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Alice T Shaw - One of the best experts on this subject based on the ideXlab platform.
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resistance to lorlatinib in ROS1 fusion positive non small cell lung cancer
Journal of Clinical Oncology, 2020Co-Authors: Jessica J Lin, Ibiayi Dagogojack, Charlotte E Lee, Justin F Gainor, Harper Hubbeling, Theodore O Johnson, Jochen K Lennerz, Beow Y Yeap, Alice T ShawAbstract:9611Background: Lorlatinib is a potent, brain-penetrant ROS1/ALK tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer...
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imaging features and patterns of metastasis in non small cell lung cancer with ret rearrangements
Cancers, 2020Co-Authors: Subba R Digumarthy, Jessica J Lin, Marguerite Rooney, Emily Chin, Alice T Shaw, Beow Y Yeap, Dexter P Mendoza, Justin F GainorAbstract:Rearranged during transfection proto-oncogene (RET) fusions represent a potentially targetable oncogenic driver in non-small cell lung cancer (NSCLC). Imaging features and metastatic patterns of advanced RET fusion-positive (RET+) NSCLC are not well established. Our goal was to compare the imaging features and patterns of metastases in RET+, ALK+ and ROS1+ NSCLC. Patients with RET+, ALK+, or ROS1+ NSCLC seen at our institution between January 2014 and December 2018 with available pre-treatment imaging were identified. The clinicopathologic features, imaging characteristics, and the distribution of metastases were reviewed and compared. We identified 215 patients with NSCLC harboring RET, ALK, or ROS1 gene fusion (RET = 32; ALK = 116; ROS1 = 67). Patients with RET+ NSCLC were older at presentation compared to ALK+ and ROS1+ patients (median age: RET = 64 years; ALK = 51 years, p < 0.001; ROS = 54 years, p = 0.042) and had a higher frequency of neuroendocrine histology (RET = 12%; ALK = 2%, p = 0.025; ROS1 = 0%, p = 0.010). Primary tumors in RET+ patients were more likely to be peripheral (RET = 69%; ALK = 47%, p = 0.029; ROS1 = 36%, p = 0.003), whereas lobar location, size, and density were comparable across the three groups. RET+ NSCLC was associated with a higher frequency of brain metastases at diagnosis compared to ROS1+ NSCLC (RET = 32%, ROS1 = 10%; p = 0.039. Metastatic patterns were otherwise similar across the three molecular subgroups, with high incidences of lymphangitic carcinomatosis, pleural metastases, and sclerotic bone metastases. RET+ NSCLC shares several distinct radiologic features and metastatic spread with ALK+ and ROS1+ NSCLC. These features may suggest the presence of RET fusions and help identify patients who may benefit from further molecular genotyping.
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genomic landscape of entrectinib resistance from ctdna analysis in startrk 2
Annals of Oncology, 2019Co-Authors: Robe C Doebele, Anna F Farago, Alice T Shaw, J. Wolf, Rafal Dziadziuszko, A Drilo, L Dennis, Todd Riehl, C W Chang, V ChoeurngAbstract:Abstract Background Entrectinib is a small molecule inhibitor of ROS1 and TRKA,B,C, with deep and durable responses observed in ROS1 fusion-positive NSCLC (ROS1+) and NTRK1,2,3 fusion-positive solid tumours (NTRK+). Despite clinically meaningful activity, progression on entrectinib eventually occurs. Understanding the mechanisms of resistance could inform subsequent new personalised therapeutic options in these patients. Methods Blood samples were collected at baseline and at the time of progression from most patients in the NTRK+ and ROS1+ patient populations enrolled on STARTRK-2 (NCT02568267). These were tested using the Foundation Medicine FoundationOne Liquid NGS-based test that assesses base substitutions, indels and rearrangements from 324 genes (including ROS1 and NTRK1,2,3), as well as copy number alterations from select genes using circulating tumour DNA (ctDNA) extracted from the plasma of patients from pre-treatment and following progression on entrectinib. Results Of the 54 patients with NTRK+ tumours, 29 had paired samples at baseline and at progression at the time of data cut-off. Ten patients (34%) had a