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. 2019 Aug 1;26(4):e551–e557. doi: 10.3747/co.26.5137

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective

DG Bebb *,a,✉, J Agulnik †, R Albadine †, S Banerji ‡, G Bigras *, C Butts *, C Couture †, JC Cutz §, P Desmeules †, DN Ionescu ||, NB Leighl §, B Melosky ||, W Morzycki #, F Rashid-Kolvear, Clin Lab *, HS Sekhon §, AC Smith §, TL Stockley §, E Torlakovic **, Z Xu #, MS Tsao §,a,✉
PMCID: PMC6726257  PMID: 31548824

Abstract

The ros1 kinase is an oncogenic driver in non-small-cell lung cancer (nsclc). Fusion events involving the ROS1 gene are found in 1%–2% of nsclc patients and lead to deregulation of a tyrosine kinase–mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of nsclc, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology.

Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (pfs) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged nsclc, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement.

Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced nsclc, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop.

Keywords: ROS1; oncogenic drivers; non-small-cell lung cancer, advanced; nsclc, advanced; targeted therapy; crizotinib; molecular testing; nsclc, nonsquamous

INTRODUCTION

Non-small-cell lung cancer (nsclc) is the most common malignant tumour and a leading cause of death worldwide1, with an estimated 1.6 million new global diagnoses annually2. Most patients are diagnosed with advanced-stage disease, which is characterized by a poor survival rate3. Until recently, nsclc was approached therapeutically as a single-entity disease. The standard first-line treatment for advanced (unresectable or metastatic) nsclc that had the most efficacy was platinum-based doublet chemotherapy, which resulted in median survival durations of 10–12 months4–6. Subsequent recognition of the genetic diversity and heterogeneity of nsclc changed the focus to identifying new molecular subsets of nsclc, with emphasis placed on identifying driver oncogenes and novel biomarkers3,7. Identification of those driver mutations and the capability to analyze the molecular profiles of nsclc tumours dramatically altered the treatment paradigm by identifying actionable target mutations7–9, because a potentially targetable genetic driver alteration is present in nearly half of all cases of metastatic adenocarcinoma6. Those targeted treatments have proved to be more effective than standard doublet chemotherapy (either platinum- or non-platinum-based) in increasing pfs, and the resultant increases in quality of life (qol) and survival have led to the adoption of screening for predictive biomarkers as a standard of care1,9. To date, the most prevalent targetable mutations identified in nsclc predominantly involve the deregulation of tyrosine kinase receptor–mediated signalling (as seen in EGFR and ALK mutations), which drives both the initiation and progression of cancer cells3,10.

The ROS1 oncogene, which is mutated in a variety of solid tumours and which also results in the deregulation of a tyrosine kinase–mediated signalling pathway, was identified specifically in nsclc in 200711. Interchromosomal —and occasionally intrachromosomal—rearrangements of ROS1 result in gene fusions involving the 3′ region of ROS1, including the kinase domain, and several different 5′ fusion partners2,6,12, of which 26 have been identified to date13. All ROS1 fusions show conservation of the ros1 kinase domain2,12 and lead to tyrosine kinase activation2,12,13, a multi-use intracellular pathway involved in the upregulation of shp-1 and shp-2 and resultant activation of the pi3k/akt/mtor, jak/stat, and makp/erk pathways, which act in concert to promote cell survival and proliferation7,14.

ROS1 fusions exist as a distinct molecular subtype of nsclc and rarely overlap with other oncogenic drivers such as EGFR, KRAS, HER2, RET, MET, and ALK15. Specifically, ROS1 and ALK are mutually exclusive, with no evidence of co-expression, but are phylogenetically related7,15,16, sharing 70% homology and 77% similar amino acid identity within atp binding sites17. ROS1- and ALK-positive patients also share many clinicopathologic features: female sex, younger age at diagnosis (<50 years), propensity toward Asian ethnicity, never-smoking history, adenocarcinoma histology, and advanced nonresectable (compared with advanced resectable) disease at diagnosis are frequent characteristics of patients positive for either ALK or ROS17,8,15. Unique to patients with ROS1 rearrangement is the observation that ros1 expression is higher in recurrent tumours than the primary tumour (28% vs. 19%)18, and that patients who are ROS1-positive, compared with those who are ALK-positive, have lower rates of extrathoracic metastases, including lower rates of brain metastases at initial metastatic diagnosis, and a cumulative lower incidence of brain metastases18,19.

After the discovery of the ROS1 fusion gene as an oncogenic driver in nsclc, and in light of the close homology between the ALK and ROS1 tyrosine kinase domains, the utility of crizotinib as a ros1 inhibitor was explored19,20. Oral crizotinib, an atp-competitive small-molecule tyrosine kinase inhibitor, was developed as a c-met inhibitor; it was later found to have activity against ALK-rearranged tumours6,21 when a phase i single-arm analysis of crizotinib (profile 1001) yielded a response rate of 60% and pfs of 9.7 months21.

