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Wallace Akerley



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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.09 - Real-World Survival of Relapsed Compared to De-Novo Stage IV Diagnosis of Advanced Non-Small Cell Lung Cancer (Now Available) (ID 529)

      15:45 - 17:15  |  Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      Differences in tumor biology and cancer therapy in early stage lung cancer may affect overall survival (OS) of patients with relapsed stage IV disease compared to others with de-novo stage IV disease. This study aimed to compare real-world survival of these patients.

      Method

      We selected patients with advanced NSCLC diagnosed between 2011 and 2017, who received at least one line of therapy, from the US Flatiron Health electronic health record-derived database. Patient data was collected through June 2018, providing at least 6 months of follow-up.

      OS was defined as time from advanced or metastatic diagnosis to the event of death, censored at last clinic visit or end of oral therapy. The unadjusted OS of patients was estimated using the Kaplan-Meier method. We fit multivariable Cox proportional hazards models to compare the hazard of death between groups.

      Result

      de-novo vs relapsed image final.jpg

      The study included 30,310 patients with median age of 68.8 years, 46.7% female, and 76.8% non-Hispanic white. We observed 22.8% had relapsed and 77.2% were de-novo stage IV. Relapsed patients had median OS of 15.5 months (95% CI: 14.9-16.2). Patients with de-novo stage IV had median overall survival of 12.0 months (95% CI: 11.7-12.2). The force of mortality among relapsed stage IV patients was 24% lower than the rate of death among de-novo stage IV patients (Hazard Ratio [HR]: 0.76; 95% CI 0.73-0.79; p <0.001), adjusting for age, gender, state, histology, smoking, race/ethnicity, and stratifying by year of diagnosis. Sensitivity analyses of an unadjusted model (HR 0.79, p <0.001) and a sub-group analysis of patients with advanced diagnoses in 2016-2017 (HR 0.74, p <0.001) suggested the results were robust.

      Conclusion

      Among patients with stage IV NSCLC that received at least one treatment, those who relapsed had better OS than those who presented with de-novo stage IV disease. These findings have implications for future clinical trial design.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-35 - Real World Characterization of Advanced Non-Small Cell Lung Cancer in Never Smokers (Now Available) (ID 453)

      09:45 - 18:00  |  Author(s): Wallace Akerley

      • Abstract
      • Slides

      Background

      NSCLC in never smokers is vastly different from those with a history of smoking in terms of etiology, driver-mutations and response to immunotherapy. We have previously demonstrated a hereditary contribution in never smokers which is not identified in smokers1. This study compares the real-world survival of NSCLC in never smokers to those with a smoking history by mutation status.

      Method

      The study included patients in the Flatiron Health nationwide electronic health record-derived database who were diagnosed with NSCLC, received biomarker testing results (EGFR, BRAF, ALK, and ROS1), and initiated therapy between 2011-2017 with follow-up through June 2018. Overall survival (OS) of patients by smoking and driver mutation groups was summarized via Kaplan-Meier survival estimates, and compared in the context of a multivariate Cox proportional hazard model adjusted by age at stage IV diagnosis, gender, state of residence, histology, smoking status, and race/ethnicity, stratified by categories of advanced diagnosis date within practices.

      Result

      The study included 30,310 patients with median age of 68.8 years, 46.7% female, 76.8% non-Hispanic white, and 12.6% never smokers. Actionable mutations were reported in 9.0%, differentially as 34.2% in non-smokers and 5.5% in smokers. OS differed by smoking and driver-mutation categories (adjusted and stratified p<0.001). The median OS for patients with wild-type mutation status and history of smoking was 9.6 months, for mutated smokers was 19.4 months (adjusted and stratified hazard ratio [HR] relative to WT smokers 0.65 (95% CI 0.60-0.71)) , for wild-type never-smokers was 15.1 months (0.78 (0.73-0.83) relative to WT smokers), and for mutated never-smokers was 25.5 months (0.52 (0.48-0.58) relative to WT smokers).

      smoking and driver mutation status.jpg

      Conclusion

      Never-smokers with NSCLC survived longer than those with smoking history, in both groups of wild-type and mutation-positive patients. Findings highlight that in patients with NSCLC, a smoking history may have similar effect on hazard of death as actionable mutation status.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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