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BIOMARKER:

ALK L1196M

i
Other names: NBLST3, CD246, Anaplastic Lymphoma Kinase, Anaplastic Lymphoma Kinase (Ki-1), CD246 Antigen, Mutant Anaplastic Lymphoma Kinase, ALK, ALK Receptor Tyrosine Kinase, Anaplastic Lymphoma Receptor Tyrosine Kinase, ALK Tyrosine Kinase Receptor
Entrez ID:
1m
Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer. (PubMed, J Enzyme Inhib Med Chem)
A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat...Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM)...At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.
Journal • Epigenetic controller
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ALK (Anaplastic lymphoma kinase)
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ALK mutation • ALK L1196M
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Xalkori (crizotinib) • pracinostat (SB939)
2ms
Impact of tumor-intrinsic molecular features on survival and acquired tyrosine kinase inhibitor resistance in ALK-positive NSCLC. (PubMed, Cancer Res Commun)
V3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.
Journal
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ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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TP53 mutation • ALK positive • ALK fusion • ALK mutation • EML4-ALK variant 3 • ALK G1202R • ALK I1171N • EML4-ALK L1196M • ALK I1171 • ALK L1196M • EML4-ALK G1202R
7ms
Treatment of advanced ALK-rearranged NSCLC following second-generation ALK-TKI failure. (PubMed, Expert Rev Anticancer Ther)
In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK - TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab and platinum-based chemotherapy could be the alternative treatment option.
Review • Journal • PD(L)-1 Biomarker • Metastases
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK rearrangement • ALK G1202R • ALK L1196M
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Avastin (bevacizumab) • Tecentriq (atezolizumab) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib)
8ms
Detection of resistance mutations in patients with anaplastic lymphoma kinase-rearranged lung cancer through liquid biopsy. (PubMed, Transl Lung Cancer Res)
Our findings suggest that real-time quantitative monitoring of ALK resistance mutations during the response period could provide a time course of changes while acquiring resistance mutations. This information would be beneficial for designing an appropriate treatment strategy.
Journal • Liquid biopsy • Biopsy
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ALK (Anaplastic lymphoma kinase)
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ALK rearrangement • ALK mutation • ALK G1202R • ALK C1156Y • ALK G1269A • ALK I1171T • ALK I1171 • ALK L1196M • ALK L1152R • ALK S1206Y • ALK V1180L
9ms
Mechanisms of Acquired Resistance to ALK Inhibitors Using Plasma Sequencing - Preliminary Data from the ATORG004 Study (IASLC-WCLC 2023)
In Cohort 1 (n=21), 15 (71%) pts had progressed on alectinib, 5 (24%) on ceritinib and 1 (5%) on ensartinib. In Cohort 2 (n=18), pts had progressed on crizotinib followed by alectinib (n=9, 50%), ceritinib (n=4, 22%) or brigatinib (n=3, 17%); 2 (11%) pts progressed on crizotinib, then ceritinib followed by alectinib...Of 5 pts with ALK resistance mutations (I1171N, V1180L, L1196M, G1202R, and E1210K) who subsequently received lorlatinib, repeat ctDNA NGS after 2 months demonstrated clearance of ALK resistance mutation(s) in 4/5 (80%) pts (i.e. undetectable on repeat testing)... Resistance mechanisms to ALK inhibitors are heterogenous, including both ALK dependent and independent pathways. DDR and cell cycle gene alterations were commonly detected and may represent previously unreported acquired resistance alterations. Comprehensive ctDNA NGS analysis at progression may help detect novel resistance alterations in patients on ALK inhibitors.
