Virtual Library

Start Your Search

Sai-Hong Ignatius Ou



Author of

  • +

    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
    • +

      EP1.01-108 - EGFR Exon 18 Mutations in NSCLC: Frequent Co-Occurrence of Multiple EGFR Mutations and Assessment of Cis/Trans Status (ID 2747)

      08:00 - 18:00  |  Author(s): Sai-Hong Ignatius Ou

      • Abstract

      Background

      A subset of EGFR exon 18 (ex18) mutations including G719X are known drivers in NSCLC. However, the sensitivity profile of other ex18 mutations and frequently occurring dual ex18/ex18 and ex18/non-ex18 combinations has not been well described.

      Method

      Hybrid-capture based comprehensive genomic profiling was performed on 46,296 FFPE tissue samples from patients with NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Configuration was determined by analyzing sequencing reads that spanned both loci. The number of reads that harbored mutations at one or both positions was tabulated and used to infer cis or trans status. Patient ancestry was determined by single nucleotide polymorphism (SNP) microarray data, ancestry informative markers, and principal component analysis (PCA)..

      Result

      EGFR ex18 mutations (point mutations and indels) were identified in 1.1% (522/46,296) of NSCLCs. The median patient age was 67 years (range 30-96) and 67% of patients were female. This subset was also enriched for patients of East Asian descent when compared to EGFR wildtype NSCLC (17% v 3.9%; p < 0.001), similar to ex19del and L858R populations (19% and 24%, respectively). Median TMB was 4.35 mut/mb (range 0-70). Co-occurring EGFR mutations were identified in 69% (362/522) of cases, including most commonly S768I (20%, 103/522) and L858R (12%,61/522). T790M was detected in 6.1% (32/522) of ex18 cases. Multiple EGFR ex18 mutations occurred in 15% (76/522) of cases including 2 cases with 3 and a single case with 4 such mutations. The most commonly observed missense pairs were E709A/G719S (17/76) and E709A/G719A (16/76). Other combinations of E709X/G719X made up an additional 42% (32/76), with the remaining 14% of cases consisting of rare combinations (n<4 for all). All ex18 mutations in all cases (76/76) were in cis. Preliminary evidence from paired cases and assessment of mutant allele frequencies suggests that ex18 mutations found together in cis arise de novo. Results of in vitro studies to determine the sensitivity of single ex18 mutations as well as common pairs to all generations of EGFR inhibitors will be presented.

      Conclusion
      EGFR ex18 mutations co-occur at a high frequency with both ex18 and non-ex18 EGFR mutations, unlike classic EGFR mutations (L858R, ex19del). Female gender, East Asian ancestry, and low TMB were common in ex18 cases, similar to populations with classic EGFR mutations. In all cases with multiple EGFR ex18 mutations these mutations were always found to occur in cis. Further work to understand the evolution of these co-occurring EGFR mutations and to determine the best therapeutic strategy or strategies for this NSCLC patient population is warranted

  • +

    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.01-84 - Interaction of Lorlatinib with CYP2B6, CYP2C9, UGT, and P-gp Probe Drugs in Patients with Advanced Non-Small Cell Lung Cancer (ID 293)

      09:45 - 18:00  |  Author(s): Sai-Hong Ignatius Ou

      • Abstract
      • Slides

      Background

      Lorlatinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). Because lorlatinib is an inducer and inhibitor of various cytochrome P450 (CYP) enzymes and transporters, an evaluation of its effect on these substrates at steady state is warranted. A drug-drug interaction (DDI) sub-study was conducted in patients with advanced NSCLC to evaluate the net effect of these interactions.

      Method

      Probe drugs utilized included bupropion for CYP2B6, tolbutamide for CYP2C9, acetaminophen for uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT), and fexofenadine for P-glycoprotein-1 (P-gp). Thirty-two patients (to have at least 6 evaluable patients per probe drug) were administered a single dose of a probe drug alone on Day −2 to determine plasma exposure of the probe drug alone. Starting on Cycle 1 Day 1, patients began lorlatinib tablets 100 mg daily. On Cycle 1 Day 15, another single dose of the same probe drug was administered concurrently with lorlatinib.

      Result

      Co-administration of lorlatinib 100 mg with bupropion, a sensitive CYP2B6 probe drug, decreased bupropion geometric mean plasma AUCinf and Cmax by 25% and 27%, respectively. For tolbutamide, a sensitive CYP2C9 probe drug, lorlatinib decreased tolbutamide AUCinf and Cmax by 43% and 15%, respectively. Likewise, for acetaminophen, a sensitive UGT substrate, lorlatinib decreased acetaminophen AUCinf and Cmax by 45% and 28%, respectively. Finally, for fexofenadine, a sensitive P-gp substrate, lorlatinib decreased fexofenadine AUCinf and Cmax by 67% and 63%, respectively.

