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Validating ROS1 Rearrangements As a Therapeutic Target in Non–Small-Cell Lung Cancer Benjamin Solomon, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia See accompanying article on page 992
Initially thought to be prevalent predominantly in hematologic malignancies and sarcomas, chromosomal rearrangements leading to oncogenic gene fusions have now been described across a range of epithelial cancers, including non–small-cell lung cancer (NSCLC).1 In 2007, rearrangements involving the anaplastic lymphoma kinase (ALK) gene were described in NSCLC.2,3 Single-arm phase I and II studies led to accelerated approval of the first-in-class ALK inhibitor crizotinib for ALK-rearranged NSCLC. Two phase III studies confirmed the superiority of crizotinib over chemotherapy,4,5 establishing crizotinib as a standard of care for patients with NSCLC whose tumors test positive for ALK gene rearrangements. In the article that accompanies this editorial, Mazières et al6 report the therapeutic efficacy of targeting a second gene rearrangement in NSCLC with crizotinib, this time involving the ROS1 gene. ROS1 is an orphan receptor tyrosine kinase encoded by the ROS1 gene that is vulnerable to intrachromosomal or interchromosomal rearrangements, resulting in transforming gene fusions that occur in tumor types including glioblastomas,7 NSCLC,3 cholangiocarcinoma,8-10 ovarian cancer,11 gastric cancer,12 and colorectal cancer.13 ROS1 gene rearrangements were first recognized in NSCLC in 20073 and have since been described in 1% to 2% of patients with NSCLC.14,15 At least 11 fusion partners have been identified in NSCLC, including CD74-ROS1, SDC4-ROS1, EZR-ROS1, and SLC34A2-ROS1, all of which maintain a constant breakpoint in ROS1, preserving the kinase domain and resulting in aberrant ROS1 expression with constitutive kinase activity. These rearrangements may be detected in clinical samples by a variety of techniques, including fluorescent in situ hybridization,16 immunohistochemistry,17 reverse-transcriptase polymerase chain reaction, and next-generation sequencing. Patients with ROS1-rearranged NSCLC share many clinical features in common with ALK-rearranged NSCLC in that they are typically younger, are never-smokers, and have tumors with adenocarcinoma histology.14,15 ROS1 and ALK share substantial sequence homology in their kinase domains. Crizotinib, also a potent inhibitor of the ROS1 kinase, has activity in preclinical ROS1-rearranged NSCLC models,16,18,19 providing a rationale for its evaluation in patients with ROS1-rearranged NSCLC. Since the initial report published in Journal of Clinical Oncology in 2012 of a dramatic response to crizotinib in a 31-year-old male neversmoker whose tumor tested positive for a ROS1 gene rearrangement,16 there have been additional case reports indicating activity of crizotinib in this setting.18,20-23 Mazières et al6 now provide a substan972
© 2015 by American Society of Clinical Oncology
tial addition to the body of evidence indicating efficacy of targeting ROS1 rearrangements in NSCLC with crizotinib. In this retrospective study, conducted in 16 centers in six countries in Europe, results are presented from 32 patients with ROS1 rearrangement–positive NSCLC who received off-label treatment with crizotinib. Consistent with previous descriptions, patients were predominantly young (median age, 50.5 years), were never-smokers, and had tumors with adenocarcinoma histology. An impressive response rate of 80%, with a median progression-free survival (PFS) of 9.1 months, was seen in this European cohort of patients with ROS1-rearranged NSCLC treated with crizotinib. Mazières et al6 are to be commended on coordinating an international collaborative study, which although subject to limitations related to sample size, potential for selection bias, and reliance on investigator assessments of response, complements and provides independent validation of a recent report by Shaw et al24 of patients with ROS1-rearranged NSCLC prospectively treated in the molecularly enriched expansion cohort of the crizotinib phase I trial. This ongoing study conducted in the United States, Korea, and Australia enrolled 50 patients with NSCLC with ROS1 gene rearrangements and reported an objective response rate to crizotinib of 72% (95% CI, 58% to 84%), with a median PFS of 19.2 months (95% CI, 14.4 to not reached). No obvious relationship between ROS1 fusion partner and durability of response to crizotinib was demonstrated. The response rate to crizotinib observed in these two independent studies (80% and 72%) confirms that ROS1 rearrangement– positive NSCLC, like ALK-rearranged or EGFR mutation–positive NSCLC, represents an oncogene-addicted tumor and validates ROS1 as a therapeutic target in NSCLC. Interestingly, although Shaw et al24 reported a median PFS of 19.2 months, raising the possibility that the durability of responses to