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J.S. Lee
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O27 - Clinical Trials and Practice (ID 142)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Other Topics
- Presentations: 8
- Moderators:J.S. Lee, J. Bishop
- Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1
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O27.01 - Thromboembolism in lung cancer - an area of urgent unmet need (ID 2096)
16:15 - 16:25 | Author(s): M. Alexander, S.W. Kirsa, R. Wolfe, M. Macmanus, D. Ball, B. Solomon, K. Burbury
- Abstract
- Presentation
Background
Current management of lung cancer (LC) (chemotherapy - CHT, radiotherapy – RT, and biological therapies) occurs predominantly in the ambulatory care (AC) setting. Post-surgery hospital admission is becoming progressively shorter due to advances in technique and greater reliance on home recovery.[1,2]As such, LC management occurs outside the scope of current thromboprophylaxis (TP) guidelines.[2-8] Recommendations for TP strategies in these high thromboembolism (TE) risk patients are lacking.[9] The aim of this study was to profile TE incidence in LC patients receiving anti-cancer therapy, exploring patient-, disease- and treatment-related risk factors associated with higher thrombotic rates. This could identify high-risk populations, disease features and/or treatment periods that warrant strong recommendations for targeted preventative strategies to reduce LC-associated TE, and in particular consideration of pharmacological-TP (P-TP).Methods
Retrospective review of LC patients referred to Peter MacCallum Cancer Centre, a tertiary dedicated cancer centre, between 01/07/11 - 30/06/12 for anti-cancer therapy. Data were collected from medical, pharmacy, pathology and diagnostic imaging electronic records. Follow up was defined as time from study entry (referral date) to first occurring event; TE, death, loss to follow-up or study end. Hazard ratios were calculated using Cox proportional hazards model.Results
222 patients were followed for a median 10 months from time of first hospital registration. The cohort was predominantly newly diagnosed (77%), with advanced disease (71%), NSCLC (92%). Among NSCLC adenocarcinoma was the predominant histological subtype (77%). 30% of patients received multiple lines of therapy within the study period; 49% received CHT (alone or combination chemoradiotherapy, CRT), 73% RT (alone or CRT), 19% biologic therapy and 19% surgical intervention. 10.8% of patients had radiologically confirmed TE, giving an incidence rate of 131 events per 1000 person-years (95%CI 87-195). 83% (20/24) of events occurred in the AC setting; 71% symptomatic, 29% asymptomatic. 16 events were pulmonary embolism (PE) (5 fatal), 4 deep vein thrombosis (DVT), 1 combination DVT/PE, 1 atrial and 2 arterial thrombosis. TE occurred frequently in both NSCLC and SCLC (10.8% and 10.5% respectively), and more frequently among patients with adenocarcinoma compared to squamous cell histology (14.7% and 5.3% respectively). Presence of more advanced or metastatic disease, prior history of TE and comorbidity score>2 were associated with higher rates of TE. More than a third (38%) of TE events occurred during the CHT period, 13% post-surgery, 8% during RT and biologic therapy respectively. CHT demonstrated more than five-fold increased TE risk compared to no CHT (HR 5.7 95% CI 2.2-14.8) with a similar finding for RT (HR 5.2 95%CI 2.0-13.2). Importantly, P-TP was not routinely or systematically prescribed for ambulant LC patients during any treatment phase, at this institution.Conclusion
LC patients are at high risk of preventable and potentially life-threatening thrombotic events. TE events occur frequently in the AC setting and consideration of P-TP is warranted, but not used routinely due to a lack of high quality data. There is a demand for appropriate risk-stratification and directed preventative strategies. Prospective data and the development of dynamic risk profiles which can direct clinical practice are needed.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O27.02 - Preliminary results from the FRAGMATIC trial: A randomised Phase III clinical trial investigating the effect of FRAGMin® Added to standard Therapy In patients with lung Cancer. (ID 1799)
16:25 - 16:35 | Author(s): F. Macbeth, S. Noble, G. Griffiths, R. Chowdhury, C. Rolfe, K. Hood, S. Linnane, B. Moore, D. Cohen, R. Cowles, M. Longo, D. Knoyle
- Abstract
- Presentation
Background
Venous thromboembolism (VTE) is common in lung cancer patients and the incidence is increased by treatments including radiotherapy, surgery and chemotherapy. Research suggests a survival benefit in cancer patients receiving long term low moecular weight heparin (LMWH). LMWH may also have antimetastatic effects through the inhibition of P-selectin. This trial was developed to investigate whether or not adding LMWH to standard treatment increases overall survival. The study is funded by a research grant from Cancer Research UK (C13275/A5323) and free drug and an educational grant from Pfizer. The trial is sponsored by Velindre NHS Trust, and coordinated by the Wales Cancer Trials Unit, Cardiff, UK.Methods
An open label, multi-centre, Phase III randomised controlled trial in patients with lung cancer comparing anticancer treatment according to local practice plus dalteparin (Fragmin®), with anticancer treatment alone. Eligible patients had a histopathological or cytological diagnosis of primary bronchial carcinoma (SCLC or NSCLC) within the previous 7 weeks, performance status 0, 1, 2 or 3 and were willing and able to inject daily subcutaneous injection. The dalteparin was given as a daily 5,000 IU subcutaneous injection for 24 weeks. The primary outcome measure is overall survival and the secondary outcome measures include toxicity, VTE-free survival, metastasis-free survival, quality of life, and cost utility. To detect an advantage of 5% in overall survival at 1 year (to 30%) a total of 2200 patients were required (1100 in each arm).Results
