CRIZOTINIB TREATMENT FOR LUNG CANCER

                                                                                       AND ALK MUTATION              

 

Summary

 

A new drug called Crizotinib is showing impressive results with a group of lung cancer patients with a particular gene mutation.  Crizotinib showed an impressive response rate of close to 60% of patients with an ALK gene abnormality.  This compares with a response rate of 20-25% for most chemotherapy drugs.  Those with the mutation were primarily (but not exclusively) adenocarcinoma patients.  See Table of Studies below.  Testing of adenocarcinoma patients for the mutation would appear sensible since the response rate for patients with the mutation significantly exceeds conventional treatment.  identifying patients who could benefit from the new drug makes sense. 

 

1. Treatment Rationale

 

    A. Example of Tarceva

 

Newer cancer treatments focus on identifying a specific gene believed to be responsible for the particular tumor's creation.  With research, increasing number of distinctive characteristics are identified.  For example, the EGFR gene has been identified as the culprit in EGFR positive lung cancers leading to a response rate of about 60% far exceeding conventional chemotherapy. 

 

Another gene called ALK has been identified with similar results.  An article in the New England Journal of Medicine reports a response rate of 57% for selected patients with ALK mutations using the drug Crizotinib,  That greatly exceeds the about 20% response of standard chemotherapy, and here are some features from this important study. 

 

2. What is ALK

 

ALK stands for Anaplastic Lymphoma Kinase.  Originally associated with lymphoma, “EML4-ALK is a fusion-type protein tyrosine kinase that is generated in human non-small-cell lung cancer as a result of a recurrent chromosome inversion, Soda (4).  Chromosomal translocations and gene fusions play an important role in the initiation of tumorigenesis.  While translocations are seen in cancer, scientists associated them with hematological tumors and have only recently investigated their significance with solid tumors such as lung.  Lin, (11)  

 

Chromosomal rearrangements interrupt the ALK gene and fuse it with another gene result in the creation of an oncogenic, ALK fusion genes.  We have found a novel fusion product between the echinoderm microtubule-associated protein-like4 (EML4) and the anaplastic lymphoma kinase (ALK) in non-small cell lung cancers (NSCLCs). Tumors featuring EML4-ALK fusion constitute one subtype of NSCLC that might be highly sensitive to ALK inhibitors. Inamura (10) 

Translocation of ALK can result in fusion with the neighboring gene, EML4, in cancer cells. The fused genes then encode a fusion protein in which the intracellular tyrosine kinase domain of the ALK receptor is constitutively active. 

 

            A. Mechanism of Action of ALK

 

Several studies showed that cell lines with ALK rearrangements underwent cell cycle arrest and apoptosis when treated with ALK-selective inhibitors.  Lin (11). 

 

            B. Location of Translocation

 

There are two different locations of the fusion mirroring the various locations seen in the EGFR mutation.  Wong writes, “there were 2 cases each of variants 1 and 2 with fusion points at EML4 exons 13 and 20, respectively, one tumor, yielded a novel fusion transcript that was sequenced characterized as fusion of EML4 exon 18, and designated variant 5.”  

 

It is a tyrosine kinase.  Tyrosine kinases have been increasingly associated with cancer and identified for targets for research.   Tyrosine kinases are typically associated with cancer involve a mutated gene.  This malfunction involves a fuses gene.  The discovery of a small inversion of chromosome 2p in a significant proportion of non-small-cell lung cancer patients is therefore of potential importance. The inversion gives rise to a fusion protein comprising portions of a protein known as EML4 and the anaplastic lymphoma kinase, ALK.   

 

            C. Association with Other Cancers

 

ALK belongs to the insulin receptor subfamily of receptor  tyrosine kinases. Aberrant ALK activity has recently been shown to be present in anaplastic large cell lymphoma, as well as in solid tumors.  Zhang (14)

 

3. Crizotinib

 

A response rate of close to 60% was reported with Crizotinib for patients with the ALK mutation.   This response rate is very similar to the response rate for Tarceva with EGFR positive patients.  It appears that if the malfunctioning gene can be identified and appropriate treatment prescribed, impressive response rates can be seen. 

 

4. Animal and Cell Studies

 

Impressive results were found in cell and animal studies.  In one study, mice developed  adenocarcinoma nodules in several weeks.  Inhibition of EML4-ALK activity with a small-molecule drug induced rapid death of the tumor cells.  Soda (4).  Ttumors in the lungs of the transgenic mice changed to bullae or cysts after treatment with the ALK inhibitor, as revealed by CT scanning and pathology.  Soda (4)

 

5. Prevalence of the ALK Mutation  

 

The studies have shown differing percentages of the table indicates with an average of about 6%.  Inamura found only 5 of 149, Kwak found, while Lin found 12 of 106 or 11%.    Study methods varied.     

