Author of

• 25921

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  P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26308

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    P1.01-76 - A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers (ID 13324)

    16:45 - 18:00  |  Author(s): Linda Ahn
    • Abstract

    Background
    

    Therapeutic options for SQCLC patients are limited. The efficacy of platinum-based doublets, long the standard first-line treatments, has plateaued, with ORR=30%. Anti-tumor synergy between gemcitabine and albumin-bound paclitaxel (ABP) was demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase, leading to increased intratumoral gemcitabine (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    This was a Simon two-stage phase 2 study of ABP + gemcitabine in chemotherapy-naïve, PD-L1 low/unknown advanced SQCLC patients (NCT02525653). Primary endpoint: best ORR. H0=25% (≥6/17 responses) and HA=45% (≥16/41 responses). ABP (100mg/m²) + gemcitabine (1000mg/m²) was initially given on D1, D8, D15 of an every 4 week cycle for up to 6 cycles (A1). After clearing H0, the study was amended to a 3 week cycle (D1, D8 treatment) and to allow maintenance ABP after C4 (A2). All patients underwent NGS by MSK-IMPACT.

    4c3880bb027f159e801041b1021e88e8 Result
    

    N=27 patients were evaluable for the primary endpoint. Median age=70, age ≥70=60%, female=30%, median KPS=80%, smokers=93%. 46% of patients had PD-L1 IHC <50% (0-20%). 54% were PD-L1 unknown. Grade ≥3 related AEs included: fatigue-13%, neuropathy-4%; diarrhea-4%; lung infection-4%, anemia-9%; decreased platelet count-4%, and decreased neutrophils (4%). Four patients (17%) experienced related SAEs including, separately, G3 febrile neutropenia, G3 WBC decrease, G3 thrombocytopenia, and G3 anemia.

    ORR for the entire cohort was 63% (Figure 1). ORR in A2= 71% (10/14). 8 patients in A1 had dose modifications resulting in equivalency to the A2 schedule. ORR in the A2+A1 dose modified cohort=73% (16/22), meeting the primary endpoint early. Median PFS=8mo; OS not yet mature.

    

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    ABP + gemcitabine is an effective and well-tolerated regimen in patients with untreated advanced SQCLC with a response rate exceeding that associated with platinum regimens and first-line immunotherapy.

    6f8b794f3246b0c1e1780bb4d4d5dc53

• 25950

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  P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 27221

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    P2.13-44 - Targeting NFE2L2 Mutations in Advanced Squamous Cell Lung Cancers with the TORC1/2 Inhibitor TAK-228 (ID 12591)

    16:45 - 18:00  |  Author(s): Linda Ahn
    • Abstract

    Background
    

    Despite research efforts over the past decade, no targeted therapy options exist for patients with SQCLC. Analyses by TCGA and others (Paik Cancer Disc 2015) have identified a heretofore untargeted, frequently mutated oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of patients with SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (~aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through regulation of RagD (Shibata Cancer Res 2010). We now report translational studies and preliminary results from a phase 2 trial of the oral TORC1/2 inhibitor TAK-228 in SQCLC patients with these mutations.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells harboring an NFE2L2 E79K mutation treated with TAK-228, everolimus, rapamycin, or deforolimus with requisite vehicle controls. Patients with stage IV SQCLC harboring NFE2L2 mutations were treated on an NCI CTEP- single-institution phase 2 study of TAK228 3mg po qd (continuous, 28 day cycles; NCT02417701). Primary endpoint: ORR. Secondary endpoints: PFS/OS. The study utilizes a Simon 2-stage design with H0=5% (N≥1/5 responses), HA=40% (N≥2/10 responses).

    4c3880bb027f159e801041b1021e88e8 Result
    

    TAK-228 exhibited significantly increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK-228 alone was cytotoxic at sub-[μM] (IC50 68nM); all other rapalogs exhibited IC50s >10μM. This was associated with an 80% decrease in downstream S6 phosphorylation. Tumor response (-55% shrinkage) was also seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog tested.

    N=4 patients have been treated on study (exon 2 del, D29H, F37V, W24C). 3 are evaluable for response. 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; no other G3 AEs reported. ORR=67% (2 PR, 1 SD, 0 PD). Prolonged disease response is present, with DOR= 12mo, 10mo (ongoing), 8mo (ongoing).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    TAK228 is tolerable with evidence of pre-clinical and clinical activity in this biomarker-selected population. The trial has met its first-stage endpoint and has expanded to N=10 patients. The trial has also expanded to included patients with KRAS mutant lung cancers harboring co-alterations in NFE2L2 or KEAP1.

    6f8b794f3246b0c1e1780bb4d4d5dc53