Preclinical • BRCA Biomarker
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • EML4 (EMAP Like 4) • FGFR1 (Fibroblast growth factor receptor 1) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • KIF5B (Kinesin Family Member 5B) • CCND1 (Cyclin D1) • CCNE1 (Cyclin E1) • CDK4 (Cyclin-dependent kinase 4) • CDK12 (Cyclin dependent kinase 12) • CDK6 (Cyclin-dependent kinase 6)
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TP53 mutation • HER-2 amplification • NRAS mutation • HER-2 mutation • MET amplification • ALK rearrangement • FGFR1 amplification • ALK fusion • CDK12 mutation • ALK G1202R • ALK I1171N • EML4-ALK L1196M • ALK I1171 • ALK L1196M • ALK amplification • ALK E1210K • ALK V1180L • EML4-ALK G1202R
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Guardant360® CDx
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Ensacove (ensartinib)
9ms
Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC. (PubMed, Thorac Cancer)
The dynamic changes of genomic characteristics during lorlatinib treatment revealed the mutation landscape of Chinese patients with NSCLC after ALK-TKI resistance, indicated that the resistance profile of lorlatinib were heterogeneous, which laid the foundation for subsequent treatment to overcome lorlatinib resistance.
Journal • Circulating tumor DNA
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ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • DNMT3A (DNA methyltransferase 1) • GNAS (GNAS Complex Locus) • ERCC3 (ERCC Excision Repair 3, TFIIH Core Complex Helicase Subunit)
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ALK positive • ALK mutation • ALK G1202R • ALK F1174C • ALK L1196M • ALK D1203N
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Lorbrena (lorlatinib)
11ms
Discovery of imidazo[1,2-b]pyridazine macrocyclic derivatives as novel ALK inhibitors capable of combating multiple resistant mutants. (PubMed, Bioorg Med Chem Lett)
19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations...This was equally effective to the reference drug Repotrectinib (IC = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.
Journal
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK rearrangement • ALK G1202R • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R
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Lorbrena (lorlatinib) • Augtyro (repotrectinib)
1year
Rapid tissue donation identifies LAG3 as a potential therapeutic target for ALK fusion positive lung cancer (AACR 2023)
Analysis of two tissue microarrays comprised of 130 tumor cores from multiple tissue sites of the first 10 NSCLC RTD donors revealed that 66% of tumor cores had >1% LAG3 expression in CD3+ T cells. Among the three patients with ALK fusion-positive NSCLC, 83% (5 of 6 cores), 85% (6 of 7 cores), and 100% (18 of 18 cores) of the tissue cores had >1% LAG3 expression in T cells. The median LAG3 expression in T cells measured by mIF was 1.8% in 99 tumor cores from the ALK fusion-negative study cohort versus 7.3% in the 31 cores from the ALK fusion-positive subset (p=0.004).
PD(L)-1 Biomarker • IO biomarker
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BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • LAG3 (Lymphocyte Activating 3) • AGK (Acylglycerol Kinase)
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PD-L1 expression • BRAF mutation • ALK positive • ALK fusion • BRAF fusion • LAG3 expression • AGK-BRAF fusion • ALK L1196M
1year
Preclinical intracranial activity of NVL-655 in an alectinib-resistant patient-derived model harboring EML4-ALK fusion with G1202R mutation (AACR 2023)
Second- (ceritinib, alectinib, brigatinib, and ensartinib) and third-generation (lorlatinib) ALK TKIs have higher intracranial responses than crizotinib but are still limited by emergence of resistance mutations, most commonly G1202R-containing single and compound mutations. Patient-derived models are widely viewed as among the most disease-relevant models for evaluating new therapies and drug resistance. Using a xenograft model derived from an alectinib-relapsed patient, we showed that NVL-655 had high intracranial activity against brain tumors bearing the ALK G1202R mutation that confers resistance to multiple ALK TKIs. NVL-655 is being evaluated in a Phase 1/2 clinical trial for patients with advanced NSCLC and other solid tumors harboring ALK rearrangement or activating ALK mutation (ALKOVE-1): NCT05384626.