 

6.  Adenocarcinoma  

 

Kwak’s study found "predominantly" adenocarcinoma patients with the mutation.  Article at 1696.   Another article found adenocarcinoma patients almost exclusively.   "Eighteen of the 19 EML4-ALK tumors were adenocarcinomas."  Sakiri found all adenocarcinomas in his study of cells from bronchosopy.    Sakari (7)

 

 

7. Squamous  Cell Cancers

 

Kwak found one squamous cell patient with the mutation.   Inamura found none in 48 tumor cells sampled in his study (Inamura (10).  The possibility of squamous patients having the mutation appears small but not nonexistent.  If a squamous cell patient asked, is there anything else that can be done, even if is a 1/100 chance, perhaps the physician should mention testing. 

 

8. Large Cell and other types

 

Kwak categorizes tumors as adenocarcinoma, squamous cell carcinoma, and other.  She found two classified as other. Kwak (1).  In contrast, Inamura found no positive samples among 3 large cell and 21 small cell tumor samples. 

 

 

Study Author

Kwak (1)

Inamura (10)

Soda

Lin

Wong   

Lin

 

Overall

 

5/149

5/75

12/106

13/266

12/106

 

Adenocarcinoma

 

 

 

 

 

0/sample number unclear

 

Squamous

 

 

0/48

2/sample no unclear

0/sample number unclear

 

 

 

 

Large Cell

 

0/3/ large cell neoendocrine 

 

 

 

 

 

Small Cell

 

0/21

 

 

 

 

 

Smoking history

 

3/65

 

 

2/sample no unclear

 

 

Non-smoker

 

2/84

 

 

10/

 

 

EGFR Status

 

EGFR Pos.  0/38

EGFR Neg
5/24

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

9. Smokers and non-smokers 

 

Most of the patients were non-smokers or light former smokers.  See also Soda, Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer, Nature 448, 561-566 (August 2, 2007). However, the study found "five patients had a history of more than 10 pack years including three who had smoked for at least 35 pack years."  One could not exclude smokers and testing may make sense for that group.    

 

10. Age

 

Younger patients were more likely to have the mutation

 

11.  EGFR and ALK

 

EGFR is the other prominent tyrosine kinase.  However, the groups appear to be different.  In virtually all the studies, the two mutations were found

to be mutually exclusive.  The patient population harbouring EGFR mutations did not overlap with that harbouring the EML4–ALK fusion gene, showing that

EML4–ALK-positive cancer is a novel subclass within NSCLC. Soda (2)

 

12. Testing for the ALK Fusion Mutation

 

The studies provide a strong argument for testing adenocarcinoma patients.  Whether insurance will cover this, whether surgical tissue is needed, the ease and cost of testing are open questions. 

 

            A. Commercial entities performing testing

 

A company called Response Genetics advertises an ALK test.   www.responsegenetics.com  Another study suggests that routine laboratory testing may be able to detect the mutation:

           

            Low levels of ALK protein expression is a characteristic feature of ALK- rearranged lung adenocarcinomas.  A novel, highly sensitive IHC assay           reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.  Knutsen (6) 

 

            B. Tissue or sample needed

 

Generally a tissue is secured through a biopsy which is a surgical procedure carrying some risk and some discomfort.  Studies are looking at less intrusive alternatives, For example, one study looked at obtaining EGFR mutation results from pleural fluid which would be more easily obtained.  

 

Knutsen suggests standard testing may be able to detect the mutation.  (3)    

 

13. Insurance Coverage

 

A powerful argument can be made for use of Crizotinib for ALK positive adenocarcinoma patients,  The impressive  response data together with other material on tyrosine kinase (Hirsch 9) presents a powerful argument for use with this subgroup.  Consistent with that, a reasonable argument can be made for testing adenocarcinoma patients. 

 

14. Crizotinib’s Use for ALK negative patients  

 

Whether Tarceva, an anti-EGFR drug is effective with EGFR negative patients has been debated here and elsewhere.  There may be similar discussion of Crizitonib, and whether this gene plays any role in patients without the ALK rearrangements. 

 

15. FDA Approval and Standards

 

The manufacturer is apparently seeking expedited FDA approval of the drug.  Unfortunately standard practices and standard of care can lag as studies are examined.  Patients may want to look at testing, clinical trials and other alternatives. 