2202 patients were enrolled and randomised in 4 years. The two groups were well balanced for key variables. 60% were men; the median age was 65 years; 82% had NSCLC (5% Stages I and II, 38% Stage III, 57% Stage IV) and 18% SCLC (63% Extensive Disease); 85% had WHO PS 0 or 1; 95% received chemotherapy as first treatment. 56% of those in the dalteparin arm received at least 90 of the 168 planned injections. By 1/8/2013 there had been 1891 deaths recorded and, on advice from the Independent Data Monitoring Committee, the primary results have been released. There was no significant difference in overall survival (HR 0.97; 95% CI 0.89-1.06) nor in metastasis-free survival. Exploratory subgroup analyses do not suggest a significant survival advantage in any subgroup. Dalteparin use was not associated with a significant increase in major bleeding complications. There were 78 (7.1%) confirmed VTEs in the control group and 47 (4.1%) in the treatment group.Conclusion
This large RCT which recruited mainly good PS lung cancer patients having chemotherapy, has confirmed that prophylactic dalteparin reduces the risk of VTE events without a significant increase in major bleeding. The baseline VTE risk of 7% and relative risk reduction of 40% are consistent with previous studies. There was no significant difference in overall survival. These results do not support a policy of routine prophylactic anticoagulation of all lung cancer patients undergoing chemotherapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O27.03 - Meta-analysis of progression-free survival and objective response rate as predictors of overall survival in locally advanced or metastatic non-small-cell lung cancer (ID 3170)
16:35 - 16:45 | Author(s): E.J. Turner, P. McCloud, P. Germanos, F. Dehle, S. Norris, J. Tan, P.L. Mitchell
- Abstract
- Presentation
Background
Improving overall survival (OS) in locally advanced or metastatic non-small-cell lung cancer (NSCLC) remains a goal for clinicians. OS is often the primary endpoint in Phase III clinical trials, however with the increased use of multiple lines of treatment and crossover/rescue therapy in NSCLC trials, overall survival differences are frequently confounded. Other clinically meaningful endpoints such as progression-free survival (PFS) are becoming increasingly important. A systematic review and meta-analysis was undertaken to investigate whether the treatment effect on PFS, or objective response rate (ORR), was predictive of the treatment effect on OS in locally advanced or metastatic NSCLC.Methods
Embase, MEDLINE and the Cochrane Library databases were searched to identify relevant published randomised controlled trials (RCTs). Included RCTs compared pharmacological treatments in two or more groups in patients with locally advanced or metastatic (Stage IIIb or IV) NSCLC. The reported outcomes had to include median PFS and median OS. Data were analyzed with locally weighted least squares regression (LOWESS) to validate the linear relationship. Unweighted linear regression and weighted linear regression were used to estimate the relationship between OS treatment difference and PFS treatment difference. A similar analysis was also done to compare ORR difference and OS difference. The analysis also considered whether potential baseline prognostic factors could also change OS difference. Univariate weighted linear regression was used to assess the relationship of each prognostic factor with OS difference, followed by multivariate weighted linear regression.Results
A total of 124 RCTs (N=40,568 patients) were included in the analysis. Of the 124 trials, 98 (79%) were published since 2005. The age of patients ranged from middle aged cohorts to the elderly. There were 87 studies (70%) with first-line therapy and therapy type was predominantly chemotherapy (71 studies, 57%). The LOWESS of OS difference versus PFS difference was a relatively straight line, therefore a linear relationship appeared to be justified. Weighted linear regression showed a highly significant relationship between OS treatment difference and PFS treatment difference [slope 1.317 months (95%CI 1.000, 1.634) p<0.001 R[2] = 36.6%]. Diagnostic plots revealed several statistical outliers. A weighted linear regression of OS difference versus PFS difference with six outlier studies removed also showed a highly significant linear relationship [slope 0.994 months (95%CI 0.749, 1.240) p<0.001 R[2] = 36.7%]. The relationship between ORR difference and OS difference was also significant [slope 12.503 (95%CI 7.042, 17.963) p<0.001 R[2] = 16.0%]. Univariate weighted linear regressions showed that the only baseline prognostic factor with a significant linear relationship with OS difference was the proportion of patients with non-squamous histology. Multivariate weighted linear regression showed none of the baseline prognostic factors was significant when PFS difference or ORR difference was included in the model.Conclusion
The treatment effect on PFS was predictive of the treatment effect on OS. For a 1 month increase in PFS treatment difference, OS treatment difference increases by approximately 1.3 months. A 10% increase in ORR treatment difference was also associated with an increase in OS of 1.25 months. PFS is an important outcome for healthcare decision-making.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O27.04 - DISCUSSANT (ID 4014)
16:45 - 17:00 | Author(s): G. Richardson
- Abstract
- Presentation
Abstract not provided
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O27.05 - Is primary tumor standardized uptake value (SUV) an independent prognostic factor for non-small cell lung cancer (NSCLC)? A meta-analysis based on individual patients data. (ID 3888)
