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G. Goss
Moderator of
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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 8
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
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OA19.01 - A Standardized and Validation of Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (ID 4329)
11:00 - 11:10 | Author(s): W.G. Richards, R. Bueno, D. Beer, K.V. Ballman, R. Govindan, M.S. Tsao, M. Watson, D.T. Merrick, A. Van Bokhoven, F.A. Shepard, D.R. Gandara, W.A. Franklin, D. Harpole, G. Chen, Z.H. Chen, L. Chirieac, H. Chui, C. Genova, M. Joshi, A. Kowalewski, M. Onaitis, C.J. Rivard, T. Sporn, F.R. Hirsch
- Abstract
- Presentation
Background:
High-throughput gene expression profiling led to proposal of multiple expression-based prognostic signatures for squamous cell lung carcinoma (SCC), but none has been validated. A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report the results of the primary validation.
Methods:
Cases of primary SCC (by central pathology review) meeting clinical (Stage I-II; surgical treatment only; 3-year followup) and specimen quality criteria (Tumor cellularity >= 50%; necrosis <= 20%) were submitted. Clinical, pathological and outcome data were uploaded to a central database. Frozen tumor samples underwent centralized mRNA extraction (Qiagen Symphony), quality control (RIN >= 6.0) and microarray profiling (Affymetrix U133) in core labs. An independent statistical core assessed validation of 7 pre-existing mRNA signatures and generated new models using MCP clustering.
Results:
Among 250 cases meeting entry criteria, median age was 70 (43-92), 161 (65%) were male, and most were former (70%) or current (28%) smokers. Surgery was pneumonectomy: 5%; bilobectomy: 2%; lobectomy: 74%; sublobar: 18%. Pathologic staging was T1: 49%; T2: 50%; T3: 1%; N0: 88%; N1: 12%, and grade was G1: 4%; G2: 50%; G3: 44%. At followup, 148 (59%) were deceased. Three mRNA signatures demonstrated significant univariable association with OS and added independent prognostic value (see Figure) to a multivariable model accounting for age, sex and stage (c-index = 0.641).
Conclusion:
The validated signatures, along with two novel signatures generated from the current dataset, are currently undergoing further validation studies using two prospective co-operative group cohorts. Figure 1
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OA19.02 - Sex Differences Are Detected in the Profile of Tumor Associated Inflammatory Cells (TAICs) Are Lung Adenocarcinoma (ID 5451)
11:10 - 11:20 | Author(s): C. Behrens, E.R. Parra, J. Rodriguez-Canales, P. Villalobos, B. Sepesi, A. Weissferdt, N. Kalhor, J. Heymach, C. Moran, D.L. Gibbons, I. Wistuba
- Abstract
- Presentation
Background:
A number of studies have characterized TAICs in lung cancer and associated their levels of infiltration with patients’ outcome. There is limited information about the correlation of TAICs infiltration with clinical and pathological features of lung cancer. We investigated the association between patterns of tumor infiltrating lymphocytes and macrophages with detailed clinical and pathological features in lung adenocarcinoma.
Methods:
We studied archival tumor tissue from 93 surgically resected lung adenocarcinomas, stages I to III. Density of TAICs expressing CD3, CD4, CD8, and CD68 was evaluated using immunohistochemistry (IHC) and image analysis. TAICs density was correlated with tumor’s histological characteristics and patients’ characteristics.