 

16. Drugs Others Than Crizotinib

 

Other drugs may be developed to target the ALK mutation.  It appears Crizotinib is the only anti-ALK drug to have had a successful clinical trial.  

 

17. Stabilization of Disease  

 

The primary focus of this new drug, and the area of impressive response is with ALK positive patients.  Interestingly, even with ALK positive patients there was a large group, 33%  for which stabile disease, but no response was reported. 

 

References

 

1. Kwak, Anaplastic Lymphoma Kinase Inhibition in Non-Small Cell Lung Cancer, Oct 28, 2010,

 

2. Soda, Identification of the transforming EML4–ALK fusion gene in non-small-cell

lung cancer ,  Nature, Aug. 2, 2007

 

3. Kimura, EGFR mutation status in tumour-derived DNA from pleural effusion fluid is a practical basis for predicting the response to gefitinib, British Journal of Cancer (2006) 95, 1390–1395.

 

4. Soda, A mouse model for EML4-ALK-positive lung cancer, PNAS December 16, 2008 vol. 105 no. 50 19893-19897.

 

5. Nelson, ALK Inhibitors: Possible New Treatment for Lung Cancer, medscape.com.

 

6.  Knutsen, A Novel, Highly Sensitive Antibody Allows for the Routine Detection of ALK-Rearranged Lung Adenocarcinomas by Standard Immunohistochemistry, ical Cancer Research March 2010 16; 1561

 

7. Sakari, EML4-ALK Fusion Gene Assessment Using Metastatic Lymph Node Samples Obtained by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration, Clinical Cancer Research October 2010 16; 4938

 

8. Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK, Journal of Clinical Oncology, August 10, 2009. 

 

9. Hirsch, The Tissue Is the Issue: Personalized Medicine for Non-Small Cell Lung Cancer, Clinical Cancer Research October 2010 16; 4909

 

10. Inamura, EML4-ALK Fusion Is Linked to Histological Characteristics in a Subset of Lung Cancers,  Journal of Thoracic Oncology, January 2008 - Volume 3 - Issue 1 - pp 13-17

 

11. Lin,  Exon Array Profiling Detects EML4-ALK Fusion in Breast,

Colorectal, and Non–Small Cell Lung Cancers, Mol Cancer Res 2009;7(9). September 2009

 

12. Wong, The EML4-ALK Fusion Gene Is Involved in Various Histologic Types

of Lung Cancers From Nonsmokers With Wild-type EGFR and KRAS,

 

13. Martelli, EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues, American Journal of Pathology. 2009, 174:661-670.

 

14. Zhang, Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with

ALK expression, Molecular Cancer 2010,

 

15. Misudomi, Clinico-pathologic features of lung cancer with EML4-ALK translocation, Journal of Clinical Oncology, 28, No 15  (May 20 Supplement), 2010

 

 

 SUMMARY OF ALK MUTATION STUDIES

 

 

 

 

 

 

 

 

 

 

 

 

Study Author and Reference No

Zhang
(14)

Inamura (10)

Soda

(4)

Lin

(11)

Wong  

(12)

Martelli

(13)

Sakari

(7)

Kwak

(1)

Misudomi (15)

 

Number with ALK Fusion

12/103 (higher in Asian pop)

5/149

 

12/106

13/266

9/120

7/109

 

10/345, percentages low throughout

 

Adeno-carcinoma

10 of 62

 

2 of it appears 33 had the mutation with adenocarcinoma

The EML4-ALK fusion was detected
only in adenocarcinomas

9 of 11 Adenos had the mixed
tumor subtype, which displayed papillary, micropapillary,
and cribriform growth, 2 bronchioalveolar

3 of 63

 

 

10/314

 

Squamous

2 of 49

0/48

1/sample no unclear

0/sample number unclear

2/- with mixed squamous cell and glandular

4 of 48

0

 

0/21

 

 

Large Cell

1 of 1, finding of Alk in large cell patient

0/3/ large cell/ neo-endocrine 

 

 

 

0/3

 

 

 

 

 

 

Small Cell

 

0/21

 

 

0/34

 

 

 

 

 

Smoking history

10 of 54 nonsmokers were ALK positive ;  2 of 49 smokers ALK positive

 

 

 

the fusion gene was identified
in 12 of 141 nonsmokers (8.5%) and in 1 of 125
ever-smokers (0.8%)11 total with mutation, 1 heavy smoker, 2 passive smokers, and 8 never smokers

 

ALK positive cases were more likely to occur with never or light  smokers

 

 

 

 

You may want to discuss this and other literature with your physician.  This article is not intended to provide medical advice.