detectable NTRK solvent front mutation at disease progression (NTRK1: n = 5; NTRK3: n = 5), which were not detected in the pre-treatment sample. BRAF V600E and KRAS G12D mutations were detected at progression from a pancreatic cancer patient who had a partial response. Of the 53 patients with ROS1+ NSCLC, 18 had paired samples at baseline and at progression at the time of data cut-off. Four CD74-ROS1 and one SLC34A2-ROS1 patients showed the emergence of an acquired ROS1 resistance mutation (G2032R and F2004C/I) at disease progression (28%), which were not present before treatment. One NRAS Q61K mutation was detected at the end of treatment collection sample from a patient who had a partial response. Conclusions From blood analysis, acquired resistance mutations were detected in 34% of NTRK+ solid tumour and 28% of the ROS1+ NSCLC cohorts, all of which were mutations in the kinase domain of the oncogenic driver. One additional patient from each cohort showed the emergence of a mutation in an oncogene within the MAPK pathway. Resistance to entrectinib can occur by multiple mechanisms, which should be studied in larger cohorts. Clinical trial identification NCT02568267. Legal entity responsible for the study F. Hoffman-La Roche. Funding F. Hoffman-La Roche. Disclosure R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (self), Research grant / Funding (institution): Ignyta, Loxo, Mirati.; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond.. R. Dziadziuszko: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Travels: Roche, AstraZeneca. A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health; Research grant / Funding (institution): Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Research grant / Funding (self): Foundation Medicine; Travel / Accommodation / Expenses: Merck - Food/Beverage, Puma - Food/Beverage; Honoraria (self): Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice. A. Shaw : Honoraria (self), Advisory / Consultancy: ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, Natera, Novartis, Pfizer, Taiho Pharmaceutical, Takeda, and TP Therapeutics; Research grant / Funding (institution): Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche/Genentech, and TP Therapeutics. J. Wolf: Advisory / Consultancy, Officer / Board of Directors: AbbVie, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Takeda; Research grant / Funding (institution): BMS, Jannsen, MSD, Novartis, Pfizer. A.F. Farago: Research grant / Funding (institution): AstraZeneca, AbbVie, Genentech, BMS, Merck, PharmaMar, Amgen, Bayer, Loxo, Ignyta; Advisory / Consultancy: Genentech, Bayer, AbbVie, AstraZeneca, Boehringer Ingelheim, Loxo, PharmaMar. L. Dennis: Research grant / Funding (institution), Full / Part-time employment: Foundation Medicine. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. B. Simmons: Full / Part-time employment: Roche. C. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. C. Chang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. V. Choeurng: Full / Part-time employment: Genentech, Inc. T.R. Wilson: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech.
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crizotinib in ROS1 rearranged advanced non small cell lung cancer nsclc updated results including overall survival from profile 1001
Annals of Oncology, 2019Co-Authors: Alice T Shaw, Gregory J Riely, Benjamin Solomon, Geoffrey I Shapiro, Yungjue Bang, Marileila Varellagarcia, Dongwan Kim, D R Camidge, A J Iafrate, Tiziana UsariAbstract:ABSTRACT Background In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001. Patients and methods ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250mg twice daily. Results Fifty-three patients received crizotinib, with a median duration of treatment of 22.4months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7months; 95% CI, 15.2–45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3months (95% CI, 15.2–39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment. Conclusions These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup. Trial Registration Number ClinicalTrials.gov identifier NCT00585195
