Potential Predictive Biomarker of Response to Crizotinib in Lung Cancer
Although the duration and magnitude of clinical response are unpredictable in patients with ALK-rearranged non–small cell lung cancer (NSCLC) treated with crizotinib (Xalkori), eventually all patients develop resistance to the drug. A study by Pailler et al evaluating whether circulating tumor cells with aberrant ALK–fluorescence in situ hybridization (FISH) patterns monitored on crizotinib could predict progression-free survival in patients with NSCLC with ALK gene alterations has found that the analysis could identify a predictive biomarker of therapeutic efficacy. The study’s results showcase the potential of liquid biopsies in replacing tumor biopsies for patient monitoring in real time and clinical outcome prediction in this patient population. The study was published in Cancer Research.
Study Methodology
The study was conducted at Gustave Roussy in Villejuif, France. The researchers recruited 39 patients with stage IV ALK-rearranged NSCLC between 2011 and 2014. All patients received 250 mg of crizotinib twice daily at initiation of therapy. Peripheral blood samples were collected at baseline and at an early time point on crizotinib, usually 2 months later for 29 of these patients; 10 patients received follow-up care at a different center, and no serial blood samples were available for analysis.
All of the patients had a computed tomography scan and/or magnetic resonance imaging every 6 or 8 weeks. ALK-rearrangement was tested in tumors by FISH, immunohistochemistry, or reverse transcription–polymerase chain reaction. Circulating tumor cells were classified into distinct subsets according to the presence of ALK-rearrangement and/or ALK–copy number gain (ALK-CNG) signals.
Progression-free survival was defined as the time between the date of the start of crizotinib and the date of clinical or radiologic disease progression according to Response Evaluation Criteria in Solid Tumors. Overall survival was defined as the time between the date of the start of crizotinib and the date of death.
Study Findings
Although no significant association between baseline numbers of ALK-rearranged or ALK-CNG circulating tumor cells and progression-free survival was observed, the researchers found a significant association between the decrease in circulating tumor cell number with ALK-CNG on crizotinib and a longer progression-free survival (likelihood ratio test, P = .025). In multivariate analysis, the dynamic change of circulating tumor cells with ALK-CNG was the strongest factor associated with progression-free survival (hazard ratio = 4.485; 95% confidence interval: 1.543–13.030, P = .006).
“In this study, we showed that analysis of ALK copy number in [circulating tumor cells] before starting crizotinib treatment and after 2 months of crizotinib treatment may provide a biomarker for predicting the effectiveness of the therapeutic,” said Françoise Farace, PhD, leader of the circulating tumor cells team at Gustave Roussy, INSERM, Université Paris-Saclay, Villejuif, France, and coauthor of this study, in a statement. “This is important because there is currently no means of distinguishing those patients likely to gain long-term benefit from crizotinib from those who are not and who should consider trying some of the newer ALK-targeted therapeutics that have been more recently developed. Although this is a proof-of-concept study that needs validating in larger studies at different sites before it can be used in the clinic, the results reflect the potential of liquid biopsies to monitor treatment response in real time and tailor treatments at the individual patient level.”
Funding for this study was provided by Fondation de France, the Fondation ARC pour la Recherche sur le Cancer, Innovative Medicines Initiative 11th Call CANCER ID, Institut National du Cancer, and Agence Nationale de la Recherche.
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