Poorer Clinical Outcomes for Certain Patients Shown With ALK-Rearranged NSCLC on Second Line TKIs

Patients with ALK-rearranged non–small cell lung cancer (NSCLC) who had ALK fusion variant 3a/b in their tumor, concomitant mutations, and high PD-L1 expression were associated with an unfavorable clinical response to second-generation tyrosine kinase inhibitors (TKIs), according to study results published in Lung Cancer.¹

For patients with a variant 3a/b ALK mutation in their disease they had a median progression-free survival (PFS) of 9.93 months versus a PFS of 16.97 months in patients with other variants (HR, 1.94, P =.0014). Baseline concomitant mutations were also significantly associated with a shorter PFS while patients were on ALK targeting TKIs at 10.87 months compared to 22.47 months (HR, 1.98, P =.002).

“Recently, second-generation ALK TKIs, such as alectinib (Alecensa), brigatinib (Alunbrig), and ceritinib (Zykadia), became the standard first-line treatment in ALK-rearranged advanced NSCLC and significantly improved clinical outcomes in these patients, “the researchers wrote in a paper analyzing the results of their retrospective analysis. “However, nearly all patients inevitably developed resistance to ALK TKIs, and clinical response varies.”

Researchers enrolled 193 patients with ALK-rearranged advanced NSCLC who received second-generation ALK TKIs at Sun-yat Sen University Cancer Center from January 2015 to December 2020. The ALK fusion variants and concomitant mutations were identified with next-generation sequencing (NGS), while PD-L1 expression was assessed by immunohistochemistry. Researchers looked at these results to help clinicians determine which is the best individual paths for clinicians to lead their ALK-rearranged patients on during treatment.

Analysis of the patients’ PD-L1 status was analyzed in a subset of 68 patients with a 0% tumor proportion score (TPS) in 32.4% (n = 22) of patients, 1-49% TPS in 30.9% (21) of patients, and 50% or more TPS in 36.7% (25) of patients. Median PFS was shorter in the patients with a high PD-L1 expression compared to those with a lower TPS score, for example, patients with a TPS of 0% had a median PFS of 27.43 months on ALK TKIs compared to patients with a 50% or greater TPS that had a median PFS of 9.5 months. Moreover, patients with a 1-49% TPS had a median PFS of 30.63 months (P = 0.001).

“Such evidence suggested that tumor immune microenvironment could play an important role in the response to TKIs, (and) further studies are expected to investigate the underlying mechanisms and then develop optimal therapeutic strategies for these patients,” the researchers wrote in regard to the PD-L1 results. According to the researchers, this evidence is some of the earliest to discuss how PD-L1 status relates to second-line treatment in patients with ALK-rearranged NSCLC.

The NGS panel done for each patient showed that 96 patients had concomitant mutations with TP53 mutations being the most common in 37.8% of patients (73). Objective response rate in these patients also correlated similarly to PFS, with patients who had baseline concomitant mutations were significantly associated with poorer outcomes on ALK TKIs at 40.6% and 61.9% (P = 0.003), respectively. In a subgroup of patients with central nervous system (CNS) metastases (85) concomitant mutations were also associated with worse PFS outcomes on ALK TKIs at 9.4 months vs 16.97 months (P = 0.004) in those without.

“Our study demonstrated that high PD-L1 expression was associated with variant 3a/b and concomitant mutations. Furthermore, ALK variant 3a/b, concomitant mutations, and high PD-L1 expression predicted unfavorable clinical response to second-generation TKIs in ALK-rearranged non-small cell lung cancer,” the researchers concluded.

_Reference

_{Li M, Hou X, Chen J, et al. ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs in patients with advanced ALK-rearranged non-small cell lung cancer (GASTO 1061). Lung Cancer. 2022 Jan 12;165:54-62. doi: 10.1016/j.lungcan.2022.01.006}