Preclinical
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK rearrangement • EML4-ALK fusion • ALK fusion • ALK mutation • ALK G1202R • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Ensacove (ensartinib) • NVL-655
1year
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK mutation • ALK L1196M
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Alecensa (alectinib)
over1year
Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report. (PubMed, Cold Spring Harb Mol Case Stud)
Despite early progression within 3 mo under crizotinib, a durable response was achieved with alectinib...Another rebiopsy revealed ALK:p.L1196M, but the tumor did not respond to brigatinib or carboplatin/pemetrexed, before stabilization under lorlatinib...Lorlatinib retained efficacy in the heavily pretreated setting, while its upfront use could possibly have prevented the stepwise emergence of compound ALK mutations. Furthermore, the disease course was more aggressive and OS shorter compared to the V2/TP53wt ALK+ lung adenocarcinoma, while crizotinib, ceritinib and brigatinib did not confer the benefit expected according to NGS results, which also underline the need for more potent drugs against ALK in the high-risk setting of neuroendocrine histology.
Journal • Tumor Mutational Burden • IO biomarker
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ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • EML4 (EMAP Like 4) • RB1 (RB Transcriptional Corepressor 1)
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TP53 mutation • TP53 wild-type • TMB-L • ALK mutation • ALK G1202R • EML4-ALK L1196M • ALK L1196M • ALK V1180L • EML4-ALK G1202R • EML4-ALK variant 2 • ALK D1203N
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Xalkori (crizotinib) • carboplatin • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • pemetrexed • Alunbrig (brigatinib)
over1year
Preclinical activity of NVL-655 in patient-derived models of ALK cancers, including those with lorlatinib-resistant G1202R/L1196M compound mutation (AACR-NCI-EORTC 2022)
Five tyrosine kinase inhibitors (TKIs) have been approved for treatment of ALK-positive non-small cell lung cancer (NSCLC), including first- (crizotinib), second- (ceritinib, alectinib, and brigatinib), and third- (lorlatinib) generation therapies. NVL-655 showed activity in diverse patient-derived models of ALK-positive cancers, including ones that exhibited clinical resistance to prior-generation ALK TKIs. The broad preclinical activity of NVL-655 suggests potential utility as a best-in-class therapy for ALK-positive cancer patients.
Preclinical
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • STRN (Striatin)
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ALK positive • EML4-ALK fusion • ALK fusion • ALK mutation • ALK G1202R • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R • ALK T1151M
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • NVL-655
over1year
MET and NF2 alterations confer early resistance to first-line alectinib treatment in ALK-rearranged non-small cell lung cancer (ESMO 2022)
Of these, 52 received first-line alectinib treatment (1L) and 56 received alectinib after crizotinib resistance (2L). Also, NF2-mutant patients only had a median PFS of 4 months, significantly poorer than those without (HR 11.1, 95CI 2.17-50; p<0.001). Conclusions By analyzing different mutational profiles of ALK-rearranged patients after alectinib treatment, we proposed MET and NF2 as putative mechanisms that conferred resistance to early resistance of first-line alectinib, which shone light on future tailored treatment for ALK-positive NSCLCs.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF2 (Neurofibromin 2)
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KRAS mutation • BRAF mutation • NRAS mutation • PIK3CA mutation • ALK positive • MET amplification • ALK rearrangement • ALK mutation • MET mutation • ALK G1202R • NF2 mutation • ALK G1269A • ALK I1171N • ALK I1171T • ALK I1171 • ALK L1196M • ALK amplification • ALK V1180L • ALK E1129V • ALK rearrangement + PIK3CA mutation • MET D1228H
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Xalkori (crizotinib) • Alecensa (alectinib)
over1year
Integrated biomarker analysis of brigatinib efficacy in anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) refractory to alectinib (ESMO 2022)
Results Of the 133 pts who progressed on alectinib, with or without prior crizotinib or chemotherapy, 131 had evaluable baseline plasma data. The presence of secondary ALK mutations at baseline was associated with a similar ORR (34.5%) and median DoR (5.6 months) and shorter median PFS (3.7 months), with response/clinical benefit observed in pts with G1202R, L1196M, and I1171N ALK secondary mutations. Table: 1009P Brigatinib efficacy parameters a according to baseline ALK mutation status conclusions Brigatinib showed clinically meaningful activity in pts with alectinib-resistant ALK+ NSCLC with or without a detectable ALK fusion and/or secondary mutations.
