18 juli 2024: Bron: Annals of Oncology, Published:June 26, 2024
Uit de fase III studie MARIPOSA blijkt dat Amivantamab (lazertinib) de ziekteprogressievrije overleving (PFS) statistisch significant verbeterde in vergelijking met osimertinib bij patiënten met niet eerder behandelde lokaal uitgezaaide niet-kleincellige longkanker met een EGFR-mutatie, inclusief degenen in hoog risico subgroepen.
Activerende mutaties in het EGFR-gen komen voor bij 15% tot 50% van de niet-plaveiselcel vormen van niet-kleincellige longkanker (NSCLC). Dit zijn meestal exon 19-deleties of exon 21-substituties (zoals de L858R-mutatie).
Tyrosine Kinase Remmers (TKI's) van de derde generatie, zoals osimertinib, zijn het meest effectief geweest in deze patiëntenpopulatie en waren zelfs actief tegen de T790M-mutatie, indien aanwezig. Probleem is dat de patiënten meestal toch weer een recidief krijgen na osimertinib.
Of Amivantamab (lazertinib) dit probleem gaat oplossen is nog niet aangetoond maar uit de eerste resultaten van de MARIPOSA blijken de resultaten hoopgevend.
Dit zijn de kernpunten van deze studie:
- Amivantamab-lazertinib verbeterde de PFS significant bij patiënten met detecteerbaar ctDNA bij aanvang vergeleken met osimertinib.
- Amivantamab-lazertinib verbeterde de PFS significant bij patiënten zonder ctDNA-klaring op C3D1 vergeleken met osimertinib
- Amivantamab-lazertinib verbeterde de PFS significant bij patiënten met TP53-commutaties vergeleken met osimertinib.
- Amivantamab-lazertinib verbeterde de PFS significant bij patiënten met levermetastasen vergeleken met osimertinib.
- Negenentachtig procent van de patiënten met analyseerbaar ctDNA door NGS van MARIPOSA had ten minste één basislijnkenmerk met een hoog risico.
Zie ook deze grafiek v an de studieresultaten:
![Figure thumbnail ga1](https://www.annalsofoncology.org/cms/attachment/f600de35-3a41-43a0-bdc9-c347de82057d/ga1.jpg)
Het volledige studieverslag is gratis in te zien of te downloaden. Klik op de titel van het abstract:
Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA
Highlights
- •
Amivantamab-lazertinib significantly improved PFS in patients with detectable ctDNA at baseline versus osimertinib.
- •
Amivantamab-lazertinib significantly improved PFS in patients without ctDNA clearance at C3D1 versus osimertinib.
- •
Amivantamab-lazertinib significantly improved PFS in patients with TP53 co-mutations versus osimertinib.
- •
Amivantamab-lazertinib significantly improved PFS in patients with liver metastases versus osimertinib.
- •
Eighty-nine percent of patients with analyzable ctDNA by NGS from MARIPOSA had at least one high-risk baseline feature.
Background
Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups.
Patients and methods
This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR).
Results
Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004].
