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Min Hee Hong



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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-94 - JNJ-61186372, an EGFR-cMet Bispecific Antibody, in EGFR Exon 20 Insertion-Driven Advanced NSCLC (ID 1802)

      09:45 - 18:00  |  Author(s): Min Hee Hong

      • Abstract

      Background

      JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and cMet receptors, is currently being explored in a first-in-human study in patients with non-small cell lung cancer (NSCLC). Preliminary JNJ-372 clinical data have suggested activity in patients with diverse EGFR mutations, including Exon 20 insertions (Exon20ins), which carry primary resistance to tyrosine kinase inhibitors (TKIs; Cho BC et al. Ann Oncol 2018;29(suppl_8):mdy292.118). To better understand the mechanism of JNJ-372 activity in this patient population, we conducted preclinical studies exploring the activity of JNJ-372 in different EGFR Exon20ins models.

      Method

      BaF3 cells were transduced with retrovirus expressing various EGFR Exon20ins, as described. Cell titer glo assays were used to measure cell proliferation; western blot analysis was used to study EGFR and cMet signaling cascade events. For mouse tumor models, JNJ-372 was administered i.p. daily at 10mg/kg or 30mg/kg. Referenced patients with Exon20ins disease were administered 1050mg JNJ-372 i.v. weekly for the first 4-week cycle, then biweekly for each subsequent cycle (Park et al. J Thorac Oncol 2018;13:S344-5).

      Result

      In a dose-dependent manner, JNJ-372 inhibited the growth of BaF3 cells harboring diverse Exon20ins mutations. Mechanistic assays revealed down-modulation of EGFR and cMet receptor levels and decreases in phospho-EGFR and cMet, as well as inhibition of downstream signaling events including p-ERK, p-Akt and p-S6. Cleaved caspase-3 and BIMEL were upregulated at antiproliferative doses, suggesting caspase-mediated cell death as part of the mechanism of action. JNJ-372 demonstrated corresponding antitumor activity in PDC and PDX models harboring different Exon20ins mutations with concomitant inhibition of EGFR signaling and induction of apoptosis. In the ongoing first-in-human trial, two patients with Exon20ins disease (P772_H773insPNP and H773delinsNPY) continue to demonstrate durable clinical benefit (13 and 22 cycles), with maximum tumor reductions of –23% and –63%, respectively, as demonstrated by baseline and postbaseline CT scans.

      Conclusion

      In EGFR Exon20ins disease, JNJ-372 demonstrates preclinical antitumor activity and initial clinical responses. Preclinically, JNJ-372 induces antitumor activity in models of EGFR Exon20ins disease by decreasing EGFR and cMet receptor levels, inhibiting downstream signaling cascades, and activating apoptotic signaling. These results provide an understanding of the activity of JNJ-372 being observed in the ongoing clinical study and support the continued examination of JNJ-372 in NSCLC patients with Exon20ins and other EGFR mutations.