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    • The ORR obtained with crizotinib on our cohort was low

    2022-11-30

    The ORR obtained with crizotinib on our cohort was low compared to other studies, such as the prospective studies of A. Shaw et al. (ORR = 65% in second line), B. Solomon et al. (ORR = 74% in first line) and the more comparable large retrospective study of M. Duruisseaux et al. on the French CLINALK cohort (ORR = 50.2% in first, second and further-line settings) [[3], [4], [17]]. However, compared to these studies, our cohort was enriched in IHC/FISH equivocal/borderline-positive cases, as one of our objectives was to evaluate the use of RNA-seq as a rescue technique for these difficult cases. Overall, the correlations we found between the RNA-seq results and the clinical outcomes in the limited number of patients of our cohort who received crizotinib highlight the potential of this technique. Indeed, if only the RNA-seq-positive patients are taken into account, the response rate obtained was comparable to that of the CLINALK study (56% and 50.2%, respectively) in which crizotinib was given in various lines of treatment in a “real-life” setting, as was the case in our study. We found that crizotinib was ineffective in the two cases with no ALK fusion according to RNA-seq. Interestingly, no responses were observed in the two patients with the KLC1(9)-ALK(20) rearrangements, suggesting the lack of efficacy of crizotinib in these non-EML4-ALK variants. Lastly, we found a trend for a better median PFS and DOT in v1/v2 EML4-ALK variants cases compared to v3a/b. These data should be carefully interpreted because of the small number of patients considered. However, these results are in line with the data recently published by Woo et al. [28], showing a longer PFS with crizotinib in patients with v1/v2/others EML4-ALK variants compared to v3a/b variants. An in-vitro study by Heuckman et al. [25] showed that the AS-605240 of the different EML4-ALK rearrangement products conditioned the sensitivity to crizotinib, with EML4-ALK v2 being the most sensitive, v1 and v3b having intermediate sensitivity and v3a being the less sensitive. Our results, together with those of Woo et al. [28] support Solution hybridization assumption. Further studies on larger cohorts are warranted in order to address this question, and RNA-seq techniques offer a unique opportunity to decipher the role of EML4-ALK and non-EML4-ALK variants as predictive biomarkers of ALK inhibitors efficacy. As alectinib has recently proven its superiority to crizotinib in first-line treatment and could become the new standard of care [13], data are needed about ALK variants impact on alectinib and other next-generation ALK inhibitors sensitivity.
    Conclusion The use of accurate and highly informative tools for the detection of ALK and other gene fusions has become a necessity for the management of advanced NSCLCs. By using an RNA parallel-sequencing assay, we were able to detect EML4-ALK and non-EML4-ALK fusion variants in our cohort, and along with others, our study suggests the potential of ALK fusion variants as predictive biomarkers of crizotinib efficacy [[26], [27], [28], [29]]. Further studies on larger cohorts are warranted in order to address this question and NGS-based techniques offer a unique opportunity to decipher the role of EML4-ALK and non-EML4-ALK variants as predictive biomarkers of ALK inhibitors efficacy. Overall, in light of the present results and those of other teams [[24], [26], [27], [28], [29]], we suggest that prescreening of advanced-stage lung tumor samples with a validated ALK IHC followed by a molecular testing technique, such as RNA-seq, to identify the nature of the fusion variant, would allow additional precision to the treatment of ALK-positive NSCLs, with the advantage of NGS-based techniques to test for other targetable molecular alterations in a single test.
    Grants and funding This work received funding from the French Institut National du Cancer (INCa), the Grenoble-Alpes University Hospital (DRCI REALK project), the Grenoble Lions Club and the Groupement des Entreprises Françaises de Lutte Contre Cancer (GEFLUC) Grenoble Dauphiné-Savoie.