Home | About us | Editorial Board | Search | Ahead of print | Current Issue | Archives | Instructions | Online submissionContact Us   |  Subscribe   |  Advertise   |  Login  Page layout
Wide layoutNarrow layoutFull screen layout
Lung India Official publication of Indian Chest Society  
  Users Online: 334   Home Print this page  Email this page Small font size Default font size Increase font size


 
  Table of Contents    
EDITORIAL
Year : 2017  |  Volume : 34  |  Issue : 5  |  Page : 405-408  

Beyond epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing in advanced non-small cell lung cancer: Is the picture as “ROS1” as it appears?


Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication31-Aug-2017

Correspondence Address:
Navneet Singh
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/lungindia.lungindia_305_17

Rights and Permissions

How to cite this article:
Singh N. Beyond epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing in advanced non-small cell lung cancer: Is the picture as “ROS1” as it appears?. Lung India 2017;34:405-8

How to cite this URL:
Singh N. Beyond epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing in advanced non-small cell lung cancer: Is the picture as “ROS1” as it appears?. Lung India [serial online] 2017 [cited 2017 Sep 19];34:405-8. Available from: http://www.lungindia.com/text.asp?2017/34/5/405/213831



Lung cancer remains the most common cause of cancer-related mortality globally. The last couple of decades and in particular the last 5 years has been a very exciting period for both oncologists and patients alike. This has primarily been due to the advent of targeted therapies and subsequently immunotherapy (PD-1/PD-L1 inhibitors) as the 4th and 5th pillars for the treatment of lung cancer, respectively (based on the timelines for their development and approval).[1] Both of these have become very useful additions to the previously available treatment options [Figure 1], namely, surgical resection, chemotherapy, and radiation therapy. A large proportion of these treatment advances have been in advanced/metastatic (Stages IIIB/IV) non-small cell lung cancer (NSCLC) – the most frequent disease stage at presentation and the most frequent histological type respectively.[2],[3],[4] This has been particularly true in the case of non-squamous NSCLC (essentially lung adenocarcinoma) – which is the most common histological type seen in female nonsmokers.
Figure 1: The five pillars of lung cancer treatment

Click here to view


The discovery of epidermal growth factor receptor (EGFR) sensitizing mutations was followed by the demonstration that EGFR tyrosine kinase inhibitors (TKIs) are superior to platinum-based doublet (two drug) chemotherapy as first-line treatment of patients with advanced/metastatic NSCLC harboring these sensitizing mutations (the most common being exon 19 deletions and the point L858R mutation on exon 21).[5] This was established in seven large randomized trials featuring all the three EGFR-TKIs that are currently available for use (the first generation reversible blockers gefitinib and erlotinib as well as the second generation irreversible blocker afatinib).[6],[7],[8],[9],[10],[11],[12] A similar and perhaps greater magnitude of benefit was shown in patients with rearrangements of the anaplastic lymphoma kinase (ALK) gene with the use of crizotinib (a small molecule ALK inhibitor) namely its superiority over standard platinum based doublet chemotherapy both in the first- and second-line settings.[13],[14] Second generation ALK inhibitors, alectinib [15],[16],[17] and ceritinib,[18],[19],[20] initially researched and approved for patients intolerant to or having disease progression on crizotinib (especially brain metastases) are moving to the front line setting now.[21],[22],[23] Both EGFR sensitizing mutations and ALK rearrangements occur predominantly in adenocarcinoma histology with further enrichment being possible in female nonsmokers.[24],[25]

The role of methodology employed for testing for these druggable genetic mutations and rearrangements needs special mention. As per our own experience (unpublished data), EGFR mutation prevalence was 5% higher with the more sensitive method of real-time amplification refractory mutation system polymerase chain reaction (ARMS-PCR) as compared to the initially employed conventional gene (Sanger) sequencing (23% vs. 18%). In case of ALK gene rearrangements, the prevalence is almost double (9% vs. 5%) with the more sensitive immunochemistry (D5F3 clone) as compared to BreakApart fluorescence in situ hybridization (FISH) method. The more sensitive techniques listed above are also associated with a significant increase in the percentage of interpretable results as these require lesser tissue. With the use of real-time PCR for EGFR and of the D5F3 immunochemistry for ALK, almost 95% of our samples tested had interpretable results as compared to around 82% with the initially used techniques. Since EGFR mutations and ALK rearrangements are mutually exclusive, we currently expect one of every two females with advanced/metastatic lung adenocarcinoma tested to be a candidate for targeted therapy (37% EGFR and 13% ALK prevalence in our setting). Similarly, for nonsmoker males, this translates into three of every eight patients being tested to be positive for either EGFR or ALK (26% and 10.5%, respectively) and thus being eligible for EGFR/ALK targeted therapies. Even for current/ex-smoking males (historically believed to be not associated with the presence of druggable genetic alterations), the expected prevalence at our center for them to be candidates for targeted therapy is one of every six patients tested (11% EGFR and 6% ALK prevalence). For patients, the implications are enormous. It not only means that they can be treated initially with targeted therapy alone (without being subjected to chemotherapy) but also that this comes at the convenience of taking an oral drug at home with much lesser toxicity and much greater efficacy than conventional chemotherapy.