      Conclusion

      Critical steady-state–based DDI evaluations can be conducted in patients with cancer in carefully designed studies. Per FDA guidance, strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. Based on these criteria, lorlatinib behaved as a net weak inducer of CYP2B6, CYP2C9, and UGT; and a net moderate inducer of P-gp. The results of this sub-study can help guide recommendations for dose modifications when lorlatinib is given concomitantly with drugs that are metabolized by these enzymes or transporters. Based on the current results, only drugs that are P-gp substrates of narrow therapeutic index may require dose adjustments when used concomitantly with lorlatinib.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      P1.01-86 - Occurrence of de Novo Dual HER2/HER3 or HER2/EGFR TMD Mutations: Extending the Spectrum of Targetable Mono-HER2 TMD in NSCLC? (ID 956)

      09:45 - 18:00  |  Presenting Author(s): Sai-Hong Ignatius Ou

      • Abstract

      Background

      HER2 (ERBB2) TMD mutations have recently been described as novel solo actionable drivers in NSCLC responsive to afatinib in small series. However, dual occurrence of de novo EGFR or HER3 (ERBB3) TMD mutations together with HER2 TMD mutations, which may have implications for dimerization patterns and treatment, has not been described.

      Method

      Hybrid-capture based comprehensive genomic profiling was performed on blood-based circulating tumor DNA (n=5,200) or FFPE tissue (n= 45,780) samples collected during clinical care from 50,980 unique NSCLC patients.

      Result

      HER2 TMD mutations were identified in 0.12% (60/50,980) of cases and included V659E (n=33), V659D (n=8), G660D (n=15), V659E+G660R, V659_I661>VVEGI, G660E>R, and S653C (1 each). Within this subset, the median age of patients was 61 years (range 33-91) and 62% were female. No co-occurring known NSCLC driver alterations were detected, except one case with EGFR exon 19 deletion and one case with EGFR L858R and lung co-primary tumors noted. However, co-occurring HER3 (I649R) or EGFR (G652R) TMD mutations were found in 18% (11/60) and 5.0% (3/60) of cases, respectively. Notably, these ERBB3 or EGFR TMD mutations only co-occurred with HER2 TMD V>D (8/9 cases) or G>D (7/15 cases), but not with V>E changes (0/34 cases; p=0.0002). HER2 amplification co-occurred with V659E in 15% (5/34) of cases, and G660D mutation was seen with the oncogenic extracellular domain S310F mutation in one case. Importantly, neither EGFR G652R nor ERBB3 I649R was found in the absence of a HER2 TMD mutation. Preliminary modelling studies suggest formation of a salt-bridge which would increase propensity for HER2/HER3 and HER2/EGFR heterodimerization favoring receptor activation. Two patients in this series with V659E were previously reported to have responded to afatinib and 1 patient with G660D+I649R did not respond to afatinib. Updated clinical data for these patients and others treated with HER2-tageted therapies will be presented.

      Conclusion

      HER2 TMD mutations (V659D/E or G660D/R) are uncommon but targetable driver alterations in NSCLC. In cases with HER2 TMD V>D or G>D, a de novo co-existing EGFR or HER3 TMD mutation was frequently observed (88% and 47%, respectively), which may explain differential dimerization preference and in turn response to ERBB inhibitors. We hypothesize that dual HER2/HER3 or HER2/EGFR TMD mutants may be more aggressive than single HER2 TMD mutants due to the arginine-aspartic acid interaction, and these dual mutants may require combined kinase inhibitor + antibody therapy to block dimerization. Studies utilizing models to further characterization these co-alterations are in progress.

  • +

    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.14-24 - An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 851)

      10:15 - 18:15  |  Author(s): Sai-Hong Ignatius Ou

      • Abstract

      Background

      Osimertinib, a third-generation EGFR inhibitor, has become the first-line therapy for patients with metastatic EGFR-mutant NSCLCs since 2018. Osimertinib is well-tolerated, therefore, it opens opportunities to be combined with other therapeutic agents to enhance the treatment outcome. In preclinical models, it has been shown that upregulated VEGF signaling mediates acquired resistance to EGFR therapies. In xenograft models, combination of anti-VEGF medications with EGFR inhibitors were significantly more effective than erlotinib or gefitinib alone. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, is approved with docetaxel in as second line treatment for NSCLCs. In clinical trial evaluations, the phase 3 RELAY trial (NCT02411448) studying ramucirumab plus erlotinib in patients with metastatic untreated EGFR-mutant NSCLC patients showed a statistically significant improvement in progression-free survival in the combination group compared to erlotinib alone. A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With strong preclinical and clinical evidence showing dual inhibition of VEGF/EGFR signaling prolongs progression-free survival for EGFR-mutant lung cancers, and demonstrated safety, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.

      Method

      The OSI+RAM trial is a randomized phase 2 study with the primary endpoint being progression-free survival in osi+ram group as compared to osimertinib monotherapy group. The major inclusion criteria include patients with metastatic NSCLC harboring EGFR mutations (L858R/Exon 19 del). The major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. Based on the results from erlotinib bevacizumab (NEJ026) study, we expect an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65. The trial plans to enroll total of 150 patients, with 100 allocating to osi+ram arm and 50 to osimertinib monotherapy. Total of 9 study sites in the USA are planned. Hoosier Cancer Research Network will facilitate the execution of the trial. The trial protocol has received IND exemption from US FDA and has been approved by IRB at MD Anderson Cancer Center. The first subject is expected to be enrolled in May 2019. A planned interim analysis will be performed after the first 75 subjects are enrolled. NCT03909334.

      Result

      Section not applicable

      Conclusion

      Section not applicable