Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non-small Cell Lung Cancer in the Global Phase III ALEX Trial

Rafal Dziadziuszko, Solange Peters, Tony Mok, D Ross Camidge, Shirish M Gadgeel, Sai-Hong Ignatius Ou, Krzysztof Konopa, Johannes Noé, Malgorzata Nowicka, Walter Bordogna, Peter N Morcos, Vlatka Smoljanovic, Alice T Shaw, Rafal Dziadziuszko, Solange Peters, Tony Mok, D Ross Camidge, Shirish M Gadgeel, Sai-Hong Ignatius Ou, Krzysztof Konopa, Johannes Noé, Malgorzata Nowicka, Walter Bordogna, Peter N Morcos, Vlatka Smoljanovic, Alice T Shaw

Abstract

Purpose: We retrospectively assessed prognostic value of circulating cell-free DNA (cfDNA) using data from the phase III ALEX study in treatment-naïve, advanced ALK+ non-small cell lung cancer (NSCLC).

Patients and methods: Patients were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151). cfDNA was quantified from baseline plasma samples, with patients stratified into ≤median and >median cfDNA biomarker-evaluable populations (BEP). Effect of cfDNA concentration on outcomes was analyzed using a Cox regression model with treatment group as covariate, and in multivariate analyses.

Results: Median cfDNA concentration in the BEP was 11.53 ng/mL (n = 276). A positive correlation was found between cfDNA concentration and number of lesions, organ lesion sites, and tumor size (sum of longest diameter; all P < 0.0001). In both treatment arms, patients in the >median BEP were more likely to experience disease progression than the ≤median BEP [alectinib adjusted HR = 2.04; 95% confidence interval (CI), 1.07-3.89; P = 0.0305 and crizotinib adjusted HR = 1.83; 95% CI, 1.11-3.00, P = 0.0169]. Median progression-free survival was longer with alectinib than crizotinib in both ≤median and >median BEPs (P < 0.0001). Overall survival data remain immature; survival probability was lower in the >median versus ≤median BEP in both treatment arms (alectinib HR = 2.52; 95% CI, 1.08-5.88; P = 0.0333 and crizotinib HR = 2.63; 95% CI, 1.27-5.47; P = 0.0096).

Conclusions: These data suggest that plasma cfDNA concentration may have prognostic value in advanced ALK+ NSCLC. Prospectively designed studies are warranted to investigate this finding.

Trial registration: ClinicalTrials.gov NCT02075840.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Correlation of normalized cfDNA concentration with the presence of A, Measurable/nonmeasurable CNS lesions, B,TP53 mutation status, and C, by organ lesion site (investigator assessment). Central lines represent median values, boxes represent interquartile ranges (IQR) and the top and bottom whiskers extend to the largest and smallest value, respectively, no further than 1.5 times the IQR.
Figure 2.
Figure 2.
Correlation of normalized cfDNA concentration and A, number of lesions, B, number of organ sites, and C, tumor size (investigator assessment). Blue lines represent hazard functions as determined by Cox multivariate analyses. Grey shaded areas represent 95% CIs. ctDNA, circulating tumor DNA.
Figure 3.
Figure 3.
Kaplan–Meier analysis of A, PFS by median cfDNA BEP, B, PFS by circulating tumor DNA status, C, DoR by median cfDNA BEP, and D, OS by median cfDNA BEP. PFS and DoR were investigator-assessed.
Figure 4.
Figure 4.
Multivariate analysis of covariate effects on PFS by investigator. Unstratified Cox regression model adjusted for: cfDNA (categorical), measurable/nonmeasurable CNS lesions at baseline, TP53 mutation status, baseline SLD (cm), number of organ sites, and number of liver lesions by investigator. INV, investigator.

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