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abstract 4766 the global ROS1 initiative a patient researcher partnership generating open source oncogene driven cancer models and data
Cancer Research, 2018Co-Authors: Janet Freemandaily, Alice T Shaw, Lisa Goldman, Tori Tomalia, Christine M Lovly, Manali I Patel, Bonne J Addario, Guneet Walia, Steven W Young, Robert C DoebeleAbstract:Background: Genomic fusions between ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) and more than 20 genes drive many types of cancer. Only a handful of ROS1-positive (ROS1+) cancer models exist to use in research and developing new treatments. Few research facilities encounter ROS1+ patients–the incidence of ROS1+ cancer is only 1% to 2% in non-small cell lung cancer (NSCLC) and ROS1 testing is rarely done in other cancers. To address this, a group of ROS1+ patients and caregivers (“the ROS1ders") collaborated with advocacy organizations, researchers and industry to form the Global ROS1 Initiative. Methods: The ROS1ders and partners informed patients, caregivers, and clinicians of the initiative through social media, patient blogs, websites, distribution of fliers in several languages at cancer conferences, and contacts with their clinicians. The ROS1der online community shared ROS1+ information about treatment options and side effects, expert clinicians, clinical trials, research and general support. An epidemiologic survey captured data about ROS1 patient histories and treatments. When a member in the ROS1der community shared news of an upcoming surgery, biopsy or thoracentesis, a ROS1der leader told them of an opportunity to donate excess fresh specimens to create cancer models. Tumor samples and resulting cell lines underwent drug testing and sequencing for mechanisms of resistance. Results: The ROS1ders members include 166 patients (more than twice the largest ROS1 clinical trial cohort to date) from 16 countries representing 6 types of ROS1+ cancer. Four attempted fresh specimen donations resulted in 2 new ROS1+ cells lines, CUTO27 (CD74-ROS1) and CUTO28 (TPM3-ROS1). These cell lines have already been distributed to academic and industry partners to increase the value of these rare resources. The ROS1ders shared study results within their online group. The Initiative is now working to continue the longitudinal epidemiologic survey and create clinical studies that will generate ROS1+ cell lines and/or patient-derived xenograft (PDX) mouse models. We will conduct genomic analysis of the models to determine the presence of resistance mutations as well as ROS1 pairing partner genes. The resultant renewable tissue resources of PDX models and cell lines, when linked to the clinically annotated genomic database, will be broadly shared to help clinical and translational research understand mechanisms of response and resistance to therapies, and assist in drug development. Conclusions: This project demonstrates that partnerships between patient-caregiver groups, advocacy groups, researchers and industry, combined with social media outreach, can increase the available oncogene-driven patient data, specimens, and cancer models in small, geographically distributed patient populations. Citation Format: Janet Freeman-Daily, Lisa Goldman, Tori Tomalia, The ROS1ders, Christine M. Lovly, Manali I. Patel, Alice T. Shaw, Bonne J. Addario, Guneet Walia, Steven W. Young, Robert C. Doebele. The Global ROS1 Initiative: A patient-researcher partnership generating open-source, oncogene-driven cancer models and data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4766.
Justin F Gainor - One of the best experts on this subject based on the ideXlab platform.
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resistance to lorlatinib in ROS1 fusion positive non small cell lung cancer
Journal of Clinical Oncology, 2020Co-Authors: Jessica J Lin, Ibiayi Dagogojack, Charlotte E Lee, Justin F Gainor, Harper Hubbeling, Theodore O Johnson, Jochen K Lennerz, Beow Y Yeap, Alice T ShawAbstract:9611Background: Lorlatinib is a potent, brain-penetrant ROS1/ALK tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer...
