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M.G. Kris



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.11 - A Phase II Trial of Paclitaxel, Pemetrexed and Bevacizumab in Patients with Untreated, Advanced Lung Cancers (ID 3142)

      16:15 - 17:45  |  Author(s): M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background
      Standard front-line treatment for patients with unresectable or metastatic non-small cell lung cancer (NSCLC) is a platinum-based doublet with bevacizumab regimen, which achieves objective response rates (ORR) of 35% and median survival of 12 months. However, many patients with lung cancer are not eligible for cisplatin because of baseline neuropathy, hearing loss, renal insufficiency, or comorbid medical conditions. Although carboplatin is often substituted for cisplatin, it also is associated with similar toxicities, albeit with a smaller risk. This phase II trial of paclitaxel, pemetrexed, and bevacizumab was designed to avert the toxicities of platinum-based chemotherapeutic regimens and determine the efficacy of such a "non-platinum" containing doublet with bevacizumab.

      Methods
      Patients with untreated, advanced NSCLCs were enrolled if they had measurable disease (RECIST 1.0) and adequate organ and marrow function. Patients were excluded if they had squamous cell carcinoma; hemoptysis; symptomatic or hemorrhagic brain metastases; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess; and myocardial infarction or stroke within 6 months prior to enrollment. For six 28-day cycles, patients received: paclitaxel 90 mg/m[2] (days 1, 8, and 15), pemetrexed 500 mg/m[2] (days 1 and 15), and bevacizumab 10 mg/kg (days 1 and 15). Patients with response or stable disease continued pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. Patients were evaluated on days 1, 8 and 15 of each 28-day cycle. To assess response, CT scans were performed after cycles 1 and 2, and every 2 cycles thereafter. ORR was the primary endpoint.

      Results
      Forty-four patients were enrolled: 50% women, median age of 59 years (range, 31 to 77), 89% with Karnofsky performance status ≥80%. Mutation status was known in 38 patients (KRAS, n=16; ALK, n=3; BRAF V600E, n =2; Her2 insertion/PIK3CA, n=1; EGFR Exon 20 insertion, n=1; none, n=15). The ORR was 52% (95% CI, 37-68), with 23 partial responses and no complete responses. The median overall survival and progression-free survival were 17 months (95% CI, 12-33) and 8 months (95% CI, 6-12), respectively. Grade 3/4 toxicities included fatigue (33%); elevated liver function tests (15%); leukopenia (9%); hoarseness (7%); nausea (7%); and anemia (7%). Two patients died on study of respiratory failure, possibly related to therapy. No bleeding events were noted.

      Conclusion
      The “non-platinum” containing regimen of paclitaxel, pemetrexed and bevacizumab is an effective first-line treatment for patients with advanced NSCLCs, regardless of mutational status. Long survival was observed, with acceptable toxicities. This regimen warrants further study.

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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO08.04 - Phase 2 study of the GI-4000 KRAS vaccine following curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, G12V or G12R mutation (ID 2451)

      16:15 - 17:45  |  Author(s): M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background
      Most patients with early-stage lung cancer will die of recurrent disease despite multimodality therapy with curative intent. KRAS is the most commonly mutated oncogene in lung adenocarcinomas, and patients with resected disease are a unique population amenable to a personalized clinical trial approach. GI4000 is a vaccine created from whole, heat killed recombinant Saccharomyces cerevisiae yeast, overexpressing KRAS Q61L plus Q61(R or H) and either a G12C, G12D, G12V, or G12R mutation. This study aimed to assess the feasibility and immunogenicity of the GI4000 vaccine in patients with KRAS-mutant lung cancers and to compare the outcomes of patients to matched controls.

      Methods
      Patients with Stage I-III KRAS-mutant lung cancers who completed curative therapy were enrolled. Each patient was routinely administered the genotype-matched vaccine from the GI4000 series subcutaneously starting 1-4 months after standard treatment completion: weekly x 3, monthly x 6 and every 3 months for a total of 3 years (19 doses). KRAS-antigen T-cell response was assessed by interferon-γ ELISpot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response rate of ≥25% (N=24 patients). A comparison group matched for age, sex, KRAS genotype and stage was used to compare recurrence and survival using the Kaplan-Meier method with a hazard ratio for survival adjusted for age, sex and stage.