Results:
We found significant differences in the TAICs infiltrate density of lung adenocarcinomas based on patients’ characteristics. Overall: a) females showed higher levels of CD8+ (P=0.01) and CD3+ (P=0.03) cell density than males; b) smaller tumors (<3cms) showed more CD4+ (P=0.01) and CD3+ (P=0.03) cells than larger tumors; and, c) tumors with solid histology pattern showed higher levels of CD8+ (P=0.03) cells than non-solid pattern. No overall significant differences on TAICs infiltrates were detected by age, tobacco exposure by pack-years and TTF-1 IHC expression score. However when TAICs density of tumors was examined by sex we found the following: a) in larger tumor (>3cms), females demonstrated higher levels of CD8+ cells (P=0.0007) than males; b) tumors from females older than the median age (63 years) showed more CD4+ (P=0.04), CD8+ (P=0.009) and CD3+ (P=0.042) cells than males; c) tumors from females with <40 pack-years of tobacco history showed significantly higher levels of CD3+ (P=0.004) and CD68+ (P=0.004) cells than males; d) tumors from females with high levels of TTF1 expression (score >150) showed higher levels of CD8+ cells(P=0.03) than males; e) females with tumors having non-solid histology pattern showed higher CD8+ (P=0.02) and CD3+ (P=0.02) cells than males. Finally, tumors expressing low levels of TTF-1 and lower CD4+ cells correlated significantly with worse overall recurrence free survival and overall survival in both males (P<0.0001) and females (P=0.0072).
Conclusion:
In lung adenocarcinoma, TAICs infiltration correlates with clinical characteristics of patients and pathological features of tumors, particularly, sex, age, size and TTF-1 expression. Compared with men, lung adenocarcinomas from females showed higher levels of TAICs, particularly at older age, larger tumor size, less exposure to tobacco, and more differentiated histological patterns. (UT Lung SPORE and MD Anderson Moon Shot Program).
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- Abstract
- Presentation
Background:
The national lung cancer screening test (NLST) confirmed: low dose CT screening could reduce lung cancer mortality. However, the high false-positive rates of LDCT screening, especially the difficulty of diagnosis of micro-nodules with size less than 10 mm highlight the need of complementary biomarkers to discriminate micro-nodular lung cancer from benign pulmonary diseases.
Methods:
The blood gene expression profiles of 46 lung cancer patients, 38 pulmonary lesions and 51 healthy were investigated to identify the lung cancer-specific genetic signatures. The lung cancer patients containing micro-nodules less than 10 mm were surgically and pathologically diagnosed as lung adenocarcinoma in situ
Results:
A self-training logistic regression method was used to identify the lung cancer-specific gene signatures as we previously reported. Six genes, including DDX51, PSME2, ACTL6A, GMEB1, FAM200B, GEMIN6, were identified for discriminating lung adenocarcinoma in situ from health and benign pulmonary diseases. The performance of the six-gene panel for diagnosis of lung adenocarcinoma in situ identified was exhibited in Table 1. Through self-training SVM classifier, the logarithmic odds of each sample was calculated and exhibited, in which the cutoff value was set as zero in logarithmic odds for differentiating lung cancer from benign and control group. The predictive model based on 6-gene panel correctly classified 43 of 46 lung cancer, 39 of 42 benign pulmonary diseases with 93% accuracy, 94% sensitivity, and 93% specificity and 0.97 of ROC AUC.
Conclusion:
The predictive model based on 6-gene panel (DDX51, PSME2, ACTL6A, GMEB1, FAM200B, GEMIN6) can be used for discriminating between the malignant or benign nodules with size less than 10 mm
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OA19.04 - Discussant for OA19.01, OA19.02, OA19.03 (ID 7100)
11:30 - 11:45 | Author(s): C. Rudin
- Abstract
- Presentation
Abstract not provided
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OA19.05 - High Oncofetal Chondroitin Sulfate Expression is an Independent Prognostic Factor of Poor Survival in Early-Stage NSCLC (ID 5601)
11:45 - 11:55 | Author(s): Z. Lohinai, H.Z. Oo, G. Kumar, J.W. Allen, N.L. Tran, B. Dome, J. Moldvay, G.J. Weiss, M. Daugaard
- Abstract
- Presentation
Background:
Most human cancers express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that are normally restricted to placental tissue. Oncofetal CS chains can be conveniently detected and targeted by recombinant VAR2CSA (rVAR2) proteins derived from the malaria parasite Plasmodium falciparum. In the present study, we have analyzed the expression landscape of oncofetal CS modifications in early-stage non-small cell lung cancer (NSCLC).
Methods:
Tissue microarrays from four separate patient cohorts representing a total of 493 clinically annotated stage I-II NSCLC cases were stained for oncofetal CS using rVAR2. Data were analyzed for correlation between low and high oncofetal CS presentation by immunohistochemical (IHC) staining of tumor and stroma compartments in respect to EGFR and KRAS mutations, as well as to clinical characteristics including relapse-free survival (RFS) and overall survival (OS).