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imaging features and patterns of metastasis in non small cell lung cancer with ret rearrangements
Cancers, 2020Co-Authors: Subba R Digumarthy, Jessica J Lin, Marguerite Rooney, Emily Chin, Alice T Shaw, Beow Y Yeap, Dexter P Mendoza, Justin F GainorAbstract:Rearranged during transfection proto-oncogene (RET) fusions represent a potentially targetable oncogenic driver in non-small cell lung cancer (NSCLC). Imaging features and metastatic patterns of advanced RET fusion-positive (RET+) NSCLC are not well established. Our goal was to compare the imaging features and patterns of metastases in RET+, ALK+ and ROS1+ NSCLC. Patients with RET+, ALK+, or ROS1+ NSCLC seen at our institution between January 2014 and December 2018 with available pre-treatment imaging were identified. The clinicopathologic features, imaging characteristics, and the distribution of metastases were reviewed and compared. We identified 215 patients with NSCLC harboring RET, ALK, or ROS1 gene fusion (RET = 32; ALK = 116; ROS1 = 67). Patients with RET+ NSCLC were older at presentation compared to ALK+ and ROS1+ patients (median age: RET = 64 years; ALK = 51 years, p < 0.001; ROS = 54 years, p = 0.042) and had a higher frequency of neuroendocrine histology (RET = 12%; ALK = 2%, p = 0.025; ROS1 = 0%, p = 0.010). Primary tumors in RET+ patients were more likely to be peripheral (RET = 69%; ALK = 47%, p = 0.029; ROS1 = 36%, p = 0.003), whereas lobar location, size, and density were comparable across the three groups. RET+ NSCLC was associated with a higher frequency of brain metastases at diagnosis compared to ROS1+ NSCLC (RET = 32%, ROS1 = 10%; p = 0.039. Metastatic patterns were otherwise similar across the three molecular subgroups, with high incidences of lymphangitic carcinomatosis, pleural metastases, and sclerotic bone metastases. RET+ NSCLC shares several distinct radiologic features and metastatic spread with ALK+ and ROS1+ NSCLC. These features may suggest the presence of RET fusions and help identify patients who may benefit from further molecular genotyping.
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lorlatinib in non small cell lung cancer with alk or ROS1 rearrangement an international multicentre open label single arm first in man phase 1 trial
Lancet Oncology, 2017Co-Authors: Alice T Shaw, Justin F Gainor, Benjamin Besse, Enriqueta Felip, Todd Michael Bauer, Alejandro Navarro, Sophie Postelvinay, Melissa Lynne Johnson, Jorg Dietrich, Leonard P JamesAbstract:Summary Background Most patients with anaplastic lymphoma kinase ( ALK )-rearranged or ROS proto-oncogene 1 ( ROS1 )-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK -positive or ROS1 -positive NSCLC. Methods In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK -positive or ROS1 -positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Findings Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK -positive and 12 (23%) with ROS1 -positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK -positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63). In ROS1 -positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79). Interpretation In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK -positive or ROS1 -positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK -positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Funding Pfizer.
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lorlatinib in non small cell lung cancer with alk or ROS1 rearrangement an international multicentre open label single arm first in man phase 1 trial
Lancet Oncology, 2017Co-Authors: Alice T Shaw, Justin F Gainor, Benjamin Besse, Enriqueta Felip, Todd Michael Bauer, Alejandro Navarro, Sophie Postelvinay, Melissa Lynne JohnsonAbstract:Summary Background Most patients with anaplastic lymphoma kinase ( ALK )-rearranged or ROS proto-oncogene 1 ( ROS1 )-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK -positive or ROS1 -positive NSCLC. Methods In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK -positive or ROS1 -positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Findings Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK -positive and 12 (23%) with ROS1 -positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK -positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63). In ROS1 -positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79). Interpretation In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK -positive or ROS1 -positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK -positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Funding Pfizer.
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patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1 positive non small cell lung cancer
JCO Precision Oncology, 2017Co-Authors: Justin F Gainor, Jessica J Lin, Satoshi Yoda, Ibiayi Dagogojack, Diane Tseng, Luc Friboulet, Harper Hubbeling, Leila Dardaei, Anna F Farago, Katherine SchultzAbstract:PurposeThe ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1% to 2% of non–small-cell lung cancers (NSCLCs), which confer sensitivity to treatment with the anaplastic lymphoma kinase (ALK)/ROS1/mesenchymal-epithelial transition factor inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among patients with ROS1-positive disease are limited.Patients and MethodsWe reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we analyzed repeat biopsy specimens from a cohort of patients with ROS1-positive disease who progressed on crizotinib.ResultsWe identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. Patients with ROS1-positive disease had significantly lower rates of extrathoracic metastases (ROS1, 59.0%; ALK, 83.2%; P = ...
Benjamin Besse - One of the best experts on this subject based on the ideXlab platform.