Clinical
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • EML4-ALK fusion • ALK fusion • ALK mutation • ALK G1202R • ALK I1171N • EML4-ALK L1196M • ALK I1171 • ALK L1196M • EML4-ALK G1202R
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Xalkori (crizotinib) • Alecensa (alectinib) • Alunbrig (brigatinib)
almost2years
The Impact of CGP on the Decision-making Process in ALK+ aNSCLC After Failure of 2nd/3rd-Generation ALK TKIs (IASLC-WCLC 2022)
In 20 eligible patients (median [m]age 63 years [range, 40-89], females 75%, adenocarcinoma 100%, failure of alectinib 90%, FoundationOne Liquid CDx 80%), CGP has altered NLST recommendation in 30% of cases (Figure 2)... CGP has a significant impact on the decision-making process in ALK-rearranged aNSCLC following progression on 2nd/3rd-generation ALK TKIs.
ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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MET amplification • ALK rearrangement • ALK mutation • CDKN2A mutation • MET mutation • ALK G1202R • ALK G1269A • ALK L1196M • ALK E1210K
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FoundationOne® Liquid CDx
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Alecensa (alectinib)
almost2years
Preclinical Activity of NVL-655 in a Patient-Derived NSCLC Model with Lorlatinib-Resistant ALK G1202R/T1151M Mutation (IASLC-WCLC 2022)
Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved tyrosine kinase inhibitors (TKIs) for ALK-positive NSCLC, but durability of response is partly limited by ALK resistance mutations...Ascites mononuclear cells were isolated by Ficoll centrifugation and cultured in media (DMEM F12 Glutamax, 10% antibiotics/antimycotics, 10% FBS, hydrocortisone, adenine, RockInhibitor, and 1/10 cholera toxin)... NVL-655 has demonstrated activity in many preclinical models bearing ALK compound mutations, including the MR448re (EML4-ALK v3 G1202R/T1151M) model. The potent preclinical activity of NVL-655 suggests potential clinical utility for ALK-positive patients, including those with resistant compound mutations. The MR448re PDC and xenograft are valuable additions to the ALK therapeutic research landscape where there is limited availability of patient-derived models with lorlatinib-resistant ALK compound mutations.
Preclinical
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK rearrangement • EML4-ALK fusion • ALK fusion • ALK mutation • ALK G1202R • ALK G1269A • ALK fusion + ALK G1202R • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R • EML4-ALK G1269A • ALK T1151M
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • NVL-655
almost2years
The Impact of Comprehensive Genomic Profiling (CGP) on the Decision-Making Process in the Treatment of ALK-Rearranged Advanced Non-Small Cell Lung Cancer (aNSCLC) After Failure of 2/3-Generation ALK Tyrosine Kinase Inhibitors (TKIs). (PubMed, Front Oncol)
In 20 eligible patients (median [m]age 63 years [range, 40-89], females 75%, adenocarcinoma 100%, failure of alectinib 90%, FoundationOne Liquid CDx 80%), CGP has altered NLST recommendation in 30% of cases...mOS was 13.2 months (95% CI, 2.9-NR) and 13.0 months (95% CI, 6.0-NR) in groups 1 and 2, respectively (p-0.86). CGP has a significant impact on the decision-making process in ALK-rearranged aNSCLC following progression on 2/3-generation ALK TKIs.
