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Novel mutations in anaplastic lymphoma kinase predicting response to ALK inhibitor therapy in lung cancer patients

A lymphoma kinase and inhibitor technology, applied in the field of mutation detection, can solve problems such as resistance mutation

Inactive Publication Date: 2019-02-05
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients who were given crizotinib inevitably progressed, at least in part due to the emergence of resistance mutations

Method used

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  • Novel mutations in anaplastic lymphoma kinase predicting response to ALK inhibitor therapy in lung cancer patients
  • Novel mutations in anaplastic lymphoma kinase predicting response to ALK inhibitor therapy in lung cancer patients
  • Novel mutations in anaplastic lymphoma kinase predicting response to ALK inhibitor therapy in lung cancer patients

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1. Detection of ALK mutations in lung cancer patients

[0061] Cell-free DNA from patients was isolated before and after alectinib treatment. This cfDNA was subjected to next generation sequencing using standard Illumina HiSeq workflow and analysis as described in US20140296081. Single nucleotide variants (SNVs) in patients were identified using sequencing data, and SNVs that were present at only one of the two time points in a given patient were further examined. One variant, R1209Q, was identified in six patients. In 5 / 6 patients it was present only after alectinib therapy ( figure 1 ), providing evidence that it can confer resistance to alectinib. In the sixth patient, a known resistant variant to alectinib was detected, so a separate clone may have conferred alectinib resistance ( figure 2 ). The other variant, I1268V, was identified in one patient but only before alectinib treatment, suggesting that it may confer sensitivity to alectinib.

[0062]...

Embodiment 2

[0064] Example 2: Factors Affecting ALK Fusion Results

[0065] Table 1 shows that the hazard ratios for patients with ALK fusion variant 3 (EML4 exon 6 joined to ALK exon 20) were much higher than those for patients without ALK fusion variant 3. Figure 8 showed that patients with variant 3 fusions had significantly shorter progression-free survival (PFS) compared to patients with other ALK fusions. This was found to be true regardless of race and treatment status (ie, ALK inhibitor-treated individuals with ALK fusion variant 3 had worse outcomes than ALK inhibitor-treated individuals with a different ALK fusion). On average, individuals with variant 3 fusions were approximately 2.6 times more likely to progress (p-value 0.0012). This hazard ratio of 2.6 was derived from a Cox PH multivariate model performed on 72 patient plasma samples taken prior to treatment with alectinib. The model predicts progression-free survival (PFS) from the effect of the variant 3 fusion, adju...

Embodiment 3

[0068] Example 3: Single Nucleotide Variation (SNV) and ALK Fusion Analysis

[0069] Plasma samples were collected from 188 stage IIIB-IV NSCLC (non-small cell lung cancer) patients who had progressed after crizotinib treatment (before second line therapy (eg treatment with alectinib)). These patients had previously been determined to be ALK-fusion positive by fluorescence in situ hybridization (FISH). The presence or absence of the most common ALK fusions was detected using a circulating tumor DNA panel (Avenio ctDNA panel). Table 2 shows the frequency of detected fusions.

[0070] Table 2

[0071] fusion variant

Numbering

EML4 exon 13-ALK exon 20

26

EML4 exon 13-ALK exon 24

1

EML4 exon 14-ALK exon 20

1

EML4 exon 18-ALK exon 20

3

EML4 exon 19-ALK exon 20

1

EML4 exon 20-ALK exon 20

4

EML4 exon 21-ALK exon 20

3

EML4 exon 6-ALK exon 20

33

none detected

107

other fusi...

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Abstract

The invention comprises novel methods and compositions for detecting whether a patient will be responsive to ALK inhibitors and methods of treating the patient.

Description

field of invention [0001] The present disclosure relates to cancer diagnostics and companion diagnostics for cancer therapy. In particular, the present invention relates to the detection of mutations that can be used in diagnosis and prognosis and in predicting the effectiveness of cancer treatments. Background of the invention [0002] Gene activation via fusions in the intron of anaplastic lymphoma kinase (ALK) is a common genomic driver of non-small cell lung cancer (NSCLC). In lung cancer patients in whom ALK fusions are detected, targeted anti-ALK therapy may be prescribed. For example, the drug crizotinib (XALKORI ® ) is an inhibitor of, inter alia, the ALK protein. Crizotinib has been shown to significantly improve progression-free survival in patients with ALK fusions. However, patients inevitably progressed after being given crizotinib, at least in part due to the emergence of resistance mutations. Missense mutations known so far are L1152R, C1156Y, F1174L, L11...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886
CPCA61P35/00C12Q1/6886A61K2123/00C12Q2600/106C12Q2600/156C12Q2600/158C12Q2600/172
Inventor A.洛夫乔伊S.杨
Owner F HOFFMANN LA ROCHE & CO AG
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