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J. Noe



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)

      15:45 - 17:30  |  Author(s): J. Noe

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.

      Method:
      The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).

      Result:
      Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.

      Conclusion:
      This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-061 - An ALK Follow-On Companion Diagnostic Using CGP for Clinical Care of Patients with NSCLC (ID 10396)

      09:30 - 16:00  |  Author(s): J. Noe

      • Abstract

      Background:
      Advanced NSCLC patients may benefit from treatment with ALK inhibitors if they harbor ALK rearrangements such as an EML4-ALK fusion. While the FDA has approved companion diagnostics (CDx) using IHC and FISH-based assays for ALK, molecular diagnostic testing in NSCLC is rapidly evolving towards comprehensive genomic profiling (CGP) to test for a growing number of established predictive biomarkers. Clinical validity of ALK testing using CGP however, has not yet been demonstrated in an FDA approved manner. We present here the first follow-on CDx ALK test using CGP as a part of our universal CDx platform.

      Method:
      Clinical validity was established against the FDA-approved IHC and FISH CDx, using 291 samples from the ALEX clinical trial (NCT02075840), including ALK-negative screen-failed patients. Clinical validity was established such that the CGP concordance versus an FDA-approved test was statistically non-inferior to the performance comparison between IHC and FISH. Concordance reported in Table 1 was calculated on samples that were in agreement between IHC and FISH.

      Result:
      Concordance in patients in consensus between IHC and FISH is shown in Table 1. Positive percent agreement of 92.9% and negative percent agreement of 100% was achieved. Statistical non-inferiority demonstrates a non-inferiority margin of 5.4%. Limit of detection studies demonstrated the ability to detect ALK rearrangements down to 1.8% tumor content. Table 1.

      Companion diagnostic ALK rearrangements
      Indicated use ALK inhibitors in NSCLC
      Approved CDx comparator Ventana ALK (D5F3) CDx Assay Vysis ALK Break-Apart FISH Probe Kit
      Positive percent agreement 92.9% (78/84)
      Negative percent agreement 100% (75/75)
      Median unique sequence coverage 807X
      Precision 100%
      Limit of Detection 1.8% tumor content


      Conclusion:
      We developed and validated a follow-on CDx for ALK as part of a universal CDx platform. The platform provides a single assay with well-defined performance characteristics, identifies patients with cancer who may be eligible to receive FDA-approved targeted therapeutics, conserves tissue by avoiding serial testing and can serve as clinical trial assay for studies requiring a molecular biomarker for eligibility. The data demonstrating clinical and analytical validity of ALK may accelerate the use of CGP for routine clinical care.