      Results
      In 28 months, 33 patients were screened and 24 patients enrolled. The study met its primary endpoint with 63% of evaluable patients (50% of all patients) developing an antigen-specific immune response. 19 patients had evaluable baseline samples, 9/13 with a negative response at baseline developed a treatment emergent response and 3/6 with a pre-existing baseline response had an increased response over baseline that met pre-specified immunologic criteria. There were no treatment-related Grade 3/4 or severe AEs. The median number of vaccinations received was 15 (range 1-19). 1 patient withdrew consent due to local injection site reaction and 2 died of recurrent disease during study. The baseline characteristics and clinical outcomes of the trial patients and a group of matched controls is presented in the Table below.

      GI4000 vs. Matched controls GI4000 N=24 N(%) Matched controls N=64 N(%)
      Stage I II III _____ 12 (50) 5 (21) 7 (29) _____ 42 (66) 2 (3) 20 (31)
      Age at diagnosis (median) 63 66
      Sex Male Female _____ 7 (29) 17 (71) _____ 21 (33) 43 (67)
      Recurrence free survival per year 1 2 3 _____ 86% 68% 60% _____ 85% 71% 69%
      Overall survival per year 1 2 3 _____ 100% 100% 92% _____ 93% 88% 83%
      Hazard ratio for survival (p-value) 0.58 (0.29)

      Conclusion
      The GI4000 vaccine is safe, feasible and immunogenic after completion of curative-intent therapy in patients with KRAS-mutant lung cancers. Recurrence rates are equivalent but overall survival trends favorably when compared to matched controls. Exploratory analysis of survival in the immune responders versus matched controls is underway. A randomized study with prospective biomarker analyses is warranted.

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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)

      10:30 - 12:00  |  Author(s): M.G. Kris

      • 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)

      16:15 - 17:45  |  Author(s): M.G. Kris

      • 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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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.09 - A Phase II study of <sup>18</sup>F-FDG PET guided optimization of neoadjuvant chemotherapy for resectable non-small cell lung cancer (ID 2442)

      10:30 - 12:00  |  Author(s): M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background
      Perioperative chemotherapy improves overall survival in patients with resectable non-small cell lung cancers. In contrast to adjuvant chemotherapy, neoadjuvant chemotherapy enables radiographic assessment of chemotherapy effect and hence, the option to switch non-responding patients to a potentially more effective regimen. Responses to neoadjuvant chemotherapy assessed by PET imaging correlate better with clinical outcomes than does CT imaging. We have initiated a Phase II trial of PET response guided chemotherapy, where chemotherapy administration decisions are based on comparisons of baseline PET imaging, imaging after 2 cycles of platinum-based chemotherapy, and imaging after ‘switch’ chemotherapy in patients with an initial suboptimal response.

      Methods
      This Phase II trial (NCT01443078) is enrolling patients with clinical Stage IB-IIIA non-small cell lung cancers deemed operable by a thoracic surgeon. To be eligible, the primary lung mass must be >2 cm with a SUV ≥4.5. Patients with diabetes requiring insulin are excluded. Patients are initially treated with cisplatin (or carboplatin if cisplatin ineligible) + gemcitabine (squamous cell) or pemetrexed (non-squamous). After 2 cycles, if repeat PET imaging shows less than a 35% decrease in SUV of the primary tumor, patients are switched to vinorelbine + docetaxel every 2 weeks with pegylated filgrastim support (2 doses = 1 cycle). The primary endpoint of this study is partial metabolic response after 2 cycles of switch vinorelbine + docetaxel as assessed by PERCIST (SUV decrease of ≥30% using the pre-switch scan as the new baseline). We considered a >20% partial metabolic response rate in those who received vinorelbine + docetaxel worthy of further study. Therefore this study was powered to see at least 6 of 25 partial metabolic responses to vinorelbine + docetaxel, estimating a total patient accrual of 100 patients.