17:00 - 17:10 | Author(s): M. Paesmans, C..O. Wong, E. Patz, R. Komaki, S. Eschmann, R. Govindan, J. Vansteenkiste, A. Meert, W.K. De Jong, N.K. Altorki, K. Higashi, A. Van Baardwijk, G. Borst, L. Ameye, J. Lafitte, T. Berghmans, C. Hossein-Foucher, A. Scherpereel, C. Garcia, P. Flamen, R. Rami-Porta, J. Sculier
- Abstract
- Presentation
Background
[18]F-fluoro-2-deoxy-D-glucose positron emission tomography complements conventional imaging for staging lung cancer although its ability to predict outcome is less well established. Two literature-based meta-analyses suggest a prognostic value in univariate analysis. To assess FDG-PET value in predicting survival adjusted for some known prognostic factors, we carried out a meta-analysis based on individual patients data from multiple independent studies.Methods
Following literature search, and after writing of a protocol for the meta-analysis, we contacted the authors of identified studies and requested individual patients data; we also tried to collect some unpublished data. Data analysis used Cox regression models stratified for the study with overall survival as primary outcome. SUV max was used as a binary covariate (median value for each study).Results
Data were collected for 1526 patients (57% of the identified patients) from 11 publications and 1 unpublished series (median age : 64 years, 60% male patients, squamous cell in 34%, adenocarcinoma in 47%, stages I-II in 58%). Combined univariate hazard ratio (HR) was 1.43 (95% CI : 1.22-1.66); no statistically significant interaction between SUV and one of six additional freatures (age, gender, histology,stage, tumors size –in stages I-III patients- and surgical treatment), was found except for stage (p=0.05) with a decreased prognostic value of SUV for stage IV patients. Without considering SUV, multivariate analysis identified, in stage I-III patients, age, stage, tumor size and surgical treatment as independent prognostic factors. The addition of SUV improved that model : HR estimate for SUV effect was 1.58, statistically significant (95% CI : 1.27-1.96), p<0.0001. No interaction was found with SUV. When tumor size was not included in the tested covariates, we found SUV of additional value (adjustment for age, stage, surgical treatment) with a HR of 1.35 (95% CI : 1.15-158). Interaction between SUV and stage was detected, restricting the significant impact of SUV on survival to stage I-III patients.Conclusion
Conclusions : Although suffering from selection bias and lack of homogeneous SUV assessment, these data suggest that SUV at the time of diagnosis is an independent prognostic marker for patients with stage I-III NSCLC. The utility of SUV in predicting survival in stage IV patients requires further studies.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O27.06 - Resistance training in patients with radically treated respiratory cancer: mature results of a multi-centre randomised phase 3 trial (REINFORCE) (ID 678)
17:10 - 17:20 | Author(s): J.P. Van Meerbeeck, B. Salhi, C. Haenebalcke, S. Perez-Bogerd, M.D. Nguyen, T.L.A. Malfait, K.Y. Vermaelen, V.F. Surmont, G. Van Maele, R. Colman, E. Derom
- Abstract
- Presentation
Background
There is a lack of data on the effect of conventional resistance training (CRT) on exercise capacity, muscle strenght and quality of life (QoL) in patients with lung cancer. Whole body vibration (WBV) is proposed as an alternative to CRT. We investigated the effect of a radical treatment and of two post-treatment resistance training programmes on the 6-minutes walking distance (6MWD).Methods
Selected patients with clinical stage I-IIIB (non-) small cell lung cancer or I-II mesothelioma were evaluated before (M1) and at completion (M2) of their radical treatment, and thereafter randomised to either control (CON), CRT or WBV. 6MWD was measured at M1, M2 and at least 12 weeks (w) after randomisation (M3) considering a minimal clinically important difference (MCID) of 54 m. Assuming that this MCID would occur in 10% of the CON-group and aiming for an increase to at least 50% in the combined intervention groups (CRT and WBV), a sample size of 25 participants in each arm was required for a power of 90%. Secondary endpoints were estimated by appropriate MCID's for maximal exercise capacity (Wmax), muscle strenght (Quadriceps Force (QF)) and QoL (physical functioning (PF), fatigue (F), pain (P) and dyspnea D)). Multiple imputation was used to correct for patients not finishing the intervention.Results
Of the 86 patients completing radical treatment, 70 were randomised: 24 to CON, 24 to CRT and 22 to WBV. Characteristics at M1 were well balanced. Radical treatment significantly decreased 6MWD, Wmax, QF, PF and increased P, F and D at M2. At M3, 20 of 37 (54%) patients in the combined CRT-WBV-group reached the MCID for 6MWD vs. 5 of 21 CON (24%) patients (p=0·031). 6MWD increased with 95 m (58–132) in CRT (p<0·0001), 37 m (-1–76) in WBV (p=0·06) and 1 m (-33–36) in CON (CRT vs. CON p=0·0006 and WBV vs. CON p=0·16). CRT and WBV patients recovered and exceeded their M16MWD, albeit not significantly. A significant mean increase in Wmax occurred in both CRT and WBV but not in CON, while QF increased only significantly in CRT. The mean score for PF at M3 improved in CON and WBV but only significantly with WBV. The mean score for P and F at M3 did not change significantly, however the MCID for F was reached in 37% of CRT, 44% of WBV and 30% of CON-patients. The mean score for D at M3 decreased significantly after WBV only. Multivariate analysis showed that there was no significant interaction between rehabilitation and surgery with regard to the MCID in 6MWD (p=0.96).Conclusion