Based on those results and preliminary data from a single-arm phase ii study (profile 1005), accelerated regulatory approval for the use of crizotinib in ALK-positive locally advanced or metastatic nsclc, was awarded by the U.S. Food and Drug Administration and Health Canada in 2011 and 2012 respectively6,8,14,22,23. Subsequently, both in vivo and in vitro, crizotinib was found to be a highly robust inhibitor of the ros1 fusion protein, showing up to 5 times greater potency in the suppression of ros1 activity and downstream signalling—and resultant superior inhibition of ros1-driven tumour growth—than what had been observed in ALK-rearranged tumours19. Subsequent clinical trials of crizotinib in ROS1-rearranged nsclc yielded response rates of 70%–80%, and approval for crizotinib in the management of ROS1-positive locally advanced or metastatic nsclc was granted in 2016 by the U.S. Food and Drug Administration and in 2017 by Health Canada for use in the first- and subsequent-line settings24. To date, crizotinib remains the only approved targeted agent for ROS1-rearranged advanced nsclc14,20, and ROS1-rearranged nsclc is now the 3rd genetically distinct population of nsclc that can be managed through approved, effective targeted therapy7,25.

ROS1 TESTING

Testing Method

Reliable and efficient detection of tumours harbouring ROS1 fusions is required to identify patients whose treatment protocols should include ros1 inhibition. Currently, no companion diagnostic that reliably selects patients with ROS1 alterations has been approved.

At present, ROS1 fusion in tumour cells can be detected using a variety of techniques: fluorescence in situ hybridization (fish), immunohistochemistry (ihc), reverse transcriptase polymerase chain reaction (rt-pcr), and next-generation sequencing of rna and dna26–28.

ROS1 break-apart fish is currently considered the “gold standard” and is used globally for many ROS1–crizotinib studies because of its low tissue requirement and high sensitivity and specificity29–31. However, fish has some limitations: it is labour-intensive and more costly than ihc, and interpretation of the results requires experience25 because false-negative results can occur when the ROS1 fusion partner gene is located within several megabases of the ROS1 gene on chromosome 632,33. Next-generation sequencing and rt-pcr both show utility. The former allows for multiplex testing, has the potential to identify the ROS1 fusion partner, and can detect novel fusions, but has a higher tissue requirement, is relatively more expensive than ihc or fish, and yields more information than is often clinically relevant29. The latter is limited given the requirement for multiple primer sets and an incapacity to identify novel or rare ROS1 fusions32. In comparison, ihc is widely used in routine pathology practice, is less expensive and usually automated32, and generally shows good sensitivity (compared with fish results) for ROS1 screening when ihc uses the commercially available D4D6 antibody clone25. However, ihc positive staining has greater discordance with fish, because some tumours can yield samples that are ihc-positive, but that test negative for rearrangement by fish8,29,34. The Canadian ROS Initiative, which involves 14 pathology laboratories in Canada and 1 in Japan, is working to validate ihc and fish testing for ROS1 translocations in nsclc tumour samples35 and is using a strategy of ihc as a screening test, followed by confirmation of ihc-positive cases by fish26,34. The high level of optimization and validation for a specific purpose, as it applies to all predictive assays, also applies to ros1 ihc testing28,36–39. Looking to the future, effective screening methods for ROS1 rearrangements that hinge on inexpensive, rapid, sensitive, reliable methods and development of a minimally invasive method that can also identify the fusion partner, secondary mutations, or tumour heterogeneity would be of considerable clinical utility40,41.

Testing Recommendations

Screening for actionable mutations in nsclc are recommended by the U.S. National Comprehensive Cancer Network’s clinical practice guidelines in oncology, the European Society for Medical Oncology’s guidelines, the American College of American Pathologists, the International Association for the Study of Lung Cancer, the Association for Molecular Pathology, the Expert Committee of Lung Cancer Canada, and the American Society of Clinical Oncology. Unanimously, those groups recommend that ROS1 testing be performed for all patients with advanced lung adenocarcinoma9,26,35,42,43. The 2018 updated joint guideline from the American College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology26 (endorsed by the American Society of Clinical Oncology43) now advises that all patients with advanced-stage adenocarcinoma, regardless of other clinical characteristics, be offered either a comprehensive lung panel [EGFR, ALK, ROS1, BRAF, MET, ERBB2 (HER2), KRAS, and MET] or targeted testing for genes in the “must test” category (EGFR, ALK, ROS1), with the option of offering expanded panels that include additional genes [BRAF, MET, ERBB2 (HER2), and RET] to patients who are clinical trial candidates, the latter possibly after testing negative in single-panel KRAS testing26.

Because targeted massively parallel or dna- or rna-based next-generation sequencing panels that enable the simultaneous analysis of a large number of genes and of multiple actionable fusion transcripts, including ROS1, are integrated into the health care setting, comprehensive testing of patients presenting with advanced lung adenocarcinoma might prove to be efficient and cost-effective. It would allow for extensive molecular characterization of limited amounts of tumour tissue and achieve the mandate for ROS1 testing to be integrated for all patients with advanced lung adenocarcinoma as the standard of care44,45.