      Results
      27 patients have been enrolled. 5 are undergoing platinum-based chemotherapy and have not yet been reassessed. 22 patients have been reimaged after 2 cycles of platinum-based chemotherapy, 13 (59%) have had a > 35% decrease in SUV and continued on platinum-based chemotherapy. 9 (41%) patients have had a <35% decrease in SUV after platinum-based therapy and were assigned to switch chemotherapy. 7 received vinorelbine + docetaxel, and 5 (71%, 95% CI 29-96%) have had a PERCIST partial metabolic response after 2 cycles, 1 progressive disease and 1 is pending reassessment. 17 patients have been surgically explored with 13 (76%) R~0~ resections.

      Conclusion
      Preliminary results from this ongoing trial suggest that patients with resectable non-small cell lung cancers who have a suboptimal PET-assessed response to standard histology-selected, platinum-doublet neoadjuvant chemotherapy can be effectively treated with vinorelbine and docetaxel followed by surgery. This study is on-going. Assessment of pathologic response in resected patients and clinical follow-up in all patients will be available by the time of presentation.

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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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      P1.06-047 - Tumor expression of TTF1 is associated with a doubling of overall survival in patients with advanced lung adenocarcinomas (ID 2819)

      09:30 - 16:30  |  Author(s): M.G. Kris

      • Abstract

      Background
      Expression of thyroid transcription factor 1 (TTF1) is commonly assessed to diagnose lung adenocarcinomas. TTF1 may also be an oncogenic driver. The prognostic impact of TTF1 expression in lung cancers has been evaluated. However, small sample sizes, population heterogeneity, and lack of control for genotype or targeted therapies have limited the interpretation and use of TTF1 as a prognostic variable.

      Methods
      We examined 638 consecutive patients with newly diagnosed (i.e. not recurrent disease) stage IV lung adenocarcinomas between 01/2009 and 09/2011. TTF1 was assessed by immunohistochemistry (8G7G3/1, DAKO, dilution 1:100); binary results were recorded (positive = any nuclear reactivity; negative = no reactivity). The association between TTF1 status and clinical variables (Chi-squared and t-tests), median survival (Kaplan-Meier methods, compared using logrank test), and outcomes with specific chemotherapies (Cox proportional hazard) and were assessed. Multivariate analysis of overall survival (Cox proportional hazard) was performed.

      Results
      TTF1 was assessed in 484 (76%) patients; 80% were TTF1+. TTF1 positivity associated with improved survival in all cohorts examined, although the EGFR cohort is limited by the small number of TTF1 negative tumors. TTF1+ was more common in EGFR (93%) than KRAS (76%) mutants (p<0.01). Figure 1 To reduce confounding from the effect of targeted therapy on survival, subsequent analyses excluded those with EGFR (n=129) mutations or ALK (n=12) rearrangements: In multivariate analysis, the HR for survival in TTF1+ patients was 0.42 (p<0.001), exceeding the prognostic impact of good performance status (KPS≥80, HR=0.54, p<0.001). There was no association between TTF1 and age (p=0.96), sex (p=0.41), smoking status (p=0.68), or performance status (p=0.07). TTF1 status did not predict improved outcomes with specific chemotherapies.

      Conclusion
      TTF1+ robustly and independently associates with improved survival in advanced lung adenocarcinomas. TTF1 exceeds the prognostic impact of clinical features (e.g. KPS) more commonly used to stratify patients. TTF1 should be assessed in all lung adenocarcinomas and should be used to stratify patients enrolled in clinical trials. Randomized trials are needed to conclusively assess if TTF1 predicts differential sensitivity to chemotherapies.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-019 - FGFR1 amplification is associated with improved survival in patients with early-stage squamous cell carcinomas of the lung (SQCLC) (ID 2987)

      09:30 - 16:30  |  Author(s): M.G. Kris

      • Abstract

      Background
      The spectrum and frequency of oncogenes in squamous cell lung cancers (SQCLCs) is actively being defined. Amplification of fibroblast growth factor receptor 1 (FGFR1) is the most common targetable oncogenic driver in SQCLCs, occurring in ~20%. Clinical trials of FGFR1 inhibitors for advanced SQCLCs are ongoing. The frequency, clinicopathologic features, and prognosis of FGFR1 amplification in early-stage SQCLCs have been reported but with discrepant results.