Journal
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ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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MET amplification • ALK rearrangement • ALK mutation • CDKN2A mutation • MET mutation • ALK G1202R • ALK G1269A • ALK L1196M • ALK E1210K
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FoundationOne® Liquid CDx
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Alecensa (alectinib)
almost2years
First-in-human phase I results of APG-2449, a novel FAK and third-generation ALK/ ROS1 tyrosine kinase inhibitor (TKI), in patients (pts) with second-generation TKI-resistant ALK/ROS1+ non–small cell lung cancer (NSCLC) or mesothelioma. (ASCO 2022)
Another pt with the G1202R mutation following alectinib treatment had tumor shrinkage of 27.9%. APG-2449 has a favorable safety and PK profile and was well tolerated in 84 subjects. Preliminary efficacy was observed in pts whose disease was resistant to second-generation TKIs, especially among those with brain metastases, and in TKI-naïve pts. Biomarker data indicated potential target engagement on FAK and immunomodulatory effects of APG-2449.
Clinical • P1 data
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IFNG (Interferon, gamma)
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ALK mutation • ALK G1202R • ALK C1156Y • ALK G1269A • ALK I1171 • ALK L1196M • ALK E1210K • ALK I1171S • ALK V1180L
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Alecensa (alectinib) • APG-2449
almost2years
Longitudinal monitoring by next-generation sequencing of plasma cell-free DNA in ALK rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors. (PubMed, Cancer Med)
cfDNA-NGS facilitates detection of ALK fusions and resistance mutations, assessment of prognosis, and monitoring dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK-TKI.
Journal • Next-generation sequencing
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ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53)
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ALK rearrangement • ALK fusion • ALK mutation • ALK G1202R • ALK G1269A • ALK L1196M • ALK F1174L + ALK G1202R • ALK T1151R
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Guardant360® CDx
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Xalkori (crizotinib) • Zykadia (ceritinib)
2years
Evaluation of Lorlatinib Cerebrospinal Fluid Concentrations in Relation to Target Concentrations for ALK Inhibition. (PubMed, J Clin Pharmacol)
Estimated CNS concentrations exceeded the derived CNS C in all patients for wild-type ALK and the ALK L1196M mutation and in 35.8% of patients for the ALK G1202R mutation. Projected lorlatinib CNS concentrations were consistent with the high intracranial response rates reported in clinical trials and provide further evidence of the potent CNS penetration of lorlatinib.
Journal
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ALK positive • ALK mutation • ROS1 positive • ALK G1202R • ALK L1196M
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Lorbrena (lorlatinib)
2years
Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients. (PubMed, ESMO Open)
Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.
Journal • Real-world evidence • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
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TP53 mutation • ALK positive • ALK fusion • ALK mutation • ALK G1202R • EML4-ALK L1196M • ALK F1174C • ALK L1196M • EML4-ALK G1202R • ALK D1203N • EML4-ALK F1174C
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib)
2years
Acquired TPM3-NTRK1 fusion resistant to larotrectinib in a non-small cell lung cancer with EML4-ALK fusion progressed on lorlatinib (AACR 2022)
Herein, we present an acquired TPM3-NTRK1 fusion resistant to larotrectinib in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib.Case Presentation: A 48-year-old male with stage IV adenocarcinoma of lung with metastatic disease of bone was initially treated with carboplatin, pemetrexed, and pembrolizumab...Upon progression of disease (PD), systemic therapy regimen was switched to combination of carboplatin, paclitaxel, and bevacizumab...Subsequently, he was started on alectinib 600 mg twice a day given EML 4-ALK fusion mutation [4.8% of variant allele frequency (VAF)] in circulating tumor DNA (ctDNA) NGS assay...We report the case of acquired TPM3-NTRK1 fusion resistant to larotrectinib and acquired ALK L1196M in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Further investigations are warranted to explore the mechanism of resistance to ALK TKIs.