EVIDENCE OF BENEFIT WITH CRIZOTINIB FOR TARGETED INHIBITION OF ROS1-REARRANGED TUMOURS

Clinical Trials

PROFILE 1001: ROS1-Positive Expansion Cohort

Originally designed as a single-arm, multi-cohort, multicentre phase i study to determine the efficacy and safety of crizotinib to treat ALK-rearranged locally advanced or metastatic nsclc2, the profile 1001 trial was amended to add an expansion cohort of ROS1-positive nsclc patients after in vitro evidence showed that crizotinib was an effective suppressor of ros1 activity, leading to decreased downstream signalling and inhibition of tumour growth6,7. The expansion cohort contained 53 ROS1-positive patients, determined by fish, with no previous use of alk or c-met inhibitors. The objective response rate by independent radiology review was 70% [95% confidence interval (ci): 56% to 82%], with a median duration of response of 17.6 months17, median pfs of 19.3 months (95% ci: 14.8 months to not reached), and a demonstrated 91% (95% ci: 79% to 96%) survival probability at 6 months46. The safety profile of crizotinib in patients with ROS1-positive disease was similar to that seen in the ALK-positive treatment environment: grades 1 and 2 adverse events including nausea, vomiting, edema, diarrhea, and vision disturbances were experienced by 38%–85% of patients. Grade 3 adverse events such as hypophosphatemia (13%), neutropenia (9%), and elevated transaminases (4%) were present, but no grade 4 adverse events or deaths attributable to treatment were reported46. Additionally, response to crizotinib in ROS1-positive disease was achieved regardless of previous lines of therapy6 and independent of the percentage of ROS1-rearranged cells detected46.

In parallel to the results from the crizotinib-treated ALK-positive disease in the same trial, crizotinib treatment in ROS1-positive disease similarly demonstrated that crizotinib is associated with a well-tolerated, rapid, and durable response10. The outcome measures from the study were the first to confirm the clinically meaningful benefit and safety of crizotinib in patients with ROS1-altered advanced nsclc46 and led to the approval of crizotinib use in that population47.

EUCROSS

A collaboration between the Lung Cancer Group in Cologne and the Spanish Lung Cancer Group resulted in the development of a prospective phase ii trial to evaluate the use of crizotinib in ROS1-positive lung adenocarcinoma, regardless of previous lines of treatment. The study enrolled 34 patients identified as ROS1-positive by fish, who were treated with crizotinib. Of the 34 patients, 20 had sufficient tumour tissue to perform cage (cap analysis of gene expression) to verify ROS1 status, identifing the exact break-apart point and fusion genes48. ROS1 fusion was confirmed in 18 patients; the 2 remaining patients were ultimately determined to be negative for ROS1 rearrangement and quickly experienced primary progression. Analysis of the 18 patients with dually confirmed ROS1 rearrangement showed an objective response rate of 83% (95% ci: 67.7% to 94.2%). The assessment of safety considered all 34 patients, and adverse events (any grade) were reported in just under 50% of the group48.

The study confirmed that crizotinib is a safe treatment and, in the subset of validated ROS1-positive patients, highly effective. The lack of concordance observed between fish and cage sequencing of ROS1 in 2 of 20 patients who underwent validation of their ROS1 status, and the failure of crizotinib to show clinical benefit in those deemed ROS1 wild-type through cage sequencing, highlights the efficacy of cage sequencing in the identification of clinically sensitive ROS1 gene rearrangements, and the need for orthogonal validation of ROS1 status48.

ACSe Study

A multicentric trans-tumour study, the phase ii acse trial (NCT0163950 at http://ClinicalTrials.gov/), designed by the French National Cancer Institute, is considering the efficacy and safety of crizotinib as monotherapy in patients with ALK-, ROS1- (by fish), or MET-positive tumours experiencing progression after at least 1 standard treatment (unless performance status has precluded first-line chemotherapy). The trial was designed to include 23 unique “cohorts,” including a ROS1-rearranged nsclc cohort, with the goal of avoiding uncontrolled off-label use and allowing for nationwide safe access to crizotinib for patient populations demonstrating clinical benefit from this agent49.

Preliminary results from the 29 patients in the ROS1-rearranged nsclc cohort (secondarily confirmed by ihc) demonstrated an objective response rate of 63% (95% ci: 41% to 81%) and a 53% disease control rate at 6 months. Grade 1 adverse events were recorded in approximately 50% of patients, and grade 3 or greater adverse events were recorded in 31% of patients. Study completion and updated trial results were anticipated in spring 201949.

The preliminary results of acse reinforce the importance of integrating ros1 biomarker screening as part of routine care, because crizotinib has been demonstrated to be a safe, effective treatment with clinical benefit for patients harbouring ROS1 rearrangements49.

OxOnc Development Study

OxOnc (NCT01945021 at http://ClinicalTrials.gov/) was a phase ii trial conducted as an open-label, multinational, and multicentre single-arm study of crizotinib in East Asian patients with advanced (locally advanced or metastatic) ROS1-positive nsclc, not previously receiving targeted therapy for alk or ros147,50.

