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Geoffrey R Oxnard



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.02 - In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC (Now Available) (ID 968)

      15:15 - 16:45  |  Author(s): Geoffrey R Oxnard

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR Exon 20 insertions (Ex20Ins) are the 3rd most common class of EGFR activating mutation, but patients with NSCLC harboring EGFR Ex20Ins lack effective approved EGFR-TKIs. Newer-generation TKIs and combination strategies with EGFR-monoclonal antibodies (moAbs) may enhance activity against EGFR Ex20Ins.

      Method

      Xenografts derived from CRISPR-modified H2073 cells with Ex20Ins (A763_Y764InsFQEA, D770_N771InsSVD or V769_D770InsASV) and Ex20Ins patient-derived xenografts (PDXs) (D770_N771InsSVD, A797_V769dupASV, D770_N771_InsG, H773_V774_InsNPH) were treated with vehicle, osimertinib , cetuximab, and osimertinib+cetuximab. Ex20Ins spheroid models (D770_N771InsSVD and M766_A767InsASV) were treated with cetuximab at fixed dose and increasing concentrations of osimertinib. Ex20Ins PDX (A763_Y764InsFQEA) was also treated with afatinib and erlotinib; Ex20Ins PDX (D770_N771InsSVD) was treated with these combinations plus afatinib+cetuximab. Immunoblotting for pharmacodynamic studies of on-target and downstream proteins, phospho-proteins and apoptosis markers were performed at relevant timepoints for D770_N771InsSVD PDX and CRISPR model. A phase 1 clinical trial with a dose expansion cohort in Stage IV EGFR Ex20Ins NSCLC is currently open to accrual at osimertinib 80 mg qd and the EGFR-moAb necitumumab 800 mg IV D1 and D8 of 21D cycle with response assessment by RECIST 1.1 (NCT02496663).

      Result

      The combination of osimertinib and cetuximab achieved significant tumor growth inhibition compared to osimertinib alone across PDX and CRISPR cell line xenograft models (p=0.05), except for the A763_Y764InsFQEA PDX model where osimertinib alone and osimertinib+cetuximab were equivalently effective (both p<0.001 compared to control). Spheroid models for D770_N771InsSVD and M766_A767InsASV showed significantly increased cytotoxicity from the addition of cetuximab across multiple doses of osimertinib. Osimertinib+cetuximab was superior to erlotinib, cetuximab, afatinib and afatinib+cetuximab in a D770_N771InsSVD PDX model (p<0.001). In this model, inhibition of p-EGFR, p-ERK, p-HER2 and increased caspase 3 cleavage were noted, consistent with significant tumor growth inhibition. In the phase 1 EGFR Ex20Ins expansion cohort of necitumumab in combination with osimertinib, 6/18 patients enrolled with 4 patients evaluable for response; 2 patients achieved a partial response and median PFS was 5.3 months.

      Conclusion

      In vivo and ex vivo modeling in CRISPR cell line xenografts, PDXs and organoids demonstrated preclinical activity of dual EGFR blockade with osimertinib and EGFR monoclonal antibody in the 5 most common EGFR Ex20Ins representing a frequency of ~60% of detectable EGFR Ex20Ins in clinical practice. Osimertinib alone was as active as osimertinib plus cetuximab in A763_Y764InsFQEA, consistent with known sensitivity of this proximal insertion to single-agent EGFR-TKI. In a phase 1 study, osimertinib and the EGFR moAb necitumumab demonstrates preliminary clinically activity in EGFR Ex20Ins NSCLC.

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    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
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      P1.01-134 - SAVANNAH: Phase II Trial of Osimertinib + Savolitinib in EGFR-Mutant, MET-Driven Advanced NSCLC, Following Prior Osimertinib (ID 2209)

      09:45 - 18:00  |  Author(s): Geoffrey R Oxnard

      • Abstract
      • Slides

      Background

      The toxicity profile of the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET-amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of patients) and AURA3 (19% of patients) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations.

      Method

      Eligible patients will have histologically or cytologically confirmed EGFR-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC), and MET-driven (MET+) disease by central fluorescence in situ hybridization (FISH), central immunohistochemistry (IHC), or local next-generation sequencing (NGS; retrospectively confirmed by central FISH/IHC). Patients must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Patients will receive osimertinib plus savolitinib in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in patients who are MET+ by central FISH. Secondary endpoints include: ORR (MET+ by central IHC and all patients); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance (MET+ by central FISH, central IHC, and all patients); safety, and pharmacokinetics (all patients). Based on the TATTON study, we anticipate enrolling ~172 patients with MET+ disease, to include ≥117 patients with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P1.01-46 - Response Assessment Using Plasma Cell-Free DNA (cfDNA) – When Is the Optimal Time to Assess Response? (ID 958)

      09:45 - 18:00  |  Author(s): Geoffrey R Oxnard

      • Abstract

      Background

      Plasma cfDNA analysis is routine for non-invasive genotyping of advanced NSCLC, however response assessment using plasma cfDNA is not well characterized. We hypothesized that response in cfDNA would be an early process occurring well before routine imaging timepoints.