PD(L)-1 Biomarker
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ALK (Anaplastic lymphoma kinase) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • EML4 (EMAP Like 4) • TPM3 (Tropomyosin 3) • NTRK (Neurotrophic receptor tyrosine kinase)
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NTRK1 fusion • ALK positive • EML4-ALK fusion • ALK fusion • ALK mutation • TPM3-NTRK1 fusion • EML4-ALK L1196M • ALK L1196M
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Keytruda (pembrolizumab) • Avastin (bevacizumab) • carboplatin • Vitrakvi (larotrectinib) • paclitaxel • Alecensa (alectinib) • Lorbrena (lorlatinib) • pemetrexed
2years
Longitudinal minimally invasive monitoring of resistance mutations in ALK rearranged lung cancer patients (AACR 2022)
ALK rearrangements are detected in approximately 4% of patients with advanced non-small cell lung cancer (NSCLC), and the tyrosine kinase inhibitors (TKIs) crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib have been approved by the FDA for the treatment of ALK-positive NSCLC. The dPCR method was highly sensitive in detecting gene mutations with low allele frequency. It was also found to be able to monitor variable resistance mutations over time during ALK-TKI treatment. In addition, we found that the appearance of G1202R did not always indicate clinical acquisition of resistance that required drug modification.
Clinical
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK rearrangement • ALK mutation • ALK G1202R • ALK C1156Y • ALK G1269A • ALK I1171T • EML4-ALK L1196M • ALK I1171 • ALK L1196M • ALK L1152R • ALK S1206Y • ALK V1180L • EML4-ALK G1202R • EML4-ALK G1269A • ALK L1196M + ALK C1156Y • EML4-ALK I1171T • EML4-ALK S1206Y
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib)
over2years
A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC. (PubMed, EMBO Mol Med)
More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement...These preclinical data support XMU-MP-5 as a novel selective ALK inhibitor with high potency and selectivity. XMU-MP-5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.
Journal
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EML4 (EMAP Like 4)
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ALK positive • ALK rearrangement • ALK G1202R • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R
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Xalkori (crizotinib)
over2years
Clinicopathological features and resistance mechanism in HIP1-ALK-rearranged lung cancer: A multicenter study. (PubMed, Genes Chromosomes Cancer)
One patient who received first-line lorlatinib treatment achieved partial response for >26.5 months...Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants...Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.
Clinical • Journal
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BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • HIP1 (Huntingtin Interacting Protein 1)
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BRAF mutation • ALK rearrangement • ALK fusion • ALK mutation • BRAF fusion • EML4-ALK L1196M • ALK L1196M • ALK L1152V
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Xalkori (crizotinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
over2years
A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review. (PubMed, JTO Clin Res Rep)
Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.
Review • Journal
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK mutation • EML4-ALK variant 3 • ALK G1202R • ALK G1269A • EML4-ALK L1196M • ALK F1174C • ALK L1196M • ALK S1206Y • EML4-ALK G1202R • EML4-ALK G1269A • EML4-ALK F1174C • EML4-ALK S1206Y
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib)
over2years
Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing. (PubMed, Eur J Cancer)
The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.
Clinical • Journal • Next-generation sequencing
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase)
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BRAF V600E • EGFR mutation • NRAS mutation • PIK3CA mutation • BRAF V600 • ALK rearrangement • KIT mutation • PIK3CA E545K • MET mutation • ALK G1202R • NRAS G12 • ALK G1269A • ALK I1171T • PIK3CA E545 • ALK I1171 • ALK L1196M • ALK E1210K • ALK D1203N • ALK G1128A • ALK rearrangement + PIK3CA mutation • EGFR P753S • NRAS G12V • KIT D820E
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib)
almost3years
One-step polymerase chain reaction-free nanowire-based plasma cell-free DNA assay to detect EML4-ALK fusion and to monitor resistance in lung cancer. (PubMed, Oncologist)
We developed a novel one-step polymerase chain reaction-free nanowire (NW)-based plasma cell-free DNA (cfDNA) assay. In this study, we evaluated the clinical utility of this novel method for the diagnosis of EML4-ALK fusion in advanced non-small cell lung cancer (NSCLC). The NW-based assay and FISH test showed high concordance rate in 99 patients with advanced NSCLC. Serial cfDNA assessment demonstrated this method provided early detection of resistance before radiologic progression during crizotinib treatment. Taken together, plasma cfDNA genotyping by the NW-based cfDNA assay may be useful for the rapid diagnosis of ALK fusion, classifying variants, and early detection of resistance.
