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M. Redman
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MINI 29 - Meta Analyses and Trial Conduct (ID 156)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 15
- Moderators:D. Morgensztern, M. Redman
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2a-3b
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MINI29.01 - Squamous Cell Carcinoma of Lung in the United States: Analysis of the National Cancer Database (NCDB) (ID 2747)
18:30 - 18:35 | Author(s): M. Behera, T.K. Owonikoko, Y. Liu, T.W. Gillespie, M. Yuan, R.N. Pillai, C. Steuer, K.A. Higgins, S. Pakkala, C.P. Belani, F. Khuri, S.S. Ramalingam
- Abstract
Background:
Lung squamous cell carcinoma (SCC) is the second most common histological sub type of lung cancer and accounts for about 30% of all non-small cell lung cancers (NSCLC). We analyzed the NCDB, an oncology outcomes database administered by the American College of Surgeons and the American Cancer Society, to study the epidemiology, patterns of care, outcomes and temporal changes in incidence of SCC.
Methods:
The NCDB was queried from 1998 to 2011 for SCC using ICD-O-3 codes. Temporal changes in incidence were estimated in intervals (1998-1999, 2000-2003, 2004-2007, 2008-2011). The univariate association with covariates between SCC and other subtypes of NSCLC was assessed using Chi-square test or ANOVA. The univariate (UV) and multivariable analysis (MV) with OS were conducted by Cox proportional hazards model and log-rank tests. All statistical analyses were conducted using SAS Version 9.3.
Results:
A total of 435,358 pts with SCC were included in the analysis and accounted for 28% of all NSCLC pts in NCDB. Pt characteristics: median age 70 (18-90 yrs); males 64%; whites 87%; academic centers 27%; metro locations 78%; government insured 72%; Charlson/Deyo comorbidity score (CDS) 0 in 55% and ≥2 in 15%, and stage III/IV- 34/31%. Chemotherapy was used in 39% of pts, radiation in 46% and surgery in 32%. Approximately 19% of the pts did not receive any of the three treatments. Incidence of SCC decreased over time (35%, 28%, 26%, 27%) vs. increasing trend in non-SCC (65%, 72%, 75%, 72%); p<0.001). The trend was similar across all races and sex. SCC was associated with a higher co-comorbidity burden than non-SCC across all stages (CDS 0: 55% vs. 62%; CDS 1: 31% vs. 27%; CDS ≥2: 15% vs. 11%; p<0.001). SCC was associated with inferior 5 yr survival vs. non-SCC in all stages (stage I- 30% vs. 41%, stage II- 16% vs. 21%, stage III- 8.5% vs.10%, stage IV- 1.9% vs. 2.5% respectively; p<0.0001). The 1 yr survival in stage IV SCC is 19.6% vs. 22.2% in non-SCC (p<0.0001). Males had worse survival (HR 1.11 (1.09-1.13; p<0.001). Pts at community centers had worse survival vs. academic centers (HR 1.27 (1.23-1.30; p<0.001). An increasing trend in chemotherapy use was observed (31% in 1998 to 43% in 2011) vs. a decreasing trend in use of radiation (52% in 1998 to 46% in 2011) and surgery (32% in 1998 to 27% in 2011). Chemotherapy was received by 48% of patients with stage IV SCC. Chemotherapy use across other stages: 0/I- 18%, II- 46%, III- 60%. Males were more likely to receive any treatment (OR 1.12 (1.08-1.15); p<0.001). Pts that received any treatment had significantly better 5 year survival than those who did not receive any (20.3% vs. 3.3%, p<0.0001)
Conclusion:
SCC accounted for 28% of all cases of NSCLC in the United States, was associated with higher comorbidities and a significantly worse survival compared to non-SCC of the lung. Chemotherapy was used in only 48% of pts with stage IV SCC.
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MINI29.02 - Effect of Statins and Metformin on Survival in Patients with Non-Small Cell Lung Cancer (ID 363)
18:35 - 18:40 | Author(s): N. Duma, M. Kang, K. Abu-Ihweij, M. Choudhary, A. Gandhi, M. Gutierrez
- Abstract
- Presentation
Background:
Lung cancer is the number one cause of cancer-related death worldwide; with the incidence of non-small cell lung cancer (NSCLC) risen dramatically, the importance of understanding the influence of comorbidities and their treatments takes a great importance. The aim of this study was to investigate the effect of statins and metformin on survival in patients with NSCLC.
Methods:
We reviewed the records of all patients diagnosed with NSCLC at our institution from 2011 to 2013. Demographics, tumor characteristics, comorbidities, statin/ metformin use and survival were analyzed. Cox regression was used for multivariate analysis.
