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Respir Med Case Rep
Respir Med Case Rep
Respiratory Medicine Case Reports
2213-0071
Elsevier

S2213-0071(24)00114-X
10.1016/j.rmcr.2024.102091
102091
Case Report
Unusual presentation of ROS1 rearranged metastatic non-small cell lung cancer
Chen Lanyi Nora a
Keating Claire b
Leb Jay c
Saqi Anjali d
Shu Catherine A. Cas2145@cumc.columbia.edu
a⁎
a Division of Hematology and Oncology, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA
b Division of Pulmonary Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA
c Department of Radiology, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA
d Department of Pathology, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA
⁎ Corresponding author. 161 Fort Washington Avenue New York, NY, 10032, USA. Cas2145@cumc.columbia.edu
18 8 2024
2024
18 8 2024
51 1020918 5 2024
14 8 2024
14 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
The spectrum of clinical and radiographic presentations of lung adenocarcinoma is increasingly broad, including in the metastatic setting. Here, we report on a patient who initially presented with a mild chronic cough that remained stable over a decade, with serial CT scans showing gradual worsening of multifocal areas of consolidation and ground-glass opacities of the bilateral lungs. The patient was ultimately diagnosed with ROS1 rearranged lung adenocarcinoma and achieved a dramatic response with entrectinib. This case highlights the variable presentation of non-small cell lung cancer (NSCLC) and the importance of comprehensive molecular testing for newly diagnosed metastatic NSCLC.

Keywords

ROS1 rearrangement
NSCLC
Targeted therapies
Molecular testing
Handling Editor: DR AC Amit Chopra
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pmc1 Introduction

The treatment of non-small cell lung cancer (NSCLC) has been transformed by the discovery of targetable genetic driver mutations. Gene rearrangements in ROS1, a receptor tyrosine kinase, are found in 1–2% of NSCLCs. Similar to other actionable molecular mutations in genes like EGFR and ALK, ROS1 rearrangements are identified more frequently in female patients, younger patients, patients who are never or light smokers, and in tumors with adenocarcinoma histology [1]. The kinase inhibitors crizotinib, entrectinib, and repotrectinib are currently FDA approved for the treatment of metastatic ROS1 rearranged NSCLC [[2], [3], [4], [5], [6], [7]].

The presentation of metastatic lung cancer is highly variable and can depend on factors such as age, sex, and smoking history [[8], [9], [10]]. Although there are limited data to suggest distinct clinical presentations or disease patterns that are unique to ROS1 rearranged NSCLC, driver mutation status is known to influence the clinical behavior of NSCLC [11]. Atypical presenting symptoms and radiographic patterns, including pneumonic-type lung cancer, are challenging clinical scenarios that lead to diagnostic and treatment delays [12,13]. In this report, we present the case of a patient with metastatic ROS1 rearranged NSCLC whose cancer remained undiagnosed for several years, due in part to unusual radiographic findings and an indolent pace of clinical progression. A diagnosis of lung cancer remains elusive in many instances, warranting continued attentiveness among practitioners.

2 Case presentation

In 2018, a 75-year-old woman with a history of hyperlipidemia, migraines, and a 10–15 pack year smoking history presented for evaluation of a chronic intermittent cough that started in 2013. She is Caucasian, English-speaking, and a retired physical education teacher who remains active. Her cough occurred throughout the day and was mildly productive of non-bloody sputum. Pulmonary function testing was normal. Inhalers and high frequency chest wall oscillation (SmartVest therapy) were trialed with no symptomatic improvement. A computed tomography scan (CT) of the chest performed in January 2020 showed parenchymal opacities with interstitial and ground-glass density predominantly involving the right lower lobe (RLL) and right middle lobe (RML). The patient's cough was stable but persisted, and serial CT scans performed over the next two years showed a gradual worsening of multifocal solid and ground-glass opacities and bilateral interstitial thickening against a background of centroacinar emphysema.

