Author of

• 25921

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  P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 2
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26278

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    P1.01-46 - Circulating Tumor DNA Analysis for Predicting Response to Osimertinib and Disease Progression in EGFR-Mutant Non-Small-Cell Lung Cancer (ID 14242)

    16:45 - 18:00  |  Author(s): Chul Kim
    • Abstract

    Background
    

    Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive modality to detect biomarkers associated with a broad array of malignancies, including lung cancer. We aimed to assess whether ctDNA could be used to predict response to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and disease progression.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Plasma samples were serially collected at every clinic visit from patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) enrolled in a clinical trial of osimertinib treatment, local ablative therapy (LAT) upon progression, followed by osimertinib re-challenge (NCT02759835). Patients with no prior EGFR-TKI treatment or patients with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, patients with ≤5 progressing sites undergo LAT and resume osimertinib. ctDNA was detected using droplet-digital PCR EGFR mutation detection assays. The changes in ctDNA mutant allele levels were correlated with response to treatment and tumor progression. To identify additional genetic changes that may be related to osimertinib resistance, an enhanced Tagged-Amplicon Sequencing NGS assay (InVisionSeq^TM) was utilized which covers SNVs, InDels and amplifications in 36 genes commonly mutated and therapeutically actionable in NSCLC.

    4c3880bb027f159e801041b1021e88e8 Result
    

    353 samples from 17 patients were analyzed. At baseline, EGFR mutations were detected in 15 (88%) patients. One patient with overall low metastatic tumor burden and another patient with most tumor burden in the brain did not have detectable ctDNA at baseline. For patients treated with osimertinib before first progression, 12 (86%) achieved a partial response (PR) and 2 (14%) had stable disease (SD) as their best response. ctDNA decreased after initiation of osimertinib in these patients with 7 (50%) patients having no detectable ctDNA within 28 days. In those with ongoing PR (n=5) and prolonged stable disease (n=1), ctDNA remains undetectable (n=5) or low (n=1). Among 7 patients who had first progression, 5 (71%) patients had an increase in corresponding mutant EGFR allele in ctDNA 2-4 months before radiographic progression. While exploration of osimertinib resistance mechanisms by InVisionSeq^TM is ongoing, early results demonstrate that allele frequencies of mutations in genes, including EGFR, PIK3CA, and TP53 closely reflected response and resistance to osimertinib. MET and EGFR amplification, as well as emergence of EGFR C797S mutant were identified as key resistance mechanisms by ctDNA analysis. Full details on all patients will be presented at the meeting.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Quantitative assessment of plasma ctDNA is a relatively non-invasive tool to monitor the therapeutic response to treatment with EGFR-TKI and for early detection of resistance mechanisms for clinical decision making.

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  • 26279

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    P1.01-47 - Phase I/II Trial of Dasatinib and Osimertinib in Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14220)

    16:45 - 18:00  |  Presenting Author(s): Chul Kim
    • Abstract

    Background
    

    The presence of epidermal growth factor receptor (EGFR) mutations is associated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but a subset of patients (pts) do not respond to EGFR-TKIs or have very short duration of response, suggesting intrinsic resistance. Moreover, acquired resistance to EGFR-TKIs is inevitable for most patients. We showed that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of intrinsic resistance to EGFR-TKIs through the activation of the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically in preclinical models.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    This was an open-label, phase I/II trial of osimertinib and dasatinib, a multi-kinase inhibitor with activity against Src, in EGFR-TKI treatment-naïve pts with advanced EGFR-mutant NSCLC (NCT02954523). Pts with pleural or pericardial effusions at study entry were excluded. The primary endpoint of the phase I part was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation included 2 dose levels (dose level 1: osimertinib 80 mg QD, dasatinib 50 mg BID, dose level 2: osimertinib 80 mg QD, dasatinib 70 mg BID). In addition, 2 dose levels below the starting dose level could be explored if dose reductions were necessary.

    4c3880bb027f159e801041b1021e88e8 Result
    

    7 pts (4 at dose level 1, 3 at dose level 2) were enrolled to date. None of them had dose limiting toxicities (DLTs), but given frequent dose reductions and toxicities beyond the DLT period at dose level 2, dose level 1 is being further assessed (up to 6 pts at dose level 1). The most common treatment-related adverse events (TRAEs) included pleural effusion (n=6), AST elevation (n=5), ALT elevation (n=5), rash (n=5), and diarrhea (n=4), most of which were grade 1 or 2. 3/2/1 pts had grade 1/2/3 pleural effusion, respectively. 4 pts had grade 3 TRAEs, which included pleural effusion, fatigue, neutropenia, anemia, and headaches. No grade 4 or 5 toxicities were observed. Among 6 evaluable pts, 4 confirmed partial response (PR)/1 unconfirmed PR/1 stable disease were observed. Responses were durable with all the PRs ongoing.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    The combination of dasatinib and osimertinib showed no new safety signals and demonstrated evidence of anticancer activity. Treatment-related toxicities were manageable with dasatinib dose reductions and supportive measures. The safety and efficacy of dasatinib and osimertinib will continue to be explored.

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• 25949

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  P2.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 961)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 27154

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    P2.12-03 - Phase I/II Trial Of 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) And Nivolumab for Patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC) (ID 12015)

    16:45 - 18:00  |  Presenting Author(s): Chul Kim
    • Abstract

    Background
    

    Despite initial sensitivity to chemotherapy, most patients with ES-SCLC relapse quickly. Studies have shown that somatostatin receptors are expressed in SCLC. Lutathera is a ¹⁷⁷Lutetium-labeled somatostatin analog that targets somatostatin receptor positive cancer cells, which is approved for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Lutathera and nivolumab, an anti-PD-1 antibody, may have synergistic effects on the generation of anticancer immunity and this combination given as maintenance treatment may delay progression in patients with ES-SCLC.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    This is a multicenter phase I/II trial of Lutathera and nivolumab in patients with ES-SCLC (NCT03325816). The phase I portion includes patients with either relapsed/refractory ES-SCLC or non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary neuroendocrine tumors. The primary objective is to determine the recommended phase 2 dose (RP2D) of Lutathera when given with nivolumab. The phase I portion follows the standard 3+3 design, assessing two dose levels (dose level 1: Lutathera 3.7 GBq Q8W for 4 doses with nivolumab 240 mg Q2W; dose level 2: Lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W). In the phase II portion, patients with ES-SCLC not progressing after completion of first-line platinum-based chemotherapy are randomly assigned to either maintenance combination with Lutathera and nivolumab or observation. The primary endpoint for the phase II part is progression-free survival. Crossover is allowed at progression for those assigned to the observation group.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Three patients were enrolled at dose level 1. All patients had ES-SCLC at study entry with 2 patients with progressive disease and 1 patient with stable disease after platinum-based chemotherapy. No dose-limiting toxicities (DLTs) were observed at dose level 1. Treatment-related adverse events include anemia (n=1), arthralgia (n=1), and non-cardiac chest pain (n=1), all of which were grade 1 events per CTCAE 4.03. At first tumor assessment performed 8 weeks after starting treatment, one patient achieved a partial response and two patients had progressive disease per RECIST. Assessment of dose level 2 is underway. Updated safety and efficacy results will be presented.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Early evidence from the phase I/II trial of Lutathera and nivolumab suggests that the combination is safe, well tolerated and showed initial signs of antitumor activity. The safety and efficacy of the combination will be further explored.

    6f8b794f3246b0c1e1780bb4d4d5dc53