Results:
A total 205 patients were studied. Median age at diagnosis was 65 years (40-91), there were more males than females (56% vs. 44%, p<0.01. 74% (152) were current or former smokers with average 40 pack years (5-60). The Median BMI was 26.5kg/m2 (18-44), ECOG status was 1 (0-4) and serum creatinine of 1.0 (0.4-3.5). Regarding comorbidities: 48% (98) had hypertension, 45% (93) hyperlipidemia, 22% (44) COPD and 19% (39) diabetes mellitus. At diagnosis, 66% (136) of the patients had stage III/IV disease vs. 25% (69) with stage I/II, p<0.0001. Adenocarcinoma was the most common histologic subtype (61%), followed by squamous cell carcinoma (27%). 42% received surgery, 80% systemic chemotherapy and 32% radiation. Median survival was 1520 days (95% CI: 1310-1765). 42% (87) of the patients were taking statins and 13% (27) metformin. About the statin use, 58% of the patients were using statins for 25-48 months, 12% for >48 months, 11% for 13-24 months and 18% for less than 12 months. Female gender (OR: 1.98, p<0.001), age<65 years (OR: 0.89, p<0.01) and statin use (OR: 0.78, p<0.02) were independent predictors of survival by multivariate analysis. Metformin use was not a predictor of survival by univariate or multivariate analysis in this group of patients.
Conclusion:
In our cohort, we observed that almost half of the patients had hypertension and hyperlipidemia with statin use been a significant predictor of survival. Statins are one of the mostly widely prescribed drugs in the US; their proven anti-inflammatory effects may play a role in inhibiting cancer growth. However, the exact mechanisms by which statins inhibit cancer proliferation remains unclear. While other observational studies have looked at statins and risk of developing cancer, we specifically looked at the effect of statins on survival in patients on statin therapy prior to cancer diagnosis. More studies are needed to enhance our understanding of the effect of statins on lung cancer.
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MINI29.03 - Prognostic Value of Biomarkers Associated with Glucose Metabolism and Systemic Inflammation in Advanced On-Small Cell Lung Cancer (NSCLC) (ID 3061)
18:40 - 18:45 | Author(s): M.J. Fidler, G.C. Lobato, S. Kerns, S. Basu, C.L. Fhied, R. Pithadia, I. Tarhoni, M. Batus, P. Bonomi, J.A. Borgia
- Abstract
- Presentation
Background:
Alterations in glucose metabolism and appetite stimulating hormones have been correlated with inflammation but there is little information on frequency and prognosis in newly diagnosed stage IV non-small cell lung cancer (NSCLC) This study objective was to identify associations of circulating biomarkers of glucose metabolism and inflammation with prognosis in pre-treatment sera from stage IV NSCLC patients selected for platinum doublet based chemotherapy.
Methods:
Pretreatment serum from 118 Pts with frontline stage IV NSCLC were evaluated with the Bio-Plex Pro Human Diabetes Assay panel (adiponectin, adipsin, c-peptide, ghrelin, gastrin inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon, IL-6, insulin, leptin, Plasminogen activator inhibitor-1, resistin, TNFα, vistatin) and HSTCMAG-28SK | MILLIPLEX MAP Human High Sensitivity T Cell Panel - Immunology Multiplex Assay (Fractalkin, GM-CSF, IFNγ, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, IL-23, ITAC, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-3α, TNFα) on a FlexMAP 3D system (Luminex Corp.). Pts were treated with standard platinum doublets based chemotherapy. Associations of biomarkers with progression free and overall survival (PFS,OS) outcomes were assessed using multivariate Cox PH analyses.
Results:
Most patients had metabolic levels below the prognostic threshold. However, high levels of insulin, GIP, glucagon, visfatin, ghrelin, GLP-1 were significantly associated (p<0.05) with shorter PFS. Low levels of adipisin (deficiency of which is associated with obesity) was associated with shorter PFS (p=.0185). High levels of pro-inflammatory markers: ITAC, GM-CSF, Fratalkine, INF-ϒ, IL-12p70, IL-13, IL17A, IL-4, IL-23, IL8.4, MIP-α, MIP-1 were also associated with poor PFS (p<0.05) (See Table I for more details on select biomarkers) High levels of these endocrine markers (except insulin and GIP) were associated with shorter OS as were ITAC, GMCSF, IL12p70, IL-13, IL4, IL23, IL5 (p<0.05). Table I. Biomarker correlation with progression free survivalMarker Cutoff-pg/mL N < N > Median PFS < Median PFS> Logrank p Insulin 1004.9 82 36 6.08 4.04 0.026161 Glucagon 361.2 110 8 5.46 1.71 0.010219 Visfatin 8298.3 109 9 5.65 1.45 8.77E-06 Ghrelin 2897.2 104 14 6.02 2.12 0.009423 GLP.1 268.8 109 9 5.65 1.97 0.000618 ITAC 104.7 99 19 5.82 2.96 0.012529 Fractalkine 271.7 97 21 6.08 3.16 0.0067 IL.12.p70. 17.0 109 9 5.65 3.16 0.010631 IL.13 14.9 105 13 5.82 2.76 0.001533 IL.17A 49.4 102 16 5.82 3.65 0.004862 IL.4 66.1 104 14 6.02 2.96 0.000917 IL.8.4 3.0 25 93 12.8 4.8 0.008985
Conclusion:
Imbalances in the glucose metabolism pathway and increased levels of pro-inflammatory circulating markers were uncommon but consistently associated with a poor prognosis in stage IV NSCLC patients early in their treatment cycle. Alterations in these systems have been associated with cancer cachexia and may be targets for intervention in improving prognosis for select patients with NSCLC.