Journal • Polymerase Chain Reaction
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EML4 (EMAP Like 4)
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ALK positive • EML4-ALK fusion • ALK fusion • ALK mutation • EML4-ALK L1196M • ALK L1196M
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Xalkori (crizotinib)
almost3years
TPX-0131, a Potent CNS-Penetrant, Next-Generation Inhibitor of Wild-Type ALK and ALK-Resistant Mutations. (PubMed, Mol Cancer Ther)
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer...The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations)...Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK fusion • ALK mutation • ALK G1202R • ALK L1196M
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Xalkori (crizotinib) • Lorbrena (lorlatinib) • TPX-0131
over3years
Brigatinib in Japanese Patients With ALK-Positive Non-Small Cell Lung Cancer Previously Treated With Alectinib and Other Tyrosine Kinase Inhibitors: Outcomes of the Phase 2 J-ALTA Trial. (PubMed, J Thorac Oncol)
Brigatinib showed clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without prior crizotinib).
Clinical • P2 data • Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK G1202R • ALK I1171N • ALK I1171 • ALK L1196M • ALK V1180L
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Xalkori (crizotinib) • Alecensa (alectinib) • Alunbrig (brigatinib)
over3years
Novel resistance mechanisms including L1196Q, P1094H, and R1248_D1249insertion in three patients with non-small-cell lung cancer following ALK tyrosine kinase inhibitor treatment. (PubMed, J Thorac Oncol)
The combination of a genetic analysis and computational simulation model may make a prediction of resistance mechanisms for overcoming ALK-TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.
Clinical • Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK G1269A • ALK I1171N • ALK I1171 • ALK L1196M • ALK amplification
over3years
ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4) • KIF5B (Kinesin Family Member 5B) • STRN (Striatin)
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ALK positive • ALK rearrangement • ALK fusion • ALK mutation • ALK G1202R • ALK negative • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R
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Guardant360® CDx
over3years
[VIRTUAL] Detection of anaplastic lymphoma kinase (ALK) mutations using circulating tumour DNA (ctDNA) in advanced nonsquamous nonsmall cell lung cancer (nonSqNSCLC) in Asia (ESMO Asia 2020)
Detection rate and distribution of ALK fusion partners are comparable to existing data of tumor ALK testing. Further data on ALK treatment outcomes of patients with detectable ALK fusion on plasma ctDNA is warranted.
ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4) • KIF5B (Kinesin Family Member 5B) • STRN (Striatin)
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ALK positive • ALK rearrangement • ALK fusion • ALK mutation • ALK G1202R • ALK negative • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R
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Guardant360® CDx
over3years
[VIRTUAL] Detection of anaplastic lymphoma kinase (ALK) mutations using circulating tumour DNA (ctDNA) in advanced nonsquamous nonsmall cell lung cancer (nonSqNSCLC) in Asia (ESMO Asia 2020)
Detection rate and distribution of ALK fusion partners are comparable to existing data of tumor ALK testing. Further data on ALK treatment outcomes of patients with detectable ALK fusion on plasma ctDNA is warranted.
ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4) • KIF5B (Kinesin Family Member 5B) • STRN (Striatin)
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ALK positive • ALK rearrangement • ALK fusion • ALK mutation • ALK G1202R • ALK negative • EML4-ALK L1196M • ALK L1196M • EML4-ALK G1202R
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Guardant360® CDx
over3years
Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity. (PubMed, Clin Cancer Res)
ALK resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK mutation • ALK G1202R • ALK L1196M • ALK L1196M + ALK G1202R
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Guardant360® CDx
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Alecensa (alectinib) • Lorbrena (lorlatinib)