Of 127 patients with ROS1-positive disease (detected by rt-pcr) enrolled, 72% (95% ci: 63% to 79%) achieved an objective response. Median time to objective response was 1.9 months (range: 1.5–15.8 months), and the median duration of response was 19.7 months (95% ci: 14.1 months to not reached). Median pfs was 15.9 months (95% ci: 12.9 months to 24 months), with a disease control rate of 80% (95% ci: 72% to 87%) after 16 weeks on treatment, and a survival probability of 83% (95% ci: 75% to 89%) after 12 months of treatment47. Treatment-related adverse events were noted in 96.1% of patients, mostly grade 1 or 2 in severity, and included elevated transaminases, vision disorders, nausea, diarrhea, and vomiting. Grades 3 and 4 events were reported in 25.2% of patients and included neutropenia and elevated transaminases. Dose reductions or interruptions attributable to grade 1 or 2 and grade 3 or 4 adverse events occurred in 15.7% and 22.8% of patients respectively, with 1 patient discontinuing crizotinib because of a grade 1 adverse event (diarrhea)47. Assessments of qol using the European Organisation for Research and Treatment of Cancer 30-question core Quality of Life Questionnaire and the 13-question lung cancer module revealed either stable (37%) or improved (46.8%) global qol scores, compared with baseline scores, after 20 cycles of treatment, with statistically significant and clinically meaningful improvements in many lung cancer–related symptoms reported during those first 20 cycles, although significant deterioration from baseline was observed for gastrointestinal symptoms47.

This study provided clinical confirmation of the benefit of crizotinib through a high overall response rate, a rapid and durable response, and overall qol improvement, confirming the known safety profile of crizotinib. On the basis of the study results, crizotinib was approved for the treatment of ROS1-positive nsclc in Japan, Taiwan, Korea, and China in 201747.

Retrospective Reviews

EUROS1

The euros1 European retrospective review (France, Switzerland, Italy, Germany, Poland, Netherlands) was designed to characterize the outcomes of patients with ROS1-positive (identified by fish) stage iv nsclc with an adenocarcinoma histology, who had undergone documented (off-label) crizotinib therapy and 0 to 3 or more prior lines of therapy6,51.

In the 32 patients identified as meeting the study criteria, median pfs was 9.1 months, with an objective response rate of 80%, a disease control rate of 86.6%, and no reports of unexpected or serious adverse events51.

The review confirmed that ROS1-rearranged nsclc is very sensitive to crizotinib1. In the retrospective euros1 trial, unlike the prospective clinical trials, comorbidities or health status did not unselect patients for inclusion, and yet the response rate was similar to that in the profile 1001 ROS1-positive expansion cohort. Results from euros1 demonstrated that the findings from the highly selected patient populations in the phase i clinical trials of crizotinib could be replicated in the real-world general population of patients with ROS1-rearranged nsclc51.

China: Efficacy of Crizotinib and Pemetrexed-Based Therapy in Chinese Patients with ROS1-Rearranged NSCLC

This retrospective review of 51 Chinese patients with ROS1-rearranged disease (determined by rt-pcr) who received either crizotinib, pemetrexed, or non-pemetrexed therapy demonstrated statistically significant differences in pfs, with crizotinib demonstrating the highest pfs (294 days), followed by pemetrexed-based chemotherapy (179 days) and non-pemetrexed chemotherapy (110 days).

Those findings corroborate previous results showing that, compared with patients having other identified driver mutations and receiving pemetrexed, patients with ROS1 rearrangement experience increased clinical benefit from pemetrexed chemotherapy25, suggesting that ROS1 rearrangement might be a marker of increased pemetrexed sensitivity1. Further, despite the efficacy of pemetrexed in this population of patients with ROS1 rearrangement, those results reinforce the superior efficacy of crizotinib in the treatment of Chinese patients with ROS1-rearranged nsclc.

MEETING THE CHALLENGE OF PROGRESSIVE DISEASE

Acquired Resistance

Development of acquired resistance to crizotinib in ROS1-rearranged tumours poses a serious clinical challenge, given that most patients treated using this agent will acquire resistance19 and that the duration of response to crizotinib cannot yet be predetermined and seems to have no relation to the ROS1 fusion partner52. Resistance to crizotinib, and resulting disease progression, comes about by a variety of mechanisms: development of secondary mutations within the kinase domain, which impedes drug binding14; epithelial-to-mesenchymal transition47,53; or upregulation and activation of compensatory pathways14 such as EGFR, RAS, and KIT19.

Development of secondary crizotinib-resistant mutations appears to account for most acquired resistance, and the molecular changes involved in crizotinib resistance show a high level of heterogeneity53. The most common secondary mutation, G2032R [c.6094G>A (p.Gly2032Arg)], accounts for 41% of identified secondary mutations19, and it is unclear whether crizotinib use selects for pre-existing resistant clones or whether the evolution of crizotinib-resistant cells occurs during a period of exposure19. Given the diverse mechanisms that lead to crizotinib resistance, sequential treatment targeting crizotinib-resistant cells, or dual inhibition of ROS1 and potentially upregulated pathways, might show efficacy in minimizing and managing resistance to crizotinib14.

