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Viswam S Nair



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    P2.05 - Interventional Diagnostic/Pulmonology (ID 168)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.05-01 - Broad Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer (ID 615)

      10:15 - 18:15  |  Presenting Author(s): Viswam S Nair

      • Abstract

      Background

      We hypothesized that tumor-derived mutations from non-small cell lung cancer (NSCLC) are readily detectable in bronchoalveolar lavage (BAL). To explore our hypothesis, we employed the CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) method to identify somatic mutations in BAL compared to blood.

      Method

      We profiled 200 matching lavage, plasma, and PBMC samples from a total of 38 NSCLC patients and 21 controls. We first applied a tumor-informed calling approach to most sensitively detect mutations in BAL and plasma. We then applied a tumor-naïve mutation calling strategy to explore the effect of field cancerization in at risk patients with lung nodules or who smoked. Last, we developed a BAL mutation classifier to differentiate patients with cancer from those without and compared the performance of this classifier to BAL cytology.

      Result

      Tumors were primarily lung adenocarcinomas (84%) and mostly early stage disease (I-II 71%; III-IV 29%). We called a median of 4 mutations per tumor. TP53 and KRAS were the most frequently detected variants in tumor (47% and 35% respectively) and lavage cell free (cf) DNA (38% and 26% respectively). Using a tumor-informed approach, we detected significantly more variants in lavage cfDNA than in plasma from cancer patients (p<0.001) and variants were more frequently called in lavage cfDNA than in plasma from cancer patients (77% vs. 41%, p=0.004). As expected, tumor-naïve calling resulted in fewer variants detected in both sample types when compared to tumor-informed calling but we identified more tumor mutations (p<0.001) and more putative cancer driver mutations (p< 0.003) in lavage cfDNA than in plasma. Mutations of cancer driver genes at the patient level and average %VAF at the gene level were significantly lower in lavage cfDNA controls compared to cancer patients (p=0.017 and p=0.016 respectively). Since we also detected mutations in controls, presumably secondary to field cancerization and somatic mosaicism, we developed a risk score of mutation features to classify whether a BAL specimen was likely to come from a cancer patient or control. At a risk score level that identified all non-cancers as benign (A), this BAL classifier of 11 mutation features identified more cancers than cytology for all stages of lung cancer (65% vs 12%, p=0.001) and in stage I/II disease (50% vs. 20%, p=0.25; B).

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      Conclusion

      We show here that BAL genomic profiling may augment plasma profiling and BAL cytology for diagnosing and profiling NSCLC. Validation studies will be required to confirm our findings.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-69 - Lorlatinib Rescue Therapy for Life Threatening CNS Disease in Crizotinib-Resistant ROS1-Positive Non–Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2877)

      10:15 - 18:15  |  Author(s): Viswam S Nair

      • Abstract
      • Slides

      Background

      C-ros proto-oncogene-1 (ROS1) chromosomal translocations result in constitutively activated receptor tyrosine kinase in 1-2% of NSCLC. Although crizotinib, a first-generation Tyrosine Kinase Inhibitor (TKI) of Anaplastic Lymphoma Kinase (ALK) and ROS1 translocations, has demonstrated efficacy in treatment of ROS1 NSCLC, patients invariably acquire resistance mutations, with a high incidence of brain metastasis at relapse owing to poor CNS drug penetration. Lorlatinib is a novel, third-generation TKI with improved CNS penetration and preclinical activity against crizotinib-resistance mutations, which recently demonstrated efficacy in a phase I/II trial. We report a patient who developed secondary crizotinib-resistance and was successfully treated with lorlatinib.

      Method

      A 73-year-old, female, never-smoker with recently diagnosed stage-IV ROS1-rearranged NSCLC presented with refractory seizures and coma. The patient was on first-line treatment with crizotinib for 6-months, with an excellent systemic response at 2 months. Brain MRI after presentation demonstrated multiple intracranial metastasis with vasogenic edema (Fig.1A). Neurologic status was unchanged despite mannitol, steroids and anti-epileptics.

      Result

      As salvage therapy, the patient received bevacizumab for vasogenic edema and lorlatinib (100mg/daily). After 48-hours, substantial clinical improvement in neurologic function and mental status was observed. A repeat MRI (D+4) demonstrated a slight interval decrease in the largest metastasis and associated edema. At 1-month follow-up, the patient continued to improve clinically with no evidence of lorlatinib toxicity. Brain MRI showed a decrease in the sizes and/or resolution of all previously noted lesions and no new metastases or significant peritumoral edema (Fig.1B).

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      Conclusion

      Since clinical trials typically exclude patients with symptomatic, untreated CNS disease, efficacy of newer, targeted agents in mutated-NSCLC is unclear. Here we report on a patient with life threatening, acute neurologic deterioration who derived a meaningful clinical reduction in CNS lesions at 1 month, with favorable CNS response at 2 months. In addition, we observed early evidence of tumor regression on MRI after 4 days of lorlatinib therapy. Of note, her rapid clinical response may have in part been attributable to the addition of bevacizumab. Another important consideration for our patient is that she avoided whole-brain radiation in the acute setting, and its potential adverse sequalae. We note a limitation was the absence of available testing for secondary resistance mutations that developed in this patient, which was highly susceptible to lorlatinib. However, current clinical guidelines (NCCN) do not specifically recommend resistance mutation testing upon progression, and outside of a clinical trial, the current algorithm supports lorlatinib as the agent of choice post-crizotinib failure.

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