Given the slow progression of imaging findings without acutely worsening symptoms, a chronic infection or underlying interstitial abnormality were suspected. Bronchoalveolar lavage (BAL) was performed in May 2021 as part of an infectious work-up, and microbial studies identified penicillium. The patient subsequently completed a 6-month course of itraconazole but had no symptomatic improvement. CT chest scans performed in December 2022 demonstrated further progression with increasingly dense consolidations and more nodular-appearing areas in both lungs (Fig. 1A). She was then given a course of oral antibiotics, again without any subsequent changes in symptoms or imaging findings.Fig. 1 Axial CT images of the lung (5mm slice thickness) before and after initiation of entrectinib. A) Imaging from December 2022 demonstrates dense multifocal opacities with areas of nodularity and interlobular thickening. B) Imaging from July 2023 after 6 weeks of treatment with entrectinib shows a marked decrease in multifocal opacities.

Fig. 1

In January 2023, 10 years after the initial onset of symptoms, she sought a second opinion at our pulmonary clinic. She reported a stable, chronic productive cough. Due to the persistent nature of her symptoms and imaging abnormalities, malignancy was suspected. A bronchoscopy with BAL and transbronchial biopsies in the right upper, middle, and lower lobes were performed in April 2023.

Pathology revealed a TTF-1 and Napsin-A positive invasive adenocarcinoma with lepidic and papillary patterns, consistent with lung origin (Fig. 2). PET-CT demonstrated hypermetabolic interstitial thickening with superimposed ground-glass, patchy consolidation and bronchiectasis involving all 5 lobes, most severe within the RML, without evidence of extrathoracic FDG-avid lesions. An MRI of the brain did not show metastatic disease. A DNA-based next-generation sequencing (NGS) test was negative, and a reflex RNA-based NGS assay was performed, identifying an EZR-ROS1 gene fusion.Fig. 2 Hematoxylin and eosin stain (at 100X original magnification) shows invasive non-mucinous adenocarcinoma.

Fig. 2

In June 2023, the patient was started on first line entrectinib 600mg daily. Within two weeks, her chronic cough completely resolved. She reported immediate taste changes, which is a commonly observed side effect with entrectinib, and a sunburn-like skin sensation, which is uncommon. Entrectinib was subsequently dose-reduced to 400mg, and her symptoms improved. In July 2023, just 6 weeks after starting treatment, CT scan of the chest showed a marked decrease in ground glass and patchy consolidations, representing a response to treatment (Fig. 1B). A follow-up CT scan in October 2023 showed stable disease with minimal disease burden.

3 Discussion

We showcase an example of ROS1 rearranged metastatic NSCLC with a strikingly indolent clinical presentation and atypical imaging findings, leading to a delay in diagnosis. This case demonstrates that even in the metastatic setting, NSCLC can present surreptitiously, with relatively few symptoms and/or misleading radiographic features. Furthermore, the work-up exhibited here highlights important considerations when it comes to molecular testing of NSCLC. Although most institutions now have established processes for molecular genotyping that is in accordance with guidelines [14,15], a fundamental understanding of specific assays and their strengths and limitations remains useful at the practitioner level.

The atypical clinical and radiographic presentation in this case is notable. Given the chronic nature of the patient's cough and slow pace of radiographic progression, treatment for infection and interstitial lung abnormality were initially trialed. However, gradual progression of the multifocal opacities raised mounting suspicion for malignancy, especially in the absence of acute symptoms. In this case, the delay in cancer diagnosis could have been avoided with an earlier lung biopsy. Remarkably, the patient never developed any additional symptoms or extrathoracic metastases despite a prolonged pre-diagnosis course.

Asymptomatic, incidentally detected lung cancer is common, though more so in the early-stage setting [16]. The slow pace of progression and relative lack of symptoms observed in this case are not what we would consider characteristic for metastatic disease. Although there were no extrathoracic metastases, a high burden of disease eventually amassed in the bilateral lungs that continued to manifest clinically as only a chronic, unchanging cough. This discordance between clinical and radiographic findings likely contributed to the delay in diagnosis.

