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Short progression-free survival of ALK inhibitors sensitive to secondary mutations in ALK-positive NSCLC patients.

ABSTRACT: BACKGROUND:Most non-small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK-TKI therapies; however, little clinical data exists on the clinical efficacy of ALK-TKI tailored to secondary mutation. METHODS:A retrospective study was conducted to analyze the patterns of ALK-TKI treatment and clinical outcomes, including progression free survival (PFS), of ALK-positive NSCLC patients who received rebiopsy. Based on the rebiopsy results, secondary mutations in the ALK gene that were shown to be associated with the efficacy of ALK-TKI therapy in the preclinical or clinical setting were defined as "sensitive mutations (SM)". RESULTS:Among 71 patients who received ALK-TKI for NSCLC at our institution, 20 patients received rebiopsy, and secondary SM were found in eight patients. The objective response rate (ORR) of the cases with SM who received ALK-TKI therapy was 88.9%, while the ORR of the patients without SM who received ALK TKI or chemotherapy was 20.0%; however, the PFS of the patients with SM was relatively short (with SM vs. without SM: 5.6 months vs. 5.1?months). CONCLUSIONS:The selection of ALK-TKI based on the rebiopsy result was associated with a high ORR and relatively short PFS. The mechanism responsible for the short PFS of sensitive ALK-TKI to secondary mutation should be clarified.

SUBMITTER: Haratake N

PROVIDER: S-EPMC6718030 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Short progression-free survival of ALK inhibitors sensitive to secondary mutations in ALK-positive NSCLC patients.

Haratake Naoki N Seto Takashi T Takamori Shinkichi S Toyozawa Ryo R Nosaki Kaname K Miura Naoko N Ohba Taro T Toyokawa Gouji G Taguchi Kenichi K Yamaguchi Masafumi M Shimokawa Mototsugu M Takenoyama Mitsuhiro M

Thoracic cancer 20190723 9

<h4>Background</h4>Most non-small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK-TKI therapies; however, little clinical data exists on the clinical efficacy of ALK-TKI tailored to secondary mutation.<h4>Methods</h4>A retrospective study was conducted to analyze the patterns of ALK-TKI treatment and clinical outcomes, i ...[more]

PMID: 31338990

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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.

Dataset Information

Short progression-free survival of ALK inhibitors sensitive to secondary mutations in ALK-positive NSCLC patients.

Publications

Short progression-free survival of ALK inhibitors sensitive to secondary mutations in ALK-positive NSCLC patients.

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