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Jillian Wilhelmina Paulina Bracht



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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-14 - HLA-E and FAT1 in Head and Neck and Lung Cancer. The Effect of Osimertinib or Olmutinib with Artesunate (Dihydroartemisinin) (ID 912)

      09:45 - 18:00  |  Author(s): Jillian Wilhelmina Paulina Bracht

      • Abstract
      • Slides

      Background

      Cisplatin and cetuximab have little effect in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LSCC). HLA-E expression suppressed the cetuximab effect and HLA-E is overexpressed in both HNSCC and LSCC. In addition, FAT1 inactivating mutations are present in 30% of HNSCCs and 19% of LSCCs. Dihydroartemisinin (DHA) inhibits STAT3 and increases cisplatin effect in HNSCC. Osimertinib and olmutinib increase intracellular accumulation of doxorubicin by blocking the efflux function of ABC transporters. We posit that osimertinib or olmutinib, plus DHA, could have activity in the HNSCC cell lines, FaDu and CAL27, with loss of FAT1 expression.

      Method

      Osimertinib and olmutinib plus DHA were tested in the FaDu and CAL27 cell lines. Tumor cell proliferation assays (MTTs) and mouse xenografts were performed, and western blotting analysis was carried out. FaDu CTXR clone #3 (cetuximab-resistant, a gift from Bhola) and SCCNC4 (EGFR exon 20 S768_D770 dup, a gift from Hermsen) were also examined.

      Result

      1. DHA decreased HLA-E protein levels in a dose dependent manner in the FaDu CTXR.

      2. DHA was able to induce the expression of FAT1 in FaDu and CAL27 cells.

      3. Osimertinib plus DHA had a synergistic effect (<1, Combination index (CI)=0.468 and 0.593 in FaDu and CAL27, respectively). Olmutinib with DHA was also synergistic (CI=0.773 and 0.762 in FaDu and CAL27).

      4. Osimertinib plus DHA was validated in vivo in FaDu and CAL27 mice xenografts with significant tumor regression.

      5. Osimertinib plus DHA suppress the expression of onco-effectors: STAT3, Src, YAP and AXL.

      6. Osimertinib plus DHA was also synergistic in SCCNC4 (CI=0.596).

      Conclusion

      The findings indicate that DHA can revert resistance to cetuximab by repressing the expression of HLA-E. The combination of DHA plus osimertinib was active in the parental FaDu, but not in FaDu CTXR. For tumors with lack of FAT1 expression, the use of DHA reactivates FAT1 and YAP1 inhibition was noted. DHA has been tested for the treatment of systemic lupus erythematosus (SLE), orally, daily for 2 years. The results encourage development of clinical trials with DHA to re-sensitize HNSCC and LSCC cells to cetuximab-based therapy.

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      P1.03-31 - BRAF Mutations: Classes I, II and III in NSCLC Patients Included in the SLLIP Trial, Targeted Treatment According to Class (Now Available) (ID 897)

      09:45 - 18:00  |  Presenting Author(s): Jillian Wilhelmina Paulina Bracht

      • Abstract
      • Slides

      Background

      BRAF V600 mutations have been found in 2% of non-small cell lung cancer (NSCLC) patients, with FDA approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class 2, with intermediate to high kinase activity and RAS independence, or class 3, with impaired kinase activity, upstream signaling dependence and consequently sensitivity to receptor tyrosine kinase (RTK) inhibitors. Non-V600 tumors require combinatory therapy with RAF/MEK inhibitors and blockers of RTK signaling, like SHP2 (PTPN11) inhibitors.

      Method

      Plasma DNA of 185 newly diagnosed advanced lung adenocarcinoma patients was examined for BRAF and other mutations with a clinically validated cell-free DNA (cfDNA) assay (Guardant360, Guardant Health Inc. CA, U.S), and results were correlated with patient outcome. In addition, two NSCLC cell lines and one Triple Negative Breast Cancer (TNBC), H1395 (class 2 BRAF mutation), H1666 (class 3 BRAF mutation) and MDA-MB-231 (class 2 BRAF mutation) were treated with single or combined BRAF, MEK and SHP2 inhibitors and cell viability was assessed.

      Result

      BRAF mutations were found in 17/185 (9%) and BRAF amplification in five patients (3%). Three patients had BRAF V600E mutations (2%) and 14 patients non-V600 BRAF mutations (8%), including four class 2 and four class 3 mutations. Patients were treated with chemotherapy and/or immunotherapy, or targeted therapy for other co-alterations. PFS was 1.8, 6.1, 5.0, 5.3 and 5.3 months for Class 1, 2, 3, other BRAF, and BRAF amplification, respectively. These low survival rates indicate that new treatment options are urgently needed. In vitro results confirm sensitivity of class 3, and resistance of class 2 BRAF mutations to single SHP2 inhibition with RMC-4550 and SHP099, with similar results in TNBC and lung cancer cells. Combined dabrafenib and trametinib treatment indicated antagonistic effects, especially in the class 3 BRAF mutant cell line. Concomitant MEK and SHP2 inhibition was synergistic in both class 2 and 3 BRAF mutations.