Upon our review of serial imaging for this case, earlier CT scans showed multifocal ground glass and interstitial opacities that gradually increased in density and nodularity. Pure ground glass opacities (GGOs) are associated with a broad differential that includes inflammatory processes, but in some cases may represent pre-malignant lesions. Carcinomas arising from GGOs may remain undiagnosed for years, and prior work suggests that these cancers usually behave indolently [17]. It is unknown whether there was ever a radiographic correlate of pre-malignant disease in this case, though all aspects of the patient's course – clinical and radiographic – suggest a gradual process.

Ultimately, the radiographic findings in this case were thought to be consistent with a “pneumonic-type” adenocarcinoma, which as the name suggests, mimics pneumonia and presents as multifocal subsolid nodules, masses, or consolidations [18,19]. Although a pneumonic radiographic pattern is usually seen with mucinous histology, this patient was diagnosed with a non-mucinous adenocarcinoma [19]. Little has been published about the correlation between the pneumonic radiographic presentation and tumor genotype. One study found that patients with pneumonic-type lung cancer have significantly higher incidence of EGFR mutations [20], but the frequency of a pneumonic radiographic pattern in ROS1-rearranged NSCLC is not well-described.

Specific radiographic features of EGFR mutated and ALK rearranged NSCLC have been described, but the literature surrounding ROS1 rearranged NSCLC is more limited [[21], [22], [23], [24]]. Some studies have suggested that ROS1 rearranged tumors are more likely to be peripheral tumors, more likely to exhibit lymphangitic carcinomatosis, and less likely to present with extrathoracic metastases [[25], [26], [27]]. There is growing interest in the use of radiomics, the extraction of quantitative imaging features, and radiogenomics, the correlation between imaging features and tumor genomic profile, as diagnostic and prognostic tools in NSCLC [28]. For instance, radiomic methods to distinguish NSCLC from non-malignant conditions or to predict survival outcomes have been reported, as well as radiogenomic methods to predict EGFR mutation status and response to targeted therapies [28,29]. In the future, these methods may enhance the diagnosis of clinically atypical NSCLC, help distinguish between molecular subtypes, and predict tumor behavior.

This case also highlights the pathologic work-up for ROS1 gene fusions. ROS1 gene rearrangements occur at various breakpoints in the ROS gene, resulting in fusion proteins that are known to activate multiple downstream signaling pathways including RAS, PI3K and JAK-STAT, leading to cell growth, proliferation, and survival [30]. Immunohistochemistry (IHC) is sometimes used as a screening technique to detect a ROS1 gene fusion, though results often require confirmation by a fluorescence in situ hybridization (FISH) break-apart assay or next-generation sequencing (NGS) [1]. RNA-based NGS panels, which are generally superior to DNA-based panels in detecting gene rearrangements, should be used when available [14,[31], [32], [33]]. At our institution, a DNA-based NGS assay is performed first for all newly diagnosed NSCLC. This test has high sensitivity for a panel of known lung cancer mutations including BRAF, EGFR, KRAS, and MET but has lower sensitivity for gene rearrangements including ROS1 fusions. If the DNA panel is negative, as was the case with this patient's tumor, targeted RNA-based sequencing using ArcherDX, an anchored multiplex PCR panel, is performed reflexively. Here, a gene fusion between ROS1 and EZR, a common fusion partner, was detected on the reflexive RNA panel [1].

Targeted tyrosine kinase inhibitors (TKI) are the standard of care for metastatic ROS1 rearranged NSCLC. Crizotinib is a ROS1/MET inhibitor that was FDA-approved in 2016 that also has activity in ALK rearranged NSCLC. Although several small prospective studies and retrospective studies support the use of crizotinib for ROS1 rearranged NSCLC [[2], [3], [4]], it has poor CNS penetration, which has led many to prefer the more brain-penetrant entrectinib, a ROS1/tropomysin receptor kinase that was FDA-approved in 2019 [5,6]. In a pooled analysis of 3 phase I-II trials including 161 patients with ROS1 fusion-positive NSCLC, the objective response rate to entrectinib was 67 %, the 12-month progression-free survival rate was 55 %, and 12-month overall survival rate was 81 % [34]. Most recently, repotrectinib received FDA approval for both TKI-naïve and TKI-refractory ROS1 rearranged NSCLC [7]. The patient in this report was treated with entrectinib and achieved a significant radiographic and clinical response.