Results:
There were 351 patients with low (IHC score 0-1) and 142 with high (IHC score 2-3) expressing tumors. We identified 331 adenocarcinomas, 145 squamous cell carcinomas, and 12 cases with other NSCLC subtypes. There were 314 stage I and 179 stage II cases by AJCC 7[th] edition. High oncofetal CS expression was significantly associated with shorter RFS (vs. high expressiors; 58 vs. 39 months, respectively, p=0.034) and OS (vs. high expressors; 69 vs. 51 months, respectively, p=0.044). High oncofetal CS expression was significantly associated with shorter RFS vs. low expression in men (p=0.024), smokers (p=0.011), and in patients with squamous cell tumors (p=0.012). High oncofetal CS was also significantly associated with shorter OS in men (p=0.005) and smokers (p=0.028). There were no significant RFS or OS differences in oncofetal CS expressions when stratifying the patients according to their EGFR or KRAS statuses. In multivariate survival analyses, histology, stage, and high oncofetal CS expression was significantly associated with shorter RFS vs. high expression (HR, 1.8; 95% CI, 1.32–2.48; p < 0.001).
Conclusion:
This is the first study showing that high oncofetal CS expression is an independent prognostic factor of poor RFS in NSCLC and validates high oncofetal CS expression as a prognostic factor of poor OS. In contrast to non-smoker females, oncofetal CS appears to be a prognostic for OS in males and smokers. Our work promotes oncofetal CS as a candidate target for rVAR2-based therapeutic intervention in NSCLC patients with poor RFS/OS.
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OA19.06 - Adjuvant Chemotherapy Decisions Based on Molecular Risk Status Improves Outcomes in Early Stage, Non-Small Cell Lung Cancer (ID 5321)
11:55 - 12:05 | Author(s): G.A. Woodard, J.C. Crockard, C.T. Zoon-Besselink, J. Kratz, M.A. Gubens, T.M. Jahan, C.M. Blakely, K.D. Jones, M.J. Mann, D. Jablons
- Abstract
- Presentation
Background:
A clinically certified, 14-gene quantitative PCR expression assay has been found to assess mortality risk more accurately than clinicopathologic criteria in early-stage, non-squamous, non-small cell lung cancer (NSCLC). Clinically validated molecular stratification may provide a more informative approach to identify early stage NSCLC patients who are most likely to benefit from chemotherapy than current National Comprehensive Cancer Network (NCCN) high-risk clinicopathologic features.
Methods:
Prospective molecular risk-stratification by the 14-gene quantitative PCR expression assay was performed on 91 consecutive patients with stage I-IIA non-squamous NSCLC after complete surgical resection at a single institution. Information from molecular risk profiling was used in conjunction with pathologic stage and NCCN criteria to make adjuvant chemotherapy recommendations. Fisher’s exact test was used to compare recurrence rates, and Kaplan-Meier analysis and log-rank tests were used to evaluate differences in disease free survival.
Results:
Median age was 69 years, 57% were female and median follow up was 23±2 months. Among all patients, 33 (36%) met NCCN high-risk criteria for adjuvant chemotherapy and 27 (30%) were molecular high risk. Recommendations for adjuvant chemotherapy were discordant in 18 (55%) of NCCN high-risk patients and in 12 (44%) who were molecular high-risk. Twelve (44%) of molecular high-risk patients agreed to receive adjuvant chemotherapy. Whereas recurrence was observed in 33% of molecular high-risk patients who did not receive adjuvant chemotherapy, none of the molecular high-risk patients who underwent chemotherapy recurred (log-rank p=0.001).
Conclusion:
This prospective single-institution study demonstrates the clinical utility of molecular testing of early-stage NSCLC to supplement pathologic stage and NCCN guidelines in making adjuvant chemotherapy recommendations. Molecular risk scores better differentiated prospective recurrence rates than did NCCN risk criteria. This study provides preliminary evidence that molecular testing followed by adjuvant chemotherapy in molecularly high-risk patients may prevent a significant number of recurrences and improve outcomes.
