There were no drug-related discontinuations or deaths. Objective response rate (blinded independent central review) was 6.5% (15.0% for PD-L1 ≥25%, 2.6% for <25%). Median time to response was 2.7 months (range, 1.2-5.5); median duration was 12.4 months (range, 3.5-20.5+). Median progression-free survival was 1.4 months; median overall survival (OS) was 8.4 months. OS rate was 62% at 6 months and 38% at 12 months (42% for PD-L1 ≥25%, 36% for <25%).

Conclusions: Durvalumab safety in HNSCC was manageable and consistent with other cohorts of the study. Early, durable responses in these heavily pretreated patients warrant further investigation; phase III monotherapy and combination therapy studies are ongoing. CLINICAL TRIAL REGISTRY: clinicaltrials.gov NCT01693562; MedImmune study 1108.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2018.12.029DOI Listing
March 2019

Landscape of Acquired Resistance to Osimertinib in -Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired Fusion.

Cancer Discov 2018 12 26;8(12):1529-1539. Epub 2018 Sep 26.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired fusion. Although fusions have been identified in resistant -mutant non-small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of fusions in an -mutant cancer, we expressed CCDC6-RET in PC9 ( del19) and MGH134 ( L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with -mutant NSCLC and -mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. SIGNIFICANCE: The role of fusions in resistant -mutant cancers is unknown. We report that fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-1022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279502PMC
December 2018

Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an Gene Fusion.

JCO Precis Oncol 2018 23;2018. Epub 2018 Jul 23.

Memorial Sloan Kettering Cancer Center, New York NY.

Purpose: Gene rearrangements involving can generate fusion oncoproteins containing the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small cell lung cancer (NSCLC), with frequency previously estimated to be <1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of fusion-positive NSCLCs are not well characterized.

Methods: We compiled a database of NSCLC cases harboring fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology.

Results: We identified 11 NSCLC cases harboring gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved (7 cases) and (4 cases), with 5 and 2 distinct fusion partners, respectively. Cohort patients were 55% male, with a median age at diagnosis of 47.6 years (range 25.3-86.0) and a median pack year history of 0 (range 0-58). 73% of patients had metastatic disease at diagnosis. No concurrent alterations in , , , , or other known oncogenic drivers were identified. Nine cases were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features; one was squamous cell carcinoma; and one was neuroendocrine carcinoma. By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of fusions in NSCLC of 0.23% (95% CI 0.11-0.40).

Conclusion: fusions occur in NSCLCs across genders, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for fusions using a multiplexed NGS-based fusion assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132056PMC
http://dx.doi.org/10.1200/PO.18.00037DOI Listing
July 2018

Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma.

Cancer Discov 2018 07 17;8(7):822-835. Epub 2018 May 17.

Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that (KL) or (KP) comutations define distinct subgroups of -mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups ( < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with -mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free ( < 0.001) and overall ( = 0.0015) survival compared with ; LUAC. Among 924 LUACs, alterations were the only marker significantly associated with PD-L1 negativity in TMB LUAC. The impact of alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In -mutant murine LUAC models, loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify alterations as a major driver of primary resistance to PD-1 blockade in -mutant LUAC. This work identifies alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in -mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-0099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030433PMC
July 2018

Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.

N Engl J Med 2017 08 6;377(9):829-838. Epub 2017 Jun 6.

From Lausanne University Hospital, Lausanne (S.P.), and F. Hoffmann-La Roche, Basel (A.Z., E.M., S. Golding, B.B., J.N.) - both in Switzerland; University of Colorado, Denver (D.R.C.); Massachusetts General Hospital, Boston (A.T.S.); University of Michigan, Ann Arbor (S. Gadgeel); Samsung Medical Center, Sungkyunkwan University School of Medicine (J.S.A.), and Seoul National University Hospital (D.-W.K.) - both in Seoul, South Korea; Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (S.-H.I.O.); Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France (M.P.); Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland (R.D.); Catalan Institute of Oncology, Barcelona (R.R.); Roche Innovation Center, New York (P.N.M.); and State Key Laboratory of South China, Chinese University of Hong Kong, Hong Kong (T.M.).

Background: Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease.

Methods: In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival.

Results: During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib).

Conclusions: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1704795DOI Listing
August 2017

Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity.

Cardiooncology 2017 19;3. Epub 2017 Jan 19.

Department of Medicine, Duke University Medical Center, Durham, NC USA 27710.

Background: Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects.

Methods: The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, I, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4.

Results: Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0-5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited I which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of I, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.

Conclusions: Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40959-017-0020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310672PMC
January 2017

Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.