Conclusions
Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
Graphical abstract
References
- Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180. https://www.sciencedirect.com/science/article/
- Jänne PA, Johnson BE. Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res. 2006;12:4416s-4420s. https://aacrjournals.org/clincancerres/article/
- Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023;389(22):2039-2051. https://www.nejm.org/doi/
- Cho BC, Ahn M-J, Kang JH, et al. Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301. J Clin Oncol. 2023;41(26):4208-4217. https://ascopubs.org/doi/
- Cho BC, Kim DW, Spira AI, et al. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nat Med. 2023;29(10):2577-2585. https://www.nature.com/articles/
- Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024 Jun 26. Doi: 10.1056/NEJMoa2403614. Online ahead of print. https://www.nejm.org/doi/
- Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA. Ann Oncol. 2024 Jun 26. Doi: 10.1016/j.annonc.2024.05.541. Online ahead of print. https://www.sciencedirect.com/science/article/
References
-
Circulating tumor DNA kinetics predict progression-free and overall survival in EGFR TKI-treated patients with EGFR-mutant NSCLC (SWOG S1403).Clin Cancer Res. 2022; 28: 3752-3760
-
Circulating tumor DNA clearance predicts prognosis across treatment regimen in a large real-world longitudinally monitored advanced non-small cell lung cancer cohort.Transl Lung Cancer Res. 2020; 9: 269-279
-
Predictive and prognostic potential of TP53 in patients with advanced non-small-cell lung cancer treated with EGFR-TKI: analysis of a phase III randomized clinical trial (CTONG 0901).Clin Lung Cancer. 2021; 22: 100-109.e103
-
Characterization of liver metastasis and its effect on targeted therapy in EGFR-mutant NSCLC: a multicenter study.Clin Lung Cancer. 2017; 18: 631-639.e632
-
Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases.Sci Rep. 2024; 14: 5820
-
Different prognostic implications of hepatic metastasis according to front-line treatment in non-small cell lung cancer: a real-world retrospective study.Transl Lung Cancer Res. 2021; 10: 2551-2561
-
Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib.Lung Cancer. 2015; 88: 187-194
-
Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors.Med Oncol. 2016; 33: 129
-
The prognostic value of longitudinal circulating tumor DNA profiling during osimertinib treatment.Transl Lung Cancer Res. 2021; 10: 326-339
-
TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy-EGFR mutated non-small cell lung cancer IV patients treated with osimertinib.Transl Lung Cancer Res. 2022; 11: 4-13
-
Association between TP53 mutations and efficacy of osimertinib for brain metastasis from EGFR-mutant lung cancer.Ann Oncol. 2019; 30: V149
-
Pérol M, Chouaid C, Bjerrum A, et al. Prognostic factors and outcomes of patients with advanced non–small cell lung cancer while on osimertinib treatment: a retrospective database study. Presented at: the European Lung Cancer Congress (ELCC); 20-23 March 2024; Prague, Czech Republic.
-
Clinical efficacy of osimertinib in EGFR-mutant non-small cell lung cancer with distant metastasis.BMC Cancer. 2022; 22: 654
-
Distinct progression and efficacy of first-line osimertinib treatment according to mutation subtypes in metastatic NSCLC harboring EGFR mutations.JTO Clin Res Rep. 2024; 5100636
-
Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018; 378: 113-125
-
Overcoming therapy resistance in EGFR-mutant lung cancer.Nat Cancer. 2021; 2: 377-391
-
A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.Cancer Res. 2016; 76: 3942-3953
-
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.Mol Cancer Ther. 2020; 19: 2044-2056
-
Antitumor activity of amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR exon 20 insertion-driven NSCLC.Cancer Discov. 2020; 10: 1194-1209
-
Amivantamab, an epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) bispecific antibody, designed to enable multiple mechanisms of action and broad clinical applications.Clin Lung Cancer. 2023; 24: 89-97
-
Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.Ann Oncol. 2023; 35: 77-90
-
Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions.N Engl J Med. 2023; 389: 2039-2051
-
Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.J Clin Oncol. 2021; 39: 3391-3402
-
A phase 1/2 study of lazertinib 240 mg in patients with advanced EGFR T790M-positive NSCLC after previous EGFR tyrosine kinase inhibitors.J Thorac Oncol. 2022; 17: 558-567
-
Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study.Lancet Oncol. 2019; 20: 1681-1690
-
Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-mutated Advanced NSCLC. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2403614.
-
ClinVar: public archive of relationships among sequence variation and human phenotype.Nucleic Acids Res. 2014; 42: D980-D985
-
OncoKB: a precision oncology knowledge base.JCO Precis Oncol. 2017; 2017PO.17.00011
-
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016; 34: 155-163
-
QIAGEN. Human Somatic Mutation Database (HSMD). https://digitalinsights.qiagen.com/hsmd/. Accessed March 27, 2024.
