ALK L1196M

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Molecular profile	Therapy	Type	Level	Direction · significance	Rating (1–5)	Status	Evidence	Source
Lung Adenocarcinoma3
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	C	Supports Resistance	4	accepted	EID237 A 28 year-old patient with non-small cell lung cancer was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid i… (full text at CIViC) PMID 20979473 · Choi et al., 2010 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	C	Supports Resistance	2	submitted	EID4040 In a stage IV Hodgkin's lymphoma patient with metastatic lung adenocarcinoma harboring an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK L1196M�co-mutation, ALK … (full text at CIViC) PMID 27507192 · Zhang et al., 2017 · Open in CIViC	civic

Molecular profile

Therapy

Type

Level

Direction · significance

Rating (1–5)

Status

Evidence

Source

Lung Adenocarcinoma3

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

accepted

EID237

A 28 year-old patient with non-small cell lung cancer was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid i… (full text at CIViC)

PMID 20979473 · Choi et al., 2010 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID4040

In a stage IV Hodgkin's lymphoma patient with metastatic lung adenocarcinoma harboring an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK L1196M�co-mutation, ALK … (full text at CIViC)

PMID 27507192 · Zhang et al., 2017 · Open in CIViC

civic

Variation	Clinical significance	Review status	Stars	Conditions	Origin	Submitters	Last evaluated	Source
376135	Likely pathogenic	no assertion criteria provided	0	Lung cancer	somatic	1	—	clinvar

Variation

Clinical significance

Review status

Stars

Conditions

Origin

Submitters

Last evaluated

Source

376135

Likely pathogenic

no assertion criteria provided

Lung cancer

somatic

—

clinvar

Lung Non-Small Cell Carcinoma12
EML4::ALK Fusion AND ALK G1202R AND ALK L1196M	Lorlatinib	Predictive	C	Supports Resistance	3	submitted	EID7591 Repeat biopsies were taken for 20 ALK-positive NSCLC patients, including 11 with pre- and post-lorlatinib biopsies. 19 of 20 patients received crizotinib and at least one second line ALK inhibitor. On… (full text at CIViC) PMID 29650534 · Yoda et al., 2018 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Alectinib	Predictive	D	Supports Sensitivity Response	3	accepted	EID141 CH5424802 treatment resulted in significant tumor regression in xenograft models produced from Ba/F3 cells expressing EML4-ALK or EML4-ALK with the L1196M mutation. PMID 21575866 · Sakamoto et al., 2011 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Ceritinib	Predictive	D	Supports Sensitivity Response	4	accepted	EID1341 The crizotinib-resistant MGH045 cell line with EML4-ALK L1196M was treated with crizotinib or ceritinib. In nude mice with MGH045 xenografts, tumor response to crizotinib did not differ appreciably fr… (full text at CIViC) PMID 24675041 · Friboulet et al., 2014 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	C	Supports Resistance	3	submitted	EID4034 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. Two ALK+ patients had ALK L1196M co-mutatio… (full text at CIViC) PMID 22235099 · Doebele et al., 2012 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	C	Supports Resistance	2	submitted	EID4036 In a stage IV non-small cell lung cancer patient with an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK L1196M co-mutation, ALK L1196M was reported to be refract… (full text at CIViC) PMID 23344087 · Kim et al., 2013 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	D	Supports Resistance	4	accepted	EID442 The L1196M mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. PMID 22277784 · Katayama et al., 2012 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	D	Supports Resistance	2	submitted	EID4037 In an in vitro study, a Ba/F3 cell line expressing EML4-ALK fusion (a known sensitizing alteration to crizotinib) and an ALK L1196M co-mutation, demonstrated resistance to crizotinib treatment compare… (full text at CIViC) PMID 21502504 · Katayama et al., 2011 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	D	Supports Resistance	2	submitted	EID4038 In an in vitro study, a Ba/F3 cell line expressing EML4-ALK fusion (a known sensitizing alteration to crizotinib) and an ALK L1196M co-mutation, demonstrated resistance to crizotinib treatment compare… (full text at CIViC) PMID 21948233 · Heuckmann et al., 2011 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Ensartinib	Predictive	B	Supports Sensitivity Response	4	submitted	EID7865 Treatment of crizotinib resistant patients harboring ALK L1196M by ensartinib resulted in an objective response rate of 25% and disease control rate of 91% in a multicentre phase II clinical trial. PMID 31628085 · Yang et al., 2020 · Open in CIViC	civic
v::ALK Fusion AND ALK L1196M	Ceritinib	Predictive	C	Supports Sensitivity Response	2	submitted	EID2343 In a prospective study (NCT01283516) of 130 cancer patients, non-small cell lung cancer patients (n=2) harboring a L1196M mutation in the ALK portion of the ALK rearrangement were associated with a 50… (full text at CIViC) PMID 24670165 · Shaw et al., 2014 · Open in CIViC	civic
v::ALK Fusion AND ALK L1196M	Ceritinib	Predictive	C	Supports Sensitivity Response	3	submitted	EID7611 A case study of a 58 year old woman with ALK-rearranged NSCLC found the resistance mutation L1196M following treatment with crizotinib and alectinib. Treatment with ceritinib resulted in tumour regres… (full text at CIViC) PMID 29796191 · Makuuchi et al., 2018 · Open in CIViC	civic
v::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	C	Supports Resistance	2	submitted	EID4035 In a non-small cell lung cancer patient with a liver metastatic tumor harboring an ALK gene rearrangement and an ALK L1196M co-mutation, ALK L1196M was reported to be refractory to 7-month crizotinib … (full text at CIViC) PMID 23434628 · Huang et al., 2013 · Open in CIViC	civic