J Thorac Oncol 2015 Dec;10(12):1670-4

*Department of Medicine, Massachusetts General Hospital, Boston, MA; †Department of Pathology, Massachusetts General Hospital, Boston, MA; ‡Memorial Sloan Kettering Cancer Center, New York, NY; ‖Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; §Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; ¶Department of Medicine, Georgetown University Medical Center, Washington, DC; #University of California Irving Health, Orange, CA; **Dana-Farber Cancer Institute, Boston, MA; ††Beth Israel Deaconess Medical Center, Boston, MA; and ‡‡Ignyta, Inc., San Diego, CA.

Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.

Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.

Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.

Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.JTO.0000473485.38553.f0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643748PMC
December 2015

RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.

Nat Med 2015 Sep 24;21(9):1038-47. Epub 2015 Aug 24.

Department of Medicine, University of California at San Francisco, San Francisco, California, USA.

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.3930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734742PMC
September 2015

Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.

Lancet Oncol 2015 Jul 4;16(7):830-8. Epub 2015 Jun 4.

Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, China. Electronic address:

Background: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations.

Methods: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393.

Findings: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1-84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8-42·8) in group 2 and two (8·7%, 1·1-28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6-14·7) in group 1, 2·9 months (1·2-8·3) in group 2; and 2·7 months (1·8-4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4-26·9) in group 1, 14·9 months (8·1-24·9) in group 2, and 9·2 months (4·1-14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4-93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9-80·2) with Leu861Gln, and eight (100·0%, 63·1-100·0) with Ser768Ile.

Interpretation: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations.

Funding: Boehringer Ingelheim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(15)00026-1DOI Listing
July 2015

Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases.

J Clin Oncol 2015 Jun 26;33(17):1881-8. Epub 2015 Jan 26.

Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.

Purpose: Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied.

Patients And Methods: Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).

Results: At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.

Conclusion: Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.59.0539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451171PMC
June 2015

Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial.

Lancet Oncol 2014 Dec 5;15(13):1433-1441. Epub 2014 Nov 5.

State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China.

Background: Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer.

Methods: In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients.

Findings: Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4-84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2-98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded.

Interpretation: Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.

Funding: Pfizer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(14)70461-9DOI Listing
December 2014

Crizotinib in ROS1-rearranged non-small-cell lung cancer.

N Engl J Med 2014 Nov 27;371(21):1963-71. Epub 2014 Sep 27.

From the Massachusetts General Hospital Cancer Center (A.T.S., L.P.L., Z.Z., J.W.C., A.J.I.), Dana-Farber Cancer Institute (G.I.S.), and Beth Israel Deaconess Medical Center (D.B.C.) - all in Boston; University of California at Irvine, Irvine (S.-H.I.O.), and Pfizer Oncology, La Jolla (W.T., S.M.S., L.M.T., J.G.C., K.D.W.) - both in California; Seoul National University Hospital, Seoul, South Korea (Y.-J.B.); University of Colorado, Aurora (D.R.C., M.V.-G., R.C.D.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.); University of Chicago, Chicago (R.S.); Memorial Sloan Kettering Cancer Center, New York (G.J.R.); Karolinska Institutet, Stockholm (Z.Z.); and Rho, Chapel Hill, NC (P.S.).

Background: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.

Methods: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.

Results: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.

Conclusions: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1406766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264527PMC
November 2014

Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments.

Cancer 2014 09 20;120(17):2694-703. Epub 2014 May 20.

Head and Neck Medical Oncology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

Background: In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient-reported outcomes were assessed.

Methods: Patients (N = 52) with metastatic or unresectable, locally advanced medullary or differentiated thyroid cancer that was refractory or not amenable to iodine-131 received a starting dose of axitinib 5 mg twice daily. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters, and patient-reported outcomes assessed with the MD Anderson Symptom Inventory questionnaire.

Results: The overall ORR was 35% (18 partial responses), and 18 patients had stable disease for ≥16 weeks. The median PFS was 16.1 months, and the median OS was 27.2 months. All-causality, grade ≥3 adverse events (>5%) were fatigue, dyspnea, diarrhea, decreased weight, pain in extremity, hypertension, decreased appetite, palmar-plantar erythrodysesthesia, hypocalcemia, and myalgia. Patients who had greater axitinib exposure had a longer median PFS. Quality of life was maintained during treatment with axitinib, and no significant deterioration in symptoms or interference in daily life caused by symptoms, assessed on MD Anderson Symptom Inventory subscales, were observed.

Conclusions: Axitinib has activity and a manageable safety profile while maintaining quality of life, and it represents an additional treatment option for patients with advanced thyroid cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.28766DOI Listing
September 2014

Human papilloma virus in non-small cell lung cancer in never smokers: a systematic review of the literature.

Lung Cancer 2014 Jan 31;83(1):8-13. Epub 2013 Oct 31.

Department of Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Osaka, Japan.