This case highlights several important points regarding the diagnosis and work-up of NSCLC. First, the clinical and radiographic appearance of metastatic adenocarcinoma is variable. Diagnostic delays are common when patients with lung malignancy present with limited symptoms and/or atypical patterns on imaging, so practitioners should remain vigilant [12]. Future advances in radiogenomics may improve the diagnostic accuracy of NSCLC and its molecular subtypes. However, it remains crucial to recognize that NSCLC, including ROS1 rearranged invasive adenocarcinoma, presents with a broad range of findings. This consideration becomes even more compelling when treatment with an effective targeted agent is potentially delayed.

This case also emphasizes the importance of informed, comprehensive molecular testing for all newly diagnosed metastatic lung adenocarcinoma [15]. Although molecular testing for targetable mutations has now been firmly established as standard of care for newly diagnosed adenocarcinoma, it is imperative that providers understand the strengths and limitations of specific NGS modalities and panels. While sensitivity and specificity are assay-dependent, DNA-based NGS may not have high sensitivity to detect all gene fusions [31]. We underscore the role of reflexive RNA-based NGS when DNA-based panels are unrevealing.

4 Conclusion/take home points

• The presentation of metastatic NSCLC is variable and includes relatively asymptomatic patients with atypical findings on imaging that may mimic pneumonia or other inflammatory processes.

• Comprehensive molecular testing, including reflex to an RNA-based panel when DNA-based panels are unrevealing, is important for all newly diagnosed metastatic lung adenocarcinoma.

• There should be a low threshold to obtain prompt lung biopsy when malignancy is on the differential for atypical imaging findings.

Consent for publication

Written informed consent for publication was obtained and documented on our institutional consent from the patient included in this report.

Availability of data and materials

All data included in this study are clinical data that was obtained via our electronic health record.

Funding

Not applicable.

CRediT authorship contribution statement

Lanyi Nora Chen: Writing – review & editing, Writing – original draft, Visualization, Investigation, Conceptualization. Claire Keating: Writing – review & editing, Conceptualization. Jay Leb: Writing – review & editing, Visualization, Conceptualization. Anjali Saqi: Writing – review & editing, Visualization, Conceptualization. Catherine A. Shu: Writing – review & editing, Writing – original draft, Supervision, Investigation, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Catherine Shu reports a relationship with Arcus Biosciences Inc that includes: consulting or advisory. Catherine Shu reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory. Catherine Shu reports a relationship with Genentech that includes: consulting or advisory. Catherine Shu reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Catherine Shu reports a relationship with Beth Israel Deaconess Medical Center that includes: consulting or advisory. Catherine Shu reports a relationship with Takeda that includes: consulting or advisory. Catherine Shu reports a relationship with Gilead that includes: consulting or advisory If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Anjali Saqi reports a consulting/advisory relationship with the following: Veracyte, Boehringer Ingelheim, Genentech, Roche, Bristol Myers Squibb, Abbvie, Fieldworks, Medscape, Dedham, Qessential, Noreen Ellis, PeerView, Gilead.

