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M. Ladanyi



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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)

      11:00 - 11:05  |  Author(s): M. Ladanyi

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.

      Methods
      A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.

      Results
      Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.

      Conclusion
      Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.

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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.04 - Defining BAP1 Syndrome: Preliminary results from an epidemiologic ascertainment study (ID 3437)

      16:30 - 16:35  |  Author(s): M. Ladanyi

      • Abstract
      • Presentation
      • Slides

      Background
      Identifying tumorigenic mutations in malignant pleural mesothelioma (MPM) is essential to advance therapy. Somatic mutations in the BRCA-1 associated protein-1 (BAP1) gene occur in about 20% of MPM tumors (Bott et al., Nature Genetics, 2011). In a retrospective analysis evaluating demographics, exposures, and survival, a history of smoking was the only clinical feature associated with the presence of BAP1 mutations (Zauderer et al., in press, J Thorac Oncol, 2013). Germline BAP1 mutations have also been identified in families predisposed to MPM (Testa et al., Nature Genetics, 2011). BAP1 germline mutations have also been associated with other tumors including atypical Spitz nevi, uveal melanoma, and renal cell carcinoma. These discoveries suggest that BAP1 mutations in mesothelioma represent part of a new hereditary cancer syndrome but the exact clinical phenotype remains unclear. To establish the frequency of germline BAP1 mutations in MPM patients and to accurately assess exposure history and family histories in these patients, we have undertaken a clinical trial to prospectively collect this information from patients with MPM.

      Methods
      All consenting patients provide a saliva or blood specimen from which germline DNA is extracted. Existing tumor samples are collected and analyzed for BAP1 mutation. Everyone completes a questionnaire regarding asbestos exposure, personal cancer history, and family history of malignancy. First, we will perform a de-identified assessment of the prevalence of germline BAP1 mutation. Patients whose tumors harbor BAP1 mutation and/or meet prespecified high risk criteria will be approached for identified germline testing after appropriate pre-test counseling. Mutations identified through research testing with be confirmed with clinical testing and additional genetic counseling will be undertaken. Testing will be offered to family members of patients with identified BAP1 germline mutations. Please see Figure 1 for study flow. Figure 1

      Results
      During the first 3 months that this protocol was open, we accrued 26 patients with mesothelioma, 15 of whom qualify for identified research testing. We will present results from ongoing testing at the meeting.

      Conclusion
      Recruiting patients to perform both de-identified and identified germline testing is feasible. Given the paucity of information regarding penetrance and appropriate screening interventions, BAP1 germline testing should continue only in the context of research programs. Additional preclinical work is ongoing to exploit this potential therapeutic target. Supported, in part, by a grant from the Mesothelioma Applied Research Foundation.

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)

      11:25 - 11:30  |  Author(s): M. Ladanyi

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

      Methods
      Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

      Results
      For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

      Conclusion
      As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.09 - Patterns of metastasis and survival in patients with PI3K-aberrant and FGFR1 amplified stage IV squamous cell lung cancers (SQCLCs) (ID 1666)

      17:05 - 17:10  |  Author(s): M. Ladanyi

      • Abstract
      • Presentation
      • Slides

      Background
      The majority of actionable drivers in SQCLCs occur in the PI3K (30%) and FGFR1 (20%) pathways. The biologic behaviors and natural histories of these subtypes are not well characterized. Characterization of these data may help to elucidate the biologic relevance of these putative oncogenic events.

      Methods
      As of October 2011, all patients with SQCLCs at MSK have undergone prospective, multiplex testing of their FFPE tumors for FGFR1 amplification (FISH, FGFR1:CEP8 ≥ 2.2), PIK3CA mutations (Sequenom and exon sequencing), PTEN loss (IHC, Cell Signaling), and PTEN mutations (exon sequencing), among others. The PI3K abberant group was defined as PIK3CA mutant, PTEN complete loss, or PTEN mutant. Patient characteristics, outcomes, and metastatic sites were identified. Survival probabilities were estimated using the Kaplan-Meier method. Group comparisons were performed with log-rank tests and Cox proportional hazards methods.

      Results
      77 stage IV SQCLC patients were analyzed. Genotypes were: FGFR1 amplified (23%); PTEN loss (22%), PIK3CA mutant (8%), PTEN mutant (7%). Events were non-overlapping save for 2 cases with PTEN nonsense mutations and PTEN loss. The sole significant clinical difference (KPS, age, sex, lines of tx, smoking status) was sex (women in PI3K group 52% vs. in others 23%, p=0.02). Metastatic patterns for PI3K and FGFR1 vs. all others were:

      Site PI3K p FGFR1 p Other Total
      Brain 6 (22%) 0.002 0 (0%) 0.6 0 (0%) 6 (7%)
      Pleura 5 (19%) 0.4 5 (28%) 0.7 9 (28%) 19 (25%)
      Liver 5 (19%) 0.4 1 (6%) 1 1 (3%) 7 (9%)
      Bone 8 (30%) 0.8 3 (17%) 0.7 10 (31%) 21 (27%)
      Lung 12 (44%) 0.8 10 (56%) 0.2 12 (38%) 34 (44%)
      Adrenal 3 (11%) 1 3 (17%) 1 4 (13%) 10 (13%)
      Pericardium 1 (4%) 1 1 (6%) 0.3 0 2 (3%)
      Median OS for PI3K vs. all others: 9mo (95%CI:8-NR) vs. 16mo (95%CI:11-NR), p=0.004. Median OS for FGFR1 vs. all others: 20mo (95%CI:11-NR) vs. 10mo (95%CI:9-16), p=0.06. Multivariate analysis for risk of death: PI3K HR=3.3 (95%CI:1.5-7, p=0.003); FGFR1 HR=0.5 (95%CI:0.2-1.1, p=0.06); Age ≥65, HR=1.3 (95%CI:0.6-2.8, p=0.5); KPS≤70, HR=3.2 (95%CI:1.6-.6.4, p<0.001); Lines of therapy ≥ 2, HR=2.3 (95%CI=0.8-5.7, p=0.08), male gender, HR=0.7 (95%CI:0.3-1.4, p=0.3).