Non-small cell lung cancer (NSCLC) in never smokers has emerged as a global public health issue. The cause is still unclear, and few studies have focused on the prevalence of human papillomavirus (HPV) in the never smokers. We performed a systematic search of PubMed for articles of HPV infection in human subjects with NSCLC up to September 2012. Although smoking status was not fully reported in all studies, we contacted the authors by e-mail to supplement this information. Differences in the distribution of patients with and without HPV infection were tested with the Chi squared test. We identified 46 eligible articles, including 23 from Asian countries (N=2337 NSCLC cases), 19 from European countries (N=1553) and 4 from North and South America (N=160). The HPV prevalence was 28.1% (95% confidence interval (CI) 26.6-30.3%), 8.4% (95% CI 7.1-9.9%) and 21.3% (95% CI 15.2-28.4%), respectively. Eleven studies from East Asia (N=1110) and 4 from Europe (N=569) provided information on smoking status. The number of never smoker was 392 patients (33.9%) in East Asia and 54 patients (14.8%) in Europe. The HPV prevalence in East Asian countries was similar between never and ever smokers (33.9% vs 39.2%, P=0.080). Based on the literature confirming the presence of HPV in lung cancer in never smokers, the virus plays a role in carcinogenesis in the disease. There were different patterns of HPV prevalence between Asian and European countries in the never smokers as well as in ever smokers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2013.10.002DOI Listing
January 2014

Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer.

J Thorac Oncol 2012 Nov;7(11):1625-30

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase have been described in a variety of human malignancies including non-small-cell lung cancer (NSCLC), cholangiocarcinoma and glioblastoma multiforme. Recently, clinicopathologic characteristics of c-ros oncogene 1, receptor tyrosine kinase (ROS1)-rearranged NSCLC patients have been described. Furthermore, anaplastic lymphoma kinase inhibitor, novel class of drugs targeting this tyrosine kinase receptor is currently under clinical trial in this molecular subset of NSCLC patients. This review will focus on the current knowledge of ROS1 rearrangements in NSCLC, methods to detect ROS1 rearrangement, and targeting ROS1-rearranged NSCLC patients with anaplastic lymphoma kinase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0b013e31826baf83DOI Listing
November 2012

Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.

Lancet Oncol 2012 Oct 4;13(10):1011-9. Epub 2012 Sep 4.

University of Colorado Denver, Aurora, CO, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(12)70344-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936578PMC
October 2012

Chemotherapy is beneficial for elderly patients with advanced non-small-cell lung cancer: analysis of patients aged 70-74, 75-79, and 80 or older in Japan.

Clin Lung Cancer 2012 Nov 18;13(6):442-7. Epub 2012 May 18.

National Hospital Organization (NHO) Kinki-Chuo Chest Medical Center, Osaka, Japan.

Background: It remains to be determined in elderly patients with advanced non-small-cell lung cancers (NSCLCs) if there is a benefit of chemotherapy in patients aged 80 or older.

Methods: Using a database from the Japan National Hospital Organization Study Group for Lung Cancer from 1990 to 2005, 3 cohorts based on the age of diagnosis were examined in patients with stage IIIB and IV NSCLC. Cohort 1 was for 70- to 74-year-old patients, cohort 2 for 75- to 79-year old, and cohort 3 for 80 years and older (80+). Multivariate analysis of survival for each cohort was performed using the Cox regression method using the following covariates: age, PS, histology, stage, smoking status, and chemotherapy.

Results: There were 1617 patients in cohort 1, 1349 in cohort 2, and 1010 in cohort 3. The number of patients treated with chemotherapy were 991 (61%) in cohort 1, 648 (48%) in cohort 2, and 286 (28%) in cohort 3. Multivariate analysis for overall survival (OS) showed that chemotherapy was a significant prognostic factor among cohort 1 (hazard ratio [HR], 0.540; 95% confidence interval [CI], 0.481-0.607; P < .0001) and cohort 2 (HR, 0.715; 95% CI, 0.632-0.810; P < .0001) and showed a benefit trend among cohort 3 (HR, 0.869; 95% CI, 0.742-1.018; P = .0940).

Conclusions: After adjustment for PS, a trend of survival benefit of chemotherapy remained in patients aged 80 or older.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2012.03.010DOI Listing
November 2012

Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy.

Future Oncol 2012 Apr;8(4):451-62

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

It is increasingly recognized that differences in overall survival and toxicity exist between Asian and caucasian patients with small-cell and non-small-cell lung cancer, with a longer survival, higher response rates and greater toxicity to chemotherapy and targeted therapy reported in Asian patients. Two global studies are used to illustrate how the proportions of Asian patients can influence survival outcome. Ethnicity is an important and complex characteristic that should considered in the design and conduct of a global clinical study, as the safety, tolerability and response may vary between Asian and caucasian patients. Whether ethnic differences in lung cancer survival are attributed to genetic differences among races or are simply a surrogate marker of differences in access to healthcare because of socioeconomic differences is unclear. Carefully designed prospective studies investigating ethnic-specific determinants of sensitivity and toxicity to systemic therapy are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon.12.25DOI Listing
April 2012

Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.