List of abbreviations

BAL – Bronchoalveolar lavage

CT – Computed Tomography

FISH – Fluorescent in situ hybridization

GGO – Ground glass opacity

IHC – Immunohistochemistry

NGS – Next-generation sequencing

NSCLC – Non-small cell lung cancer

RML – Right middle lobe

RLL – Right lower lobe

TKI – Tyrosine kinase inhibitor
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References

1 Gendarme S. Bylicki O. Chouaid C. Guisier F. ROS-1 fusions in non-small-cell lung cancer: evidence to date Curr. Oncol. 29 2 2022 Jan 641 658
2 Shaw A.T. Ou S.-H.I. Bang Y.-J. Camidge D.R. Solomon B.J. Salgia R. Crizotinib in ROS1-rearranged non-small-cell lung cancer N. Engl. J. Med. 371 21 2014 Nov 1963 1971 25264305
3 Shen L. Qiang T. Li Z. Ding D. Yu Y. Lu S. First-line crizotinib versus platinum-pemetrexed chemotherapy in patients with advanced ROS1-rearranged non-small-cell lung cancer Cancer Med. 9 10 2020 May 3310 3318 32167664
4 Moro-Sibilot D. Cozic N. Pérol M. Mazières J. Otto J. Souquet P.J. Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial Ann. Oncol. 30 12 2019 Dec 1985 1991 31584608
5 Patil T. Smith D.E. Bunn P.A. Aisner D.L. Le A.T. Hancock M. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib J. Thorac. Oncol. 13 11 2018 Nov 1717 1726 29981925
6 Drilon A. Somwar R. Wagner J.P. Vellore N.A. Eide C.A. Zabriskie M.S. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer Clin. Cancer Res. 22 10 2016 May 2351 2358 26673800
7 Drilon A. Ross C.D. Lj J. Sang-We K. Sb J. Rafal D. Repotrectinib in ROS1 fusion–positive non–small-cell lung cancer N. Engl. J. Med. 390 2 2024 Jan 10 118 131 38197815
8 Sacher A.G. Dahlberg S.E. Heng J. Mach S. Jänne P.A. Oxnard G.R. Association between younger age and targetable genomic alterations and prognosis in non–small-cell lung cancer JAMA Oncol. 2 3 2016 Mar 1 313 320 26720421
9 May L. Shows K. Nana-Sinkam P. Li H. Landry J.W. Sex differences in lung cancer Cancers 15 12 2023 Jun
10 Lee J.Y. Na I.I. Jang S.-H. Hwang Y Il Choe D.H. Kim C.H. Differences in clinical presentation of non-small cell lung cancer in never-smokers versus smokers J. Thorac. Dis. 5 6 2013 Dec 758 763 24409352
11 Doebele R.C. Lu X. Sumey C. Maxson D.A. Weickhardt A.J. Oton A.B. Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer Cancer 118 18 2012 Sep 4502 4511 22282022
12 Li Q. Fan X. Huo J. Luo T. Huang X. Gong J. Differential diagnosis of localized pneumonic-type lung adenocarcinoma and pulmonary inflammatory lesion Insights Imaging 13 1 2022 49 35316418
13 Ellis P.M. Vandermeer R. Delays in the diagnosis of lung cancer J. Thorac. Dis. 3 3 2011 Sep 183 188 22263086
14 Mosele F. Remon J. Mateo J. Westphalen C.B. Barlesi F. Lolkema M.P. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group Ann. Oncol. 31 11 2020 Nov 1491 1505 32853681
15 Kalemkerian G.P. Narula N. Kennedy E.B. Molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: American society of clinical oncology endorsement summary of the college of American pathologists/international association for t J Oncol Pract 14 5 2018 Mar 28 323 327 29589987
16 Polanco D. Pinilla L. Gracia-Lavedan E. Mas A. Bertran S. Fierro G. Prognostic value of symptoms at lung cancer diagnosis: a three-year observational study J. Thorac. Dis. 13 3 2021 Mar 1485 1494 33841941
17 Herskovitz E. Solomides C. Barta J. Evans N. Kane G. Detection of lung carcinoma arising from ground glass opacities (GGO) after 5 years - a retrospective review Respir. Med. 196 March 2022 106803