      Conclusion
      Patients with stage IV PI3K-aberrant SQCLCs have poorer survival compared to other patients with SQCLCs while patients with FGFR1 amplified SQCLCs have a trend towards better survival. Brain metastases in SQCLC are rare, and occurred exclusively in patients with PI3K-aberrant tumors. These data suggest that PI3K pathway activation confers a distinct biology, and that targeting this in SQCLC patients with brain metastases may be an effective therapeutic strategy. Whole exome and RNA-sequencing data from 8 resected SQCLC brain metastases (4 paired with lung primaries) will be presented.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-059 - Comparison of the characteristics and clinical course of patients with metastatic KRAS mutant lung cancers (ID 3484)

      09:30 - 09:30  |  Author(s): M. Ladanyi

      • Abstract

      Background
      Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts withKRAS/EGFR wild type tumors(Johnson et al, Cancer 2013). Whether outcomes for patients with KRASmutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer.

      Methods
      We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival.

      Results
      KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n=157) were more likely to be never-smokers (p<0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p=1) or when comparing current/former smokers to never smokers (p=0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C=366, G12V=141, G12D=114, G12A=68, G13C=27, G13D=23, G12S=19, G12F=11)(p=0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p=0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.11-2.08 p=0.008).

      Conclusion
      Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Among patients with KRAS mutant metastatic lung cancers, those with codon 13 mutations have shorter survival compared to pts with KRAS codon 12 mutations.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-026 - RET Fusion-Positive Advanced Lung Cancers: Response to First-Line Chemotherapy and Survival in Comparison to ROS1 and ALK Fusion-Positive and EGFR- and KRAS-Mutant Lung Cancers (ID 1964)

      09:30 - 09:30  |  Author(s): M. Ladanyi

      • Abstract

      Background
      RET fusions are novel targetable drivers in non-small cell lung cancers. While the clinicopathologic profile of patients with RET fusion-positive tumors has been described in early-stage disease, little is known regarding clinical behavior in advanced unresectable disease.

      Methods
      Patients with advanced unresectable (stage IIIB/IV) pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, MAP2K1, ERBB2, PIK3CA, and AKT, and fusions of ALK or ROS1) were screened for RET fusions via dual-probe break apart FISH testing. Upstream partners were identified via RT-PCR and next-generation sequencing whenever possible. A retrospective review of patient records was conducted to determine response to systemic therapy and overall survival (OS). OS was calculated from diagnosis of metastatic disease and compared to patients with ALK and ROS1 fusion-positive, and EGFR- and KRAS-mutant lung cancers. Survival curves were estimated using the Kaplan-Meier method. Differences in survival between groups were assessed by the log-rank test.

      Results
      A RET fusion was found in 16% (n=12/76, 95%CI 8%-24%) of pan-negative tumors and 19% (n=10/48, 95%CI 10%-33%) of pan-negative tumors from never-smokers. Patients with RET fusion-positive tumors were predominantly never-smokers (83%, n=10/12, 2 patients with 7 and 10 pack-year histories, respectively) with advanced-stage disease at diagnosis (92%, n=11/12 stage IIIB/IV). Fusion partners were identified in 6 patients (4 KIF5B-RET, 1 TRIM33-RET, 1 NCOA4-RET). Eight patients (67%) received first-line platinum-based therapy, 6 of whom (50%) received maintenance pemetrexed and/or bevacizumab. Partial responses (PRs) were seen in 3 patients (38%) and stable disease (SD) in 5 patients (62%). 1-year OS on chemotherapy and median progression-free survival were 47% and 7.3 months, respectively. 1-year and 2-year OS for patients whose tumors harbored RET, ROS1, or ALK fusions, or EGFR or KRAS mutations is summarized below (Table). OS was not significantly different between RET, ROS1, ALK, or EGFR cohorts when RET was compared to each of the latter three cohorts separately. The presence of a RET fusion was associated with improved OS compared to the presence of a KRAS mutation (HR 0.39, 95%CI 0.21-0.74, p=0.004). Of the 11 patients with RET fusion-positive lung cancers, 4 patients (36%) were treated with cabozantinib on a phase 2 protocol (NCT01639508) with disease shrinkage of -66%, -32%, -23%, and -19% via RECIST v1.1.

      Driver Detected OS 1-year [95%CI] OS 2-year [95%CI]
      RET (n=12) 100% 71% [25%-92%]
      ROS1 (n=9) 88% [39%-99%] 88% [39%-99%]
      ALK (n=44) 91% [77%-97%] 73% [55%-85%]
      EGFR (n=102) 85% [76%-91%] 58% [47%-67%]
      KRAS (n=117) 60% [50%-66%] 26% [18%-35%]

      Conclusion
      Response to platinum-based first-line therapy in patients with RET fusion-positive tumors is comparable to historical controls. Survival in patients with RET fusion-positive disease is comparable to patients with EGFR mutations and other recurrent gene fusions (ROS1 and ALK) and improved compared to patients with KRAS mutations. Cabozantinib is worthy of further study in RET fusion-positive lung cancers.

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)

      09:21 - 09:33  |  Author(s): M. Ladanyi

      • Abstract
      • Slides

      Background
      Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.

      Methods
      Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.

      Results
      Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).

      Conclusion
      Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.

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