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Angela Pang



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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
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      P1.01-38 - A Phase II With a Lead-In Phase I Study to Examine Safety and Efficacy of Hydroxychloroquine and Gefitinib in Advanced NSCLC   (ID 11325)

      16:45 - 18:00  |  Author(s): Angela Pang

      • Abstract
      • Slides

      Background

      Tyrosine kinase inhibitors (TKIs) benefit advanced non-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations, but resistance invariably develops. Preclinical work demonstrated re-sensitization to EGFR-TKIs in cells with acquired resistance, and increased sensitivity of EGFR-mutant cells to erlotinib and hydroxychloroquine (HCQ) combination. We examine the safety and efficacy of HCQ with gefitinib in an Asian cohort of NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled stage IIIB/IV lung adenocarcinomas with sensitizing EGFR mutations. In the early phase of the study, non-smokers with unknown EGFR status were allowed. In the phase I lead-in study (Nov 2008-Jan 2010), maximum tolerable dose (MTD) of HCQ and gefitinib was ascertained via a 3+3 dose escalation schema.

      In the phase II single-arm study (March 2010-May 2016), all patients were treated with gefitinib 250mg om and MTD (600mg om) of HCQ, and stratified into TKI-naïve and TKI-treated cohorts. In the TKI-treated cohort, patients must have prior response to gefitinib for more than 12 weeks and developed resistance. Primary end point (PEP) in the TKI-naïve cohort was objective response rates (ORR) and progression-free survival (PFS). In the TKI-treated cohort, PEP was ORR, and to determine if combination treatment can re-sensitize acquired resistance to EGFR TKIs.

      4c3880bb027f159e801041b1021e88e8 Result

      75 patients were treated. EGFR mutations were identified in 77.3%. In the phase I cohort (n=13), MTD of HCQ was 600mg. HCQ-gefitinib combination was well tolerated. Common adverse events were rash and diarrhea, mainly from gefitinib. There was no dose-limiting toxicity. In TKI-naïve cohort (n=37) of the phase II study, ORR was 75.8% (95% CI 57.7-88.9). Median PFS was 9.4 months (95% CI 6.8-12.0). Four patients who were non-evaluable had early toxicities, including pneumonitis and hepatitis flare. In the TKI-treated cohort (n=25), 52% had received 2 or more lines of prior treatment. Disease control rate with TKI re-challenge was 50% (95% CI 21.9-70.9), ORR was 4.2% (95% CI 0.1-21.1). Median PFS was 2.4 months, and median overall survival was 9.9 months (95% CI 5.7-14.0). Three patients achieved a progression-free interval of more than 7 months after re-challenge (7.6; 11.2; 15.9 months).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combination of HCQ-gefitinib is safe. In the TKI-naïve cohort, combination treatment did not improve PFS over reported average of 10 months for 1st-generation EGFR TKIs. However, in the TKI-treated cohort, re-responses and disease control to 1st-generation EGFR TKIs were seen, suggesting either a re-treatment effect or disease stabilization with addition of HCQ in acquired EGFR resistance.

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