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MINI29.04 - The Use of Metformin and Proper Glycemic Control Are Associated with Improved Survival in Non-Small Cell Lung Cancer Patients (ID 1612)
18:45 - 18:50 | Author(s): O. Arrieta Rodriguez, E. Varela-Santoyo, E. Soto-Pérez-De-Celis, R. Sánchez-Reyes, M. De La Torre-Vallejo, A.F. Cardona
- Abstract
- Presentation
Background:
Previous population-based studies have shown an association between metformin use and improved survival among diabetic patients with lung cancer. We sought to analyze the effect of diabetes and its treatment in terms of survival in Mexican patients with lung cancer treated at a single institution
Methods:
1106 patients were included. Outcomes were compared between patients with (n=186) and without diabetes (n=920). Characteristics associated with antidiabetic treatment and with proper glycemic control (defined as mean plasma glucose <130mg/dL) were examined. Overall survival (OS) among the different patient populations was analyzed using Kaplan-Meier curves and multivariate analysis was used to determine the influence of patient and tumor characteristics on survival
Results:
OS for the entire population was 18.3 months (95% CI 16.1-20.4). There was no difference in OS between diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). Diabetic patients taking metformin had a superior OS than those taking other antidiabetic treatment (25.6 vs 13.2 months, p = 0.001), and those with proper glycemic control had a better OS than those without proper glycemic control (40.5 vs 13.2 months, p<0.001). Both the use of metformin (HR 0.57 p = 0.017) and proper glycemic control (HR 0.40, p =0.002) were significant protective factors in the diabetic patient population.
Conclusion:
Proper glycemic control and metformin use have a beneficial effect on the survival of patients with diabetes and lung cancer. Studies using metformin in lung cancer should include measures of proper glycemic control as fundamental variables.
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MINI29.05 - Discussant for MINI29.01, MINI29.02, MINI29.03, MINI29.04 (ID 3385)
18:50 - 19:00 | Author(s): D.J. Stewart
- Abstract
- Presentation
Abstract not provided
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MINI29.06 - Are Clinical Trial Eligibility Criteria an Accurate Reflection of a Real World Population of Advanced Lung Cancer Patients? (ID 1398)
19:00 - 19:05 | Author(s): K. Al-Baimani, H. Jonker, T. Zhang, G. Goss, S.A. Laurie, G. Nicholas, P. Wheatley-Price
- Abstract
- Presentation
Background:
Modern systemic treatment options for advanced NSCLC have largely been established from clinical trials (CTs). It is estimated that less than 10% of cancer patients enter a CT, but this subgroup drives oncology practice and impacts treatment decisions for other cancer patients. The advantage of CTs comes from solid internal validity and stringent methodology. Nonetheless, the generalizability of CTs could be questioned due to the high selectivity of eligibility criteria. We investigated clinical trial eligibility in an unselected NSCLC population
Methods:
With ethics approval, a retrospective chart review was performed of patients with de novo advanced NSCLC assessed by medical oncologists at a large academic cancer centre, serving a mixed urban and rural population, between September 2009 and September 2012. Data collected included patient demographics, stage, performance status, histology, treatment details and outcome. Two sets (A and B) of arbitrary eligibility criteria were created using common criteria from phase 3 CTs. These criteria were applied to this cohort to identify the proportions of patient who would hypothetically qualify for CT enrollment. Criteria A required: ECOG 0 or 1, absence of brain metastases, Creatinine < 120 and the absence of second malignancy. Criteria B, allowing broader inclusion, only required ECOG 0-2 and Creatinine < 120. We investigated survival among eligible/ineligible and treated/untreated patients.
Results:
528 patients were included: 55% male; 50% ECOG 0-1; 58% adenocarcinoma, 22% squamous cell; 7% stage IIIB and 93% stage IV. Using the strict CT criteria (A), only 144 (27%) patients were considered eligible. Of those, 79% actually received systemic therapy. From 384 patients who would have been ineligible for the CT, 178 patients (46%) still received systemic therapy. There was a trend to longer median overall survival (mOS) in the eligible treated compared to eligible non-treated patients (11.6 vs 8.1 months p=0.12). mOS was significantly longer in the non-treated eligible cohort compared to the non-treated ineligible cohort (8.1 vs 3.8 months p=0.003). The eligible treated and non-eligible treated had similar mOS ( 11.6 vs 10.2 months, p= 0.10). When less strict eligibility criteria (B) were applied, 343 patients (65%) would have been eligible, of whom 240 patients (70%) actually received systemic therapy. From the remaining ineligible 185 patients, only 51 (28%) received treatment. The mOS was similar in the treated patient whether eligible or ineligible (10.9 vs 10.1 months, p=0.57). As seen in criteria A, significantly longer mOS was observed in the eligible untreated compared to the ineligible untreated ( 4.9 vs 3.5 months p<0.001).