Lancet Oncol 2011 Oct 18;12(11):1004-12. Epub 2011 Sep 18.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Background: ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.

Methods: We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients.

Findings: Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244).

Interpretation: In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC.

Funding: Pfizer Inc, V Foundation for Cancer Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(11)70232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328296PMC
October 2011

Ethnic difference in hematological toxicity in patients with non-small cell lung cancer treated with chemotherapy: a pooled analysis on Asian versus non-Asian in phase II and III clinical trials.

J Thorac Oncol 2011 Nov;6(11):1881-8

Medical Oncology, Sakai Hospital, Kinki University School of Medicine, Osaka, Japan.

Introduction: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied.

Methods: We performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian. We chose three treatment regimens used for NSCLC globally: cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV), and carboplatin plus paclitaxel (CP). We applied sensitivity analysis to examine unreported ethnic differences in hematological toxicities by changing the percentage of Asian patients from 0 to 18% in trials reported from the United States and Europe.

Results: We identified 12 phase II trials and 38 phase III trials of NSCLC with a total of 11,271 patients. Among these, 14 trials had reported ethnic origins. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, odds ratio of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian, when treated with CG (OR = 1.55-3.45, p < 0.001), CV (OR = 2.99-4.43, p < 0.001), and CP (OR = 4.79-6.22, p < 0.001). Grade 3/4 anemia was also significantly higher in Asians with CG (OR = 3.10-3.27, p < 0.001), CV (OR = 1.99-2.43, p < 0.001), and CP (OR = 1.34-1.52, p < 0.001-0.004). However, no significant difference was observed in thrombocytopenia with CG (OR = 0.66-2.04, p < 0.001-1.000), CV (OR = 0.42-0.57, p = 0.097-0.323), or CP (OR = 1.21-1.39, p = 0.114-0.152).

Conclusions: Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly whites) in the treatment of chemotherapy for NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0b013e31822722b6DOI Listing
November 2011

Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke.

Clin Lung Cancer 2012 Jan 17;13(1):75-9. Epub 2011 May 17.

Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2011.04.001DOI Listing
January 2012

Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials.

J Thorac Oncol 2011 Jun;6(6):1030-8

Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.

Introduction: Although interethnic differences in survival to cytotoxic chemotherapy in patients with non-small cell lung cancer exist, an analysis of survival outcomes based on ethnicity has not yet been fully evaluated systematically using large patient cohorts. Furthermore, recent trial results may be confounded by the use of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).

Methods: A meta-analysis was performed using trials identified through MEDLINE. Summary data on median overall survival (OS), time to progression, progression-free survival, and overall response rate (ORR) were collected from randomized controlled trials. Outcomes were compared between Asian and Caucasian studies.

Results: Of the 1182 citations identified, 391 treatment arms (Asian 90 and Caucasian 301) were analyzed. The median OS and ORR in Asian and Caucasian studies for all chemotherapy regimens was 10.1 and 8.0 months (p < 0.001) and 32.2 and 25.9% (p < 0.001), respectively. The median OS in Asian and Caucasian studies for monotherapy, platinum doublets, and three drugs or more combination was 9.9 and 6.8 months, 10.4 and 8.6 months, and 9.4 and 8.0 months, respectively (all p < 0.001). In studies published pre-EGFR TKI, the median OS and ORR in Asian and Caucasian studies for all chemotherapy regimens was 9.1 versus 7.3 months (p < 0.001), respectively, and 29.0 and 23.0% (p < 0.006), respectively. The median OS in Asian and Caucasian studies for monotherapy, platinum doublets, and three drugs or more combination pre-EGFR TKI was 8.9 and 6.5 months (p < 0.005), 9.1 and 7.5 months (p < 0.001), and 9.3 and 7.6 months (p < 0.003), respectively. In third-generation platinum doublets, the median OS in Asian and Caucasian studies was 11.3 and 9.5 months (p < 0.001), respectively, and ORR was 35.0 and 29.8% (p < 0.001), respectively.

Conclusion: Ethnic differences in survival and response rate to chemotherapy exist and should be considered in clinical trial designs especially in the global context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0b013e3182199c03DOI Listing
June 2011

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

N Engl J Med 2010 Oct;363(18):1693-703

Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

Background: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.

Methods: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.

Results: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.

Conclusions: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1006448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014291PMC
October 2010
-->