Accumulation of concomitant mutations involved in drug resistance in sequential ALK TKI treatments of ALK-positive NSCLC

ALK TKIs have shown promising clinical outcomes for ALK-positive lung cancer patients. Response to various TKIs is influenced by distinct resistant-mechanisms for different ALK fusion variants.

An investigation of genomic alterations in homogenous resistant-mechanisms reported their diversity and complexity in response to next-generation ALK TKIs. Cohort 1 included 475 ALK-positive lung cancer patients out of a total 11,842 who underwent next-generation sequencing to assess the distribution of ALK fusion variants. Cohort 2 included 52 NSCLC patients with a similar distribution of ALK fusion variants as those in cohort 1. Mutation profiles of 416 cancer-relevant genes in their post-ALK TKI tumour samples were analysed. The crizotinib-only treatment group included 35 patients; 17 other patients (the multi-TKI group) received multiple lines of ALK TKIs, including lorlatinib, alectinib, ceritinib, and brigatinib.

The two most common ALK fusion variants in in both cohorts were EML4-ALK v3 and v1. In the crizotinib group, 17 (49%) patients had 18 different ALK activating mutations; the number in the multi-TKI group was 10 (59%). Both groups had different mutation patterns. G1202R, found in 35% of patients, was the most frequent ALK activating mutation. L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Compared with the latter, there was significant enrichment of concomitant ALK activating mutations in the multi-TKI group (P=0.31).

A trend showed an increased number of multi-TKI patients with by-pass/downstream pathway activation of ALK vs the crizotinib cohort (P=0.056). This led to higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI (29%) group vs crizotinib-treated patients (6%; P=0.031). Regardless of fusion variant types, crizotinib-treated patients with concomitant TP53 mutation had significantly shorter PFS compared with TP53 wildtype patients. The median PFS was 8 vs 13 months (HR 1.494; P=0.019). These findings suggest a higher frequency of concomitant mutations after multiple TKI treatments. They also indicate that concomitant TP53 mutation might be a biomarker for worse clinical outcomes in patients treated with crizotinib (see Figure). Concomitant ALK activation mutations are more common after multi-TKI treatments. In patients treated with crizotinib alone, TP53 mutation might be a prognostic biomarker of worse clinical outcomes

Figure: TP53 might be a negative prognostic factor in ALK+ NSCLC patients treated with crizotinib alone.