Radical treatment significantly impairs exercise capacity, muscle strength and QoL. CRT significantly improves and restores functional exercise capacity, whilst WBV does not fully substitute for CRT. Resistance training by CRT should be offered to radically treated lung cancer and mesothelioma patients. Supported by research grant 070708 of the Belgian Government Agency of Innovation by Science and Technology for applied Biomedical Research (NCT: 00752700)Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O27.07 - Molecular multidisciplinary tumor board (MMTB) for lung cancer patients: 2-year experience report (ID 2865)
17:20 - 17:30 | Author(s): B. Besse, L. Lacroix, L. Faivre, V. Kahn-Charpy, M. Ngo Camus, N. Auger, V. Koubi-Pick, J. Adam, V. Thomas De Montpreville, P. Dorfmuller, C. Le Pechoux, M. Macerelli, T. Le Chevalier, J. Soria, B. Lacas, J. Pignon, A. Rahal, V. Polo, D. Planchard
- Abstract
- Presentation
Background
Molecular analysis (MoA) of non-small cell lung cancer has led to definition of many subgroups that require dedicated treatments, strategy and trials. We created a monthly MMTB dedicated to lung cancer patients (pts) with potential driving molecular abnormalitie(s). MMTB includes physicians from the lung tumor board and the phase I unit, pathologists and biologists. A medical report summarizes the findings and treatment recommendations. We report 2 years of activity of MMTB.Methods
All consecutive files discussed in MMTB in Gustave Roussy were reviewed. Tumor and pts characteristics were collected as well as treatment. Pts outcome was calculated from the MMTB.Results
245 pt files were discussed between February 2010 and March 2012. 53% were male, 27% never-smokers, 89% had PS 0 or 1, median age was 59. Clinical initial stage was III-IV in 17 pts (7%) and 78%/11%/11% were adenocarcinoma/squamous cell carcinomas/others NSCLC. Time from diagnosis to MMTB was 7 months (m) (1-222), 102 (42%) of pts received more than 1 line of treatment before MMTB. Biopsy for MoA mostly came from CT guided biopsies (61%), surgery (22%) or endoscopy (15%). Biopsy was repeated in 20% of pts to get enough material for MoA. The MoA results were ALK rearrangement in 10%, exon 18/19/21 EGFR mutation (mut) in 2/14/8%, KRAS mut in 30%, PI3KCA mut in 0.4%, BRAF mut in 3%, HER2 mut in 1%, FGFR1 amplification in 3%, other rare mutations in 14%. MMTB recommendations were: a clinical trial in 75 pts (31%), receive an EMA-approved drug in 49 pts (20%), an off-label commercial drug in 18 pts (7%), an expanded access program in 18 pts (7%), none in 85 pts (35%). Out of the 160 MMTB pts with treatment recommendations, 63 (42%) received the proposed targeted therapy and 16 (11%) might receive it at the time of disease progression. After MMTB, 84 pts (34%) received 1 line, 66 pts (27%) 2 lines or more, 56 pts (23%) no treatment (unknown in 39 pts). Median follow-up is 20.6 m. Progression-free (in 224 pts) and overall survivals (OS, in 221 pts) from MMTB are 3.5 and 13.4 m. In univariate analysis for OS, the pts who received the recommended treatment from the MMTB had a better prognosis (hazard ratio [HR]: 0.56, p=0.002), confirmed in multivariate analysis (HR=0.61 [95% confidence interval: 0.42-0.88], p=0.009) after taking into account histology, previous platinum-based treatment and the number of previous treatment lines.Conclusion
MMTB leads to treatment recommendations in a majority of the pts, fosters inclusion in clinical trials or expanded access programs, and limits the use of off labelled drugs. Updated data will be presentedOnly Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O27.08 - DISCUSSANT (ID 4015)
17:30 - 17:45 | Author(s): A.Y. Chang
- Abstract
- Presentation
Abstract not provided
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PC02 - EGFR as a Target in Early Stage Disease (ID 71)
- Event: WCLC 2013
- Type: Pro/Con Session
- Track: Medical Oncology
- Presentations: 4
- Moderators:N. Pavlakis, J.S. Lee
- Coordinates: 10/29/2013, 14:00 - 15:30, Parkside Auditorium, Level 1
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PC02.1 - Introduction: Detection of EGFR Mutations (ID 628)
14:05 - 14:20 | Author(s): F. Hirsch
- Abstract
- Presentation
Abstract not provided
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PC02.2 - Pro: Patients with EGFR Mutations Should Receive Adjuvant EGFR TKIs (ID 629)
14:20 - 14:40 | Author(s): K. Nakagawa
- Abstract
- Presentation
Abstract
In lung cancer field, the direction of treatment strategy is in the midst of great change since molecular-targeted-drug was introduced. One of the revolutionary drugs is EGFR-TKI for EGFR positive lung cancer. It contributes to the treatment not only of advanced lung cancer, but also resectable early lung cancer in stage II and III. Although it is common to conduct surgery as the standard of care for early-stage lung cancer treatment, Stage II and III cases show poor prognosis even though complete resection is done. According to Asamura et al, 5-year survival of stage IIA, IIB and IIIA Japanese patients are 61%, 47% and 32% respectively. In response to these results, many investigators have been trying neoadjuvant and adjuvant chemotherapy in combination with surgery. In many cases, relapse after standard resection is distant metastasis, thus it is suspected that in order to achieve better prognosis, possible micrometastasis in whole body needs to be eradicated. Currently combination therapy with platinum-doublet is commonly chosen as the strong treatment regimen for controlling the micrometastasis in advanced cancer cases. Gefitinib is an EGFR-TKI (tyrosine kinase inhibitor) approved for the treatment of unresectable or recurrent NSCLC. Since its approval in Japan in July 2002, it has been approved in about 70 countries and used as the therapeutic medication for advanced recurrent NSCLC (at the point of August 2010). When