Anti-ALK autoantibodies in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC): A monocentric experience

Importance: Deregulation of anaplastic lymphoma kinase (ALK) occurs in 3-7% of advanced NSCLC mainly because of chromosomic rearrangements at the ALK locus. Next to its oncogenic function, ALK chimeric oncoprotein is a possible antigen for human immune system. The prognostic value of natural anti-ALK immunogenicity remains poorly explored in ALK ​+ ​NSCLC. We hereby report preliminary results of a plasmatic anti-ALK a-abs titration assessment in a cohort of ALK ​+ ​NSCLC pts. Objective: To evaluate the prevalence of pre-existing circulating anti-ALK a-abs in ALK ​+ ​NSCLC pts. Key secondary objectives are the assessment of anti-ALK a-abs prognostic value and association with brain metastases (BM). Design: This monocentric case series included 60 ALK ​+ ​NSCLC pts progressing on any anti-ALK TKIs between October 2015 and February 2021 ​at Gustave Roussy Cancer Campus. Fifty-six plasma samples were analyzed through a semiquantitative immunocytochemical technique. Plasma samples were obtained from two prospective studies approved by our Institutional Review Board: the MATCH-R trial (NCT02517892) and the MSN trial (RECF1256). Participants: We included pts diagnosed with unresectable stage III or IV NSCLC, either by contemporaneous or historical biopsy. ALK-rearrangement was identified by FISH, IHC or NGS. Pts were aged more than 18-year-old and had previously signed informed consent for one of the studies. Pts had received at least one anti-ALK-TKI during the disease history. Pts were not eligible if they had been diagnosed with a second cancer. Main outcomes and measures: The prevalence of plasmatic anti-ALK a-abs titer was reported as percentage. Progression-free survival, overall survival, and time to BM were analyzed using Kaplan-Meier methods. Results: We found an anti-ALK a-abs titer in 5 (9 ​%) pts. anti-ALK a-abs did not contribute to prolongation of survival. Although not significant, there was a trend towards protection against BM in the presence of anti-ALK a-abs. Conclusions and relevance: Because ALK fusion proteins are exclusively produced intracellularly, not all ALK autoantibodies may have direct anti-tumor impact with favorable prognostic value. This is the first investigation to explore the impact of circulating anti-ALK a-abs on BM. Prospective studies with longer follow-up are warranted to further explore the impact of anti-ALK a-abs on BM.