Although secondary mutations in ROS1 and ALK show overlapping sensitivity profiles40, sequential therapy using second-generation alk inhibitors to combat crizotinib resistance in ROS1-rearranged tumours seems limited in ROS1-positive nsclc. Secondary mutations in ROS1 tend to harbour off-target mechanisms of resistance, such as bypass tracks20, and most show decreased sensitivity to second-generation alk inhibitors19. Indeed, the second-generation alk inhibitors—ceritinib, brigatinib, and entrectinib (startrk-1, startrk-2, and alka-372-001 trials54)—have been associated with clinically meaningful responses in crizotinib-treated patients with ROS1-rearranged tumours and with increased disease control rates for intracranial disease20; however, none has shown effective inhibition against ROS1-rearranged tumours harbouring the common secondary G2032R mutation19, limiting use of those agents as second-line therapy20.

Therapeutic Options Beyond Progression

Targeted agents such as DS-605-1, repotrectinib [TPX-005 (see NCT03093116 at http://ClinicalTrials.gov/)], lorlatinib (NCT01970865), cabozantinib, and foretinib have demonstrated anti-ROS1 activity in the second-line setting, including activity against G2032R, with all but the latter two agents demonstrating good tolerability, with safety and efficacy data that are being confirmed in ongoing clinical trials19,47,55,a. Cabozantinib has been shown to be effective, but to be associated with higher toxicity, and it is therefore limited as a therapeutic agent for some patients3,14,16,47. Foretinib has been withdrawn from the market (NCT02034097).

With a current paucity of suitable second-line treatments for use in crizotinib-resistant ROS1-rearranged tumours, two methods of management have shown promise as second-line treatments. The conventional cytotoxic chemotherapy agent pemetrexed has been associated with an objective response rate of 40%–58% and a pfs of 6.8–7.5 months in various lines of treatment and is therefore a viable treatment option for patients with ROS1-rearranged crizotinib-resistant disease1,25. Alternatively, crizotinib resistance resulting from crizotinib-mediated upregulation of bypass signalling pathways (EGFR, RAS, and KIT)19 could be managed through targeted agents designed to modulate those upregulated systems, such as afatinib or PF29984 (EGFR)53 and ponatinib (KIT)14.

As the options for treatment beyond crizotinib are explored, it remains true that desirable treatments post-crizotinib have to be highly potent agents with central nervous system penetrability and activity against ROS1 G2032R20. Appropriate treatments and management strategies for patients with ROS1-rearranged disease could then rely on a personalized approach in which repeat molecular characterization, both temporally and spatially, which captures the heterogeneity of ROS1-rearranged tumours and tailors therapies appropriately, should be engaged14.

RECOMMENDATIONS

As Canadian physicians involved in the management of patients with advanced lung cancer, we recommend molecular testing (inclusive of ihc), comprising detection of ROS1 rearrangements, directly or indirectly by detecting ROS1 chimeric rna or fusion protein expression in tumours, because such testing is critical to the appropriate and timely therapeutic management of nsclc. The testing should be offered as part of the standard of care to patients presenting with advanced disease, regardless of clinical characteristics35. Given that ROS1-rearranged nsclc represents a molecularly distinct subset of nsclc, the ideal standard of care for these patients is targeted therapy with a ros1-inhibiting agent.

Crizotinib has demonstrated clinical benefit and a favourable benefit–risk profile for patients with advanced nsclc and ROS1 rearrangement, and it is the first targeted agent approved for ROS1-positive tumours. Response rates achieved with crizotinib, regardless of treatment line (63%–83%), in this susceptible population are greatly superior to the 10%–35% and 5%–22% response rates obtained with use of the traditional cytotoxic therapies in the first-line and second-line settings respectively6. Low rates of ROS1 rearrangement in the population make the initiation of phase iii randomized clinical trials untenable at present, but the observed objective response rate, prolonged pfs, and similar efficacy across all lines of therapy as evidenced by a variety of phase i and ii studies, retrospective analyses, and single-institution experiences in diverse patient populations with advanced nsclc lend credence to the efficacy of crizotinib as an effective pharmaceutical to manage ROS1-altered lung cancer in larger patient populations. In light of current results and experiences, we support and recommend the use of crizotinib in this patient group.

ACKNOWLEDGMENTS

The authors acknowledge Amanda Williams Gibson for her project management and compilation of this article. Amanda Williams Gibson was compensated by a grant from Pfizer. During the process of preparing this article, Pfizer did not influence the content or consensus of the article, did not read or review the article, and did not provide any form of compensation to the named authors of this article.

Footnotes

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: JA, SB, ACS have received personal fees from Pfizer, outside the submitted work; RA received personal fees from Pfizer during the conduct of the study; DGB received grants from Pfizer during the conduct of the study and personal fees from AstraZeneca, Roche, Bristol–Myers Squibb, Boehringer Ingelheim, Pfizer, Merck, Bayer, Lilly, and Takeda outside the submitted work; GB and WM are members of the Pfizer advisory board; CB and CC have received other consideration from Pfizer outside the submitted work; PD received grants from Pfizer during the conduct of the study and other consideration from Bayer, Bristol–Myers Squibb, AstraZeneca, and Pfizer outside the submitted work; HSS has received other consideration from Pfizer Canada, Bayer, Merck, and EMD Serono Canada outside the submitted work; TLS has received grants and personal fees from AstraZeneca and personal fees from Bristol–Myers Squibb, Janssen, Pfizer, and Novartis outside the submitted work; ET has received grants from, and been an advisory board member for, Pfizer, Bristol–Myers Squibb, Merck, AstraZeneca, Roche, and Janssen outside the submitted work; MST received grants and personal fees from Pfizer during the conduct of the study and has received grants and personal fees from AstraZeneca and Merck, and personal fees from Bristol–Myers Squibb and Bayer outside the submitted work; JCC, DNI, NBL, BM, FRK, and ZX have no conflicts to disclose.

