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B. Halmos



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    MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA04.01 - Non-Amplification Mutation of ERBB2 in EGFR-Mutated Lung Cancer (ID 6138)

      16:00 - 17:30  |  Author(s): B. Halmos

      • Abstract
      • Presentation
      • Slides

      Background:
      Amplification of ERBB2 in EGFR-mutant lung cancers is a reported mechanism of acquired resistance to tyrosine kinase inhibitor (TKI) therapy. Comprehensive genomic profiling (CGP) of NSCLC tumors shows mutation of ERBB2, most often affecting the encoded HER2 receptor at residue S310, is also prevalent, particularly in the context of EGFR L858R.

      Methods:
      CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,887 consecutive cases of lung cancer. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes. Short variants (SV) include base substitutions or indels.

      Results:
      A total of 2,516 (16.9%) samples featured EGFR alterations, including amplification (amp) and SV. Of these, 2.9% (73/2,516) harbored alterations in ERBB2 (amp and/or SV). 18 samples (0.7%) harbored SV alterations in ERBB2, 14 of which were mutations at S310. ERBB2 S310 mutations were most often found with EGFR L858R. The ratio of observed to expected mutation at HER2 S310 in EGFR-mutated lung cancers was 2.12, and the ratio for HER2 S310 in combination with EGFR L858R was 5.03. The co-occurrence of HER2 S310 and EGFR L858R was highly significant (p<0.00005). The combination of EGFR and ERBB2 alterations was more common in women. The ratio of male:female patients with any lung cancer in this dataset was 1:1.1, whereas the ratio of male:female with any EGFR alteration was 1:1.7 and for both EGFR and ERBB2 alterations (amp or SV) was 1:3.4. Patients with a combination of EGFR and ERBB2 alterations have been shown to respond to treatment with the pan-ERBB inhibitor afatinib, or combinations of afatinib with the HER2-targeted therapy trastuzumab.

      Conclusion:
      Short variant alterations in ERBB2 may be an additional mechanism for tumors to acquire resistance to treatment with EGFR-targeted TKIs. Mutations at residue S310, in the extracellular domain of HER2, are the most common ERBB2 SV observed in EGFR-mutant lung cancer, and are significantly associated with EGFR L858R. The co-occurence of alterations in ERBB2 and EGFR is far more common in women than in men. Treatment with the pan-ERBB inhibitor afatinib, alone or in combination with agents targeting HER2, has been shown to benefit patients with lung cancer harboring mutations in both EGFR and ERBB2.

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    OA20 - Immunotherapy and Markers (ID 401)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      OA20.07 - HHLA2, a New Immune Checkpoint Member of the B7 Family, is Widely Expressed in Human Lung Cancer and Associated with Mutational Status (ID 5184)

      11:00 - 12:30  |  Author(s): B. Halmos

      • Abstract
      • Presentation
      • Slides

      Background:
      Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.

      Methods:
      We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients.

      Results:
      Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR–mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.

      Conclusion:
      HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-056 - Distinct PD-L1 Expression in Different Components of Pulmonary Sarcomatoid Carcinoma and Its Association with MET Mutation (ID 5228)

      14:30 - 15:45  |  Author(s): B. Halmos

      • Abstract
      • Slides

      Background:
      Pulmonary Sarcomatoid Carcinoma (PSC) is a unique and highly aggressive subtype of non-small cell lung cancer (NSCLC), characterized by a component of sarcoma or sarcoma-like differentiation. It is generally resistant to platinum-based chemotherapy. However, frequent KRAS and the MET exon 14 skipping mutations have been reported in this subtype. Recently, immunotherapy with antibodies against PD-1/PD-L1 has led to clinical benefits in managing NSCLC. Immune biomarker expression of PD-L1 in differential components of PSC and its relationship with other molecular markers has not been defined and thus there is critical need to investigate its expression profile in this deadly disease.

      Methods:
      We investigated PD-L1 expression by immunohistochemistry (IHC) using tissue microarrays from a cohort of 41 patients with PSC (antibody: PD-L1/CD274 (SP142)). Positive cases were defined as PD-L1 ≥ 1%. The clinical and molecular characterization of these cases was previously reported (PMID: 26215952). Among the 41 cases, 36 had sufficient tumor tissue for PD-L1 assessment, 8 (20%) were identified with MET exon 14 skipping mutation and 6 (15%) were found to have KRAS mutations.

      Results:
      The PD-L1 expression was positive in 75% (27/36) of cases. Among the positive cases, 78% expressed PD-L1 ≥ 50%, whereas 22% had PD-L1 staining of 1-49%. Interestingly, only 33% (9/27) had PD-L1 expression in both epithelial and sarcomatoid components, whereas the remaining 66% detected PD-L1 in just one component. The PD-L1 expression was statistically different between the two components (P=0.007). Moreover, all 8 patients with MET exon 14 skipping mutation were PD-L1 positive (6 with PD-L1 ≥ 50%), whereas 5 of 6 patients with KRAS mutation expressed PD-L1 (2 with PD-L1 ≥ 50%). The average age at diagnosis was similar between the PD-L1 positive vs. negative groups (71 years). There was a trend of shorter overall survival in patients whose tumors were positive for PD-L1 (671 vs. 985 days).

      Conclusion:
      In our particular cohort of PSC patients, high PD-L1 (≥ 50%) was expressed in the large majority of cases which favors potential application of immunotherapy in this disease. In addition, it appears that the expression of PD-L1 is different in the epithelial and sarcomatoid components which could affect scoring in practice. Furthermore, the overall positivity of PD-L1 expression in the unique molecular subtype of PSC patients with MET exon 14 skipping mutation indicates potential interplay between the two biomarkers and suggests that exploration of combination MET and immunotherapy in this subtype is warranted.