Conclusion:
While clinical trial criteria restrict study entry to the fittest patients, these results suggest that they do not reflect the broader patient population, as many ‘ineligible’ patients received therapy. Extrapolation of treatment paradigms to non-trial eligible populations is common, and may be reasonable based on these results. We observed similar survival among treated patients, whether trial eligible or not. This suggests that clinical judgement is more important than trial eligibility. In order to broaden trial participation, we could hypothesize that trial eligibility criteria could be relaxed.
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MINI29.07 - CNS Disease Enrollment Criteria for NSCLC Drug Trials (ID 908)
19:05 - 19:10 | Author(s): E.M. Berge, C.E. McCoach, X. Lu, A.E. Barón, R. Camidge
- Abstract
- Presentation
Background:
CNS metastases are common in NSCLC, yet clinical trials of new drugs in NSCLC have widely varying inclusion and exclusion criteria in relation to CNS disease. CNS disease that has received local therapy may be dormant, confounding any subsequent drug benefit, whereas untreated CNS disease may reduce PFS if CNS and systemic drug exposure differs. Recently, RANO guidelines propose explicitly explored activity in CNS disease within solid tumor drug trials. The true extent of variation in CNS related enrollment criteria in NSCLC clinical trials has not been documented before.
Methods:
ClinicalTrials.gov was interrogated on September 11, 2014 looking for interventional drug trials including advanced NSCLC. The following characteristics were extracted: 1) trial phase; 2) experimental arm therapy (chemotherapy, targeted therapy, immunotherapy, anti-angiogenic); 3) location (US, International only, US + International); 4) sponsor (Industry, University/IIT, Cooperative Group, NCI); 5) CNS disease allowance (strict exclusion, allowed after local treatment (surgery/radiation), unrestricted/untreated disease allowed). Industry sponsorship was divided into ‘large pharmaceutical’, (top decile by number of sponsored trials) and ‘small pharmaceutical’ (lower 9 deciles). Exclusion of CNS metastasis was treated as a binary variable and grouped as ‘strict exclusion’ vs. ‘allowed CNS metastasis’ (‘allowed with treatment’ and ‘allowed untreated’). Univariable and multivariable logistic regression models were fit to test the association between exclusion of CNS metastasis and trial characteristics. Statistical significance was set at 0.05 with no adjustment for multiple testing.
Results:
Of 735 trials involving NSCLC, 325 (44%) were excluded from analysis mostly because of allowance of early stage NSCLC (50%, n=164), or no active therapy inclusion (45%, n=146). In the remaining 406 trials, patients with CNS metastases were excluded in 58 (14%), allowed after local treatment in 165 (41%), and allowed with no prior treatment in 104 (26%). CNS criteria were not referenced in the available information in 79 (19%) trials which were excluded from further analysis. On univariable analysis, the odds of CNS metastasis exclusion on trial were significantly lower in trials with vs. without targeted therapy (OR 0.44, 95% CI: 0.25-0.78, p=0.005) and significantly higher in trials with vs. without immunotherapy (OR 2.13, 95% CI: 1.06-4.28, p=0.04). No other univariable associations were significant. In multivariable analysis, after adjustment for all other factors, only trials located at international only vs. US only sites had greater odds of exclusion of CNS metastasis (OR 1.64, 95% CI 0.84-3.22; p=0.03).
Conclusion:
Although univariable analysis suggests class of agent may influence trial design, in multivariable analysis trial location was the only variable associated with strict exclusion of CNS metastases. This raises the possibility of exclusion based on historical/cultural rather than scientific factors. With 18% of trials (58/327) excluding all CNS disease and 50% (165/327) only allowing CNS disease if previously treated, less than a third of NSCLC trials permit unequivocal assessment of CNS activity (104/327). Given the high frequency of CNS disease in NSCLC, sponsors should consider consciously tailoring trial designs to more explicitly explore efficacy in this patient population.
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MINI29.08 - Innovation in Non-Small Cell Lung Cancer (NSCLC): Where Are the Clinically Meaningful Outcomes? (ID 1280)
19:10 - 19:15 | Author(s): L.M. Hess, S.L. Able, G.C. Carter, J.A. Treat
- Abstract
- Presentation
Background:
The American Society of Clinical Oncology (ASCO) recently developed a set of recommended targets for clinically meaningful outcomes to encourage patients, advocates and investigators to expect more of clinical trials in the future and to encourage investigators to design trials and select agents that have the most promise. A systematic literature review was conducted to identify where and how research has successfully met the bar for meaningful improvements in NSCLC patient survival.