REFERENCES

  • 1.Zhang L, Jiang T, Zhao C, et al. Efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese nsclc patients with ROS1 rearrangement. Oncotarget. 2016;7:75145–54. doi: 10.18632/oncotarget.12612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non–small cell lung cancer. Clin Cancer Res. 2012;18:4570–9. doi: 10.1158/1078-0432.CCR-12-0550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Quintanal-Villalonga A, Paz-Ares L, Ferrer I, Molina-Pinelo S. Tyrosine kinase receptor landscape in lung cancer: therapeutic implications. Dis Markers. 2016;2016 doi: 10.1155/2016/9214056. 9214056. [Erratum in: Dis Markers 2018;2018:3714684] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S on behalf of the esmo Guidelines Working Group. Metastatic non-small-cell lung cancer (nsclc): esmo clinical practice guidelines for diagnosis, treatments and follow-up. Ann Oncol. 2014;5(suppl 3):ii27–39. doi: 10.1093/annonc/mdu199. [DOI] [PubMed] [Google Scholar]
  • 5.Ramalingam S, Belani C. Systemic chemotherapy for advanced non–small cell lung cancer: recent advances and future directions. Oncologist. 2008;13(suppl 1):5–13. doi: 10.1634/theoncologist.13-S1-5. [DOI] [PubMed] [Google Scholar]
  • 6.Kazandjian D, Blumenthal GM, Luo L, et al. Benefit–risk summary of crizotinib for treatment of patients with ROS1 alteration–positive, metastatic non–small cell lung cancer. Oncologist. 2016;21:974–80. doi: 10.1634/theoncologist.2016-0101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Gainor JF, Shaw AT. Novel targets in non–small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18:865–75. doi: 10.1634/theoncologist.2013-0095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Marchetti A, Barberis M, di Lorito A, et al. ROS1 gene fusion in advanced lung cancer in women: a systematic analysis, review of the literature, and diagnostic algorithm. JCO Precis Oncol. 2017;1:1–9. doi: 10.1200/PO.16.00010. [DOI] [PubMed] [Google Scholar]
  • 9.Kerr KM, Bubendorf L, Edelman MJ, et al. Second esmo Consensus Conference on Lung Cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014;25:1681–90. doi: 10.1093/annonc/mdu145. [DOI] [PubMed] [Google Scholar]
  • 10.Melosky B, Agulnik J, Albadine R, et al. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer. Curr Oncol. 2016;23:196–200. doi: 10.3747/co.23.3120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–203. doi: 10.1016/j.cell.2007.11.025. [DOI] [PubMed] [Google Scholar]
  • 12.Bubendorf L, Buttner R, Al-Dayel F, et al. Testing for ROS1 in non–small cell lung cancer: a review with recommendations. Virchows Arch. 2016;469:489–503. doi: 10.1007/s00428-016-2000-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Uguen A, De Braekeleer M. ROS1 fusions in cancer: a review. Future Oncol. 2016;12:1911–28. doi: 10.2217/fon-2016-0050. [DOI] [PubMed] [Google Scholar]
  • 14.Alrifai D, Forster MD, Janes SM. Emerging resistant pathways in lung cancer: what has ROS-1 taught us? Transl Lung Cancer Res. 2018;7(suppl 1):S9–12. doi: 10.21037/tlcr.2017.11.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Korpanty GJ, Graham DM, Vincent MD, Leighl NB. Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1 and KRAS. Front Oncol. 2014;4:204. doi: 10.3389/fonc.2014.00204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Katayama R, Kobayashi Y, Friboulet L, et al. Cabozantinib overcomes crizotinib resistance in ROS1 fusion positive cancer. Clin Cancer Res. 2015;21:166–74. doi: 10.1158/1078-0432.CCR-14-1385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Shaw AR, Ou SH, Bang YJ, et al. Crizotinib in ROS1 rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–71. doi: 10.1056/NEJMoa1406766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Lee HJ, Seol HS, Kim JY, et al. ROS1 receptor tyrosine kinase, a druggable target, is frequently overexpressed in non–small cell lung carcinomas via genetic and epigenetic mechanisms. Ann Surg Oncol. 2013;20:200–8. doi: 10.1245/s10434-012-2553-6. [DOI] [PubMed] [Google Scholar]
  • 19.Gainor JF, Tseng D, Yoda S, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol. 2017;1:1–13. doi: 10.1200/PO.17.00063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Dagogo-Jack I, Shaw AT. Expanding the roster of ROS1 inhibitor. J Clin Oncol. 2017;35:2595–7. doi: 10.1200/JCO.2017.73.2586. [DOI] [PubMed] [Google Scholar]
  • 21.Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011–19. doi: 10.1016/S1470-2045(12)70344-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Mullard A. 2011 fda drug approvals. Nat Rev Drug Discov. 2012;11:91–4. doi: 10.1038/nrd3657. [DOI] [PubMed] [Google Scholar]