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lorlatinib in non small cell lung cancer with alk or ROS1 rearrangement an international multicentre open label single arm first in man phase 1 trial
Lancet Oncology, 2017Co-Authors: Alice T Shaw, Justin F Gainor, Benjamin Besse, Enriqueta Felip, Todd Michael Bauer, Alejandro Navarro, Sophie Postelvinay, Melissa Lynne Johnson, Jorg Dietrich, Leonard P JamesAbstract:Summary Background Most patients with anaplastic lymphoma kinase ( ALK )-rearranged or ROS proto-oncogene 1 ( ROS1 )-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK -positive or ROS1 -positive NSCLC. Methods In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK -positive or ROS1 -positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Findings Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK -positive and 12 (23%) with ROS1 -positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK -positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63). In ROS1 -positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79). Interpretation In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK -positive or ROS1 -positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK -positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Funding Pfizer.
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lorlatinib in non small cell lung cancer with alk or ROS1 rearrangement an international multicentre open label single arm first in man phase 1 trial
Lancet Oncology, 2017Co-Authors: Alice T Shaw, Justin F Gainor, Benjamin Besse, Enriqueta Felip, Todd Michael Bauer, Alejandro Navarro, Sophie Postelvinay, Melissa Lynne JohnsonAbstract:Summary Background Most patients with anaplastic lymphoma kinase ( ALK )-rearranged or ROS proto-oncogene 1 ( ROS1 )-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK -positive or ROS1 -positive NSCLC. Methods In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK -positive or ROS1 -positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Findings Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK -positive and 12 (23%) with ROS1 -positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK -positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63). In ROS1 -positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79). Interpretation In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK -positive or ROS1 -positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK -positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Funding Pfizer.
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efficacy and safety of lorlatinib in patients pts with alk non small cell lung cancer nsclc with one or more prior alk tyrosine kinase inhibitor tki a phase i ii study
Journal of Clinical Oncology, 2017Co-Authors: Alice T Shaw, Ross D Camidge, Ross A. Soo, Benjamin Besse, Takashi Seto, Enriqueta Felip, Todd M Bauer, Shirish M Gadgeel, Chiachi Lin, Rita ChiariAbstract:9006Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were eva...
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crizotinib resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1 and alk rearranged lung cancers
Clinical Cancer Research, 2016Co-Authors: Francesco Facchinetti, Yohann Loriot, Meishiue Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Francoise FaraceAbstract:Background: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non–small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far. Methods: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)–ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations. Results: Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient9s clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations. Conclusions: Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983–91. ©2016 AACR.
Myungju Ahn - One of the best experts on this subject based on the ideXlab platform.
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repotrectinib tpx 0005 is a next generation ROS1 trk alk inhibitor that potently inhibits ROS1 trk alk solvent front mutations
Cancer Discovery, 2018Co-Authors: Alexander Drilon, Ross D Camidge, Jessica J Lin, Myungju Ahn, Viola W Zhu, Byoung Chul Cho, Dongwan Kim, Jeeyun Lee, Judy Nguyen, Dayong ZhaiAbstract:The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA–C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1–3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA–C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion–positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. SIGNIFICANCE: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1–3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1–3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1–10. ©2018 AACR.
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safety and antitumor activity of the multitargeted pan trk ROS1 and alk inhibitor entrectinib combined results from two phase i trials alka 372 001 and startrk 1
Cancer Discovery, 2017Co-Authors: Alexander Drilon, Myungju Ahn, Anna F Farago, Jeeyun Lee, Todd Michael Bauer, Salvatore Siena, Manish Patel, Jennifer J Wheler, Stephen V Liu, Robert C DoebeleAbstract:Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naive to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.