Methods:
A systematic search strategy was implemented in MedLine and EMBASE to identify randomized phase III trials reporting overall survival (OS) outcomes from 1974-present. Eligible studies were those that reported OS data in terms of a hazard ratio (HR) or median OS. Patients in the eligible randomized trials were NSCLC patients treated in the first (1L) or post-first line (2L+) setting. Data were extracted related to study population, histology, interventions, and survival from trials of patients with advanced or metastatic disease. All eligibility determinations and extracted data were reviewed by two researchers for accuracy.
Results:
The search strategy identified 2051 articles that were reviewed for eligibility. Of these, 245 were eligible for inclusion. 198 (80.8%) studied 1L, 45 (18.4%) 2L+, and 2 investigated both lines. Of all articles, 51 (20.8%) found significant improvement in survival (Figure 1). Of these, 45 (88.2%) were 1L (41 studies). 14/41 (34.1%) were terminated early or had major protocol changes during study enrollment, and 5/41 (12.2%) reported inconsistent outcomes. In significant 1L studies, the median OS improvement ranged from 0.3-7.0m and HRs ranged from 0.35 to 0.87. The 4 2L+ positive studies, OS improvement ranged from 1.4-2.8m and HRs from 0.70-0.86. Of all 198 1L publications, 12 studies met the significant HR <0.80 bar and an additional 12 studies reported statistically significant gains of ≥2.5m OS. Figure 1. Publications reporting significant improvement in survival Figure 1
Conclusion:
There is a need to improve survival outcomes for patients in NSCLC. In 1L, few studies would have met the ASCO target. Only four 2L+ trials were identified with significant improvements in NSCLC. The results of this systematic literature review inform the interpretation of research and the new bar recommended for meaningful outcomes.
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MINI29.09 - Recommendations for Standardized Efficacy Data Specifications in Lung Cancer (ID 1599)
19:15 - 19:20 | Author(s): S. Khozin, G. Blumenthal, A. Khomyanina, B. Brodsky, R. Fitzmartin, P. Keegan, R. Pazdur
- Abstract
- Presentation
Background:
There are general standards for common clinical trial data elements submitted to US Food and Drug Administration (FDA) in a new drug application (NDA) or biologic license agreement (BLA). There is, however, considerable heterogeneity in the structure of data elements that are unique to a particular therapeutic area. As part of an effort organized by Coalition for Accelerating Standards and Therapies (CFAST), we developed specifications for efficacy data standardization in lung cancer.
Methods:
Using FDA guidance documents, NDA and BLA reviews, sample case report forms, and clinical trial datasets, we identified data elements in lung cancer clinical trials that are essential in evaluating the efficacy of new drugs and biologics. We constructed a concept map outlining the data elements and specifying their relational structure.
Results:
Data elements were captured under two main categories: efficacy endpoints (Figure 1) and covariates (Figure 2). Efficacy endpoints consist of overall survival, progression-free survival, objective response rate, duration of response, and disease-free survival. All lesions are assigned an organ-specific code. Data on tumor kinetics are captured as continuous variables supporting precise estimation of response while capturing all the requirements of Response Evaluation Criteria in Solid Tumors, version 1.1. Covariates were divided into disease and patient characteristics. Disease characteristics include specifications on molecular, immunohistochemical, and histological classification of tumors and detailed staging variables. Molecular definitions follow established nomenclature and include information on mutation subtypes as indicated. Patient characteristics include information on prior therapy, race and ethnicity. Figure 1 Figure 2
Conclusion:
The data elements we have identified (Figures 1 and 2) include concepts not adequately captured in current data standards and highlight important regulatory needs for the efficacy evaluation of new drugs and biologics in lung cancer. These specifications will be integrated with CFAST’s efforts to promote the development of lung cancer-specific data standards.
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MINI29.10 - Discussant for MINI29.06, MINI29.07, MINI29.08 (ID 3386)
19:20 - 19:30 | Author(s): M. Redman
- Abstract
- Presentation
Abstract not provided
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MINI29.11 - Assessing Patient-Reported Symptoms in Non-Small Cell Lung Cancer Clinical Trials (ID 2195)
19:30 - 19:35 | Author(s): A.K. Campbell, M. Martin, J. Lungershausen, J.M. Arduino, T.M. Atkinson, J..K. McCarrier, S.J. Coons, A. Liepa
- Abstract
- Presentation
Background:
In collaboration with the FDA, the Patient-Reported Outcome (PRO) Consortium’s Non-Small Cell Lung Cancer (NSCLC) Working Group (WG) has completed the initial development of a new PRO measure to assess symptom-related treatment benefit in clinical trials of advanced NSCLC to support labeling claims.
Methods:
Symptoms relevant to NSCLC patients were identified from the literature. This was followed by concept elicitation interviews conducted with patients at six US sites. Interview transcripts were coded using Atlas.ti software and concepts were grouped by similar content and subsequently reviewed by the NSCLC WG members and an expert panel in order to identify the symptoms most relevant for assessing treatment benefit. Preliminary items were generated and combined into a draft measure for cognitive testing with NSCLC patients for both item refinement and for assessing measurement equivalence between the original paper format and an electronic PRO (ePRO) data collection format (i.e., tablet).