Gefitinib was initially released, 3 to 5% of drug-related ILD (Interstitial Lung Disease) and deaths were reported in Japan. After cohort study, it has been reported that those who are male, smoker, have the past illness of ILD and have low PS showed the higher ILD incidence rate than other cohorts. In 2004, it has been reported that Gefitinib shows the remarkably high response rate for EGFR positive patients, and subsequent studies demonstrated that EGFR mutation is an efficacy predictive biomarker.It is commonly known that Gefitinib induces apoptosis in EGFR positive patients. In fact, some clear anti-tumor effect have been observed in many clinical studies targeting on EGFR positive advanced NSCLC patients. The result of post-marketing Phase III clinical trial targeting on Asian patients untreated with chemotherapy (IPASS trial)was reported in September 2008. According to pre-planned subgroup analysis based on biomarker, in EGFR positive patient group Gefitinib cohort showed the significant prolongation of PFS (Progression Free Survival) compared to Carboplatin plus Paclitaxel cohort (HR 0.48, 95% CI 0.36～0.64, p<0.0001). In addition, Gefitinib cohort showed better efficacy, QOL, safety and tolerability. However, in terms of OS (Overall Survival), the difference was not observed in two cohorts (HR 1.00, 95% CI 0.76～1.33, p=0.990). On the other hand, in EGFR negative patient group, Carboplatin plus Paclitaxel cohort significantly prolonged PFS compared to Gefitinib cohort (HR 2.85, 95% CI 2.05～3.98, p<0.0001). It was reported from Japan that in the two Phase III controlled study targeting on EGFR positive advanced lung cancer patients untreated with chemotherapy, Gefitinibcohort showed better PFS (Hazard Ratio of less than 0.5) than standard chemotherapy cohort of Cisplatin plus Docetaxel (HR 0.489, 95% CI 0.336～0.710, p<0.0001) or Carboplatin plus Paclitaxel (HR 0.357, 95% CI 0.252～0.507, p<0.001) in both studies. However, the comparison of 2-year survival in the controlled study of Carboplatin plus Paclitaxel, there was no statistically significant difference (Gefitinib: 61.4%, Standard Chemotherapy of CBDCA plus PTX: 46.7%) (P=0.31). In addition, in two cohorts (Gefitinibvs CDDP plus DOC) there was no statistically significant difference in OS among them (HR 1.638, 95％CI 0.749～3.582, p=0.21), thus the superiority of Gefitinib was not demonstrated in terms of OS. In the above-mentioned three prospective controlled trial, it was demonstrated that Gefitinib dramatically prolongs PFS in EGFR positive NSCLC patients compared to standard chemotherapy, and shows high anti-tumor effect and improvement of QOL, but not in terms of OS. It is suspected this is partially because of the fact that in chemotherapy cohort many patients received Gefitinib after relapse. To sum up, Gefitinib shows higher anti-tumor effect than standard chemotherapy if the target patients are EGFR positive, and thus is an appropriate option as the adjuvant treatment regimen after complete resection. It was impliedfrom Phase I trial that Gefitinib shows anti-tumor effect for the solid tumor patients who did not benefit from standard of care or have no other treatment options and thus effective for various types of cancer. In Phase II monotherapy trial, Gefitinib showed clinically significant and continuous anti-tumor effect in locally-advanced or metastatic NSCLC patients previously treated with chemotherapy. Additionally, it improved the cancer symptoms in these patients. Orally administering 250mg or 500mg once per day showed the same level of efficacy. Although in Phase III monotherapy trial targeting on advanced NSCLC patients the efficacy of Gefitinib was demonstrated, there was no statistically significant difference in terms of OS, which is the primary endpoint. However, the response rate of Gefitinib cohort was higher than that of placebo cohort. In Phase III combination chemotherapy trial, standard chemotherapy (Gemcitabine/Cisplatin, Paclitaxel/Carboplatin) and Gefitinib 250mg per day or 500mg per day were evaluated. In this study however, statistically or clinically significant data superior to combination of standard chemotherapy with placebo was not observed. In conclusion, there are three reasons why patients with EGFR mutations should receive adjuvant EGFR-TKIs. Firstly, EGFR-TKI induces apoptosis and its exposition to EGFR positive patients potentially induces eradication of micrometastasis remaining after surgery. Secondly, for the EGFR positive patients, EGFR-TKI is superior to standard platinum-doublet in terms of safety and tolerability. Lastly, EGFR-TKI is the most potent anti-cancer drug for EGFR positive patients at the moment, which shows remarkable anti-tumor effect, prolongs PFS and improves QOL compared to platinum-doublet. Therefore, despite the issue of ILD remains, EGFR-TKI is to be considered as an appropriate treatment option in adjuvant setting for the EGFR positive patients. In order to prove this point, West Japan Oncology Group (WJOG) is currently conducting IMPACT trial, which is a prospective Phase III study.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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PC02.3 - Con: Patients with EGFR Mutations Should Not Receive Adjuvant EGFR TKIs (ID 630)
14:40 - 15:00 | Author(s): C.K. Liam
- Abstract
- Presentation
Abstract
