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:
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
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Amivantamab-lazertinib significantly improved PFS in patients with detectable ctDNA at baseline versus osimertinib.
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Amivantamab-lazertinib significantly improved PFS in patients without ctDNA clearance at C3D1 versus osimertinib.
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Amivantamab-lazertinib significantly improved PFS in patients with TP53 co-mutations versus osimertinib.
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Amivantamab-lazertinib significantly improved PFS in patients with liver metastases versus osimertinib.
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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
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Article info
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Published online: June 26, 2024
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Graphical Abstract
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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.
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