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phase ii study of crizotinib in east asian patients pts with ROS1 positive advanced non small cell lung cancer nsclc
Journal of Clinical Oncology, 2016Co-Authors: Koichi Goto, Myungju Ahn, Dongwan Kim, James Chihhsin Yang, Takashi Seto, Jinji Yang, Noboru Yamamoto, Toshiaki Takahashi, Takeharu Yamanaka, Allison KemnerAbstract:9022Background: Approximately 1–2% of NSCLCs harbor a rearrangement of the ROS1 gene, an oncogene for which screening is difficult due to its low incidence. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, showed marked antitumor activity in ROS1-positive advanced NSCLC (Shaw, N Engl J Med 2014). In the present study, we assessed the antitumor activity and safety of crizotinib in East Asian pts with ROS1-positive advanced NSCLC. Methods: In this ongoing open-label, single-arm phase II study (NCT01945021), pts with ROS1-positive, ALK-negative advanced NSCLC who had received ≤ 3 lines of prior systemic therapy were administered crizotinib at a starting dose of 250 mg BID. Treatment was continued until RECIST-defined progression (determined by independent radiology review [IRR]), unacceptable toxicity, or withdrawal of consent, or at the investigator’s discretion for ongoing clinical benefit. The primary endpoint was ORR by IRR. Results: Between September 2013 and January 2015, 12...
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phase ii study of crizotinib in east asian patients with ROS1 positive advanced non small cell lung cancer
Journal of Clinical Oncology, 2016Co-Authors: James Chihhsin Yang, Myungju Ahn, Dongwan Kim, Takashi Seto, Jinji Yang, Noboru Yamamoto, Toshiaki Takahashi, Takeharu Yamanaka, Jianying Zhou, Allison KemnerAbstract:Purpose Approximately 1% to 2% of non-small-cell lung cancers (NSCLCs) harbor a c-ros oncogene 1 ( ROS1) rearrangement. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, has shown marked antitumor activity in a small expansion cohort of patients with ROS1-positive advanced NSCLC from an ongoing phase I study. We assessed the efficacy and safety of crizotinib in the largest cohort of patients with ROS1-positive advanced NSCLC. Patients and Methods This phase II, open-label, single-arm trial enrolled East Asian patients with ROS1-positive (assessed through validated AmoyDx assay [Amoy Diagnostics, Xiamen, China] at three regional laboratories) advanced NSCLC who had received three or fewer lines of prior systemic therapies. Patients were to receive oral crizotinib at a starting dose of 250 mg twice daily and continued treatment until Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1-defined progression (by independent radiology review [IRR]), unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) by IRR. Results In the efficacy and safety analyses, 127 patients were included, with 49.6% still receiving treatment at data cutoff. ORR by IRR was 71.7% (95% CI, 63.0% to 79.3%), with 17 complete responses and 74 partial responses. ORRs were similar irrespective of the number of prior lines of therapy, and responses were durable (median duration of response, 19.7 months; 95% CI, 14.1 months to not reached). Median progression-free survival by IRR was 15.9 months (95% CI, 12.9 to 24.0 months). No new safety signals associated with crizotinib were reported. Conclusion This study demonstrated clinically meaningful benefit and durable responses with crizotinib in East Asian patients with ROS1-positive advanced NSCLC. Crizotinib was generally well tolerated, with a safety profile consistent with previous reports.
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will the requirement by the us fda to simultaneously co develop companion diagnostics cdx delay the approval of receptor tyrosine kinase inhibitors for rtk rearranged ROS1 ret axl pdgfr α ntrk1 non small cell lung cancer globally
Frontiers in Oncology, 2014Co-Authors: Ross A. Soo, Akihito Kubo, Tomoya Kawaguchi, Myungju AhnAbstract:The discovery of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) in 2007 and the approval of crizotinib for the treatment of advanced ALK-rearranged NSCLC in 2011 represents a landmark in the development of targeted oncology therapy. The approval of crizotinib was accompanied simultaneously by the approval of approval of the Vysis (Abbott Molecular) break-apart fluorescence in situ hybridization test as the companion diagnostic (CDx) test to detect ALK rearrangement. Pfizer, the manufacturer of crizotinib, sponsored the screening of thousands of patients and the standardization of the ALK FISH test as part of the approval process for crizotinib, a first in class ALK inhibitor. Many pharmaceutical companies are now using the FDA-approved ALK FISH assay to enroll patients onto trials for their own respective ALK inhibitors. In essence they are “piggybacking” on the FDA-approved ALK FISH assay without having to pay for the development of a CDx, nor screening for ALK-rearranged NSCLC patients in the protocols because screening for ALK rearrangement is now the standard of care in NSCLC after the approval of crizotinib. Since 2007, rearrangement in more RTKs such as ROS1, RET, AXL, PDGFR-α, and NTRK1 have been discovered in NSCLC but the incidence of each subtype of RTK-rearranged NSCLC is quite rare. Crizotinib has now demonstrated significant clinical activity in ROS1-rearranged NSCLC patients. Whether crizotinib will gain official FDA approval for use in ROS1-rearranged NSCLC, on the other hand, remains unclear as there is no test for ROS1 rearrangement currently being developed to support US FDA approval as a CDx. This may be due in part to the fact that the full cost associated with the development of a pre-market approved (PMA)-approved CDx must be borne by the company seeking the first drug approval in a new indication. Given the low incidence of ROS1 rearrangement in NSCLC, and the availability of crizotinib in most countries
Dongwan Kim - One of the best experts on this subject based on the ideXlab platform.