Results:
For concept elicitation, the 51 patients interviewed had a mean age of 64.9 years [range 46-86], 51% were female, and 75% were white (non-Hispanic). Current NSCLC staging was: Stage I (12%), III (37%), and IV (51%). A total of 19 (37%) were treatment-naïve, 18 (35%) had received first-line treatment only, and 14 (27%) had received second- or third-line treatment. The most commonly expressed symptom was fatigue, described by patients as tiredness, lack of energy, tiring easily, and weakness. Other symptom concepts expressed included general pain, chest pain, cough, shortness of breath, difficulty breathing, appetite change, and coughing up blood. Items were drafted to assess either symptom frequency or severity for nine distinct symptoms using a 7-day recall period. Cognitive interviews were conducted in 3 waves to support iterative refinement. 20 additional NSCLC patients participated [mean age 65.2 years (range 44-83); 40% female; 75% white (non-Hispanic); 50% Stage III and 50% Stage IV]. During cognitive interviews, an 11-point numeric rating scale (NRS) and a 5-point verbal rating scale (VRS) were tested. Results indicated the 5-point VRS was better understood than the 11-point NRS. Further item refinement resulted in a 7-item measure covering pain (2 items: pain in chest, pain elsewhere), cough, shortness of breath, fatigue (2 items: energy, tiredness), and appetite. Patients reported no differences between tablet and paper data collection formats in regard to how they would interpret and respond to the items.
Conclusion:
NSCLC symptoms elicited from patients, across varied disease stages and treatments, were concordant with the pathophysiology of NSCLC. A new symptom-based PRO measure is being developed in accordance with the FDA’s PRO Guidance. The content is supported by existing literature, patient-reported experiences, and expert opinion. The draft measure (i.e., Non-Small Cell Lung Cancer Symptom Assessment Questionnaire [NSCLC-SAQ]) has been programmed onto an ePRO tablet for quantitative testing. Once complete, the NSCLC-SAQ and supporting evidence will be submitted to the FDA for its qualification as an efficacy endpoint measure to quantify treatment benefit for product evaluation and labeling.
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MINI29.12 - Patients with Advanced Non-Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials? (ID 663)
19:35 - 19:40 | Author(s): C. Lim, M. Sung, N. Nouriany, M. Sawczak, T. Paul, N. Perera-Low, A. Foster, D. Zawisza, R. Feld, G. Liu, F. Shepherd, N. Leighl
- Abstract
- Presentation
Background:
The evolution of targeted therapy in non-small cell lung cancer (NSCLC) has led to growing complexity of clinical research and a heightened expectation of clinical benefit for participants. Clinical trials in NSCLC increasingly require mandatory tumour samples or research biopsies, both potential barriers for trial participation. We assessed the impact of performing research biopsies in advanced NSCLC on clinical trial enrollment.
Methods:
We conducted a retrospective chart review of patients with advanced NSCLC evaluated for systemic therapy clinical trials at the Princess Margaret Cancer Center from January 2007 to March 2015.
Results:
Of 55 clinical trials reviewed, 38 required tumor samples for enrolment. Six mandated fresh tumor biopsies, whereas archival samples were permitted for 32 trials. All studies were linked to investigational therapy except one trial of molecular profiling not linked to an investigational treatment. Confirmation of a pre-specified biomarker was required in 23 trials in order to receive investigational treatment. Trial participation was offered to 640 patients at 940 unique study encounters, with some patients enrolling in multiple trials. Of 549 encounters where study treatment was offered, 60% proceeded to receive study treatment. Those considering trials without mandatory tissue requirements were more likely to proceed to study enrolment than those considering trials with these requirements (83% vs. 55%, p<0.0001). Those considering trials permitting use of archival tissue were more likely to begin study treatment than those considering trials mandating fresh research biopsies (59% vs. 38%, p=0.0007). For trials requiring current tumour samples, 127 research biopsies were performed. Participants proceeded to study treatment in 51% of these encounters. Study treatment was not offered for the remaining encounters due to lack of the pre-specified biomarker (28%), insufficient biopsy tissue (6%) or non-biopsy related exclusion criteria (15%). Among all 549 trial encounters, the most common barriers to trial enrollment included lack of the pre-specified biomarker (35%), withdrawal of consent (20%), other study exclusion criteria (16%), insufficient biopsy tissue (10%), deteriorating clinical status (10%) and death (5%). Of 391 encounters for the molecular profiling trial, 72% successfully completed molecular profiling. Twenty-two percent had insufficient tissue for analysis and 3% died prior to completion of molecular profiling.