Adjuvant therapies are required to prevent disease recurrence and improve patient survival after surgery in early stage (stage I–IIIA) non-small cell lung cancer (NSCLC). In advanced disease, patients whose tumours have activating EGFR mutations have an approximately 60%-75% response rate to EGFR tyrosine kinase inhibitors (TKIs) treatment as first-line therapy and a progression-free survival that is significantly superior to standard chemotherapy. Although adjuvant TKI therapy is an appealing treatment strategy, can the remarkable efficacy of EGFR TKI in advanced EGFR-mutant NSCLC be extrapolated to stage I-IIIA disease? While adjuvant cisplatin-based chemotherapy prolongs survival with just 3-4 months of treatment, no trial to date has studied the value of a few months of adjuvant EGFR TKI. The phase III BR.19 trial by the National Cancer Institute of Canada designed to study 1,160 patients with fully resected stage IB, II and IIIA NSCLC randomised to receive 2 years of adjuvant gefitinib at 250 mg daily or 2 years of adjuvant placebo was greatly underpowered because enrolment was stopped prematurely when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in a patient population not enriched for the presence of EGFR mutations with inoperable stage III NSCLC. EGFR mutation status was tested post-hoc in two thirds of 537 patients enrolled. There was no overall survival (OS) benefit for adjuvant gefitinib over placebo (HR 1.58; 95% CI, 0.83 - 3.0; P = 0.16) in 76 patients with EGFR mutant tumours. Despite an underpowered study, the negative finding should caution us about recommending adjuvant EGFR TKI therapy outside of a protocol setting. The phase III Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) compares 2 years of adjuvant erlotinib, at 150 mg orally per day, to 2 years of placebo following complete resection of stage I-IIIA NSCLC in 945 patients who were selected based on having either EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by FISH. At the 2009 ASCO meeting, the RADIANT investigators presented the results of the biomarker analyses from the first 655 patients enrolled which showed an EGFR mutation-positive rate of 12%, which suggests that in the final result there will be approximately 38 EGFR mutation-positive patients on the placebo arm and about 76 on the erlotinib arm. This study is unlikely to provide sufficient power to a draw a firm conclusion about genotype-directed adjuvant therapy for patients with EGFR mutations. Investigators from the Memorial-Sloan Kettering Cancer Center reported a retrospective series of 167 patients at their centre with resected stages I-III NSCLC which were EGFR mutation-positive, among whom 32% received adjuvant EGFR TKI therapy. An improved 2-year disease-free survival (DFS) was observed in patients who received adjuvant TKI therapy compared to those who did not (89% vs 72%) (HR, 0.53; 95% CI, 0.28 - 1.03; P = 0.06). A trend toward more favorable 2-year OS in recipients of EGFR TKI therapy was also seen (96% vs 90%; HR 0.62, CI 0.26-1.51, P = 0.296). When the number of patients with resected EGFR mutant lung cancers was increased to 222, the same investigators in a more recent publication, showed treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, DFS HR 0.43 (95% CI: 0.26-0.72, P = 0.001), and a trend toward improved OS. The phase II SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) trial is a single-arm, prospective study of two years of adjuvant erlotinib in 100 patients with resected, state IA to IIIA EGFR mutation positive NSCLC. Preliminary results presented at the 2012 ASCO meeting for the first 36 patients showed a DFS of 94% compared to a historical control of 70% with a median follow-up of 2.7 months. The answer provided by the SELECT trial is also unlikely to be definitive. The phase II/III Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) trial by the French Collaborative Intergroup compares 4 cycles of standard cisplatin/pemetrexed (CP) adjuvant chemotherapy (arm A, n = 74) with customised adjuvant treatment (arm B, n = 76) based on EGFR and ERCC1 status in patients with completely resected stage IIA, IIB or IIIA (non-N2) (6[th] TNM edition) nonsquamous NSCLC. In the experimental arm, EGFR mutated patients received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. EGFR mutation was identified in only 10 patients (3 in arm A, 7 in arm B). All 7 patients with EGFR mutation in arm B received erlotinib for a median duration of 276 days. The phase III was cancelled due to the unexpected unreliability of the ERCC1 immunohistochemistry read-out. Two randomised studies comparing gefitinib 250 mg daily for 2 years with adjuvant chemotherapy (4 cycles of cisplatin/vinorelbine) in patients with surgically resected stage IIA, IIB and IIIA EGFR mutation-positive adenocarcinoma are ongoing in Japan and in China (ADJUVANT CTONG 1104). In conclusion, it remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, and it is premature to recommend adjuvant EGFR TKI therapy outside well-designed clinical trials as there is currently no conclusive data on its role in early- and locally advanced NSCLC harbouring EGFR mutations. Given the consistent development of acquired resistance to EGFR TKI therapy in patients with metastatic NSCLC, there is good reason to question whether it is advisable to use EGFR TKI for adjuvant therapy in patients who have no evidence of disease and who can develop resistance to an otherwise effective treatment. Furthermore, the optimal duration of adjuvant therapy is yet to be defined and it is unknown whether EGFR TKI is merely by suppressing the growth of residual disease after surgery rather than eradicating minimal residual disease. Given the fact that adjuvant therapy needs to be given post-operatively for a prolonged period, the quality of life of patients while on therapy and the financial cost involved also need to be considered.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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PC02.4 - Adjudication and Discussion (ID 631)
15:00 - 15:25 | Author(s): M. Kris
- Abstract
- Presentation
Abstract not provided
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MO12 - Prognostic and Predictive Biomarkers III (ID 96)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:B. Han, M. Edelman
