Abstract 6642: Rapid tissue donation identifies LAG3 as a potential therapeutic target for ALK fusion positive lung cancer
Authors: Ozakinci Hilal , Nazario Gina , Furlan Karina Colossi , Chen Dung-Tsa , Rose Trevor , Schabath Matthew B. , Haura Eric B. , Pellini Bruna , Beg Amer , Boyle Theresa A. 
Published: June 2023

Introduction: The rapid tissue donation (RTD) program provides post-therapy primary and metastatic tumor tissue samples at the time of death for the study of resistance mechanisms and the tumor microenvironment to inform therapeutic opportunities. NCCN guidelines (NCCN v5.2022) recommend against PD-1/PD-L1 inhibitor monotherapy in the second-line setting for ALK fusion+ non-small cell lung cancer (NSCLC) due to lack of efficacy, irrespective of tumoral PD-L1 expression. We observed high LAG3 protein expression by multiplex immunofluorescence (mIF) in postmortem ALK fusion-positive tumor tissue samples from 3 RTD donors who were treated with ALK inhibitors. Further studies are recommended to investigate the therapeutic potential of LAG3 inhibitors in this patient population.

Case Series: Of the 38 patients with lung cancer tissue collected by RTD, 3 patients had ALK fusion and were treated with ALK inhibitors. Despite the initial response, all 3 patients succumbed to the disease. Tissue samples were collected from primary and multiple metastatic sites after death. Immune checkpoint markers, including LAG3, were quantitated via multiplex immunofluorescence staining, and genomic analyses were performed.

Results: Analysis of two tissue microarrays comprised of 130 tumor cores from multiple tissue sites of the first 10 NSCLC RTD donors revealed that 66% of tumor cores had &gt;1% LAG3 expression in CD3+ T cells. Among the three patients with ALK fusion-positive NSCLC, 83% (5 of 6 cores), 85% (6 of 7 cores), and 100% (18 of 18 cores) of the tissue cores had &gt;1% LAG3 expression in T cells. The median LAG3 expression in T cells measured by mIF was 1.8% in 99 tumor cores from the ALK fusion-negative study cohort versus 7.3% in the 31 cores from the ALK fusion-positive subset (p=0.004). Postmortem genomic analyses revealed an ALK p.L1196M resistance mutation in the first patient and an AGK-BRAF fusion in the 2nd patient. No known ALK-TKI resistance mutations were detected in the 3rd patient.

Discussion: High-quality post-therapy tumor samples collected by the RTD program enable the investigation of genomic and potential immune-related resistance mechanisms. Such studies can inform potential targets for drug development and the study of new therapies to overcome treatment resistance. Our observation of high LAG3 expression in 3 RTD donors with ALK fusion-positive NSCLC suggests the need for further studies to explore the potential for LAG3 inhibitors in patients with NSCLC whose tumors develop resistance to ALK inhibitors.

Citation Format: Hilal Ozakinci, Gina Nazario, Karina Colossi Furlan, Dung-Tsa Chen, Trevor Rose, Matthew B. Schabath, Eric B. Haura, Bruna Pellini, Amer Beg, Theresa A. Boyle. Rapid tissue donation identifies LAG3 as a potential therapeutic target for ALK fusion positive lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6642.