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M.D. Hellmann



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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.D. Hellmann

      • 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.D. Hellmann

      • 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.D. Hellmann

      • 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.D. Hellmann

      • 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.