Conclusion:
With the evolution of personalized medicine, a growing number of NSCLC trials require tumour tissue for treatment eligibility. This has emerged as a significant barrier to clinical trial enrollment. Potential solutions include routine tissue banking at diagnosis, facilitating use of available diagnostic samples (e.g. fine needle aspirates) for trials, development of circulating DNA assays for trials, and more resources for timely tissue acquisition.
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MINI29.13 - Safety and Clinical Implications of Repeat Tumor Biopsy (RTB) in Patients with Advanced Lung Cancer: A Retrospective Institutional Study (ID 3146)
19:40 - 19:45 | Author(s): E.S. Agwa, F. Almeida, A. Haddad, B.R. Bastos, R. Lee, X. Jia, V. Velcheti, P.C. Ma
- Abstract
- Presentation
Background:
Clinical management of lung cancer and personalized cancer therapy have undergone major advances and paradigm shifts in recent years. Repeat tumor biopsy (RTB) at disease progression is not only used for diagnostic confirmation in lung cancer but also has recently been increasingly adopted to profile tumor biomarkers and identify drug resistance mechanisms. However, information on safety and clinical consensus on the use of RTB remain lacking.
Methods:
The aim of this study is to review RTB patterns and safety in advanced lung cancer patients at Cleveland Clinic and its impact on treatment (Rx) decisions. Patients who were diagnosed and underwent RTB for suspected progressive disease between 2007-2013 were included in this retrospective study. Statistical analysis is primarily descriptive.
Results:
The study involved a total of 184 (56% male) patients. Median age at diagnosis was 65Y (21-87). 100 (54%) were treated initially with single modality (Surgery = 41; Chemo = 33; Radiation = 17; targeted therapy = 9) and 83 (45%) with multimodality Rx (2-modality = 57, 3-modality = 26), 1 (1%) unknown. Number of RTB per patient: 1 in 66.3% (n=122), 2 in 20.1% (n=37), 3 in 11.4% (n=21), and 4 in 2.2% (n = 4). The most common procedure employed at 1st RTB was bronchoscopy (44.6%, n = 82), followed by CT-guided biopsy (bx) (20.7 %, n=38), surgery (10.3%, n=19), excision bx (8.2%, n=15), fine needle aspiration of skin & lymph node (LN) (7.6%, n=14), ultrasound guided bx (5.9%, n=11) & others (2.7%, n=5). Lung was the most commonly rebiopsied site (46%) followed by LN (15%). Procedure-related complications were reported in 13 of 181 (7.2%) pts at 1st RTB (data missing in 3 pts), 3 of 61 (4.9%) at 2nd RTB, 1 of 25(4%) at 3rd RTB, and 0 of 4 (0%) at 4th RTB. The 17 (6.2%) complications are shown in the table below. Histologic change was seen in 13 cases, including adeno-to-squamous carcinoma (at erlotinib resistance) and vice-versa, and non-small cell to small cell histology. The T790M-EGFR mutation was noted in 6 cases, the PIK3CA mutation in 1, and a change in ALK translocation status in 3. Medical decision-making was impacted in 16% of cases. Further molecular and genomic analysis of selected cases is in progress.RTB Complications
Complications N=17 (%) Bleeding without hemodynamic compromise 6 (35) Bleeding requiring transfusion 1 (6) Pneumothorax 5 (29) Hemodynamic instability after premedication 1 (6) Cerebral salt wasting 1 (6) Tracheaoesophageal fistula 1 (6) Severe cough 1 (6) Incomplete procedure 1 (6) Deaths 0 (0)
Conclusion:
Our study results show that RTB can be safely performed in lung cancer patients using standard techniques and can impact lung cancer diagnosis and Rx decision-making.
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MINI29.14 - Using a Bayesian Adaptive Phase II Trial Design to Test Multiple Genetic-Marker-Directed Drugs in the National Lung Matrix Trial (ID 1241)
19:45 - 19:50 | Author(s): L.J. Billingham, K. Brock, L.R. Crack, S. Popat, G. Middleton
- Abstract
- Presentation
Background:
The National Lung Matrix Trial is a flagship trial in the United Kingdom being the first to combine the development of a technology platform that screens for multiple genetic aberrations in tumours with testing of multiple novel genetic-marker-directed drugs. The trial is focused on patients with advanced non-small cell lung cancer and currently includes 8 different drugs and 23 different drug-biomarker combinations. The aim of statistical analysis is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation and this paper evaluates the novel statistical design that has been implemented.
Methods:
The primary outcome measure representing signal of activity is best objective response rate (ORR) in most cases and progression-free survival (PFS) in others. Each drug-biomarker combination could be considered as a single arm phase II trial and could have been designed using standard statistical approaches such as Simon’s two stage design. However, a Bayesian adaptive design was chosen because it gives a more realistic approach to decision-making in this complex setting. It has flexibility to make conclusions without fixing the exact sample size which will be important with the uncertainty around the prevalence of each biomarker. The design allows early stopping of recruitment to any drug-biomarker combinations that do not show sufficient promise at an interim analysis to warrant continuation. It also allows, when appropriate, for information about the primary outcome measure to be shared across different biomarker cohorts within any single drug to aid decision-making. Decision-making is based on the posterior probability distribution for the primary outcome measure, given the observed data and any prior knowledge, calculated using bayesian conjugate analysis. For ORR, the critical threshold which defines a signal of activity is 30% for single drugs and 40% for combinations and for PFS the critical threshold is median 3 months. The interim and final sample sizes were selected to ensure the design achieved pre-defined desirable operating characteristics.
