News - ALK D1203N - LARVOL VERI

10ms

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.

10 months ago

Journal • Circulating tumor DNA

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)

ALK positive • ALK mutation • ALK G1202R • ALK F1174C • ALK L1196M • ALK D1203N

Lorbrena (lorlatinib)

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.

over 1 year ago

Journal • Tumor Mutational Burden • IO biomarker

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • EML4 (EMAP Like 4) • RB1 (RB Transcriptional Corepressor 1)

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

Xalkori (crizotinib) • carboplatin • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • pemetrexed • Alunbrig (brigatinib)

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.

2 years ago

Journal • Real-world evidence • Circulating tumor DNA

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)

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

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.

over 2 years ago

Clinical • Journal • Next-generation sequencing

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)

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

Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib)

almost3years

[VIRTUAL] Clinical utility of ctDNA for detection of EGFR, ALK, BRAFV600E alterations and resistance mutations in patients with NSCLC at failure to targeted therapy (ESMO 2021)

In samples from EGFRm ex19/21 pts treated with 1st/2nd generation (gen.) TKI (n=51), the T790M mutation was detected in 27%; in those from pts treated with osimertinib (n=15), the C797S rate was 13%. In ALKr pts treated with crizotinib (n=17), ≥1 ALK resistance mutations were found in 12% (1 G1269A+F1174L, 1 G1202R), after 2nd gen. (n=16) in 31% (3 G1202R, 1 D1203N+F1174C, 1 T1151R) and after lorlatinib (n=16) in 13% (2 G1202R)... ctDNA is feasible in pts with NSCLC harbouring EGFRm, ALKr, BRAFV600Em for detecting driver and resistance GAs at PD, providing clinical informative for treatment selection at TKI failure in 22% of cases. Outcomes of the following therapies based on ctDNA will be presented at the congress.

almost 3 years ago

Clinical • Circulating tumor DNA

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)

BRAF V600E • EGFR mutation • BRAF V600 • EGFR T790M • ALK rearrangement • EGFR C797S • ALK G1202R • ALK G1269A • ALK F1174C • ALK F1174L + ALK G1202R • ALK D1203N • ALK T1151R

InVisionFirst®-Lung

Mekinist (trametinib) • Xalkori (crizotinib) • Tagrisso (osimertinib) • Tafinlar (dabrafenib) • Lorbrena (lorlatinib)