-
Liver metastases and the efficacy of immune checkpoint inhibitors in advanced lung cancer: a systematic review and meta-analysis.Front Oncol. 2022; 12978069
-
Effectiveness and safety of amivantamab in EGFR exon 20 insertion (E20I) mutations in non-small cell lung cancer (NSCLC).Transl Lung Cancer Res. 2023; 12: 2448-2459
-
High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients.Oncotarget. 2014; 5: 5246-5256
-
Impact of epilepsy and its treatment on brain metastasis from solid tumors: a retrospective study.Front Neurol. 2022; 13967946
-
Lazertinib versus gefitinib as first-line treatment in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC): results from LASER301.J Clin Oncol. 2023; 41: 4208-4217
-
Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: the BLOOM study.J Clin Oncol. 2020; 38: 538-547
-
The role of TP53 mutations in EGFR-mutated non-small-cell lung cancer: clinical significance and implications for therapy.Cancers (Basel). 2022; 14: 1143
-
Application of circulating tumor DNA as a biomarker for non-small cell lung cancer.Front Oncol. 2021; 11725938
-
Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages.J Hematol Oncol. 2017; 10: 100
-
Early clearance of plasma epidermal growth factor receptor mutations as a predictor of outcome on osimertinib in advanced non-small cell lung cancer; exploratory analysis from AURA3 and FLAURA.Clin Cancer Res. 2023; 29: 3340-3351
-
Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC.N Engl J Med. 2023; 389: 1935-1948
Article info
Publication history
Published online: June 26, 2024
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2024 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology.
User license
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) |ScienceDirect
Access this article on ScienceDirectFigures
-
Graphical Abstract
-
Figure 1Baseline pathogenic mutation frequency and patterns. Shown here are the mutation variants observed in ≥2% of patients who received amivantamab-lazertinib (A) and osimertinib (B). EGFR amplification occurred in 20% of patients with detectable ctDNA at baseline in the amivantamab + lazertinib arm and 19% in the osimertinib arm. MET amplification occurred in one patient in each arm (neither had high-level amplification). ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; multi, multiple.
-
Figure 2Progression-free survival for patient subgroups identified by NGS. Shown are Kaplan-Meier estimates of progression-free survival for subgroups of patients with detectable baseline ctDNA (A), with TP53 co-mutations (B), and with wild-type TP53 (C). Tick marks indicate censoring of data. CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; NGS, next-generation sequencing; PFS, progression-free survival.
-
Figure 3Progression-free survival for patient subgroups identified by ddPCR. Shown are Kaplan-Meier estimates of progression-free survival for subgroups of patients with detectable baseline ctDNA (A), without cleared ctDNA at C3D1 (B), and with cleared ctDNA at C3D1 (C). Tick marks indicate censoring of data. C, cycle; CI, confidence interval; ctDNA, circulating tumor DNA; D, day; ddPCR, droplet digital polymerase chain reaction; HR, hazard ratio; NE, not estimable; PFS, progression-free survival.
-
Figure 4Progression-free survival for patients with and without baseline liver metastases. Shown are Kaplan-Meier estimates of progression-free survival for subgroups of patients with baseline liver metastases (A) and without baseline liver metastases (B). Tick marks indicate censoring of data. CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
-
Figure 5Progression-free survival for patients with and without high-risk features. Shown are Kaplan-Meier estimates of progression-free survival for subgroups of patients with high-risk features (A) and those without high-risk features (B). Patients with analyzable ctDNA at baseline were included in this pooled analysis. High-risk features include baseline detectable ctDNA or baseline metastases of the liver or brain. For patients with detectable ctDNA, it was assumed TP53 co-mutations would be identified if present. Tick marks indicate censoring of data. CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.
Tables
Gerelateerde artikelen
- Amivantamab - lazertinib verbetert de progressievrije ziektetijd significant in vergelijking met osimertinib bij patiënten met niet eerder behandelde EGFR-mutante niet kleincellige longkanker (NSCLC), inclusief degenen in hoog risico subgroepen.