  • 23.Poon CC, Kelly JJ. Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non–small cell cancer. Int J Cancer. 2017;140:1945–54. doi: 10.1002/ijc.30533. [DOI] [PubMed] [Google Scholar]
  • 24.Pfizer Canada. Xalkori approved by Health Canada for the treatment of patients with ROS1- positive locally advanced or metastatic non–small cell lung cancer [online news release] Kirkland, QC: Pfizer Canada; 2017. [Available at: https://www.pfizer.ca/xalkori%C2%AE-approved-health-canadat-reatment-patients-ros1-positive-locally-advancedor-metastatic-1; cited 9 May 2018] [Google Scholar]
  • 25.Juan O, Popat S. Crizotinib for ROS1 patients: one small step in biomarker testing, one giant leap for advanced nsclc patients. Lung Cancer. 2017;104:131–3. doi: 10.1016/j.lungcan.2016.11.007. [DOI] [PubMed] [Google Scholar]
  • 26.Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors. J Mol Diagn. 2018;20:129–59. doi: 10.1016/j.jmoldx.2017.11.004. [DOI] [PubMed] [Google Scholar]
  • 27.Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular subclass of lung cancers. J Clin Oncol. 2012;30:863–70. doi: 10.1200/JCO.2011.35.6345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Torlakovic EE, Cheung CC, D’Arrigo C, et al. on behalf of the International Society for Immunohistochemistry and Molecular Morphology and the International Quality Network for Pathology. Evolution of quality assurance for clinical immunohistochemistry in the era of precision medicine. Part 3: Technical validation of immunohistochemistry (ihc) assays in clinical ihc laboratories. Appl Immunohistochem Mol Morphol. 2017;25:151–9. doi: 10.1097/PAI.0000000000000470. [DOI] [PubMed] [Google Scholar]
  • 29.Lin JJ, Ritterhouse LL, Ali SM, et al. ROS1 fusions rarely overlap with other oncogenic drivers in non–small cell lung cancer. J Thorac Oncol. 2017;12:872–7. doi: 10.1016/j.jtho.2017.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Varella-Garcia M, Yoshida A. ROS1 testing with fish. In: Tsao MS, Hirsch FR, Yatabe Y, editors. IASLC Atlas of ALK and ROS1 Testing in Lung Cancer. 2nd ed. Aurora, CO: iaslc Editorial Rx Press; 2016. pp. 53–62. [Google Scholar]
  • 31.Scholl L, Yoshida A, Nicholson A, Lantuejoul S, Hirsch F. ROS1 testing with ihc. In: Tsao MS, Hirsch FR, Yatabe Y, editors. IASLC Atlas of ALK and ROS1 Testing in Lung Cancer. 2nd ed. Aurora, CO: iaslc Editorial Rx Press; 2016. pp. 35–40. [Google Scholar]
  • 32.Boyle TA, Masago K, Ellison KE, Yatabe Y, Hirsch F. ROS1 immunohistochemistry across major genotypes of nonsmall-cell lung cancer. Clin Lung Cancer. 2015;16:106–11. doi: 10.1016/j.cllc.2014.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Rossi G, Jocolle G, Conti A. Detection of ROS1 rearrangement in non–small cell lung cancer: current and future perspectives. Lung Cancer (Auckl) 2017;8:45–55. doi: 10.2147/LCTT.S120172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Selinger CI, Li BT, Pavlakis N, et al. Screening for ROS1 gene rearrangements in non–small cell lung cancers using immunohistochemistry with fish confirmation is an effective method to identify this rare target. Histopathology. 2017;70:402–11. doi: 10.1111/his.13076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Meloksy B, Blais N, Cheema P, et al. Standardizing biomarker testing for Canadian patients with advanced lung cancer. Curr Oncol. 2018;25:73–82. doi: 10.3747/co.25.3867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Torlakovic EE, Cheung CC, D’Arrigo C, et al. on behalf of the International Society for Immunohistochemistry and Molecular Morphology and the International Quality Network for Pathology. Evolution of quality assurance for clinical immunohistochemistry in the era of precision medicine. Part 2: Immunohistochemistry test performance characteristics. Appl Immunohistochem Mol Morphol. 2017;25:79–85. doi: 10.1097/PAI.0000000000000444. [DOI] [PubMed] [Google Scholar]
  • 37.Torlakovic EE, Neilsen S, Francis G, et al. Standardization of positive controls in diagnostic immunohistochemistry: recommendations from the International Ad Hoc Expert Committee. Appl Immunohistochem Mol Morphol. 2015;23:1–18. doi: 10.1097/PAI.0000000000000163. [DOI] [PubMed] [Google Scholar]