      Method

      We retrospectively analyzed a total of 48 baseline and serial on-treatment plasma samples collected from 16 patients enrolled across three Experimental Therapeutics Clinical Trials Network (ETCTN) phase I trials of osimertinib combinations in advanced EGFR-mutant NSCLC. For validation, we also retrospectively analyzed a total of 201 baseline and serial on-treatment samples from an institutional cohort of 67 advanced NSCLC patients receiving systemic treatment. Using droplet digital PCR (ddPCR) of key EGFR or KRAS driver mutations, plasma response was defined as any decrease in mutation concentration to below baseline levels. We compared the magnitude of initial (baseline to day 11-30) and subsequent (day 11-30 to day 36-84) plasma response. Finally, we prospectively assessed response using serial amplicon-based plasma next-generation sequencing (NGS) in a pilot cohort of 8 NSCLC patients starting systemic therapy.

      Result

      Of 15 ETCTN patients with any plasma response, best plasma response was seen at the initial response timepoint in 12 patients (80.0%) and ≥90% of the total plasma response was seen at the initial response timepoint in 14 patients (93.3%). In the validation cohort of 61 patients with any plasma response (Figure), best plasma response was seen at the initial response timepoint in 39 patients (63.9%) and ≥90% of the total plasma response was seen at the initial response timepoint in 52 patients (85.2%). Complete plasma responses (-100%) were seen as early as 11 days after initiating therapy. In the prospective clinical cohort, plasma NGS detected genomic alterations and enabled monitoring of changes in mutant allele fraction in all 8 patients. The median turnaround time of the assay was 8 days.

      figure.jpg

      Conclusion

      Plasma response is an early phenomenon, with the vast majority of plasma response seen within 30 days, and as early as 11 days. These findings suggest that early plasma cfDNA analysis may permit response assessment well before standard imaging timepoints, with potential as an early marker of drug effect. Additional investigation to understand the relationship between early plasma response, radiographic response, and durability of treatment effect is still needed.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-04 - Final Results of the Prospective Genomics of Young Lung Cancer (GYLC), an Addario Lung Cancer Medical Institute Study (ID 427)

      09:45 - 18:00  |  Author(s): Geoffrey R Oxnard

      • Abstract

      Background

      We hypothesized that young age at lung cancer diagnosis is a clinical characteristic associated with a higher likelihood for having a driver mutation. Our goals were to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for studies of heritable and environmental lung cancer risk factors.

      Method

      Eligible subjects had a diagnosis of bronchogenic lung cancer < 40 years old. We included a website to allow for virtual consenting and remote participation from anywhere in the world. An integrated data and biorepository allowed for completion of study activities and routing of specimens. We defined seven genes of interest based on the Lung Cancer Mutational Consortium (LCMC): EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET. We hypothesized that the prevalence of targetable alterations in these genes would be greater in our population compared to the LCMC and powered our study to detect an increase from 35% to 50%. Subjects with advanced adenocarcinoma who were not tested for all seven genes or who were wild type for all seven underwent additional genomic profiling using Foundation Medicine testing.

      Result

      We accrued 133 participants from July 2014 to June 2017. Notably, 44% entered the trial via the website. The mean age at diagnosis was 34 (range 16 to 39) and 57% were female; 77% were stage 4 at diagnosis and the majority had adenocarcinoma (86%). Of the 115 patients with adenocarcinoma, 83.5% were stage 4 and the focus of the comparison to the LCMC cohort. A targetable mutation was identified in 85.4%, with 76% harboring a combined ALK (38.5%), EGFR (31.3%), or ROS1 (6.3%) mutation. Of 14 patients who underwent on-protocol testing, a targetable driver was identified in eight (57%), including two with a RET rearrangement, two with ERBB2 mutations, two with MET amplification, one with an ALK rearrangement with a prior negative FISH and one with a novel EGFR-RAD fusion previously tested negative for EGFR.

      Conclusion

      We have described a genomically distinct subset of NSCLC in patients < age 40. Those with stage 4 adenocarcinoma must undergo comprehensive genomic testing to identify a targetable driver. The extremely high rate of driver mutations particularly in ALK supports the need for an Epidemiology of YLC study. Additionally, use of remote consenting and the Addario Lung Cancer Foundation's advocacy enabled rapid accrual of this rare cohort (<1%) and has laid the foundation for innovative research partnerships with other rare oncogene-driven patient groups.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Geoffrey R Oxnard

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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