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Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC.

ABSTRACT: BACKGROUND:Anaplastic lymphoma kinase (ALK) is a validated molecular target in non-small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance. METHODS:We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. Functional in vitro studies were further undertaken to elucidate the mechanism of resistance. RESULTS:ALK T1151Sins mutation was detected when the patient developed resistance to ceritinib, and undetectable when she responded to lorlatinib. MET amplification was present when the tumor developed resistance to lorlatinib, and reduced when the patient received combination therapy of lorlatinib with crizotinib, which corresponded to clinical radiologic responses. In addition, further functional in vitro studies demonstrated that ALK harboring the T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by lorlatinib. CONCLUSIONS:Clinical evidence and in vitro validation revealed the clinical usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA in revealing the underlying resistance mechanism and guiding the precise administration of ALK inhibitors in patients with advanced ALK-positive NSCLC.

SUBMITTER: Guo J

PROVIDER: S-EPMC5915031 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC.

Guo Jing J Guo Lihong L Sun Li L Wu Zhenzhen Z Ye Junyi J Liu Jing J Zuo Qiang Q

Cancer biology & therapy 20180306 5

<h4>Background</h4>Anaplastic lymphoma kinase (ALK) is a validated molecular target in non-small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance.<h4>Methods</h4>We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. ...[more]

PMID: 29400604

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Project description:Background: ALK inhibitors have shown positive advance in the treatment of ALK+ NSCLC. They have achieved better results in prolonging the progression free survival and improving quality of life in comparison to chemotherapy. We have assembled the evidence related to the efficacy and safety of these agents in the treatment of ALK positive NSCLC. Materials and Methods: A comprehensive search was conducted using electronic databases of PubMed, Medline and Cochrane Library to identify the studies involving comparison of ALK inhibitors to chemotherapy and Next generation ALK inhibitors to crizotinib. PFS was the primary outcome while other outcomes like ORR, adverse events, quality of life and OS were also analyzed and compared. Hazard ratios and odds ratios obtained were analyzed using fixed effect or random effects model in Review Manager Software. Results: A total of 12 studies (n = 3,297) met the criteria for inclusion in this review and meta-analysis. ALK inhibitors including crizotinib, ceritinib and alectinib revealed significantly better PFS (HR 0.42 [0.35, 0.50; p < 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p < 0.00001] as compared to chemotherapy in the first line as well as second line treatment settings. Intracranial response rate was better with ALK inhibitors (ceritinib and alectinib) as compared to chemotherapy OR 6.51 [2.86, 14.83; p < 0.00001]. No significant increase in grade 3 or 4 adverse events was observed with crizotinib (OR 1.21 [0.82, 1.77; p = 0.34]) or ceritinib (OR 1.49 [0.86, 2.57; p = 0.17]) when compared to chemotherapy individually. Quality of life indicators assessed were significantly improved with ALK inhibitors. Next generation agents (ceritinib, alectinib and brigatinib) revealed significant improvement in PFS (HR 0.50 [0.43, 0.57; p < 0.00001]), ORR (OR 1.57 [1.21, 2.04; p = 0.0006]) in comparison to crizotinib. Next generation agents (Alectinib and brigatinib) yielded better response intra-cranially than crizotinib in terms of objective response rate (OR 5.87 [3.49, 9.87; p < 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p < 0.0001]). Alectinib by far resulted in fewer adverse events than chemotherapy or crizotinib. Conclusions: Overall ALK inhibitors are safe and effective treatment option in ALK+ non-small cell lung cancer. Of the ALK inhibitors, Next generation agents in particular alectinib and brigatinib are safer and more effective intra-cranially and can be preferred as first option.

Project description:IntroductionThe Blood First Assay Screening Trial revealed the clinical applicability of blood-based next-generation sequencing to identify patients with ALK-positive NSCLC for alectinib treatment. To understand the relationship between tissue-based versus blood-based testing, we retrospectively investigated concordance between VENTANA ALK (D5F3) CDx immunohistochemistry and the FoundationACT (FACT; Foundation Medicine, Inc.) plasma assay, and compared clinical efficacy between phase 3 ALEX study subpopulations.MethodsPatients with advanced ALK-positive (by immunohistochemistry) NSCLC were randomized 1:1 to alectinib 600 mg or crizotinib 250 mg, twice daily. Assessable baseline plasma samples were analyzed for ALK positivity by FACT; positive percent agreement with immunohistochemistry was evaluated. Progression-free survival (PFS), duration of response, and objective response rate were compared between intention-to-treat (ITT) and biomarker-evaluable populations, and plasma ALK-positive and plasma ALK-negative subpopulations.ResultsIn the ITT population (303 patients; alectinib, 152; crizotinib, 151), all patients had ALK-positive tumors by immunohistochemistry. In the biomarker-evaluable population (149 patients; alectinib, 76; crizotinib, 73), 105 had plasma ALK-positive and 44 had plasma ALK-negative tumors. Positive percent agreement between immunohistochemistry and FACT was 70.5% (105 of 149; 95% confidence interval: 62.5-77.7). Baseline characteristics were generally balanced, with some exceptions, notably tumor burden. Median PFS in plasma ALK-positive and ALK-negative patients was 22.4 months and not estimable with alectinib and 7.3 months and 12.9 months with crizotinib, respectively; median duration of response was 25.9 months and not estimable with alectinib and 5.6 months and 11.5 months with crizotinib, respectively.ConclusionsReasonable concordance between FACT and immunohistochemistry was observed; both methods are valuable in identifying ALK-positive patients, separately or concurrently. Alectinib was found to have superior PFS in the plasma ALK-positive population, as in the ITT population.

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Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC.

Publications

Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC.

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