  • 38.Torlakovic EE, Francis G, Garratt J, et al. on behalf of the International Ad Hoc Expert Panel. Standardization of negative controls in diagnostic immunohistochemistry: recommendations from the International Ad Hoc Panel. Appl Immunohistochem Mol Morphol. 2014;22:241–52. doi: 10.1097/PAI.0000000000000069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Cheung CC, D’Arrigo C, Dietel M, et al. on behalf of the International Society for Immunohistochemistry and Molecular Morphology and the International Quality Network for Pathology. Evolution of quality assurance for clinical immunohistochemistry in the era of precision medicine. Part 4: Tissue tools for quality assurance in immunohistochemistry. Appl Immunohistochem Mol Morphol. 2017;25:227–30. doi: 10.1097/PAI.0000000000000469. [DOI] [PubMed] [Google Scholar]
  • 40.Facchinetti F, Loriot Y, Kuo MS, et al. Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1 and ALK-rearranged lung cancers. Clin Cancer Res. 2016;22:5983–91. doi: 10.1158/1078-0432.CCR-16-0917. [DOI] [PubMed] [Google Scholar]
  • 41.Sacher AG, Paweletz C, Dalhberg SE, et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol. 2016;2:1014–22. doi: 10.1001/jamaoncol.2016.0173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Riely GL. What, when and how of biomarker testing in non–small cell lung cancer. J Natl Compr Canc Netw. 2017;15:686–8. doi: 10.6004/jnccn.2017.0073. [DOI] [PubMed] [Google Scholar]
  • 43.Kalemakerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology clinical practice guideline update. J Clin Oncol. 2018;36:911–19. doi: 10.1200/JCO.2017.76.7293. [DOI] [PubMed] [Google Scholar]
  • 44.Tsoulos N, Papadopoulou E, Metaxa-Mariatou V, et al. Tumor molecular profiling of nsclc patients using next-generation sequencing. Oncol Rep. 2017;38:3419–29. doi: 10.3892/or.2017.6051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Michels S, Wolf J. Stratified treatment in lung cancer. Oncol Res Treat. 2016;39:760–6. doi: 10.1159/000453406. [DOI] [PubMed] [Google Scholar]
  • 46.Shaw A, Riley GJ, Bang YJ, et al. Crizotinib in advanced ROS1-rearranged non–small cell lung cancer (nsclc): updated results from profile 1001. Ann Oncol. 2016;27:416–54. doi: 10.1093/annonc/mdw383.07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Wu YL, Yang CH, Kim DW, et al. Phase ii study of crizotinib in East Asian patients with ROS1-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36:1405–11. doi: 10.1200/JCO.2017.75.5587. [DOI] [PubMed] [Google Scholar]
  • 48.Michels S. eucross: a European phase ii trial of crizotinib in advanced adenocarcinoma of the lung harbouring ROS1 rearrangements—preliminary results [abstract MA07.05] J Thorac Oncol. 2017;12(suppl):S379–80. doi: 10.1016/j.jtho.2016.11.428. [DOI] [Google Scholar]
  • 49.Moro-Sibilot D, Falvre L, Zalcman G, et al. Crizotinib in patients with advanced ROS1- rearranged non–small cell lung cancer (nsclc). Preliminary results of the acse phase ii trial [abstract 8065] J Clin Oncol. 2015;33 doi: 10.1200/jco.2015.33.15_suppl.8065. [Available online at: https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.8065; cited 15 July 2019] [DOI] [Google Scholar]
  • 50.Goto K, Yang JCH, Kim DW, et al. Phase ii study of crizotinib in East Asian patients with ROS1- positive advanced non–small cell lung cancer [abstract 9022] J Clin Oncol. 2016;34 doi: 10.1200/JCO.2017.75.5587. [Available online at: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.9022; cited 15 July 2019] [DOI] [PubMed] [Google Scholar]
  • 51.Mazieres J, Zalcman G, Crino L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the euros1 cohort. J Clin Oncol. 2015;33:992–9. doi: 10.1200/JCO.2014.58.3302. [DOI] [PubMed] [Google Scholar]
  • 52.Solomon B. Validating ROS1 rearrangements as a therapeutic target in non–small cell lung cancer. J Clin Oncol. 2015;33:972–4. doi: 10.1200/JCO.2014.59.8334. [DOI] [PubMed] [Google Scholar]
  • 53.Song A, Kim TM, Kim DW, et al. Molecular changes associated with acquired resistance to crizotinib in ROS1-rearranged non–small cell lung cancer. Clin Cancer Res. 2915;21:2379–87. doi: 10.1158/1078-0432.CCR-14-1350. [DOI] [PubMed] [Google Scholar]
  • 54.Doebele RC, Ahn M, Siena S, et al. Efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion–positive non–small cell lung cancer (nsclc) [abstract OA02.01] J Thorac Oncol. 2018;13(suppl):S321–2. doi: 10.1016/j.jtho.2018.08.239. [DOI] [Google Scholar]
  • 55.Drilon A, Somwar R, Wagner JP, et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib in a patient with ROS1-rearranged lung cancer. Clin Cancer Res. 2016;22:2351–8. doi: 10.1158/1078-0432.CCR-15-2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

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