We are now moving fast forward to an era wherein commercially available highly sensitive methods such as digital droplet PCR and next generation sequencing (NGS) platforms are being used to test for these targetable mutations/rearrangements in tissue- and nontissue-based specimens as well.[26] In the case of EGFR, using peripheral blood [popularly called 'liquid biopsy'] for mutation testing in circulating tumor DNA (ctDNA; also sometimes referred to as circulating cell-free tumor DNA or cfDNA) is already approved and validated for routine clinical practice. As compared to DNA within circulating tumor cells, ctDNA or cfDNA is more frequently and easily detectable. This platform is used for detecting sensitizing EGFR mutations in treatment naïve patients with advanced/metastatic NSCLC (for offering therapy with first/second generation EGFR TKIs) and subsequently also once these patients have experienced disease progression to test for the acquired T790M resistance conferring mutation on exon 20 (to offer therapy with the third generation EGFR TKI – osimertinib).[27] The ultra-sensitive NGS platforms are also being utilized to find targetable genetic alterations other than EGFR/ALK in particular ROS1 rearrangements, HER2 mutations, BRAF V600E mutations, MET amplification, and MET exon 14 skipping mutations.

The article by Suryavanshi et al. (accompanying this editorial) in the current issue of this journal is an attempt to identify the prevalence of ROS1 rearrangements in a cohort of 105 lung adenocarcinoma patients which is commendable.[28] The finding of 3 patients positive by FISH is in concordance with world literature as the published prevalence is 2%–3%. Would the prevalence have been higher had the cohort had been screened with immunochemistry first followed by FISH for confirmation (something analogs to what happened to ALK testing) or if a more sensitive technique like NGS been employed? These are questions that may need to be addressed in future studies. From a treatment perspective, crizotinib, a small molecule ALK inhibitor, is equally efficacious, if not more, for patients with ROS1 gene rearrangements with objective responses ranging from 72% to 80%.[29],[30] For routine clinical practice, what does this study do? Does it make ROS1 testing as “ROS1” (rosy) as it appears to be?

The answer to this is both yes and no. Yes because we are delighted to find that Indian patients have at least a similar prevalence of ROS1 rearrangements as reported from other parts of the world. ROS1 is another “druggable” genetic alteration in advanced/metastatic NSCLC (apart from EGFR and ALK) whose occurrence is mutually exclusive from the other driver mutations/rearrangements.[31]No because of two reasons – first, the drug crizotinib is marketed only by the innovator and costs approximately 75,000 Indian rupees (1175 US$) per month in a country with a GDP per capita of approximately 1800 US$ although the compassionate access program that is currently being offered by the company is enabling ALK +ve patients living below the poverty line to have access to this drug without paying for it. Second, for 100 lung cancer patients presenting to the clinic, the actual statistics turn out to be as shown in [Table 1]. This has been aptly called “Targeting the 1% in Lung Cancer.”[32]
Table 1: Prevalence of targetable genetic mutations and rearrangements - percentage wise and actual numbers

Click here to view


So what does it mean – should we really invest our resources and efforts in finding out patients with targetable genetic mutations/alterations in lung cancer who constitute a minority (15% or less)?[33] The answer is clearly a BIG YES – the effort is definitely worth it. The phenomenal radiological responses, as well as clinical benefit (including improvement in survival) observed with administration of a targeted drug in advanced/metastatic NSCLC patients with a driver mutation/rearrangement, is not matched by any type of chemotherapy, radiation or its combination. It needs to be clarified here that the benefit of PD-1/PD-L1 immune check point inhibitors (immunotherapy) is largely restricted to patients WITHOUT a targetable genetic mutation/rearrangement in whom first and often second line therapies are targeted drugs. Testing for EGFR mutations and ALK rearrangements is part of normal protocol for diagnostic evaluation and management of all patients with advanced/metastatic lung adenocarcinoma. This awareness is required to be disseminated among ALL physicians (pulmonologists/medical oncologists/radiation oncologists) involved in the treatment of this disease as well as for those working in the laboratory (pathologists/molecular biologists). It is mandatory for them not only to advise patients about the need for such testing but also to guide them regarding the existence of facilities where such testing is available/offered. Occasionally (as in the case of ROS1 and other relatively uncommon mutations/rearrangements), this exercise amounts to “finding a needle in a haystack.” However, due to mutual exclusivity from EGFR and ALK, the option to test ROS1 (and the others druggable targets) should be offered to patients especially if (a) both of the former have already been tested and are negative and (b) the patient is a young never/light smoker with nonsquamous histology – all three being clinical surrogates that enrich the probability for their presence/detection. Ultimately, the use of targeted therapies in the presence of a positive predictive biomarker improves both the quality and quantity of life in the setting of advanced/metastatic NSCLC – a benefit which is something no health-care professional treating this disease can remain oblivious to. For a given patient, it often implies a world of difference and gives hope of leading a meaningful life for a reasonable period – something that perhaps he/she had completely given up when the diagnosis was shared with him/her.