crizotinib may be greater in ROS1 rearrangement–positive NSCLC compared with ALK rearrangement–positive NSCLC, Mazières et al6 report a more modest PFS of 9 months, similar to what has been observed in ALK-positive NSCLC. Although there are potential differences in the populations under evaluation in the studies, including, for example, the proportion of Asian patients in each study, the differences seem most likely attributable to sample size and duration of follow-up. The PFS data are relatively preliminary in both studies, with many patients still in follow-up; however, the prospective study by Shaw et al had a larger sample size and potentially longer duration of follow-up than the retrospective study of Mazières et al and may therefore provide a more precise estimate of PFS. Journal of Clinical Oncology, Vol 33, No 9 (March 20), 2015: pp 972-974
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OF SASKATCHEWAN on September 27, Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 2015 from 128.233.210.97
Editorial
Importantly, these two single-arm studies draw attention to broader challenges in the design and conduct of trials leading to regulatory approval of drugs active in populations with rare molecular drivers. The traditional pathway to approval involving a phase I study, followed by phaseIIandIIIstudies,maynotbepracticalorarguablyevennecessaryfor highly effective drugs targeting oncogenes such as ROS1. Accrual to ROS1-targeting clinical trials is hampered by the low frequency of ROS1 gene rearrangements and off-label availability of crizotinib, as reflected by the 3 years it took to enroll 50 patients onto the study by Shaw et al.24 Relatively small, well-designed, single-arm studies conducted in homogenous, biomarker-selected populations can provide adequate proof of concept to support approval of drugs, provided that they show large effects on relevant clinical end points, such as overall response rate or PFS, obviating the need for a phase III study.25,26 Indeed, many oncology approvals by the US Food and Drug Administration in similar settings have been based on nonrandomized studies using the primary end point of overall response rate,27 with good records of efficacy and safety beyond initial approval.28 For drugs targeting other recently identified rare gene fusions in NSCLC, including those involving RET,29 NTRK1,30 NRG1,31 FGFR1,32 and FGFR3,32,33 which occur with frequencies below 1%, the challenge for regulatory approval is even greater. However, the demonstrated feasibility and effectiveness of large-scale, multiplex, molecular-testing efforts in lung cancer to identify patients with rare molecular drivers and link them to appropriate clinical trials, such as was done by the Lung Cancer Mutational Consortium34 or in the French national testing program,35 indicate that this is not an impossible task. The recently launched Lung Cancer Master Protocol (LungMAP) clinical trial (ClinicalTrials.gov identifier NCT02154490) will under one protocol simultaneously evaluate multiple drugs directed at multiple targets in parallel phase II and III trials, with patient allocation to treatment arm based on genomic results from a nextgeneration sequencing platform. These phase II and III studies are specifically designed with the aim of regulatory approval of the agent under study, together with the relevant companion diagnostic. This approach holds promise for accelerating the evaluation and approval of targeted therapies in biomarker-defined populations in lung cancer and can serve as a model for trials in rare populations within other malignancies. The validation of ROS1 gene rearrangements as an actionable target in NSCLC, along with EGFR mutations and ALK gene rearrangements, confirms the value of screening large populations to identify small groups with rare molecular drivers. Numerous other potentially targetable molecular drivers have been identified in even smaller subsets of patients with NSCLC. Although challenges remain in the implementation of multiplex testing strategies across populations, conduct of clinical trials, and regulatory approvals of targeted therapies and companion diagnostics, these obstacles no longer seem insurmountable. Continued progress toward precision medicine for NSCLC will require efficient and innovative strategies to transform more promising targets into validated treatments. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the author are available with this article at www.jco.org. REFERENCES 1. Shaw AT, Hsu PP, Awad MM, et al: Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 13:772-787, 2013 www.jco.org
2. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007 3. Rikova K, Guo A, Zeng Q, et al: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190-1203, 2007 4. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013 5. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014 6. Mazières J, Zalcman G, Crinò L, et al: Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 33:992-999, 2015 7. Birchmeier C, Sharma S, Wigler M: Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A 84:9270-9274, 1987 8. Peraldo Neia C, Cavalloni G, Balsamo A, et al: Screening for the FIG-ROS1 fusion in biliary tract carcinomas by nested PCR. Genes Chromosomes Cancer 53:1033-1040, 2014 9. Liu P, Wu Y, Sun L, et al: ROS kinase fusions are not common in Chinese patients with cholangiocarcinoma. Nan Fang Yi Ke Da Xue Xue Bao 33:474-478, 2013 10. Gu TL, Deng X, Huang F, et al: Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PloS One 6:e15640, 2011 11. Birch AH, Arcand SL, Oros KK, et al: Chromosome 3 anomalies investigated by genome wide SNP analysis of benign, low malignant potential and low grade ovarian serous tumours. PloS One 6:e28250, 2011 12. Lee J, Lee SE, Kang SY, et al: Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer 119:1627-1635, 2013 13. Aisner DL, Nguyen TT, Paskulin DD, et al: ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers. Mol Cancer Res 12:111-118, 2014 14. Gainor JF, Shaw AT: Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18:865-875, 2013 15. Chin LP, Soo RA, Soong R, et al: 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 7:1625-1630, 2012 16. Bergethon K, Shaw AT, Ou SH, et al: ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863-870, 2012 17. Rimkunas VM, Crosby KE, Li D, et al: Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: Identification of a FIG-ROS1 fusion. Clin Cancer Res 18:4449-4457, 2012 18. Davies KD, Le AT, Theodoro MF, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 18:4570-4579, 2012 19. Yasuda H, de Figueiredo-Pontes LL, Kobayashi S, et al: Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. J Thorac Oncol 7:1086-1090, 2012 20. Bos M, Gardizi M, Schildhaus HU, et al: Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer 81:142-143, 2013 21. Awad MM, Katayama R, McTigue M, et al: Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395-2401, 2013 22. Chiari R, Buttitta F, Iacono D, et al: Dramatic response to crizotinib in ROS1 fluorescent in situ hybridization- and immunohistochemistry-positive lung adenocarcinoma: A case series. Clin Lung Cancer 15:470-474, 2014 23. Li H, Pan Y, Wang R, et al: Response to crizotinib observed in metastatic mediastinum lymph node from a non-small cell lung cancer patient harboring EZR-ROS1 fusion. J Cancer Res Clin Oncol 141:185-187, 2015 24. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-smallcell lung cancer. N Engl J Med 371:1963-1971, 2014 25. Chabner BA: Early accelerated approval for highly targeted cancer drugs. N Engl J Med 364:1087-1089, 2011 26. Sharma MR, Schilsky RL: Role of randomized phase III trials in an era of effective targeted therapies. Nat Rev Clin Oncol 9:208-214, 2012 27. Gaddipati H, Liu K, Pariser A, et al: Rare cancer trial design: Lessons from FDA approvals. Clin Cancer Res 18:5172-5178, 2012 28. Tsimberidou AM, Braiteh F, Stewart DJ, et al: Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. J Clin Oncol 27:6243-6250, 2009 29. Lipson D, Capelletti M, Yelensky R, et al: Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18:382-384, 2012 30. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19:1469-1472, 2013 31. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-422, 2014 32. Wang R, Wang L, Li Y, et al: FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer. Clin Cancer Res 20:4107-4114, 2014
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OF SASKATCHEWAN on September 27, Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 2015 from 128.233.210.97
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33. Capelletti M, Dodge ME, Ercan D, et al: Identification of recurrent FGFR3TACC3 fusion oncogenes from lung adenocarcinoma. Clin Cancer Res 20:65516558, 2014 34. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:19982006, 2014
35. Nowak F, Calvo F, Soria JC: Europe does it better: Molecular testing across a national health care system—The French example. Am Soc Clin Oncol Educ Book 2013:332-337, 2013
DOI: 10.1200/JCO.2014.59.8334; published online ahead of print at www.jco.org on February 9, 2015
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JOURNAL OF CLINICAL ONCOLOGY
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Editorial
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Validating ROS1 Rearrangements As a Therapeutic Target in Non–Small-Cell Lung Cancer The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Benjamin J. Solomon Consulting or Advisory Role: Pfizer, Novartis, Roche/Genentech, Clovis Oncology, Merck, Bristol-Myers Squibb, AstraZeneca
www.jco.org
Research Funding: Pfizer (Inst) Travel, Accommodations, Expenses: Roche/Genentech
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OF SASKATCHEWAN on September 27, Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 2015 from 128.233.210.97
33