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OA19.07 - Difference of Postoperative Survival Due to the Type of EGFR Gene Mutation in Surgically Resected Lung Adenocarcinomas (ID 4726)
12:05 - 12:15 | Author(s): K. Hayasaka, S. Shiono, Y. Matsumura, N. Yanagawa, H. Suzuki, J. Abe, M. Sagawa, A. Sakurada, M. Katahira, Y. Machida, S. Takahash, Y. Okada
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) gene mutation is a robust prognostic factor in patients with advanced lung adenocarcinomas. Recently, on the other hand, there are some reports proposing the difference of survival due to the type of EGFR mutation. In this study, we analyzed the difference of postoperative survivals between two most common mutations, that is, exon 19 deletions (DEL) and exon21 L858R (PM), using multi-institutional data of patients with surgically resected lung adenocarcinomas.
Methods:
We retrospectively collected 1,063 consecutive patients who underwent surgical resections for lung adenocarcinoma between 2005 and 2012 in five institutions, and who were examined their EGFR mutation status. The patients with minor EGFR mutations were excluded. We compared their clinicopathological characteristics among DEL, PM, and wild type (WT) group. We also analyzed postoperative recurrence-free survival (RFS) and overall survival (OS) according to the type of EGFR mutation.
Results:
The number of patients with DEL, PM, and WT was 218 (20.5%), 301 (28.3%), and 544 (51.2%) respectively, and their median follow-up period was 47.6 months. The patients of PM were older and earlier pathological staged than those with DEL, whereas no significant difference was observed among other clinicopathological factors. Five-year RFS and OS of DEL, PM, and WT were 67.3/85.9%, 76.4/88.6%, 59.2/71.5%, respectively, and both survivals of each mutant were significantly better than those of WT. Regarding the difference between DEL and PM, RFS curve of DEL was significantly worse than that of PM (p = 0.027), but OS curves of both mutant weren’t significantly different. (p = 0.16). In multivariate analysis, the type of EGFR mutation (DEL vs PM) was not an independent factor both in RFS and OS.
Conclusion:
Exon 21 L858R might be a more favorable recurrence-risk factor than exon 19 deletions in patients with surgically resected lung adenocarcinomas.
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OA19.08 - Discussant for OA19.05, OA19.06, OA19.07 (ID 7003)
12:15 - 12:30 | Author(s): K. Olaussen
- Abstract
- Presentation
Abstract not provided
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Author of
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ED08 - Early-Stage NSCLC: State-of-the-Art Treatment and Perspectives (ID 276)
- Event: WCLC 2016
- Type: Education Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:T. Le Chevalier, M. Tsuboi
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall C2
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ED08.03 - Adjuvant Chemotherapy of Completely Resected (ID 6471)
15:10 - 15:30 | Author(s): G. Goss
- Abstract
- Presentation
Abstract:
Adjuvant Chemotherapy of Completely Resected NSCLC Glenwood D. Goss Lung cancer remains the leading cause of cancer death world-wide and accounts for approximately 28% of all cancer deaths(1,2). Surgical resection is the cornerstone of therapy for early stage disease, but relapse is high with 30-60% of patients with resected NSCLC still dying of their disease. Despite the results of a 1995 meta-analysis demonstrating a non-significant 5% survival advantage at five years with the addition of adjuvant cisplatin-based chemotherapy, no large randomized studies conclusively demonstrated a benefit following resection until 2003(3). Five large randomized trials were undertaken to determine if adjuvant platinum-based chemotherapy after curative surgery for NSCLC conferred a survival advantage: ALPI; IALT; JBR10; CALGB 9633; and ANITA (4,5,6,7,8). Three of these five trials showed statistically significant improvements in overall survival, ranging from 4% [IALT] to 15% [JBR10] at 5 years, corresponding to an absolute improvement in relapse-free survival from 49% to 61%. Of the two trials that did not demonstrate improved survival, one [ALPI] suffered from poor compliance to the treatment regimen (69%), and the second was a smaller trial (n=344) limited to patients with stage IB disease [CALGB 9633], which was likely underpowered to detect a statistically significant improvement in overall survival. Interestingly, despite being limited to patients with stage IB disease, CALGB 9633 did demonstrate an overall survival hazard ratio comparable to the other adjuvant trials (HR=0.8) that included patients with more advanced disease, despite not achieving statistical significance. Since the publication of original adjuvant chemotherapy trials, a number of meta-analyses have confirmed the benefit of adjuvant platinum-based chemotherapy after surgical resection for NSCLC(9,10). In these meta-analyses, all-stage (IB-IIIA) hazard ratios were in the range of HR=0.86, corresponding to an absolute benefit for chemotherapy on overall survival of 4-5% at 5 years. The benefit, however, was demonstrated to be stage dependent (albeit using older staging criteria versions), with the benefit only reaching statistical significance for stages II and III. While the role of adjuvant chemotherapy in stage I disease is controversial (11), subgroup analyses in a number of trials in high-risk patients with stage IB disease (tumours≥4cm) suggests that there may be an overall survival advantage with adjuvant chemotherapy in this subgroup of patients, comparable to those observed in stage II and III disease [Strauss 2008]. In 2009 the long term follow up of the IALT study (with a median follow up of 7.5 years) was reported. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06) suggesting that those patients receiving adjuvant chemotherapy had a higher death rate from non- lung causes after 5 years(12). However these conclusions were not support by the findings of Butts and colleagues reporting on JBR10 with a median follow-up was 9.3 years (range, 5.8 to 13.8). Adjuvant chemotherapy continued to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). Adjuvant chemotherapy resulted in significantly prolonged disease specific survival (HR, 0.73; 95% CI, 0.55 to 0.97;P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms. They concluded that prolonged follow-up of patients from the JBR.10 trial continues to show a survival benefit for adjuvant chemotherapy(13). Recently in a post hoc analysis of ECOG 1505, a trial of adjuvant chemotherapy +/- bevacizumab for early stage NSCLC, Wakelee and colleagues had the opportunity to compare four different cisplatin doublet regimens namely, cisplatin with one of vinorelbine, docetaxel, gemcitabine or pemetrexed. Median follow-up time for each chemotherapy doublet was: vinorelbine 54.3 months; docetaxel 60.3 months; gemcitabine 57.0 months; and pemetrexed 40.6 months respectively. The arms were well balanced for the major prognostic factors apart from smoking where the rate was slightly lower in the pemetrexed arm. There was no difference in the median number of cycles between arms. Both in the nonsquamous and squamous subgroups there was no difference in overall survival (nonsquamous logrank p=0.18 and squamous p=0.99) and disease free survival (nonsquamous p=0.54 and p=0.83). The authors concluded that there did not appear to be a difference in outcome between cisplatin doublet regimens(14). Despite the established benefit of adjuvant chemotherapy after curative surgery for NSCLC there is still much to be done with approximately 50 % of patients still dying from disease. Furthermore, not all patients with early stage disease are eligible or willing to undergo chemotherapy following complete surgical resection [Booth 2010]. As such, the long-term prognosis of patients with NSCLC, even among those with early stage disease, remains poor. Therefore it is imperative that we find new and better therapies to improve upon the results of surgical resection and adjuvant chemotherapy. . References: 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012. 2. Jemal A, Siegel R, Ward E et al. Cancer Statistics 2007. CA Cancer J Clin 2007; 57: 43-66. 3. L. A. Stewart, S. Burdett, J. F. Tierney, J. Pignon on behalf of the NSCLC Collaborative GroupSurgery and adjuvant chemotherapy (CT) compared to surgery alone in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomized clinical trials (RCT). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 25, No 18S (June 20 Supplement), 2007: 7552 4. Scagliotti GV, Fossati R, Torri V et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 1453–61. 5. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Eng J Med 2004; 350: 351-60. 6. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Eng J Med 2005; 352: 2589-97. 7. Strauss GM, Herdone JE, Maddaus et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-51. 8. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomized controlled trial [published erratum appears in Lancet Oncol 2006; 7: 797]. Lancet Oncol 2006; 7: 719-27. 9. Pignon JP, Tribodet GV, Scagliotti G et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26: 3552-9. 10. NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010; 375: 1267-77. 11. Wakelee H, Dubey S, Gandara D et al. Optimal adjuvant therapy for non-small cell lung cancer – how to handle stage I disease. Oncologist 2007; 12: 331-7. 12. Arriagada R, Dunant A, Pignon JP, et al. Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer JCO January 1, 2010 vol. 28no. 1 35-42 13. Butts C, Ding K, Seymour L,et al. Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non–Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10. Journal of Clinical Oncology, January 1, 2010 vol. (28) 1 29-34. 14. H.A. Wakelee[1], S.E. Dahlberg[2], S.M. Keller te al. E1505: Adjuvant chemotherapy +/bevacizumab for early stage NSCLC: Outcomes based on chemotherapy subsets. ASCO Annual Meeting, 2016 Abstr 8507: E1505 Chemotherapy subsets. 15. Booth CM, Shepherd FA, Peng Y et al. Adoption of adjuvant chemotherapy for NSCLC: a population-based outcome study. J Clin Oncol 2010; 28: 3472-8.