- Osimertinib versus Gefitinib gevolgd door Osimertinib als onderhoudsbehandeling bij gevorderde EGFR-mutante niet-kleincellige longkanker vermindert hersenuitzaaiingen maar overleving blijft gelijk copy 1
- Verdwijnen van EGFR T790M-mutatie hangt samen met vroegtijdige behandelingsfalen en ontwikkeling van resistentie tegen Osimertinib bij niet-kleincellige longkanker
- Sterke PD-L1 expressie voorspeller van slechtere progressievrije overleving en veroorzaakt nieuwe mutaties bij gebruik van Tyrosine Kinase remmers (EGFR-TKI)bij patienten met longkanker met EGFR mutaties.
- Gefitinib - Iressa plus Fuzheng Kang’ai geeft meer complete remissies (plus 14,3 procent) en langere mediane overall overleving met minder bijwerkingen in vergelijking met alleen gefitinib bij longkankerpatienten met EGFR mutatie copy 1
- EORTC start grote Europese studie naar onderliggende genetische factoren bij niet-klein-cellige longkanker met EGFR mutatie
- EGFR genentest - cobas EGFR Mutation Test - voor longkanker en het daarop gebaseerde medicijn Tarceva - erlotinib krijgt officieel goedkeuring van FDA
- Epidermal growth factor receptor (EGFR) kan vooraf door Japanse meetmethode, de fast TaqMan PCR analyse worden vastgesteld bj longkankerpatiënten en daarmee beter beoordelen of Iressa of Tarceva dan nut heeft als behandeling
- Vaccin gemaakt op basis van epidermal growth factor (EGF) geeft significant meer overlevingen en significant betere kwaliteit van leven bij patienten met vergevorderde niet-klein-cellige longkanker, (stadium IIIB en IV) copy 1
- Bijwerkingen zoals huidirritaties en acne achtige plekken blijken juist een goed effect van Tarceva en Iressa aan te tonen
- Tarceva - Erlotinib verdriedubbelt mediane overlevingstijd (4,6 vs 13,1 maanden) bij patienten met vergevorderde niet klein-cellige longkanker die een positieve tumorexpressie hebben voor EGFR remmers als Tarceva en Iressa.
- Tarceva - Erlotinib geeft hoog significant langere ziektevrije tijd en overleving als eerste lijnsbehandeling voor niet-klein-cellige longkanker met juiste EGRF receptor expressie.
- Iressa - Gefitinib, een EGRF remmer verdubbelt ziektevrije tijd voor longkankerpatienten (5,4 t.o. 10,8 maanden) in vergelijking met standaard aanpak van chemo.
- EGRF remmers en effect bij longkanker: Groot wetenschappelijk achtergrond artikel over recente ontwikkelingen van EGRF remmers (Epidermale Groei Factor Receptor) bij de behandeling van longkanker. Door prof. dr. Giuseppe Giaconne
- Tarceva - Erlotinib en Iressa - Gefitinib zijn uitstekende medicijnen voor longkankerpatienten met juiste EGRF expressie en geeft significant betere levensduur en betere kwaliteit van leven.
- EGRF remmers zoals Tarceva (en Iressa) zijn significant effectief en levensverlengend tegenover placebo bij inoperabele longkanker. Maar alleen bij bepaalde tumorreceptoren en bepaalde mutatie. Artikel geplaatst 30 mei 2010
- Iressa - Gefitinib and Tarceva - erlotinib, what kind of products are they:
- Iressa - Gefitinib geeft beduidend langere ziektevrije overleving dan chemo bij patienten met niet-klein-cellige longkanker met positieve EGFR receptoren. Artikel geplaatst 5 januari 2010
- EGFR remmers zoals Tarceva - Erlotinib en Iressa - Gefitinib: een overzicht van artikelen en recente ontwikkelingen.
Plaats een reactie ...
Reageer op "Amivantamab - lazertinib verbetert de progressievrije ziektetijd significant in vergelijking met osimertinib bij patiënten met niet eerder behandelde EGFR-mutante niet kleincellige longkanker (NSCLC), inclusief degenen in hoog risico subgroepen."