 
   References Top

1.
Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr., Wu YL, et al. Lung cancer: Current therapies and new targeted treatments. Lancet 2017;389:299-311.  Back to cited text no. 1
    
2.
Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Unchanging clinico-epidemiological profile of lung cancer in north India over three decades. Cancer Epidemiol 2010;34:101-4.  Back to cited text no. 2
[PUBMED]    
3.
Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Quantified smoking status and non-small cell lung cancer stage at presentation: Analysis of a North Indian cohort and a systematic review of literature. J Thorac Dis 2012;4:474-84.  Back to cited text no. 3
[PUBMED]    
4.
Kaur H, Sehgal IS, Bal A, Gupta N, Behera D, Das A, et al. Evolving epidemiology of lung cancer in North India: reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key. Indian J Cancer [ePub Ahead of Print].  Back to cited text no. 4
    
5.
Singh N, Bal A, Aggarwal AN, Das A, Behera D. Clinical outcomes in non-small-cell lung cancer in relation to expression of predictive and prognostic biomarkers. Future Oncol 2010;6:741-67.  Back to cited text no. 5
[PUBMED]    
6.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.  Back to cited text no. 6
[PUBMED]    
7.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.  Back to cited text no. 7
[PUBMED]    
8.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.  Back to cited text no. 8
[PUBMED]    
9.
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.  Back to cited text no. 9
[PUBMED]    
10.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.  Back to cited text no. 10
[PUBMED]    
11.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.  Back to cited text no. 11
    
12.
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213-22.  Back to cited text no. 12
[PUBMED]    
13.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94.  Back to cited text no. 13
    
14.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77.  Back to cited text no. 14
[PUBMED]    
15.
Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119-28.  Back to cited text no. 15
[PUBMED]    
16.
Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol 2016;34:661-8.  Back to cited text no. 16
[PUBMED]    
17.
Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol 2016;17:234-42.  Back to cited text no. 17
[PUBMED]    
18.
Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97.  Back to cited text no. 18
[PUBMED]    
19.
Crinò L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: Results from ASCEND-2. J Clin Oncol 2016;34:2866-73.  Back to cited text no. 19
    
20.
Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017;18:874-86.  Back to cited text no. 20
    
21.
Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): An open-label, randomised phase 3 trial. Lancet 2017;390:29-39.  Back to cited text no. 21
[PUBMED]    
22.
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017; Jun 6. doi: 10.1056/NEJMoa1704795.  Back to cited text no. 22
    
23.
Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 2017;389:917-29.  Back to cited text no. 23
    
24.
Maturu VN, Singh N, Bal A, Gupta N, Das A, Behera D. Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival. Lung India 2016;33:257-66.  Back to cited text no. 24
[PUBMED]  [Full text]  
25.
Bal A, Singh N, Agarwal P, Das A, Behera D. ALK gene rearranged lung adenocarcinomas: Molecular genetics and morphology in cohort of patients from North India. APMIS 2016;124:832-8.  Back to cited text no. 25
[PUBMED]    
26.
Hiley CT, Le Quesne J, Santis G, Sharpe R, de Castro DG, Middleton G, et al. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Lancet 2016;388:1002-11.  Back to cited text no. 26
[PUBMED]    
27.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629-40.  Back to cited text no. 27
    
28.
Suryavanshi M, Panigrahi MK, Kumar D, Verma H, Saifi M, Dabas B, et al. ROS1 rearrangement and response to crizotinib in stage IV non-small cell lung cancer. Lung India 2017 [ePub Ahead of Print].  Back to cited text no. 28
    
29.
Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963-71.  Back to cited text no. 29
[PUBMED]    
30.
Mazières J, Zalcman G, Crinò L, Biondani P, Barlesi F, Filleron T, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 2015;33:992-9.  Back to cited text no. 30
    
31.
Lin JJ, Ritterhouse LL, Ali SM, Bailey M, Schrock AB, Gainor JF, et al. ROS1 fusions rarely overlap with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol 2017;12:872-7.  Back to cited text no. 31
[PUBMED]    
32.
Gold KA. ROS1 – Targeting the one percent in lung cancer. N Engl J Med 2014;371:2030-1.  Back to cited text no. 32
[PUBMED]    
33.
Singh N, Aggarwal AN, Behera D. Management of advanced lung cancer in resource-constrained settings: A perspective from India. Expert Rev Anticancer Ther 2012;12:1479-95.  Back to cited text no. 33
[PUBMED]    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
  
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed251    
    Printed1    
    Emailed0    
    PDF Downloaded75    
    Comments [Add]    

Recommend this journal