- Coordinates: 10/29/2013, 10:30 - 12:00, Parkside Ballroom B, Level 1
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MO12.11 - The predictive role of common BIM deletion polymorphism and BIM expression on the EGFR-TKI therapy in never-smoking lung adenocarcinoma (ID 2161)
11:30 - 11:35 | Author(s): J.S. Lee
- Abstract
- Presentation
Background
The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein. Recent data suggest that pretreatment BIM level may predict responsiveness to EGFR-TKI in EGFR-mutant non-small cell lung cancer (NSCLC). In addition, a common BIM deletion polymorphism contributes to the heterogeneity of response to EGFR-TKI in EGFR-mutant NSCLC. We investigated whether BIM expression and BIM deletion polymorphism (BIM-DEL) are predictive for response rate (RR) and progression-free survival (PFS) to EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).Methods
We analyzed EGFR mutation status by Sanger sequencing, BIM-DEL genotyping by polymerase-chain reaction and BIM expression by immunohistochemistry using archival tissues or blood from 203 patients who participated in the FIRST-SIGNAL trial (1[st] line gefitinib vs. Gemcitabine/cisplatin in advanced NSLA).Results
EGFR mutation test, BIM-DEL genotyping and BIM-IHC analysis were available in 82, 126 and 60 patients, respectively. Forty-five (55%) patients had EGFR mutations, 22 (18%) showed BIM-DEL and 22 (37%) showed negative BIM expression. BIM expression was significantly associated with EGFR mutation status; more patients with EGFR-mutant NSCLC showed negative BIM expression (48% vs. 21%, P=0.030). BIM-DEL was not associated with EGFR mutation status or BIM expression. Among 181 patients who received EGFR-TKI as 1[st] or 2[nd]-line therapy, EGFR mutation, BIM-DEL and BIM expression data were available in 74, 11, 56 patients, respectively. EGFR mutation was predictive for higher RR (66% vs. 15%, P<.001) and longer PFS (4.5 vs. 1.9 months, P=.061) to EGFR-TKI therapy. Negative BIM expression also showed a trend toward higher RR (68% vs. 42%, P=.061) and longer PFS (6.9 vs. 2.3 months, P=.233) with EGFR-TKI. However, BIM-DEL was not predictive for RR (41% vs. 47%, P=.645) or PFS (3.5 vs. 3.7 months, P=.892) to EGFR-TKI.Conclusion
Both BIM-DEL and BIM expression were not predictive for responsiveness to EGFR-TKI in NSLA. The trend between negative BIM expression and favorable response to EGFR-TKI may be resulted from higher frequency of EGFR mutation in these patients.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O01 - Prognostic and Predictive Biomarkers I (ID 94)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:T. Mitsudomi, V. Gregorc
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Auditorium, Level 1
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O01.06 - Dynamic change in plasma EGFR mutation DNA in response to first line therapy for advanced stage non-small cell lung cancer (NSCLC) (ID 2496)
11:25 - 11:35 | Author(s): J.S. Lee
- Abstract
- Presentation
Background
Diagnostic utility study of EGFR mutation analysis of tumor and plasma from FASTACT 2 confirmed that the plasma EGFR mutation DNA (pEGFRmut) is a sensitive and specific biomarker. (Wu et al, Lancet Oncology 2013; T. Mok, ASCO 2013). Primary objective of this study is to investigate the dynamic change in pEGFRmut during course of treatment. Secondary objective is to study the diagnostic utility of pEGFRmut in patients with distant organ metastasis whom we assumed to have higher level of plasma DNA.Methods
Retrospective EGFR mutation testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific assays, cobas® 4800 EGFR_FFPET test and cobas® EGFR_blood test (in Development). Both tests are designed to detect one or more of the 42 known EGFR mut. One FFPET section was used for tissue test and 2-ml plasma was used for blood test. We studied the plasma samples collected at baseline, post cycle 3 (C3) and at tumor progression according to RECIST criteria (PD).Results
Complete analysis of plasma samples at baseline, C3 and PD was available in 305 of 451 pts(67.6%). Incidence of pEGFRmut positive at baseline, C3 and PD was 35% (106/305),15% (47/305)and 27% (81/305), respectively. 98 of 106 pEGFRmut patients harbor the Exon 19 deletion or L858R at baseline. (C arm 51; CE arm 47). At C3, 21 (41%) pts lose pEGFRmut positivity in C arm comparing to 39 (83%) in CE arm. At PD, 8 of the 21pts in C arm and 18 of the 39 in CE arm regained pEGFRmut positivity. Table 1 summarized the median pEGFRmut copies/PCR. There was a considerable decline at C3 in both C and CE arm. However, pEGFRmut copies/PCR rebounded to high level at PD in C arm only and remained low in CE arm. Correlation of dynamic change in pEGFRmut copies/PCR with clinical tumor response and PFS will be presented at the meeting. We have also identified 93 (out of 224 matched tissue and plasma samples) patients with known distant organ metastasis. Sensitivity of pEGFRmut in this patient subgroup is 91% (41/45), specificity at 98% (47/48) and overall concordance at 95% (88/93). Table 1Median pEGFRmut copies/PCR Baseline C3 PD C (Exon 19) 27.6 2.3 35.8 CE (Exon 19) 43.2 0 2.7 C(Exon 21) 40.9 2.6 63.9 CE (Exon 21) 87.1 0 3.5 Conclusion
This is the first study demonstrating the quantitative dynamic change in pEGFRmut in pts who received C or CE for advanced NSCLC. At RECIST progression, pEGFRmut remained low in patients who received erlotinib but not in patients who received chemotherapy only. pEGFRmut is a potential biomarker for monitoring tumor response.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O15 - NSCLC - Chemotherapy II (ID 109)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:G. Richardson, J.V. Heymach
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside Auditorium A, Level 1
