# US 2021/0239702 A1 · Methods for predicting responsiveness of lung cancer patients to her2-targeting therapies

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- Number: US 2021/0239702 A1
- Document ID: US20210239702A1
- Status: Published application
- Kind: A1
- Application number: 17/251,425
- Filed: 2019-06-13
- Published: 2021-08-05
- Earliest claimed: 2018-06-14
- Applicants: Memorial Sloan Kettering Cancer Center
- Inventors: Maurizio SCALTRITI; Bob T. LI
- Web page: https://patentgrep.com/patent/US20210239702A1

## CPC

- G01N 33/5752: of the lungs
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- C12Q 1/68: involving nucleic acids
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 2333/71: for growth factors; for growth regulators
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The present disclosure provides methods for determining whether a patient diagnosed with lung cancer will benefit from or is predicted to be responsive to treatment with a therapeutic agent that targets HER2. These methods are based on detecting elevated levels of HER2 dimerization in a biological sample obtained from a lung cancer patient. Kits for use in practicing the methods are also provided.

## Claims

### Claim 1

A method for selecting lung cancer patients for treatment with a HER2-targeted therapeutic agent comprising:
(a) detecting levels of HER2 dimerization in biological samples obtained from lung cancer patients;
(b) identifying lung cancer patients that exhibit HER2 dimerization levels that are elevated compared to that observed in a healthy control subject or a predetermined threshold; and
(c) administering a HER2-targeted therapeutic agent to the lung cancer patients of step (b), optionally wherein the lung cancer patients are human.

### Claim 2 (depends on 1)

The method of claim 1, wherein the lung cancer patients harbor a HER2 mutation selected from the group consisting of exon 20 insYVMA, exon 20 insGSP, exon 20 insTGT, exon 20 insCPG, exon 20 G778_P780dup, exon 20 G776_V777>VCV, exon 20 G776delinsVC, L755A, L755S, L755P, V659E, S310F, and V777L.

### Claim 3 (depends on 1)

The method of claim 1, wherein the lung cancer is lung adenocarcinoma, squamous cell lung cancer, large cell lung cancer, or small cell lung cancer (SCLC).

### Claim 4

(canceled)

### Claim 5 (depends on 1)

The method of claim 1, wherein HER2 dimerization comprises HER-HER2 homodimerization and/or HER2-HER3 heterodimerization.

### Claim 6 (depends on 1)

The method of claim 1, wherein HER2 dimerization levels are detected via fluorescence resonance energy transfer (FRET), fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET), Western blotting, size exclusion chromatography, analytical ultracentrifugation, scattering techniques, NMR spectroscopy, isothermal titration calorimetry, fluorescence anisotropy, mass spectrometry, fluorescence correlation spectroscopy (FCS), fluorescence recovery after photobleaching, (FRAP), or proximity imaging (PRIM).

### Claim 7 (depends on 1)

The method of claim 1, wherein the biological samples are fresh tissue samples, frozen tissue samples, or fixed-formalin paraffin-embedded tissue samples.

### Claim 8 (depends on 1)

The method of claim 1, wherein the HER2-targeted therapeutic agent comprises a HER2 antibody-drug conjugate, optionally wherein the HER2 antibody-drug conjugate comprises trastuzumab, pertuzumab, margetuximab, or ertumaxomab.

### Claim 9

(canceled)

### Claim 10 (depends on 8)

The method of claim 8, wherein the HER2 antibody-drug conjugate comprises an anthracycline, a microtubule inhibitor, a mitosis inhibitor, a topoisomerase inhibitor, a DNA damaging agent, a histone deacetylase inhibitor, a kinase inhibitor, a nucleotide analog, an amino acid analog, a vitamin analog, an anti-metabolite, emtansine, deruxtecan, lapatinib, poziotinib, neratinib, or afatinib.

### Claim 11

(canceled)

### Claim 12 (depends on 8)

The method of claim 8, wherein the HER2 antibody-drug conjugate is selected from the group consisting of ado-trastuzumab emtansine (T-DM1), A166, ALT-P7, ARX788, DHES0815A, trastuzumab deruxtecan (DS-8201), DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.

### Claim 13 (depends on 1)

The method of claim 1, wherein the lung cancer patients exhibit HER2 and/or HER3 expression levels that are elevated relative to that observed in a healthy control subject or a predetermined threshold.

### Claim 14 (depends on 1)

The method of claim 1, wherein the lung cancer patients exhibit HER2 and/or HER3 expression levels that are comparable to that observed in a healthy control subject or a predetermined threshold.

### Claim 15 (depends on 13)

The method of claim 13, wherein the HER2 and/or HER3 expression levels are measured using one or more of mass spectrometry, immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH).

### Claim 16

A method for treating lung cancer in a patient in need thereof comprising administering to the patient an effective amount of a HER2-targeted therapeutic agent, wherein the patient exhibits HER2 dimerization levels that are elevated compared to that observed in a healthy control subject or a predetermined threshold, optionally wherein HER2 dimerization comprises HER-HER2 homodimerization and/or HER2-HER3 heterodimerization.

### Claim 17 (depends on 16)

The method of claim 16, wherein the patient harbors a HER2 mutation selected from the group consisting of exon 20 insYVMA, exon 20 insGSP, exon 20 insTGT, exon 20 insCPG, exon 20 G778_P780dup, exon 20 G776_V777>VCV, exon 20 G776delinsVC, L755A, L755S, L755P, V659E, S310F, and V777L.

### Claim 18 (depends on 16)

The method of claim 16, wherein the lung cancer is lung adenocarcinoma, squamous cell lung cancer, large cell lung cancer, or small cell lung cancer (SCLC).

### Claim 19

(canceled)

### Claim 20 (depends on 16)

The method of claim 16, wherein the HER2-targeted therapeutic agent comprises a HER2 antibody-drug conjugate, optionally wherein the HER2 antibody-drug conjugate comprises trastuzumab, pertuzumab, margetuximab, or ertumaxomab.

### Claim 21

(canceled)

### Claim 22 (depends on 20)

The method of claim 20, wherein the HER2 antibody-drug conjugate comprises an anthracycline, a microtubule inhibitor, a mitosis inhibitor, a topoisomerase inhibitor, a DNA damaging agent, a histone deacetylase inhibitor, a kinase inhibitor, a nucleotide analog, an amino acid analog, a vitamin analog, an anti-metabolite emtansine, deruxtecan, lapatinib, poziotinib, neratinib, or afatinib.

### Claim 23

(canceled)

### Claim 24 (depends on 20)

The method of claim 20, wherein the HER2 antibody-drug conjugate is selected from the group consisting of ado-trastuzumab emtansine (T-DM1), A166, ALT-P7, ARX788, DHES0815A, trastuzumab deruxtecan (DS-8201), DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.

### Claim 25 (depends on 20)

The method of claim 20, wherein the patient exhibits HER2 and/or HER3 expression levels that are elevated relative to that observed in a healthy control subject or a predetermined threshold.

### Claim 26 (depends on 20)

The method of claim 20, wherein the patient exhibits HER2 and/or HER3 expression levels that are comparable to that observed in a healthy control subject or a predetermined threshold.