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Mehmet Altan



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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14277)

      11:25 - 11:35  |  Author(s): Mehmet Altan

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety

      4c3880bb027f159e801041b1021e88e8 Result

      As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-37 - Clinical Evaluation of Plasma-Based (cfDNA) Genomic Profiling in Over 1,000 Patients with Advanced Non-Small Cell Lung Cancer (ID 14332)

      16:45 - 18:00  |  Author(s): Mehmet Altan

      • Abstract

      Background

      Tumor genomic information from a simple blood collection revealing actionable mutation can improve clinical outcome without the need for an invasive tissue biopsy. We report on the clinical utility of a cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our patients with non-small cell lung cancers (NSCLC) and the outcome of treatments with targeted therapies based on the reported mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From May 2015 to February 2017, 1078 blood samples from 1011 consecutive patients with a diagnosis of NSCLC were collected and analyzed using next-generation sequencing of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) with reported sensitivity of 0.02% mutant allele fraction with high specificity (> 99.9999%) (CCR 2018 (17):3831). Patients in this retrospective study received targeted therapy as indicated by cfDNA molecular profiling. Tumor response was evaluated by RECIST V1.1 and standard clinical evaluation.

      4c3880bb027f159e801041b1021e88e8 Result

      From 1011 patients, 1078 cfDNA tests sent (additional follow-up tests: 1 in 64 patients and 2 in 3 patients). In 223/1011 (22%) patients had cfDNA report with at least 1 targetable mutations; with 48/223 (22%) patients meeting criteria for this retrospective review. Study population were 31 female:17 male, median age of 63 years (ranged:31-94). The rationale for the blood test included: insufficient tissue or not available (32%), addition to tissue molecular analysis (17%), alternative to tissue biopsy(10%), on-going treatment evaluation/resistance (41%). Mutations included:EGFR T790M (15), EGFR exon 19del (12), EGFR L858R (9), EGFR exon 20 insertion (4), EGFR others (1), ALK gene fusions (5) and MET exon 14 skipping (2). The median line of therapy was 2(ranged:1-7) with 28 patients receiving TKI as 1st line of therapy based on cfDNA mutations. With targeted treatments based on ctDNA results, the responses (RECIST V1.1) were: CR(3), PR(26), SD(14) and PD(4); median PFS was 8.5 months (ranged:1-26mos) for the overall population with 4 patients still receiving targeted therapy. Median PFS was 9.5 months (ranged:1-20 months) for those receiving TKI as 1st line.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the largest analysis of response rates with cfDNA directed therapy in advanced NSCLC and demonstrates positive clinical outcomes in patients treated with targeted therapy based on plasma identified biomarkers.

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-20 - Immunologic Characterization of Fibrinous Pericarditis as an Immune Checkpoint Blockade Toxicity in NSCLC (ID 14058)

      16:45 - 18:00  |  Presenting Author(s): Mehmet Altan

      • Abstract

      Background

      Immune checkpoint inhibitors have revolutionized the treatment paradigm in number of cancers including Non-Small Cell Lung Cancer (NSCLC) but unrestrained modulation of the immune system remains a challenge. Here, we characterized the immune infiltration in the toxicity site and compared immune profile in primary tumor in three patients treated with PD-1/PD-L1 axis inhibitors and developed fibrinous pericarditis (FP)

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used the AQUA method of quantitative immunofluorescence (QIF) to assess multiplexed panels identifying immune cell populations and their activation status in pre-treatment, post-treatment primary tumor, post-treatment metastatic tumor and the toxicity sites (including pericardial tissue) from 3 NSCLC patients. We also compared the expression of 730 immune-related genes across sites from the 3 patients with FP and 2 NSCLC patients with different toxicity sites after immunotherapy (hypophysitis and myocarditis) using Nanostring Sprint platform.

      4c3880bb027f159e801041b1021e88e8 Result

      In immune infiltration assessment, TILs markers’ expression (CD4, CD8 and CD20) did not differ between primary tumor and toxicity site. There was a trend towards higher CD3+ expression in the toxicity samples but T-cell activation markers expression, Granzyme B and Ki67, was significantly lower in the pericarditis samples. Interestingly, high Granzyme B expression in CD3- cells and CD56+ cells were seen in the pericarditis samples. CD68+ expression, as well as PD-L1 expression in macrophages, was significantly higher (p<0.0001) in the pericarditis samples. mRNA analysis confirmed the QIF findings, with the chemokine profile indicating an M1 macrophage polarization. Additionally, there was a trend towards higher NCR1, perforin1 and Granzyme B gene expression in the toxicity samples, further supporting a possible role of Natural Killer (NK) cells in the development of toxicity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings suggest that macrophages and possibly NK cells contribute to inflammatory tissue damage in immune related adverse events. Conversely, T-cells that were infiltrating the toxicity sites had low expression of activation markers, further indicating that toxicity may be mediated by other cellular pathways.

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