      Methods
      A cohort of histopathologically-defined and clinically-annotated resected SQCLCs was tested for FGFR1 amplification by FISH (Zytovision Dual Color Probe). Amplification was defined by FGFR1 copy number ≥2.2x CEP8 control copy number and was assessed by two evaluators (MW, LW) who were blinded to clinical results. Disease-free survival (DFS) defined as date of surgical resection until disease recurrent, relapse, or death, which ever occured first. DFS was estimated using Kaplan-Meier method. The association between FGFR1 status and clinical features (unpaired T-test, Fisher’s exact, Chi-square tests) and DFS (log-rank test for unadjusted analysis; Cox proportional hazards regression for multivariate analysis) were assessed.

      Results
      63 resected SQCLCs were evaluated. FGFR1 amplification was detected in 16 (24%). 56% were stage I, 24% were stage II, and 20% were stage IIIA. There was no association between FGFR1 amplification and age (p=0.86), sex (p=0.80), smoking status (p=0.37), or stage of disease (p=0.16). Median DFS was significantly longer in FGFR1-amplified cases compared to non-amplified cases: not reached vs 2.3 yrs (95% CI 1.1-3.4 yrs), p=0.02, with a corresponding unadjusted hazard ratio of 0.41 (95%CI: 0.19-0.88). Adjusted for sex and stage, multivariate analysis found FGFR1 amplification significantly associated with improved DFS (HR 0.31, 95%CI 0.1-0.89, p=0.03). Figure 1

      Conclusion
      FGFR1 amplification is associated with improved prognosis in this cohort of resected SQCLCs. The distinctive natural history substantiates FGFR1amplified SQCLCs as a unique, oncogene-defined subgroup. There was no association between FGFR1 status and sex, age, smoking status, or stage. FGFR1 amplification is common in SQCLCs.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-005 - "Intention-to-treat" outcomes of sequential patients with stage IIIA lung adenocarcinomas treated with neoadjuvant chemotherapy with intent of surgical resection (ID 1199)

      09:30 - 16:30  |  Author(s): M.G. Kris

      • Abstract

      Background
      Neoadjuvant chemotherapy followed by surgical resection is uniquely permits assessment of the in vivo response to therapy in patients with IIIA non-small cell lung cancer. Studies of neoadjuvant chemotherapy often focus only on those who are ultimately resected. We describe an “intention-to-treat” analysis of sequential patients with stage IIIA adenocarcinomas receiving neoadjuvant chemotherapy with intent of surgical resection.

      Methods
      Using natural language processing software, we searched the electronic medical record at Memorial-Sloan Kettering Cancer Center for “neoadjuvant,” “preoperative,” or “induction” in physicians’ notes. Cases were limited to those with stage IIIA lung adenocarcinoma deemed resectable by a thoracic surgeon and treated with neoadjuvant chemotherapy (without radiation), including those enrolled in prospective clinical trials. Event-free survival (date of diagnosis to recurrence, relapse or death) and overall survival (date of diagnosis to death) were assessed using Kaplan-Meier methods.

      Results
      From 2007 until 08/2012, 129 patients were identified. Median follow up is 25 months (range 1-76). The patient details are described. 94/129 (73%) were treated with cisplatin-based therapy.Figure 1 The CONSORT diagram below describes the treatment patients ultimately received. Figure 2 The median EFS and OS were 16 (95% CI 13-22) and 44 (95% CI 36-NA) months. OS at 1, 2 and 3-years were 77%, 55%, and 32%. EFS plateaued at 23%, estimating the rate of cure. Overall survival strongly favored surgical resection over salvage radiation (HR=0.5, 95% CI 0.16-1.05).

      Conclusion
      These data provide unique perspective on the outcomes of patients with IIIA adenocarcinoma treated with neoadjuvant chemotherapy with intent of surgical resection. EFS and OS compare favorably to historical outcomes in this stage of disease, demonstrating the value of the neoadjuvant approach. The inferior survival in patients treated with radiation as a “salvage” approach emphasizes the recommendation for definitive concurrent chemoradiation in those unlikely to be resectable.