+ -H+ exchange activity.3. Disrupting rafts by removal of cholesterol with methyl-b-cyclodextrin (MbCD) or destabilizing the actin cytoskeleton with cytochalasin D decreased the amount of NHE3 in early endosomes isolated by OptiPrep gradient fractionation. Specifically, NHE3 was shown to associate with endosomal vesicles immunoisolated by anti-EEA1 (early endosomal autoantigen 1) antibodycoated magnetic beads and the endosome-associated NHE3 was decreased by cytochalasin D and MbCD treatment.4. We conclude that: (i) a pool of ileal BB NHE3 exists in lipid rafts; (ii) EGF and clonidine increase the amount of BB NHE3; (iii) lipid rafts and to a lesser extent, the cytoskeleton, but not the detergent-soluble NHE3 pool, are involved in the EGF-and clonidine-induced acute increase in amount of BB NHE3; (iv) lipid rafts and the actin cytoskeleton play important roles in the basal endocytosis of BB NHE3.
9093 Background: Treatment addressing non-small cell lung cancer (NSCLC) harboring EGFR or HER2 exon 20 insertion mutations remains an unmet need. These tumors are associated with a high incidence of CNS metastases and unfavorable survival rates. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) with a structure that can overcome the steric hindrance of the exon 20 limited binding pocket. Preclinical data suggest poziotinib CNS penetration, and here we show meaningful poziotinib CNS activity in patients with NSCLC harboring exon 20 insertion mutations in an ongoing multi-cohort, multi-center Phase 2 study (ZENITH20; NCT03318939). Methods: ZENITH20 enrolled previously treated and naïve patients with advanced/metastatic NSCLC and EGFR or HER2 exon 20 insertion mutations in several cohorts: Cohort 1 (C1) EGFR previously treated; Cohort 2 (C2) HER2 previously treated and Cohort 3 (C3) EGFR treatment-naïve. All patients with stable CNS metastases at baseline were included. Poziotinib (16 mg) was administered orally QD, with follow-up for up to 24 months. The primary endpoint was Objective Response Rate (ORR) evaluated centrally using RECIST v1.1 by an independent image review committee. Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS) and safety. Primary efficacy results have been previously released. Intracranial response was determined based on the modified RECIST criteria. Results: A total of 284 patients across 3 cohorts (C1 n=115; and C2 n=90; and C3 n=79) with a median age of 60.5 years were enrolled. The median follow-up was 7.3, 8.3, and 9.2 months for all patients in C1, C2, and C3, respectively. In NSCLC patients that had baseline CNS lesions (N=36), the analysis showed a patient-based ORR of 22.2% (8/36) and a DCR of 88.9% (32/36). One patient in each cohort had a complete intracranial response and stable disease was 80.6% across 3 cohorts and 92.9% in C2. Two patients each in C1 and C3 had progressive disease (PD) and none had CNS progression in C2 (Table). Conclusions: Poziotinib exhibited clinically meaningful CNS activity in patients with EGFR or HER2 exon 20 mutations in ZENITH20 Cohorts 1-3. The majority of the patients had no CNS progression and 3/36 patients had intracranial complete responses. The preliminary data suggest that poziotinib may provide a meaningful treatment alternative for patients with NSCLC that harbor EGFR or HER2 exon 20 mutations and who present with CNS metastases that have poor prognosis. Clinical trial information: NCT03318939. [Table: see text]
Introduction: Detection of ctDNA in plasma samples permits temporal assessment of tumor mutation status during treatment. Poziotinib is an oral pan-HER TKI that has been demonstrated to be efficacious in NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in tumor genotype in both treatment naive and second line patients to evaluate correlation with clinical response. Methods: For NSCLC patients, HER2 exon 20 insertion mutations identified by tumor tissue based NGS were required for entry into the ZENITH20 study. Plasma samples were collected prior to treatment and at C3D1 (8 weeks post treatment 16mg poziotinib QD). The Guardant360® 74-gene liquid biopsy assay, which assessed changes in ctDNA and, subsequently, mean variant allele fraction (mVAF), was utilized for analysis of samples. The Guardant360 Response™ Molecular Response (MR) algorithm was calculated as a ratio of mVAF of oncogenic alterations at baseline compared to poziotinib treatment at C3D1. Results: 23 patients with tumor tissue confirmed NSCLC harboring HER2 exon 20 insertion mutations were studied. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations, resulting in a concordance of 95% versus tissue based NGS. The most prevalent HER2 exon 20 insertion alteration was the A775_G776ins YVMA variant, found in 50% of the baseline blood and tumor samples using both methods (100% concordance). 16 of 17 patients had both baseline and C3D1 samples, permitting assessment of temporal response. 15 of the 16 (94%) patients demonstrated a decrease in mVAF at C3D1 compared to the mVAF at baseline. 12 of 15 patients demonstrated an >50% reduction in mVAF at C3D1, with 7 of the 12 patients showing >95% reduction in mVAF at C3D1 with clinical outcomes of 5 PRs, 1 non-CR/non-PD and 1 SD. Interestingly, 3 of these patients showed complete clearance of ctDNA target HER2 exon 20 insertions at the C3D1 timepoint. Conclusions: Baseline plasma ctDNA genotyping correlated with tumor tissue based NGS in an NSCLC patient population with HER2 mutations. Poziotinib treatment resulted in mVAF reduction, which correlated with clinical response per RECIST1.1. Assessment of longitudinal changes in ctDNA during drug therapy may potentially be used to predict patient response and possibly tumor resistance. Further evaluation in larger cohorts and longer duration of treatment is required to help elucidate the impact of these findings. Citation Format: Arunthi Thiagalingam, Sribalaji Lakshmikanthan, Allysia J. Mak, Scott A. Shell, Sharon Leu, Rocky Washington, Lyndah Dreiling, Gajanan Bhat, Francois Lebel, John A. Barrett. Predictive ability of circulating tumor DNA by Guardant360 in poziotinib-treated patients with NSCLC harboring HER2 exon 20 insertion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3400.
3051 Background: ctDNA levels in plasma samples permits temporal assessment of tumor mutational status and tumor burden during therapy. Poziotinib is an oral HER2 TKI in development for NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in HER2 exon 20 insertion mutations and other driver mutations in first- and second-line patients comparing to clinical response per RECIST1.1. Methods: NSCLC patients harboring HER2 exon 20 insertion mutations were enrolled into the poziotinib ZENITH20 using tumor tissue based NGS. Serial plasma samples were collected at baseline, at C3D1, at Day 1 of every other cycle until disease progression. The Guardant360â 74-gene liquid biopsy assay was used to assess changes in tumor-associated somatic variants including the target variant HER2 exon20 insertion as well as other emergent driver mutations in ctDNA as expressed as percent variant allele frequency (%VAF). Results: 23 first- and second-line NSCLC patients were evaluable with tumor tissue confirmation of HER2 exon 20 insertion mutations. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations (mean % VAF 20±5) resulting in a concordance of 95% versus tissue based NGS. 7 patients had serial testing through C7D1 permitting assessment of ctDNA dynamics and comparison to clinical responses. 5 of 7 (71%) serially tested patients treated with poziotinib at 16mg QD had undetectable HER2 exon 20 insertion at C3D1 which was associated with a tumor response PR. Tumor escape (PD) was observed in 2 of the 5 patients which correlated with increases in target HER2 exon 20 insertion VAF in the plasma with the remaining 3 patients ≥PR. Notably, the rise in HER2 exon 20 in ctDNA occurred prior to tumor escape. In one patient treated with poziotinib at 16 mg QD we observed undetectable levels of the HER2 exon 20 insertion in ctDNA at C3D1 which continued through C16. This patient’s responses correlated with patient tumor response of SD at C2 which then became PR through C9 and CR through C17. Conclusions: Poziotinib treatment resulted in reductions in HER2 exon 20 insertion mutations in ctDNA preceded and correlated with the clinical tumor response. Increases in ctDNA HER2 exon 20 insertion mutations were observed prior to confirmation of tumor escape. Serial monitoring of ctDNA is a potential predictive biomarker for treatment response and disease progression. Future evaluation in a larger population is required to confirm the impact of these findings.
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