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an international real world analysis of the efficacy and safety of lorlatinib through early or expanded access programs in patients with tyrosine kinase inhibitor refractory alk positive or ROS1 positive nsclc
Journal of Thoracic Oncology, 2020Co-Authors: Viola W Zhu, Dongwan Kim, Yenting Lin, Herbert H Loong, Misako Nagasaka, Yvonne Lien Ang, Chan Young Ock, Nishan Tchekmedyian, Nicholas Syn, Thanyanan ReungwetwattanaAbstract:Abstract Introduction Lorlatinib, a next-generation central nervous system–penetrant ALK/ROS1 tyrosine kinase inhibitor (TKI), is approved to treat TKI-refractory ALK-positive (ALK+) NSCLC based on results from a phase 2 study. Methods A real-world analysis was performed on ALK+ or ROS1-positive (ROS1+) patients with NSCLC enrolled in lorlatinib early or expanded access programs in Hong Kong, Singapore, South Korea, Taiwan, Thailand, and the United States. Results A total of 95 patients with NSCLC (76 ALK+ and 19 ROS1+) were analyzed. Among ALK+ patients treated with less than two previous TKIs, two or more previous TKIs, and three or more previous TKIs, the objective response rates (ORR) and median progression-free survival (mPFS) were 42% (95% confidence interval [CI]: 26–59; n = 38) and not reached (NR) (95% CI: 4.5–NR; n = 45), 35% (95% CI: 22–49; n = 55) and 11.2 months (95% CI: 4.5–NR; n = 66), and 18% (95% CI: 4–43; n = 17) and 6.5 months (95% CI: 3.5–11.6; n = 21), respectively. The ORRs and mPFSs were 13% (95% CI: 0–53; n = 8) and 9.2 months (95% CI: 3.3–NR; n = 9) for patients treated with one second-generation ALK TKI as the only ALK TKI received. For ROS1+ patients, ORRs and mPFSs were 41% (95% CI: 18–67; n = 17) and 11.9 months (95% CI: 6.4–NR; n = 19). The intracranial ORRs were 35% (95% CI: 22–49) and 55% (95% CI: 23–83) for 52 ALK+ and 11 ROS1+ patients. mPFS was 9.3 months (95% CI: 1.0–NR; n = 13) for patients with leptomeningeal carcinomatosis. No new safety signals were noted. Conclusion Lorlatinib exhibited meaningful activity in TKI-refractory ALK+ or ROS1+ patients with NSCLC enrolled in early or expanded access programs.
