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The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

ABSTRACT: BACKGROUND:Despite recent advances in treating non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK-positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK-positive NSCLC. METHODS:Between 2011 and 2018, a total of 14 ALK-positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD-L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets. RESULTS:A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2-8) courses of therapy. The study included nine patients (64.3%) who were PD-L1-high (>50%) and four (28.6%) who were PD-L1-low (<50%). The objective response rate was 14.3% (2/14). The median progression-free survival time was 2.18?months (95% confidence interval [CI] 1.13?months-not reached [NR]). The median overall survival time was 5.67?months (95% CI 3.00?months-NR). RNA expression levels of CD274 were similar between the ALK-positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK-positive group. Cytolytic activity scores including interferon-?-related response were lower in the ALK-positive group in the NCCRI but not TCGA dataset. CONCLUSIONS:Despite high PD-L1-positive rates, ICIs show limited efficacy in ALK-positive NSCLC. Decreased interferon-?-related response may underlie these findings.

SUBMITTER: Heo JY

PROVIDER: S-EPMC6825904 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

Heo Ja Yoon JY Park Changhee C Keam Bhumsuk B Ock Chan-Young CY Kim Miso M Kim Tae Min TM Kim Dong-Wan DW Kim Se Hyun SH Kim Yu Jung YJ Lee Jong Seok JS Heo Dae Seog DS

Thoracic cancer 20190911 11

<h4>Background</h4>Despite recent advances in treating non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK-positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK-positive NSCLC.<h4>Methods</h4>Between 2011 and 2018, a total of 14 ALK-positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD-L1 expression, and treatment outcomes were analyzed. RNA expressi ...[more]

PMID: 31509890

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Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Dataset Information

The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

Publications

The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

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