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MARCH
20
2015
JOURNAL OF CLINICAL ONCOLOGY
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Validating ROS1 Rearrangements As a Therapeutic Target in Non–Small-Cell Lung Cancer Benjamin Solomon, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia See accompanying article on page 992
Initially thought to be prevalent predominantly in hematologic malignancies and sarcomas, chromosomal rearrangements leading to oncogenic gene fusions have now been described across a range of epithelial cancers, including non–small-cell lung cancer (NSCLC).1 In 2007, rearrangements involving the anaplastic lymphoma kinase (ALK) gene were described in NSCLC.2,3 Single-arm phase I and II studies led to accelerated approval of the first-in-class ALK inhibitor crizotinib for ALK-rearranged NSCLC. Two phase III studies confirmed the superiority of crizotinib over chemotherapy,4,5 establishing crizotinib as a standard of care for patients with NSCLC whose tumors test positive for ALK gene rearrangements. In the article that accompanies this editorial, Mazières et al6 report the therapeutic efficacy of targeting a second gene rearrangement in NSCLC with crizotinib, this time involving the ROS1 gene. ROS1 is an orphan receptor tyrosine kinase encoded by the ROS1 gene that is vulnerable to intrachromosomal or interchromosomal rearrangements, resulting in transforming gene fusions that occur in tumor types including glioblastomas,7 NSCLC,3 cholangiocarcinoma,8-10 ovarian cancer,11 gastric cancer,12 and colorectal cancer.13 ROS1 gene rearrangements were first recognized in NSCLC in 20073 and have since been described in 1% to 2% of patients with NSCLC.14,15 At least 11 fusion partners have been identified in NSCLC, including CD74-ROS1, SDC4-ROS1, EZR-ROS1, and SLC34A2-ROS1, all of which maintain a constant breakpoint in ROS1, preserving the kinase domain and resulting in aberrant ROS1 expression with constitutive kinase activity. These rearrangements may be detected in clinical samples by a variety of techniques, including fluorescent in situ hybridization,16 immunohistochemistry,17 reverse-transcriptase polymerase chain reaction, and next-generation sequencing. Patients with ROS1-rearranged NSCLC share many clinical features in common with ALK-rearranged NSCLC in that they are typically younger, are never-smokers, and have tumors with adenocarcinoma histology.14,15 ROS1 and ALK share substantial sequence homology in their kinase domains. Crizotinib, also a potent inhibitor of the ROS1 kinase, has activity in preclinical ROS1-rearranged NSCLC models,16,18,19 providing a rationale for its evaluation in patients with ROS1-rearranged NSCLC. Since the initial report published in Journal of Clinical Oncology in 2012 of a dramatic response to crizotinib in a 31-year-old male neversmoker whose tumor tested positive for a ROS1 gene rearrangement,16 there have been additional case reports indicating activity of crizotinib in this setting.18,20-23 Mazières et al6 now provide a substan972
© 2015 by American Society of Clinical Oncology
tial addition to the body of evidence indicating efficacy of targeting ROS1 rearrangements in NSCLC with crizotinib. In this retrospective study, conducted in 16 centers in six countries in Europe, results are presented from 32 patients with ROS1 rearrangement–positive NSCLC who received off-label treatment with crizotinib. Consistent with previous descriptions, patients were predominantly young (median age, 50.5 years), were never-smokers, and had tumors with adenocarcinoma histology. An impressive response rate of 80%, with a median progression-free survival (PFS) of 9.1 months, was seen in this European cohort of patients with ROS1-rearranged NSCLC treated with crizotinib. Mazières et al6 are to be commended on coordinating an international collaborative study, which although subject to limitations related to sample size, potential for selection bias, and reliance on investigator assessments of response, complements and provides independent validation of a recent report by Shaw et al24 of patients with ROS1-rearranged NSCLC prospectively treated in the molecularly enriched expansion cohort of the crizotinib phase I trial. This ongoing study conducted in the United States, Korea, and Australia enrolled 50 patients with NSCLC with ROS1 gene rearrangements and reported an objective response rate to crizotinib of 72% (95% CI, 58% to 84%), with a median PFS of 19.2 months (95% CI, 14.4 to not reached). No obvious relationship between ROS1 fusion partner and durability of response to crizotinib was demonstrated. The response rate to crizotinib observed in these two independent studies (80% and 72%) confirms that ROS1 rearrangement– positive NSCLC, like ALK-rearranged or EGFR mutation–positive NSCLC, represents an oncogene-addicted tumor and validates ROS1 as a therapeutic target in NSCLC. Interestingly, although Shaw et al24 reported a median PFS of 19.2 