      Conclusion

      It is evident that different classes of BRAF mutations require distinct treatments, which could even outweigh tumor type. Therefore, we should examine BRAF class in daily clinical practice. Upfront targeting of the MAPK signaling pathway combined with SHP2 inhibitors reveals synergistic interactions, and additional inquisition may pave the way for new treatment options in the most frequently found mutations in BRAF patients.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-45 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant Adenocarcinoma and Squamous Cell Carcinoma (ID 789)

      10:15 - 18:15  |  Author(s): Jillian Wilhelmina Paulina Bracht

      • Abstract

      Background

      p21-activated kinase 1 (PAK1) stimulates growth and metastasis in several types of tumors, including non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCi) is an enzyme highly expressed in NSCLC that regulates PAK1 signaling. To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR/KRAS mutant adenocarcinoma or squamous cell carcinoma (SCC) cell lines by combination therapy using PAK1 inhibitor and PKCι inhibitor.

      Method

      Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carries EGFR and KRAS mutations, respectively, and H520 (PAK1 amplified squamous cell carcinoma). Cell viability assays and western blotting were applied to evaluate the effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor). Since IPA-3 is only for laboratory use, we explored alternative PAK-1 inhibitor and tested combination effect with auranofin.

      Result

      IPA-3 plus auranofin was highly synergistic (Combination index was less than 0.4) in EGFR mutant adenocarcinoma (HCC827), KRAS mutant adenocarcinoma (H23) and SCC with PAK1 amplification (H520) cell lines in MTT assay and colony forming assay. We revealed OTSSP167 (a MELK inhibitor in phase I/II trials) inhibits phosphorylated PAK1 and combination of OTSSP167 plus auranofin showed similar synergism in the 3 cell lines. The combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET, and CDCP1.

      Conclusion

      The combination of IPA-3 plus auranofin is promising treatment in different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification. OTSSP167 also works as PAK1 inhibitor. The therapeutic effect of PAK-1 inhibitor and PKCι inhibitor was validated using OTSSP167 plus auranofin.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-79 - High Rate of Immune Related Pneumonitis in Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 1061)

      10:15 - 18:15  |  Author(s): Jillian Wilhelmina Paulina Bracht

      • Abstract
      • Slides

      Background

      Treatment with anti PD-1/PD-L1 antibodies has demonstrated survival improvement in several malignancies, including non small cell lung cancer (NSCLC), but these therapies are not exempt from risks. Meta-analysis and clinical trials have reported immune related (ir) pneumonitis of any grade in 3-5% of patients treated with anti PD-1/PD-L1 antibodies, including grade 3 or higher in 0.8% to 1.8% of patients.

      Method

      We have retrospectively reviewed clinical reports from 125 cancer patients treated at our center with anti PD-1/PD-L1 antibodies (55 were treated with nivolumab, 27 with pembrolizumab, 33 with atezolizumab, 6 with avelumab, and 4 with durvalumab) from January 2016 to January 2019.

      Result

      Nineteen patients (15.2%) developed ir pneumonitis. Four (21%) patients had recurrent pneumonitis during tapering corticoesteroid dose after an initial improvement and finally died. Patient characteristics are summarized in Table 1. Median time to pneumonitis was 4 months (m) (range 1m to 9m). Twelve patients (9.6% %) had grade 3-5 and 7 patients (5.6 %) grade 1-2 pneumonitis. Nine (7.2 %) patients died from ir pneumonitis, including 4 patients with no tumor progression (1 had received only one cycle, and 3 patients had ongoing tumor response at 10m+, 12m+ and 30m+). Ir pneumonitis was more frequent with nivolumab (any grade 21.8 %, grade 3 or higher 18.2 %, including 7 fatal cases-12.7%-), while no patient treated with atezolizumab developed pneumonitis (Table 2).

      Table 1
      Total 19

      Gender

      Women, n (%)

      7 (36,8%)

      Age

      Median (range)

      63,4 (51-82)

      Cancer type, n (rate)

      NSCLC Adenoca

      NSCLC Squamous

      SCLC

      Mesothelioma

      13 (68,4 %)

      4 (21%)

      1 (5,3%)

      1 (5,3%)

      Line of therapy, n (rate)

      Adjuvant

      First line

      Second or further line

      1 (5,2 %)

      8 (42,1%)

      10 (52,6%)

      Tumor Response, n (rate)

      CR

      PR

      SD

      PD

      NE

      2 (10,5%)

      8 (42,1%)

      5 (26,3%)

      3 (15,8%)

      1 (5,2%)

      table 2
      Drug,n patients treated Any Grade, n (%) Grade 3-5, n (%) Grade 5, n (%)
      Nivolumab, 55 12 (21,8%) 10 (18,2%) 7 (12,7%)
      Pembrolizumab, 27 3 (11,1%) 1 (3,7%) 1 (3,7%)
      Atezolizumab, 33 0 0 0
      Durvalumab, 4 2 (50%) 0 0
      Avelumab, 6 2 (33,3%) 1 (16,7%) 1 (16,7%)
      Total, 125 19 (15,2%) 12 (9,6%) 9 (7,2%)

      Conclusion

      In our experience, ir pneumonitis rate with anti PD-1/PD-L1 antibodies in lung cancer patients was 15.2%, including 7.2% of fatal complications. It suggests that previous clinical trials could have under diagnosed this serious complication. Further studies must be performed in order to specifically assess the rate of pneumonitis in patients treated with anti PD-1 and anti PD-L1 antibodies in lung cancer patients.

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