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
15:26 - 15:32 | Author(s): G. Goss
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.03 - Second-Line Afatinib for Advanced Squamous Cell Carcinoma of the Lung: Analysis of Afatinib Long-Term Responders in the Phase III LUX-Lung 8 Trial (ID 4711)
14:40 - 14:50 | Author(s): G. Goss
- Abstract
- Presentation
Background:
Squamous cell carcinoma (SCC) of the lung is a genetically complex and difficult-to-treat cancer. In LUX-Lung 8, afatinib (40mg/day) significantly improved OS (median 7.9 vs 6.8 months, HR=0.81 [95% CI, 0.69‒0.95], p=0.008), PFS (2.6 vs 1.9 months, HR=0.81 [0.69‒0.96], p=0.010) and DCR versus erlotinib (150mg/day) in patients with relapsed/refractory SCC of the lung (n=795). Notably, 12-month (36 vs 28%; p=0.016) and 18-month survival (22 vs 14%; p=0.016) was significantly higher with afatinib than erlotinib, indicating that some patients derive prolonged benefit from afatinib. Here, we present post-hoc analysis of baseline characteristics and efficacy/safety of afatinib in long-term responders (treatment for ≥12 months). Hypothesis-generating analysis of archived tumor samples and blood serum was undertaken to identify possible molecular/clinical biomarkers.
Methods:
Tumor samples were retrospectively analyzed using FoundationOne[TM] next-generation sequencing (NGS); EGFR expression was determined by immunohistochemistry. Pre-treatment serum samples were analyzed with VeriStrat[®], a MALDI-TOF mass spectrometry test, and classified as VeriStrat-Good or VeriStrat-Poor-risk.
Results:
15/398 patients treated with afatinib were long-term responders. Median duration of treatment was 16.6 months (range: 12.3‒25.8). Patient characteristics were similar to the overall dataset (median age: 65 years [range: 54‒81]; male: 80.0%; Asian: 13.3%; ECOG 0/1: 40.0%/60.0%; best response to chemotherapy CR or PR/SD: 53.3%/46.7%; current and ex-smokers: 80.0%). Median PFS was 16.2 months (range: 2.8‒24.0); median OS was 23.1 months (range: 12.9‒31.5). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (73.3%/6.7%); rash/acne (66.7%/6.7%); stomatitis (13%/7%). AEs generally occurred soon after treatment onset (median onset, days [range]: diarrhea 11 [5‒48]; rash/acne 17 [9‒107]; stomatitis 15 [11‒19]). Four patients required a dose reduction to 30mg/day due to treatment-related AEs (diarrhea, rash, stomatitis, diarrhea/rash). NGS was undertaken in 9 patients and details will be presented at the meeting. Genomic aberrations in the ErbB/FGF gene families were identified in 44.4%/55.6% of long-term responders (overall dataset: 29.4%/58.0%). Of 14 patients assessed by VeriStrat, 85.7% were VeriStrat-Good (overall dataset: 61.6%). Immunohistochemistry data was available for two patients; one overexpressed EGFR (≥10% positive cells; H-score ≥200)
Conclusion:
Baseline characteristics of long-term responders to afatinib were similar to the overall dataset. In this sub-group, afatinib conferred a survival benefit of nearly 2 years. Afatinib was well tolerated with predictable and transient AEs that occurred soon after treatment onset. The dataset was too small to identify any clear NGS/VeriStrat predictive signals. Further studies are required to predict long-term response to afatinib.