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crizotinib in ROS1 rearranged advanced non small cell lung cancer nsclc updated results including overall survival from profile 1001
Annals of Oncology, 2019Co-Authors: Alice T Shaw, Gregory J Riely, Benjamin Solomon, Geoffrey I Shapiro, Yungjue Bang, Marileila Varellagarcia, Dongwan Kim, D R Camidge, A J Iafrate, Tiziana UsariAbstract:ABSTRACT Background In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001. Patients and methods ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250mg twice daily. Results Fifty-three patients received crizotinib, with a median duration of treatment of 22.4months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7months; 95% CI, 15.2–45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3months (95% CI, 15.2–39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment. Conclusions These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup. Trial Registration Number ClinicalTrials.gov identifier NCT00585195
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repotrectinib tpx 0005 is a next generation ROS1 trk alk inhibitor that potently inhibits ROS1 trk alk solvent front mutations
Cancer Discovery, 2018Co-Authors: Alexander Drilon, Ross D Camidge, Jessica J Lin, Myungju Ahn, Viola W Zhu, Byoung Chul Cho, Dongwan Kim, Jeeyun Lee, Judy Nguyen, Dayong ZhaiAbstract:The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA–C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1–3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA–C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion–positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. SIGNIFICANCE: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1–3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1–3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1–10. ©2018 AACR.
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phase ii study of crizotinib in east asian patients pts with ROS1 positive advanced non small cell lung cancer nsclc
Journal of Clinical Oncology, 2016Co-Authors: Koichi Goto, Myungju Ahn, Dongwan Kim, James Chihhsin Yang, Takashi Seto, Jinji Yang, Noboru Yamamoto, Toshiaki Takahashi, Takeharu Yamanaka, Allison KemnerAbstract:9022Background: Approximately 1–2% of NSCLCs harbor a rearrangement of the ROS1 gene, an oncogene for which screening is difficult due to its low incidence. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, showed marked antitumor activity in ROS1-positive advanced NSCLC (Shaw, N Engl J Med 2014). In the present study, we assessed the antitumor activity and safety of crizotinib in East Asian pts with ROS1-positive advanced NSCLC. Methods: In this ongoing open-label, single-arm phase II study (NCT01945021), pts with ROS1-positive, ALK-negative advanced NSCLC who had received ≤ 3 lines of prior systemic therapy were administered crizotinib at a starting dose of 250 mg BID. Treatment was continued until RECIST-defined progression (determined by independent radiology review [IRR]), unacceptable toxicity, or withdrawal of consent, or at the investigator’s discretion for ongoing clinical benefit. The primary endpoint was ORR by IRR. Results: Between September 2013 and January 2015, 12...
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phase ii study of crizotinib in east asian patients with ROS1 positive advanced non small cell lung cancer
Journal of Clinical Oncology, 2016Co-Authors: James Chihhsin Yang, Myungju Ahn, Dongwan Kim, Takashi Seto, Jinji Yang, Noboru Yamamoto, Toshiaki Takahashi, Takeharu Yamanaka, Jianying Zhou, Allison KemnerAbstract:Purpose Approximately 1% to 2% of non-small-cell lung cancers (NSCLCs) harbor a c-ros oncogene 1 ( ROS1) rearrangement. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, has shown marked antitumor activity in a small expansion cohort of patients with ROS1-positive advanced NSCLC from an ongoing phase I study. We assessed the efficacy and safety of crizotinib in the largest cohort of patients with ROS1-positive advanced NSCLC. Patients and Methods This phase II, open-label, single-arm trial enrolled East Asian patients with ROS1-positive (assessed through validated AmoyDx assay [Amoy Diagnostics, Xiamen, China] at three regional laboratories) advanced NSCLC who had received three or fewer lines of prior systemic therapies. Patients were to receive oral crizotinib at a starting dose of 250 mg twice daily and continued treatment until Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1-defined progression (by independent radiology review [IRR]), unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) by IRR. Results In the efficacy and safety analyses, 127 patients were included, with 49.6% still receiving treatment at data cutoff. ORR by IRR was 71.7% (95% CI, 63.0% to 79.3%), with 17 complete responses and 74 partial responses. ORRs were similar irrespective of the number of prior lines of therapy, and responses were durable (median duration of response, 19.7 months; 95% CI, 14.1 months to not reached). Median progression-free survival by IRR was 15.9 months (95% CI, 12.9 to 24.0 months). No new safety signals associated with crizotinib were reported. Conclusion This study demonstrated clinically meaningful benefit and durable responses with crizotinib in East Asian patients with ROS1-positive advanced NSCLC. Crizotinib was generally well tolerated, with a safety profile consistent with previous reports.
