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M.H. Hong



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    MA 12 - Circumventing EGFR Resistance (ID 665)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 12.01 - A Phase Ib Study of the Combination of Afatinib and Ruxolitinib in EGFR Mutant NSCLC Progressed on EGFR-TKI: An Updated Analysis (ID 9021)

      11:00 - 11:05  |  Author(s): M.H. Hong

      • Abstract
      • Presentation
      • Slides

      Background:
      T790M mutation of EGFR exon 20 is observed in approximately 50% of the non-small cell lung cancer (NSCLC) patients progressed on EGFR tyrosine kinase inhibitors (TKIs). Based on a preclinical study demonstrating that pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cell lines, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.

      Method:
      We used the classical 3+3 design for dose-escalation cohort (DAC). Patients with histologically diagnosed, EGFR mutant stage IV NSCLC and documented disease progression on EGFR-TKIs were considered eligible. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT. If DLT was not observed in 9 patients at the cohort of the highest level, we planned to decide RP2D and enroll 6 additional patients in the dose-expansion cohort (DEC).

      Result:
      As of June 14, 2017, 21 patients (12 with exon19 deletion, 9 with exon21 L858R) were enrolled in DAC, 8 of which had T790M mutations. All patients were previously treated with erlotinib (n=6) or gefitinib (n=15), and previously received a median of 2 (range, 1-4) lines of chemotherapy. Because no DLT was observed in the 9 patients at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily), 6 patients with T790M mutation were enrolled in the DEC. Frequent AEs included paronychia (G1 in 11 cases, G2 in 2 cases), diarrhea (G1 in 14 cases, G2 in 2 cases, and G3 in 2 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1 in 7 cases, G2 in 3 cases). SAEs were reported in 6 patients, which were not related to the investigational products. Partial responses were observed in 7 patients (25.9%) with disease control rate (CR+PR+SD) of 96.3%. Median PFS was 5.7 months (95% CI, 4.2-7.2) and 3 patients remain on study.

      Conclusion:
      The combination of afatinib with ruxolitinib was well tolerated with clinical benefit of disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).

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