months, raising the possibility that the durability of responses to crizotinib may be greater in ROS1 rearrangement–positive NSCLC compared with ALK rearrangement–positive NSCLC, Mazières et al6 report a more modest PFS of 9 months, similar to what has been observed in ALK-positive NSCLC. Although there are potential differences in the populations under evaluation in the studies, including, for example, the proportion of Asian patients in each study, the differences seem most likely attributable to sample size and duration of follow-up. The PFS data are relatively preliminary in both studies, with many patients still in follow-up; however, the prospective study by Shaw et al had a larger sample size and potentially longer duration of follow-up than the retrospective study of Mazières et al and may therefore provide a more precise estimate of PFS. Journal of Clinical Oncology, Vol 33, No 9 (March 20), 2015: pp 972-974
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OF SASKATCHEWAN on September 27, Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 2015 from 128.233.210.97
Editorial
Importantly, these two single-arm studies draw attention to broader challenges in the design and conduct of trials leading to regulatory approval of drugs active in populations with rare molecular drivers. The traditional pathway to approval involving a phase I study, followed by phaseIIandIIIstudies,maynotbepracticalorarguablyevennecessaryfor highly effective drugs targeting oncogenes such as ROS1. Accrual to ROS1-targeting clinical trials is hampered by the low frequency of ROS1 gene rearrangements and off-label availability of crizotinib, as reflected by the 3 years it took to enroll 50 patients onto the study by Shaw et al.24 Relatively small, well-designed, single-arm studies conducted in homogenous, biomarker-selected populations can provide adequate proof of concept to support approval of drugs, provided that they show large effects on relevant clinical end points, such as overall response rate or PFS, obviating the need for a phase III study.25,26 Indeed, many oncology approvals by the US Food and Drug Administration in similar settings have been based on nonrandomized studies using the primary end point of overall response rate,27 with good records of efficacy and safety beyond initial approval.28 For drugs targeting other recently identified rare gene fusions in NSCLC, including those involving RET,29 NTRK1,30 NRG1,31 FGFR1,32 and FGFR3,32,33 which occur with frequencies below 1%, the challenge for regulatory approval is even greater. However, the demonstrated feasibility and effectiveness of large-scale, multiplex, molecular-testing efforts in lung cancer to identify patients with rare molecular drivers and link them to appropriate clinical trials, such as was done by the Lung Cancer Mutational Consortium34 or in the French national testing program,35 indicate that this is not an impossible task. The recently launched Lung Cancer Master Protocol (LungMAP) clinical trial (ClinicalTrials.gov identifier NCT02154490) will under one protocol simultaneously evaluate multiple drugs directed at multiple targets in parallel phase II and III trials, with patient allocation to treatment arm based on genomic results from a nextgeneration sequencing platform. These phase II and III studies are specifically designed with the aim of regulatory approval of the agent under study, together with the relevant companion diagnostic. This approach holds promise for accelerating the evaluation and approval of targeted therapies in biomarker-defined populations in lung cancer and can serve as a model for trials in rare populations within other malignancies. The validation of ROS1 gene rearrangements as an actionable target in NSCLC, along with EGFR mutations and ALK gene rearrangements, confirms the value of screening large populations to identify small groups with rare molecular drivers. Numerous other potentially targetable molecular drivers have been identified in even smaller subsets of patients with NSCLC. Although challenges remain in the implementation of multiplex testing strategies across populations, conduct of clinical trials, and regulatory approvals of targeted therapies and companion diagnostics, these obstacles no longer seem insurmountable. Continued progress toward precision medicine for NSCLC will require efficient and innovative strategies to transform more promising targets into validated treatments. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the author are available with this article at www.jco.org. REFERENCES 1. Shaw AT, Hsu PP, Awad MM, et al: Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 13:772-787, 2013 www.jco.org
2. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007 3. Rikova K, Guo A, Zeng Q, et al: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190-1203, 2007 4. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013 5. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014 6. Mazières J, Zalcman G, Crinò L, et al: Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 33:992-999, 2015 7. Birchmeier C, Sharma S, Wigler M: Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A 84:9270-9274, 1987 8. Peraldo Neia C, Cavalloni G, Balsamo A, et al: Screening for the FIG-ROS1 fusion in biliary tract carcinomas by nested PCR. Genes Chromosomes Cancer 53:1033-1040, 2014 9. Liu P, Wu Y, Sun L, et al: ROS kinase fusions are not common in Chinese patients with cholangiocarcinoma. Nan Fang Yi Ke Da Xue Xue Bao 33:474-478, 2013 10. Gu TL, Deng X, Huang F, et al: Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PloS One 6:e15640, 2011 11. Birch AH, Arcand SL, Oros KK, et al: Chromosome 3 anomalies investigated by genome wide SNP analysis of benign, low malignant potential and low grade ovarian serous tumours. PloS One 6:e28250, 2011 12. Lee J, Lee SE, Kang SY, et al: Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer 119:1627-1635, 2013 13. Aisner DL, Nguyen TT, Paskulin DD, et al: ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers. Mol Cancer Res 12:111-118, 2014 14. Gainor JF, Shaw AT: Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18:865-875, 2013 15. Chin LP, Soo RA, Soong R, et al: 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 7:1625-1630, 2012 16. Bergethon K, Shaw AT, Ou SH, et al: ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863-870, 2012 17. Rimkunas VM, Crosby KE, Li D, et al: Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: Identification of a FIG-ROS1 fusion. Clin Cancer Res 18:4449-4457, 2012 18. Davies KD, Le AT, Theodoro MF, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 18:4570-4579, 2012 19. Yasuda H, de Figueiredo-Pontes LL, Kobayashi S, et al: Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. J Thorac Oncol 7:1086-1090, 2012 20. Bos M, Gardizi M, Schildhaus HU, et al: Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer 81:142-143, 2013 21. Awad MM, Katayama R, McTigue M, et al: Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395-2401, 2013 22. Chiari R, Buttitta F, Iacono D, et al: Dramatic response to crizotinib in ROS1 fluorescent in situ hybridization- and immunohistochemistry-positive lung adenocarcinoma: A case series. Clin Lung Cancer 15:470-474, 2014 23. Li H, Pan Y, Wang R, et al: Response to crizotinib observed in metastatic mediastinum lymph node from a non-small cell lung cancer patient harboring EZR-ROS1 fusion. J Cancer Res Clin Oncol 141:185-187, 2015 24. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-smallcell lung cancer. N Engl J Med 371:1963-1971, 2014 25. Chabner BA: Early accelerated approval for highly targeted cancer drugs. N Engl J Med 364:1087-1089, 2011 26. Sharma MR, Schilsky RL: Role of randomized phase III trials in an era of effective targeted therapies. Nat Rev Clin Oncol 9:208-214, 2012 27. Gaddipati H, Liu K, Pariser A, et al: Rare cancer trial design: Lessons from FDA approvals. Clin Cancer Res 18:5172-5178, 2012 28. Tsimberidou AM, Braiteh F, Stewart DJ, et al: Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. J Clin Oncol 27:6243-6250, 2009 29. Lipson D, Capelletti M, Yelensky R, et al: Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18:382-384, 2012 30. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19:1469-1472, 2013 31. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-422, 2014 32. Wang R, Wang L, Li Y, et al: FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer. Clin Cancer Res 20:4107-4114, 2014
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OF SASKATCHEWAN on September 27, Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 2015 from 128.233.210.97
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33. Capelletti M, Dodge ME, Ercan D, et al: Identification of recurrent FGFR3TACC3 fusion oncogenes from lung adenocarcinoma. Clin Cancer Res 20:65516558, 2014 34. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:19982006, 2014
35. Nowak F, Calvo F, Soria JC: Europe does it better: Molecular testing across a national health care system—The French example. Am Soc Clin Oncol Educ Book 2013:332-337, 2013
DOI: 10.1200/JCO.2014.59.8334; published online ahead of print at www.jco.org on February 9, 2015
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Editorial
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Validating ROS1 Rearrangements As a Therapeutic Target in Non–Small-Cell Lung Cancer The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Benjamin J. Solomon Consulting or Advisory Role: Pfizer, Novartis, Roche/Genentech, Clovis Oncology, Merck, Bristol-Myers Squibb, AstraZeneca
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Research Funding: Pfizer (Inst) Travel, Accommodations, Expenses: Roche/Genentech
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OF SASKATCHEWAN on September 27, Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 2015 from 128.233.210.97