18 Austin J.H.M. Garg K. Aberle D. Yankelevitz D. Kuriyama K. Lee H.-J. Radiologic implications of the 2011 classification of adenocarcinoma of the lung Radiology 266 1 2013 Jan 62 71 23070271
19 Casali C. Rossi G. Marchioni A. Sartori G. Maselli F. Longo L. A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice J. Thorac. Oncol. 5 6 2010 Jun 1 830 836 20521350
20 Liu J. Shen J. Yang C. He P. Guan Y. Liang W. High incidence of EGFR mutations in pneumonic-type non-small cell lung cancer Medicine (Baltim.) 94 8 2015 Feb e540
21 Rizzo S. Petrella F. Buscarino V. De Maria F. Raimondi S. Barberis M. CT radiogenomic characterization of EGFR, K-RAS, and ALK mutations in non-small cell lung cancer Eur. Radiol. 26 2016 32 42 25956936
22 Cheng Z. Shan F. Yang Y. Shi Y. Zhang Z. CT characteristics of non-small cell lung cancer with epidermal growth factor receptor mutation: a systematic review and meta-analysis BMC Med. Imag. 17 1 2017 5
23 Choi C.-M. Kim M.Y. Hwang H.J. Lee J.B. Kim W.S. Advanced adenocarcinoma of the lung: comparison of CT characteristics of patients with anaplastic lymphoma kinase gene rearrangement and those with epidermal growth factor receptor mutation Radiology 275 1 2015 Jan 7 272 279 25575117
24 Halpenny D.F. Riely G.J. Hayes S. Yu H. Zheng J. Moskowitz C.S. Are there imaging characteristics associated with lung adenocarcinomas harboring ALK rearrangements? Lung Cancer 86 2 2014 190 194 25312988
25 Gainor J.F. Tseng D. Yoda S. Dagogo-Jack I. Friboulet L. Lin J.J. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non–small-cell lung cancer JCO Precis Oncol 1 2017 Aug 16 1 13
26 Plodkowski A.J. Drilon A. Halpenny D.F. O'Driscoll D. Blair D. Litvak A.M. From genotype to phenotype: are there imaging characteristics associated with lung adenocarcinomas harboring RET and ROS1 rearrangements? Lung Cancer 90 2 2015 321 325 26424208
27 Digumarthy S.R. Mendoza D.P. Lin J.J. Chen T. Rooney M.M. Chin E. Computed tomography imaging features and distribution of metastases in ROS1-rearranged non-small-cell lung cancer Clin. Lung Cancer 21 2 2020 Mar 153 159.e3 31708389
28 Thawani R. McLane M. Beig N. Ghose S. Prasanna P. Velcheti V. Radiomics and radiogenomics in lung cancer: a review for the clinician Lung Cancer 115 2018 34 41 29290259
29 Gevaert O. Echegaray S. Khuong A. Hoang C.D. Shrager J.B. Jensen K.C. Predictive radiogenomics modeling of EGFR mutation status in lung cancer Sci. Rep. 7 1 2017 41674
30 Davies K.D. Doebele R.C. Molecular pathways: ROS1 fusion proteins in cancer Clin. Cancer Res. 19 15 2013 Aug 4040 4045 23719267
31 Cohen D. Hondelink L.M. Solleveld-Westerink N. Uljee S.M. Ruano D. Cleton-Jansen A.-M. Optimizing mutation and fusion detection in NSCLC by sequential DNA and RNA sequencing J. Thorac. Oncol. 15 6 2020 Jun 1 1000 1014 32014610
32 Bruno R. Fontanini G. Next generation sequencing for gene fusion analysis in lung cancer: a literature review Diagnostics 10 8 2020 Jul
33 Benayed R. Offin M. Mullaney K. Sukhadia P. Rios K. Desmeules P. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with No mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden Clin cancer Res an Off J Am Assoc Cancer Res. 25 15 2019 Aug 4712 4722
34 Dziadziuszko R. Krebs M.G. De Braud F. Siena S. Drilon A. Doebele R.C. Updated integrated analysis of the efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small-cell lung cancer J. Clin. Oncol. 39 11 2021 Apr 1253 1263 33646820