Lung Non-Small Cell Carcinoma12

EML4::ALK Fusion AND ALK G1202R AND ALK L1196M

Lorlatinib

Predictive

Supports Resistance

submitted

EID7591

Repeat biopsies were taken for 20 ALK-positive NSCLC patients, including 11 with pre- and post-lorlatinib biopsies. 19 of 20 patients received crizotinib and at least one second line ALK inhibitor. On… (full text at CIViC)

PMID 29650534 · Yoda et al., 2018 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Alectinib

Predictive

Supports Sensitivity Response

accepted

EID141

CH5424802 treatment resulted in significant tumor regression in xenograft models produced from Ba/F3 cells expressing EML4-ALK or EML4-ALK with the L1196M mutation.

PMID 21575866 · Sakamoto et al., 2011 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Ceritinib

Predictive

Supports Sensitivity Response

accepted

EID1341

The crizotinib-resistant MGH045 cell line with EML4-ALK L1196M was treated with crizotinib or ceritinib. In nude mice with MGH045 xenografts, tumor response to crizotinib did not differ appreciably fr… (full text at CIViC)

PMID 24675041 · Friboulet et al., 2014 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID4034

This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. Two ALK+ patients had ALK L1196M co-mutatio… (full text at CIViC)

PMID 22235099 · Doebele et al., 2012 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID4036

In a stage IV non-small cell lung cancer patient with an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK L1196M co-mutation, ALK L1196M was reported to be refract… (full text at CIViC)

PMID 23344087 · Kim et al., 2013 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

accepted

EID442

The L1196M mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells.

PMID 22277784 · Katayama et al., 2012 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID4037

In an in vitro study, a Ba/F3 cell line expressing EML4-ALK fusion (a known sensitizing alteration to crizotinib) and an ALK L1196M co-mutation, demonstrated resistance to crizotinib treatment compare… (full text at CIViC)

PMID 21502504 · Katayama et al., 2011 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID4038

PMID 21948233 · Heuckmann et al., 2011 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Ensartinib

Predictive

Supports Sensitivity Response

submitted

EID7865

Treatment of crizotinib resistant patients harboring ALK L1196M by ensartinib resulted in an objective response rate of 25% and disease control rate of 91% in a multicentre phase II clinical trial.

PMID 31628085 · Yang et al., 2020 · Open in CIViC

civic

v::ALK Fusion AND ALK L1196M

Ceritinib

Predictive

Supports Sensitivity Response

submitted

EID2343

In a prospective study (NCT01283516) of 130 cancer patients, non-small cell lung cancer patients (n=2) harboring a L1196M mutation in the ALK portion of the ALK rearrangement were associated with a 50… (full text at CIViC)

PMID 24670165 · Shaw et al., 2014 · Open in CIViC

civic

v::ALK Fusion AND ALK L1196M

Ceritinib

Predictive

Supports Sensitivity Response

submitted

EID7611

A case study of a 58 year old woman with ALK-rearranged NSCLC found the resistance mutation L1196M following treatment with crizotinib and alectinib. Treatment with ceritinib resulted in tumour regres… (full text at CIViC)

