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  • Considering our previous results with cfDNA in

    2024-04-18

    Considering our previous results with cfDNA in EGFR TKI-resistant NSCLC patients and growing evidence about different mutations in the ALK kinase domain as responsible for acquired resistance to ALK TKIs, we planned this study. Even if a next-generation sequencing approach after PD during crizotinib treatment would have been more informative, by exploring a wider range of possible resistance mechanisms, we decided to perform ddPCR, a low-cost procedure characterized by higher sensitivity, to optimize the chances of detection of p.L1196M, p.G1269A, and p.F1174L ALK mutations, because they were the most commonly associated with acquired resistance to crizotinib. Five of 20 patients (25%) presented an ALK mutation in cfDNA at the time of the PD during crizotinib treatment. There were 2 cases who presented with p.L1196M and 1 with p.F1174L mutations, 1 with p.G1269A, and a case with p.L1196M as well as p.G1269A. Several mutations of the kinase domain of ALK have been identified in tumor biopsies. In the article published by Gainor et al, an analysis of correlation Halopemide sensitivity of ALK mutations and crizotinib, ceritinib, brigatinib, alectinib, and lorlatinib was performed. The results showed that p.L1196M, p.G1269A, and p.F1174L/C need higher concentrations of crizotinib to inhibit cell phosphorylation (half maximal inhibitory concentration (IC50) of 339.0 nM, 117.0 nM, and 115.0 nM, respectively), with respect to the lower ones needed by new ALK-TKIs. This important information put the basis on a mutational-based algorithm to treat ALK-positive patients. The frequency of ALK mutations reported in this study is lower than previously reported and can be explained with the high number of patients (n = 8) who presented brain-limited PD, reasonably driven by a pharmacokinetic mechanism. However, our data are consistent with results recently reported by Gainor et al, who showed that only 20% of crizotinib-resistant patients carried ALK mutations, contrary to > 50% of patients who had PD during second-generation ALK TKI treatment. As previously reported, the presence of a double ALK mutation (p.L1196M and p.G1269A) was observed (patient 2). In our case compound mutation suggests a possible heterogeneity of acquired resistance. Therefore, even if the event has been described also in tissue specimens, the analysis of cfDNA could represent a more comprehensive evaluation than the biopsy of a single tumor lesion. Moreover, 3 patients acquired ALK mutations concomitantly with KRAS mutations. Patient 6 with p.L1196M achieved an objective response during the subsequent line of treatment with brigatinib, along with the disappearance of ALK and KRAS mutations in cfDNA, similar to the other 2 ALK-mutated patients treated with brigatinib (patient 2 with p.L1196M and p.G1269A and patient 12 with only p.L1196M). Therefore, our results suggest that brigatinib can overcome the resistance due to these mutations, similarly to that observed with ceritinib and alectinib. The fourth ALK-mutated patient treated with brigatinib with p.G1269A and concomitant KRAS p.G12D experienced a PD at first radiological assessment. Although the brigatinib IC50 against cell lines carrying the p.G1269A is low, it is unlikely that this mutation is responsible for the PD during brigatinib treatment, whereas the KRAS mutation is more likely to be the real mechanism of resistance, as can happen for crizotinib. However, in patient 17, with ALK p.F1174L as well as KRAS mutation, who did not responded to ceritinib, we confirm the results of previous reports suggesting that ALK p.F1174 mutation confers resistance to ceritinib. The contribution of KRAS mutations in this contest is still uncertain, even if some evidence exists about KRAS mutations as a potential cause of ALK TKI resistance.
    Conclusion Our findings are limited by the small number of patients and by the absence of comparison with tissue rebiopsy. However, we confirmed, to our knowledge, for the first-time in plasma, that ALK and KRAS mutations are associated with acquired resistance to crizotinib in ALK-positive NSCLC. In particular, we showed that ALK mutations can be isolated in plasma and that their monitoring could serve as a response parameter.