Video

Dr Lam on the Tumor Microenvironment in ALK Fusion+ Lung Cancer

Author(s):

Vincent K. Lam, MD, discusses findings from a study profiling the tumor immune microenvironment in patients with ALK fusion–positive lung cancer and potential future directions for this research.

Vincent K. Lam, MD, assistant professor, oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, discusses findings from a study profiling the tumor immune microenvironment in patients with ALK fusion–positive lung cancer and potential future directions for this research.

This study, which was supported by Caris Life Science’s Precision Oncology Alliance, aimed to characterize the major immune components of the ALK fusion–positive lung cancer tumor microenvironment (TME), analyzed next-generation sequencing results from 5490 patients with non–small cell lung cancer (NSCLC) who had undergone DNA and RNA sequencing. Of these patients, 374 had ALK-rearranged NSCLC. Comparators included 3169 patients with KRAS-mutant NSCLC and 1947 patients with EGFR-mutant disease.

This research showed that ALK fusion–positive tumors had low tumor mutational burden, (median 3.0 mut/MB vs 9.0 mut/MB and 4.0 mut/MB in the KRAS- and EGFR-mutant cohorts, respectively). This finding may partially explain why many ALK fusion–positive tumors have minimal or no responses to immune checkpoint inhibitors, despite unexpectedly high PD-L1 expression that is comparable to that in KRAS-mutant tumors, Lam says.

The second part of this study, which used bioinformatics pipelines to determine the immune contexture of ALK fusion–positive tumors, found potential targets that may help inflame the TME and thus enhance immunotherapy responses, although additional research is needed in this area, Lam notes. One such target is M2 macrophages, as M2 macrophage polarization contributes to an immunosuppressive TME, Lam explains. M2 macrophages had a median cell fraction of 7.2% in ALK fusion–positive tumors compared with 5.7% and 6.5% inKRAS and EGFR mutated tumors, respectively. Another potential target is the CD73 adenosine pathway, which suppresses responses to immunotherapy in some tumors such as EGFR-mutated tumors, Lam says. In this study, CD73 expression in ALK fusion-positive tumors was similar to that of EGFR-mutated tumors and expression of adenosine receptor ADORA1 was elevated (median 11.9 vs 9.4 and 9.6 in KRAS- and EGFR-mutant cohorts, respectively). These findings demonstrate potential areas for immune modulation in ALK fusion–positive NSCLC, Lam concludes.

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