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    P2.02 - Poster Session with Presenters Present (ID 462)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      P2.02-023 - Neoadjuvant Chemotherapy and Concurrent Full-Dose Radiation Therapy Followed by Surgery for Stage IIIB Non-Small Cell Carcinoma of the Lung (ID 3674)

      14:30 - 15:45  |  Author(s): B. Halmos

      • Abstract
      • Slides

      Background:
      The role of neoadjuvant chemoradiation and surgery in patients with stage IIIB non-small cell lung cancer (NSCLC) is unclear. Previous studies have suggested that select patients may benefit from this trimodality approach. We retrospectively reviewed patients with stage IIIB NSCLC treated by trimodality intent with induction chemotherapy and concurrent full-dose radiation therapy followed by either surgery at our institution. Here we report survival and toxicity data in our cohort.

      Methods:
      Eight patients treated from 1999 to 2011 with neoadjuvant chemoradiation for stage IIIB NSCLC were included in the retrospective review. Five (63%) had pathologically proven N3 disease; 1 (13%) had radiographic evidence of N3 disease (2cm adenopathy with SUV>6); 2 (25%) had T4 disease due to involvement of multiple ipsilateral lobes. All 6 patients with N3 disease had minimal radiographically enlarged N3 nodes (fewer than 3) before treatment. Induction chemotherapy consisted of carboplatin or cisplatin doublet. Concurrent RT prescription consisted of 45Gy in 25 fractions to the mediastinum and primary tumor; most patients received a boost to at least 60Gy to gross disease. After re-evaluation, patients received surgery within three months of completion of induction therapy. Inoperable patients received consolidative chemotherapy.

      Results:
      Six patients (86%) received at least 59.4Gy to the primary tumor. Six patients underwent resection; 2 had pneumonectomy and 4 had lobectomy. A complete (R0) resection was achieved in all patients. Mediastinal nodal clearance (N2/3 negative) was seen in five (83%) patients. A complete pathological response was seen in three (50%) patients. With a median follow up of 45 months for all patients, the median overall survival (OS) was 52.8 months. The median progression-free survival (PFS) was 48.4 months. Median OS was 52.8 months for patients who achieved MNC, 5.7 months in one patient with residual mediastinal nodal disease (P=0.025), and 0.9 months in those who did not receive surgery. There was 1 grade 3 postoperative pulmonary complications and no treatment-related mortality within the follow up interval.

      Conclusion:
      Data from on our small cohort provide important preliminary evidence that neoadjuvant chemotherapy with concurrent full-dose radiation therapy followed by surgery may be a feasible treatment option for select patients with stage IIIB NSCLC. Toxicity is acceptable, and survival outcome compares favorably with that of patients with IIIA NSCLC treated with trimodality therapy.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-103 - Identification of On-Target Mechanisms of Resistance to EGFR Inhibitors Using ctDNA Next-Generation Sequencing (ID 5645)

      14:30 - 15:45  |  Author(s): B. Halmos

      • Abstract
      • Slides

      Background:
      Osimertinib (OSM) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) recently approved for use in EGFR T790M-positive non-small cell lung cancer (NSCLC) with a 65-70% response rate. However, patients invariably develop resistance to OSM, in ~30% of cases due to an acquired EGFR C797S mutation. Understanding additional, non-C797S resistance mechanisms will be critical to developing new therapeutic approaches. Here, we describe a case of T790M-positive NSCLC with progression on OSM, genotyped using cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS).

      Methods:
      A 68-year-old male with EGFR L858R-mutant metastatic NSCLC whose disease progressed despite multiple lines of EGFR inhibitors (erlotinib, afatinib, cetuximab/afatinib) and chemotherapy was found to be T790M-positive, and initiated on OSM. Initial restaging scans demonstrated response. On disease progression 7 months later, ctDNA testing was performed with a highly sensitive and ultra-specific 70-gene NGS panel (Guardant360™) that includes all EGFR exons and reports on all EGFR single nucleotide variants, indels, and amplification.

      Results:
      Twelve somatic alterations were identified, including 7 mutations in EGFR. The original L858R driver mutation was present at a mutant allele fraction (MAF) of 16.9%, and T790M at MAF of 8.4%. C797S was detected at MAF of 4.6%. Four additional subclonal TK domain mutations were identified: L792H (1.4%), L718Q (0.7%), F795C (0.4%) and L792F (0.1%). Mutations within sufficient genomic proximity were phased to determine allelic origin, and a presumptive evolutionary history was constructed. T790M and C797S were in cis, and the F795C mutation arose on that allele. L792H and L792F were in cis to T790M, but arose independently from each other and from C797S. Review of the Guardant Health database, which includes 5,609 NSCLC samples, identified 1,228 samples with EGFR activating mutations L858R and exon 19 deletion. Of these, 341 (28%) had T790M, of which 17 (5%) carried C797S. Sixteen of 17 C797S mutations were in cis with T790M, and 1 in trans. There were 3 additional cases with L718 mutation and 1 with L792.

      Conclusion:
      Deep sequencing of ctDNA can reveal the global landscape and evolution of resistance mutations within a patient’s tumor. The T790M and C797S mutations were predominantly in cis configuration, underscoring the importance of developing new EGFR TKIs. The role of mutations L792H, L792F, and F795C is currently unknown. These mutations impinge on the ATP-binding pocket, which could be a potential structural resistance mechanism. Further studies are needed to validate and functionally characterize these candidate resistance mutations.

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