Author of

• 30601

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  P2.01 - Advanced NSCLC (ID 159)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30605

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    P2.01-04 - NCI-NRG Oncology ALK PROTOCOL (NRG-LU003): A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients      (ID 2021)

    10:15 - 18:15  |  Author(s): Jeffery D. Bradley
    • Abstract

    Background
    

    Currently, the 1^stgeneration ALK inhibitor crizotinib and 2^ndgeneration ALK inhibitors ceritinib, alectinib and brigatinib are FDA-approved for the treatment of advanced ALK-positive NSCLC. The 3^rdgeneration ALK inhibitor lorlatinibrecentlyreceived accelerated approval for patients after failure of a 2^ndgeneration inhibitor.

    2^ndgeneration ALK inhibitors are widely used in crizotinib-resistant patients and have recently replaced crizotinib as first-line therapy for newly diagnosed patients. There is an urgent need to define the optimal therapy for patients who have become resistant to a second-generation ALK inhibitor. Pre-clinical data and small case series suggest that the presence/absence of ALK resistance mutations or the specigic ALK mutation may serve as a critical biomarker to guide selection of therapy, particularly in the setting of relapse on a 2^ndgeneration ALK inhibitor when ALK resistance mutations are more common,

    Method
    

    NRG-LU003 proposes to study ALK-positive non-squamous NSCLC patients who develop resistance to a second-generation ALK inhibitor, in order to establish a treatment algorithm for these patients based on resistance mechanisms.Patients will undergo tissue biopsy along with blood sampling for cfDNA analysis. One of the aims of the study is to establish the concordance between tissue and liquid biopsies; liquid biopsy may replace tissue biopsy after the first 200 patients enrolled, depending on the concordance and in consultation with CDRH/FDA. Treatments will be selected based on preclinical and clinical data demonstrating activity of treatment particular inhibitor against the specific ALK mutation or resistance mechanism identified. If no ALK resistance mutations are identified, patients will be randomized to receive either a next-generation ALK inhibitor they have not previously received or pemetrexed-based therapy with cisplatin or carboplatin.

    Target accrual is 660 patients and primary objective is to assess whether ALK kinase domain mutations (e.g., G1202/C1156/I1171/L1196/V1180/F1174 mutations) associated with drug resistance are predictive of objective response to subsequent ALK inhibitor therapy, to assess whether subsequent pemetrexed based chemotherapy improves objective response compared to ALK inhibitor therapy for patients with no ALK resistance mutations, and to evaluate objective responses of patients with specific genetic alterations (e.g., ALK L1198F, compound mutations, or high-level MET amplification) treated with crizotinib.

    Mutation	STUDY DRUG	STUDY DRUG	STUDY DRUG	STUDY DRUG	STUDY DRUG	STUDY DRUG	STUDY DRUG
    G1202, G1202del, G1202R	lorlatinib			brigatinib
    C1156Y	lorlatinib		alectinib	brigatinib
    I1171	lorlatinib	ceritinib		brigatinib
    L1196, L1196M	lorlatinib	ceritinib	alectinib	brigatinib	ensartinib
    V1180	lorlatinib	ceritinib		brigatinib
    F1174	lorlatinib		alectinib	brigatinib
    Compound mutation	lorlatinib
    ALK L1198F (alone/ in combination with another ALK mutation)						crizotinib
    MET amplification						crizotinib
    No ALK-resistance mutations*	lorlatinib	ceritinib	alectinib	brigatinib	ensartinib		Pemetrexed + Cisplatin or Carboplatin

    Result
    

    "Section not applicable"

    Conclusion
    

    This study has been approved and is open for enrollment through the National Clinical Trials Network (NCTN).

    This project is supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI)