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J.E. Chaft



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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)

      16:30 - 16:35  |  Author(s): J.E. Chaft

      • 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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    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)

      11:20 - 11:25  |  Author(s): J.E. Chaft

      • 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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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 1
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      O02.05 - Major pathologic response (≤10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas (ID 2345)

      11:15 - 11:25  |  Author(s): J.E. Chaft

      • Abstract
      • Presentation
      • Slides

      Background
      Neoadjuvant chemotherapy improves overall survival in patients with resectable stage IIIA lung adenocarcinomas. The gold-standard endpoint for clinical trials evaluating curative therapies is overall survival. Unfortunately, these trials take nearly a decade to complete and this prolonged timeline hinders the approval of promising therapies in the curative realm. Alternative endpoints that can act as a surrogate for overall survival have been evaluated, including nodal downstaging, nodal clearance, and pathologic response. We evaluated the degree to which these endpoints associate with overall survival in patients with pathologically proven stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy.

      Methods
      An electronic database search engine was used to identify all patients with resectable stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy at Memorial Sloan-Kettering Cancer Center between 1/2007-8/2012. Nodal downstaging was defined as no residual tumor tissue in the N2 nodes. Nodal clearance was defined as no residual tumor tissue in N1 and N2 nodes. Pathologic response was systemically assessed by a dedicated thoracic pathologist (WDT) who reviewed at least 1 section per centimeter of greatest gross tumor diameter. The percent viable tumor tissue in each slide was estimated to the nearest 10%. Major pathologic response (MPR) was defined as ≤10% viable tumor tissue. All pathologic analyses were performed by a dedicated thoracic pathologist (WDT). Patients with residual N2 disease at resection were offered post-operative radiation and routinely monitored thereafter. Survival proportions were estimated by the Kaplan-Meier method and compared using the log-rank test.

      Results
      69 patients with pathologically confirmed IIIA(N2) disease were identified and 46 (67%) ultimately underwent R0 resection. Among these patients, 16 had nodal downstaging, 14 had nodal clearance and 5 had a MPR. In both intention to treat analyses (N=69) and including only those who underwent resection, only MPR significantly associated with overall survival. The table below details findings from the population who had complete cancer resection.

      Endpoint (N=46) Yes (A) No (B) NA (C) HR (95% CI) ITT (A vs B+C) HR (95% CI) Resected(A vs B)
      Nodal downstaging 16 30 23 0.68 (0.32-1.56) 0.73 (0.24-2.10)
      Nodal clearance 14 32 23 0.57 (0.27-1.36) 0.96 (0.32-2.81)
      MPR 5 41 23 0.28 (0.1-0.78) 0.26 (0.07-0.95)
      NA = not assessable; ITT = intention to treat

      Conclusion
      MPR (≤10% viable tumor) effectively identifies patients with good clinical outcomes after neoadjuvant chemotherapy and can serve as a surrogate endpoint for overall survival. Furthermore, lack of MPR identifies a patient population at high risk of recurrence. Neither nodal downstaging nor nodal clearance effectively discriminated those with improved survival. Adaptive clinical trials designed to target those not achieving MPR are encouraged in attempt to improve the rate of cure in this disease.

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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 - 09:30  |  Author(s): J.E. Chaft

      • 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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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-013 - High local control rates with post-operative radiation therapy in incompletely resected non-small cell lung cancer (NSCLC) patients (ID 1659)

      09:30 - 09:30  |  Author(s): J.E. Chaft

      • Abstract

      Background
      Post-operative radiation therapy (PORT) is frequently given to patients with NSCLC who have microscopically positive margins (R1 resection) or gross residual disease (R2 resection) based on oncologic first principles. However, the data to support this practice is scarce. Here we report our institutional experience comparing patients who received PORT in the setting of R0, R1 or R2 resections.

      Methods
      Between 1999 and 2012, 203 patients with NSCLC were treated with PORT in 25-39 fractions to 45-70 Gy. All surgery and PORT were performed at our institution. Twenty-one patients had a sublobar resection, 158 had a lobectomy, and 24 underwent a pneumonectomy. PORT was given to R0 patients with pathologic N2 disease, R1 or R2 resections. Patients with negative margins were compared to patients with residual disease (R1 and R2 resections). Patients with tumor recurrence within the PORT field were recorded as local failures. Local failure-free survival (LFFS), disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test.

      Results
      Fifty-five of 203 patients had residual disease after resection; 45 had R1 and 10 had R2 resections. The predominant histology was adenocarcinoma (80%). Stage at diagnosis was stage I-II in 17 patients, stage III in 186 patients. One-hundred and twenty-six (62%) patients received neoadjuvant and 39 (19%) adjuvant chemotherapy. Median age was 60 years and median KPS before PORT was 80. Median interval from surgery or adjuvant chemotherapy to PORT initiation was 1.6 months (range of 0-3.7 months). With a median follow up of 21 months, local failure occurred in 33/148 (22%) without and 14/55 (25%) patients with residual disease. Two- and 5-year actuarial LFFS rate were 79%/66% for R0 and 75%/58% for R1/R2 resections. Two- and 5-year actuarial DFS rate were 44%/30% for R0 and 48/26% for R1/R2 resections. Two-year and 5-year overall survival (OS) for all patients were 62.4% and 33.1%. LFFS, DFS and OS were not significantly different when comparing R0 to R1/R2 resections. Radiation dose, KPS, T-stage, N-stage, lymphovascular invasion, histology and chemotherapy were all not found to be significantly associated with any endpoint. OS was significantly worse for patients with R2 resection compared to R0/R1 resection (2-year OS 20% vs 64%; p= 0.002) and patients with age >65 (p=0.03). Multivariate analysis will be presented.

      Conclusion
      PORT results in equivalent local control rates after R1 and R2 resections when compared to R0 resections. This suggests that PORT has a significant role in local control of residual disease. However, OS was significantly worse for patients with gross residual disease postoperatively.

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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 - 09:30  |  Author(s): J.E. Chaft

      • 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.