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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
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-003 - Second-Line Afatinib versus Erlotinib for Patients with Squamous Cell Carcinoma of the Lung (LUX-Lung 8): Analysis of Tumour and Serum Biomarkers (ID 5627)
14:30 - 14:30 | Author(s): G. Goss
- Abstract
Background:
LUX-Lung 8 compared second-line afatinib (40 mg/day; n=398) and erlotinib (150 mg/day; n=397) in patients with stage IIIB/IV squamous cell carcinoma (SCC) of the lung. PFS (median 2.6 vs 1.9 months, HR=0.81 [95% CI, 0.69–0.96], p=0.010) and OS (median 7.9 vs 6.8 months, HR=0.81 [0.69–0.95], p=0.008) were both significantly improved with afatinib versus erlotinib. Here we report exploratory molecular (n=245) and immunohistochemical (n=288) analyses of tumour samples to assess the frequency of short variants (SVs) and copy number alterations (CNAs) in cancer-related genes and whether these tumour genomic alterations, or EGFR expression levels, have clinical utility as prognostic/predictive biomarkers in patients with SCC of the lung. We also assessed the predictive utility of the prospectively validated VeriStrat®, a serum protein test (n=675).
Methods:
Archived tumour samples were retrospectively analysed using next-generation sequencing (FoundationOne™). Tumour EGFR expression was assessed by immunohistochemistry; EGFR positivity was defined as staining in ≥10% of cells. Pretreatment serum samples were assigned as VeriStrat-Good or VeriStrat-Poor according to a mass spectrometry signature. Cox regression analysis was used to correlate OS/PFS with genomic alterations (individual or grouped into gene families e.g. ErbB family), EGFR expression levels and VeriStrat status.
Results:
The frequency of ErbB family alterations was low (SVs: EGFR 6.5%, HER2 4.9%, HER3 6.1%, HER4 5.7%; CNAs: EGFR 6.9%, HER2 3.7%). No individual genetic alterations, or grouped ErbB family aberrations, were prognostic of OS/PFS. Treatment benefit from afatinib versus erlotinib was consistent in all molecular subgroups. Most tumours were EGFR-positive by immunohistochemistry (afatinib: 82%; erlotinib: 86%). EGFR expression was not predictive of OS or PFS benefit (EGFR-positive PFS: HR=0.76 [0.57‒1.02]; OS: HR=0.84 [0.63‒1.12]; EGFR-negative PFS: HR=0.87 [0.45‒1.68]; OS: HR=0.77 [0.40‒1.51]). In afatinib-treated patients, both PFS (HR=0.56 [0.43‒0.72], p<0.0001) and OS (HR=0.40 [0.31‒0.51], p<0.0001) were improved in the VeriStrat-Good versus the VeriStrat-Poor group. VeriStrat-Good patients had significantly longer OS and PFS when treated with afatinib versus erlotinib (median OS: 11.5 vs 8.9 months, HR=0.79 [0.63‒0.98]; PFS: HR=0.73 [0.59‒0.92]). In VeriStrat-Poor patients there was no significant difference in OS between afatinib and erlotinib (HR=0.90 [0.70‒1.16]). However, there was no significant interaction between treatment arms and VeriStrat classification.
Conclusion:
Despite comprehensive, multifaceted analysis, no biomarkers were identified that predicted the benefit with afatinib over erlotinib in patients with SCC of the lung. Afatinib is a treatment option in this setting irrespective of patients’ tumour genetics or EGFR expression levels. However, patient outcome strongly depends on VeriStrat status.