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O15.08 - DISCUSSANT (ID 3941)
11:45 - 12:00 | Author(s): J.S. Lee
- Abstract
- Presentation
Abstract not provided
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P2.03 - Poster Session 2 - Technology and Novel Development (ID 151)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.03-004 - Clinical application of targeted deep sequencing as a molecular screening for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in never-smoking lung adenocarcinoma (ID 2170)
09:30 - 09:30 | Author(s): J.S. Lee
- Abstract
Background
The molecular screening is a key step to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. We investigated the clinical relevance of targeted next generation sequencing (NGS) as a molecular screening for EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).Methods
We obtained DNA from 48 NSLA received gefitinib or erlotinib for their recurrent disease after surgery. The Sanger sequencing and peptide nucleic acid clamp polymerase chain reaction (PCR) were used to analyze EGFR, KRAS, BRAF and PIK3CA mutations. We analyzed ALK, RET and ROS1 rearrangements by fluorescent in situ hybridization or reverse transcriptase-PCR and quantitative real-time PCR. Finally, Ion Torrent NGS was performed in 31 cases harboring only EGFR exon 19 deletions (19DEL) or L858R mutation or none of above mutations.Results
After excluding mutations other than EGFR 19DEL or L858R, samples were divided into 4 groups; 1) responders to EGFR-TKIs with only 19DEL or L858R (n=15); 2) primary resistance to EGFR-TKI with only 19DEL or L858R (n=4); 3) primary resistance to EGFR-TKI without any mutations (n=8); 4) responders to EGFR-TKI without any mutations (n=4). All conventionally detected mutations were confirmed with NGS. Additionally uncovered predictive mutations include; one PIK3CA E542K and one BRAF in group 2; two KRAS (G12V and G12D), one PIK3CA E542K and one concomitant PIK3CA and EGFR L858R in group 3; one EGFR 19DEL in group 4. Newly detected mutations were validated by Sanger sequencing.Conclusion
Targeted NGS provided more accurate and clinically useful molecular classification of NSLA. It may improve personalized therapy for individual patients.
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P2.09 - Poster Session 2 - Combined Modality (ID 213)
- Event: WCLC 2013
- Type: Poster Session
- Track: Combined Modality
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.09-018 - Incorporating erlotinib into induction chemotherapy followed by concurrent chemoradiation of unresectable stage III non-small cell lung cancer according to EGFR mutation status: preliminary result of a randomized phase II study (ID 3178)
09:30 - 09:30 | Author(s): J.S. Lee
- Abstract
Background
EGFR tyrosine kinase inhibitors (TKIs) showed great survival benefit in the selected patients with stage IV non-small cell lung cancer (NSCLC) harboring TKI-sensitive EGFR mutations. Assuming that if the cases were properly selected, EGFR-TKIs would be integrated into treatment paradigms of stage III NSCLC as more effective systemic therapy, we designed this study to evaluate the efficacy and toxicity of erlotinib and chemotherapy in the combined-modality treatment of unresectable stage III NSCLC patients according to EGFR mutation status.Methods
Patients over 18 years with unresectable stage IIIA (N2) or stage IIIB NSCLC, ECOG performance status 0–1, and adequate organ function are eligible. The mutational analysis of EGFR (exon 18–21) is performed using direct sequencing in tissue sample. EGFR mutation-positive patients initially receive 3 cycles of erlotinib and then are treated by concurrent chemoradiotherapy (CRT) with either erlotinib (Arm A) or irinotecan-cisplatin (IP) (Arm B). After CRT, patients in Arm A receive consolidation therapy with 6 cycles of erlotinib while those in Arm B are observed until progression. EGFR mutation-negative or unknown patients are treated either with 3 cycles of IP followed by CRT with IP (Arm C) or vice versa (Arm D). Erlotinib is given at 150mg daily with 3-week cycle. IP is given with cisplatin 30mg/m[2] (day 1 and 8) and irinotecan 60mg/m[2] (day 1 and 8) during radiotherapy (total 60 Gy/ 2.4 Gy/fr) or with cisplatin 30mg/m[2] (day 1 and 8) and irinotecan 65mg/m[2] (day 1 and 8) during induction or consolidation therapy with 3-week cycle. The primary endpoint is response rate (RR), toxicity, and survival estimation. Erlotinib and irinotecan were provided by Roche Korea and Pfizer, Inc., respectivelyResults
From February 2008 to February 2013, 62 patients were screened and 50 patients were randomized into Arm A (n= 6), Arm B (n= 4), Arm C (n= 19), and Arm D (n= 21). The EGFR mutation status was positive in 10 (20.0%) patients, negative in 23 (46.0%), and unknown in 17 (34%). The median age was 65 years. The proportion of never smoker and adenocarcinoma histology was 80% (event/ total No. = 8/10) and 90% (9/10) in the EGFR mutation-positive group, 13% (3/23) and 48% (11/23) in the EGFR mutation-negative group, and 6% (1/17) and 18% (3/17) in the EGFR mutation-unknown group. The median follow-up time was 34.7 months (range, 3.8−53.8 months). The completion rate of planned treatment was 66.7% (4/6), 100% (4/4), 78.9% (15/19), and 76.2% (16/21) from Arm A to Arm D. For induction therapy, the RR to elrotinib of the EGFR mutation-positive group was 70.0% (7/10). Moreover, the subgroup harboring TKI-sensitive EGFR mutations (exon 19 deletion and exon 21 L858R mutations) showed the RR to erlotinib of 87.5% (7/8). The RR to IP induction therapy was 41.7% (5/12) in the EGFR mutation-negative group, 0% (0/4) in the EGFR mutation-unknown group, and thus 31.1% (5/16) in the EGFR mutation-negative or unknown patients.Conclusion
The combined-modality treatment by molecular diagnostics was feasible in stage III NSCLC and accrual is ongoing.