PMID 29796191 · Makuuchi et al., 2018 · Open in CIViC

civic

v::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID4035

In a non-small cell lung cancer patient with a liver metastatic tumor harboring an ALK gene rearrangement and an ALK L1196M co-mutation, ALK L1196M was reported to be refractory to 7-month crizotinib … (full text at CIViC)

PMID 23434628 · Huang et al., 2013 · Open in CIViC

civic

Malignant Neoplasm6
EML4::ALK Fusion AND ALK G1202R AND ALK L1196M	Alectinib + Brigatinib + Ceritinib + Crizotinib + LorlatinibSubstitutes	Predictive	D	Supports Resistance	4	submitted	EID7592 EML4-ALK expressing Ba/F3 cell lines with the compound ALK mutation G1202R/L1196M were found to be resistant to lorlatinib as well as first and second-line ALK inhibitors. H3122 lung cancer cell lines… (full text at CIViC) PMID 29650534 · Yoda et al., 2018 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	ALK Inhibitor TAE684	Predictive	D	Supports Sensitivity Response	3	submitted	EID11080 From a mutation assay that generated crizotinib resistant mutations in EML4::ALK, the five most resistant mutations found were introduced into Ba/F3 cells and tested with the ALK inhibitor TAE684. EML… (full text at CIViC) PMID 22034911 · Zhang et al., 2011 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Alectinib + Brigatinib + Ceritinib + LorlatinibSubstitutes	Predictive	D	Supports Sensitivity Response	4	submitted	EID7597 Ba/F3 cells expressing EML4-ALK variant 1 (E13; A20) or variant 3 (E6a; A20) with the L1196M resistance mutation were sensitive to second and third generation ALK inhibitors. Cell viability assays sho… (full text at CIViC) PMID 29650534 · Yoda et al., 2018 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	D	Supports Resistance	4	submitted	EID7598 In vitro experiments showed Ba/F3 cells expressing EML4-ALK variant 1 (E13; A20) or 3 (E6a; A20) with the L1196M ALK mutation were resistant to crizotinib (IC50 313.4 +/- 50.1 and 333.1 +/- 62.1). PMID 29650534 · Yoda et al., 2018 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Predictive	D	Supports Resistance	4	submitted	EID11073 Ba/F3 cells with EML4::ALK were subjected to mutagen N-ethyl-N-nitrosourea and then incubated without IL3 in 250, 500, 720, 1000, 1440, or 2000 nm crizotinib. The ten most frequently seen mutants we… (full text at CIViC) PMID 22034911 · Zhang et al., 2011 · Open in CIViC	civic
EML4::ALK Fusion AND ALK L1198F AND ALK L1196M	Crizotinib	Predictive	D	Does Not Support Resistance	3	submitted	EID7594 Ba/F3 cell lines expressing the EML4-ALK fusion with compound mutation L1196M/L1198F were sensitive to crizotinib. Cell lines expressing variant 1 (E13; A20) of EML4-ALK had an IC50 of 45.6 +/- 7.1, w… (full text at CIViC) PMID 29650534 · Yoda et al., 2018 · Open in CIViC	civic

Malignant Neoplasm6

EML4::ALK Fusion AND ALK G1202R AND ALK L1196M

Alectinib + Brigatinib + Ceritinib + Crizotinib + LorlatinibSubstitutes

Predictive

Supports Resistance

submitted

EID7592

EML4-ALK expressing Ba/F3 cell lines with the compound ALK mutation G1202R/L1196M were found to be resistant to lorlatinib as well as first and second-line ALK inhibitors. H3122 lung cancer cell lines… (full text at CIViC)

PMID 29650534 · Yoda et al., 2018 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

ALK Inhibitor TAE684

Predictive

Supports Sensitivity Response

submitted

EID11080

From a mutation assay that generated crizotinib resistant mutations in EML4::ALK, the five most resistant mutations found were introduced into Ba/F3 cells and tested with the ALK inhibitor TAE684. EML… (full text at CIViC)

PMID 22034911 · Zhang et al., 2011 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Alectinib + Brigatinib + Ceritinib + LorlatinibSubstitutes

Predictive

Supports Sensitivity Response

submitted

EID7597

Ba/F3 cells expressing EML4-ALK variant 1 (E13; A20) or variant 3 (E6a; A20) with the L1196M resistance mutation were sensitive to second and third generation ALK inhibitors. Cell viability assays sho… (full text at CIViC)

PMID 29650534 · Yoda et al., 2018 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID7598

In vitro experiments showed Ba/F3 cells expressing EML4-ALK variant 1 (E13; A20) or 3 (E6a; A20) with the L1196M ALK mutation were resistant to crizotinib (IC50 313.4 +/- 50.1 and 333.1 +/- 62.1).

PMID 29650534 · Yoda et al., 2018 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1196M

Crizotinib

Predictive

Supports Resistance

submitted

EID11073

Ba/F3 cells with EML4::ALK were subjected to mutagen N-ethyl-N-nitrosourea and then incubated without IL3 in 250, 500, 720, 1000, 1440, or 2000 nm crizotinib. The ten most frequently seen mutants we… (full text at CIViC)

PMID 22034911 · Zhang et al., 2011 · Open in CIViC

civic

EML4::ALK Fusion AND ALK L1198F AND ALK L1196M

Crizotinib

Predictive

Does Not Support Resistance

submitted

EID7594

Ba/F3 cell lines expressing the EML4-ALK fusion with compound mutation L1196M/L1198F were sensitive to crizotinib. Cell lines expressing variant 1 (E13; A20) of EML4-ALK had an IC50 of 45.6 +/- 7.1, w… (full text at CIViC)

PMID 29650534 · Yoda et al., 2018 · Open in CIViC

civic

Pleural Malignant Mesothelioma3
EML4::ALK Fusion AND ALK G1202R AND ALK I1171N AND ALK L1196M	Lorlatinib	Predictive	C	Supports Resistance	3	accepted	EID11114 This case report describes a 33 year-old non-smoker with no known exposure to asbestos who was diagnosed with stage IIIB malignant pleural mesothelioma. Panel next generation sequencing (NGS) of 520 g… (full text at CIViC) PMID 32600123 · Hu et al., 2020 · Open in CIViC	civic
EML4::ALK Fusion AND ALK I1171N AND ALK L1196M	Alectinib	Predictive	C	Supports Resistance	4	accepted	EID11115 A 33 year old male with no smoking history or known exposure to asbestos was diagnosed with malignant pleural mesothelioma (MPM). EML4::ALK was found using a panel of 520 genes in NGS, and the patient… (full text at CIViC) PMID 32600123 · Hu et al., 2020 · Open in CIViC	civic
EML4::ALK Fusion AND ALK I1171N AND ALK L1196M	Lorlatinib	Predictive	C	Supports Sensitivity Response	3	accepted	EID11113 This case report describes a 33 year-old non-smoker with no known exposure to asbestos who was diagnosed with stage IIIB malignant pleural mesothelioma. Panel next generation sequencing (NGS) of 520 g… (full text at CIViC) PMID 32600123 · Hu et al., 2020 · Open in CIViC	civic

Pleural Malignant Mesothelioma3

EML4::ALK Fusion AND ALK G1202R AND ALK I1171N AND ALK L1196M

Lorlatinib

Predictive

Supports Resistance

accepted

EID11114

This case report describes a 33 year-old non-smoker with no known exposure to asbestos who was diagnosed with stage IIIB malignant pleural mesothelioma. Panel next generation sequencing (NGS) of 520 g… (full text at CIViC)

PMID 32600123 · Hu et al., 2020 · Open in CIViC

civic

EML4::ALK Fusion AND ALK I1171N AND ALK L1196M

Alectinib

Predictive

Supports Resistance

accepted

EID11115

A 33 year old male with no smoking history or known exposure to asbestos was diagnosed with malignant pleural mesothelioma (MPM). EML4::ALK was found using a panel of 520 genes in NGS, and the patient… (full text at CIViC)

PMID 32600123 · Hu et al., 2020 · Open in CIViC

civic

EML4::ALK Fusion AND ALK I1171N AND ALK L1196M

Lorlatinib

Predictive

Supports Sensitivity Response

accepted

EID11113

PMID 32600123 · Hu et al., 2020 · Open in CIViC

civic

Evidence by cancer (24 items)

Clinical significance (1)