Results:
For both ORR and PFS as primary outcomes, sample sizes of 15 and 30 patients per drug-biomarker cohort for interim and final analyses respectively were selected as giving the required operating characteristics. Simulations of trials for single drugs with ORR as the primary outcome showed that this would ensure a high probability (82%) of correctly stopping early when the true ORR was only 10% and a high probability (90%) of correctly recommending further investigation when the true ORR was as high as 40%. Operating characteristics for the combination drug arms were similar. Operating characteristics for trial arms with PFS as the primary outcome are dependent on the recruitment rate and give high probabilities (>95%) of stopping early when the true median PFS is only 1 month and high probabilities (>80%) of recommending further investigation when the true median PFS is as high as 4 months.
Conclusion:
The Bayesian adaptive design with 15 and 30 patients per drug-biomarker cohort for interim and final analyses respectively gives a flexible, efficient design with good operating characteristics to investigate multiple genetic-marker-directed drugs within a single phase II trial.
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MINI29.15 - Discussant for MINI29.11, MINI29.12, MINI29.13, MINI29.14 (ID 3387)
19:50 - 20:00 | Author(s): B.J. Gitlitz
- Abstract
- Presentation
Abstract not provided
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MS 28 - Future Clinical Trials (ID 46)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Other
- Presentations: 4
- Moderators:S. Mandrekar, M. Redman
- Coordinates: 9/09/2015, 14:15 - 15:45, 205+207
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MS28.01 - Trial Designs (ID 1973)
14:20 - 14:40 | Author(s): M. Redman
- Abstract
- Presentation
Abstract not provided
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MS28.02 - Master Protocols (ID 1974)
14:40 - 15:00 | Author(s): S. Malik
- Abstract
- Presentation
Abstract:
Major advances in the understanding of molecular pathways that regulate tumor growth have led to development and FDA approval of new anticancer agents leading to improved survival in patients with certain cancer types. A common cancer like Non Small Cell Lung Cancer (NSCLC) is now subdivided in a number of molecularly defined subsets. Large randomized trials are not feasible anymore. This challenge to accrue to small subsets with availability of multiple drugs for each has led to novel trial design strategies like “Master Protocols” with multiple arms that are biomarker driven. Master Protocols are ideal if multiple molecular targets are known to drive tumor growth, if there is pre-clinical/clinical evidence that these targets can be pharmacologically inhibited and if the drugs to be tested are available. These protocols provide consistency of drug development approach regardless of intended target, utilize resources (including patient resources) in an efficient manner and have potential of bringing safe and effective drugs to patients faster. On the other hand these trials are time and resource intense, and some trials with public/private partnership have added need of a high level coordination. Part of NCI precision medicine initiative has led to “Master Protocols” like Lung-MAP, ALCHEMIST and NCI-MATCH. The Lung-MAP trial is evaluating patients with squamous cell lung cancer who have progressed beyond at least one line of therapy. The study divides patients into multiple treatment arms based on the molecular profiles of their cancers testing efficacy of targeted drugs. Promising results in any arm can lead to testing the drugs in that treatment arm in more patients, with the goal of more rapid drug approvals in these small subsets of squamous cell lung cancer patients. ALCHEMIST is testing the benefits of molecularly targeted adjuvant (post-surgical) treatment of patients with early-stage lung adenocarcinomas whose tumors have either an EGFR gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement. Depending on the genetic abnormality in a tumor, the patient will be randomized to receive the EGFR protein kinase inhibitor erlotinib or the ALK protein kinase inhibitor, crizotinib against a placebo. The Food and Drug Administration (FDA) has approved these molecularly targeted therapies for advanced lung adenocarcinoma in patients with the relevant genetic changes. It is expected that most patients with early lung adenocarcinoma who are screened will not be eligible for the therapeutic portion of this trial because their tumors will not have the necessary mutations. However, the tumor samples from these patients will be saved, and, if they relapse while on standard treatment, their tumors will be biopsied again and analyzed for insight into the progression of their disease and for potential therapeutic approaches suggested by this analysis. The NCI-MATCH trial will test a large number of agents in virtually any tumor type in which appropriate abnormalities are identified. This umbrella protocol will examine between 20 and 25 drugs, including those that have been FDA-approved for the treatment of cancer at another tumor site or experimental agents that have shown activity against a known target at one or more tumor sites. If the response rate to a particular agent is high, the number of patients evaluated with that treatment would be expanded to further explore whether the targeted treatment represents a substantial advance over standard chemotherapy. If a tumor becomes resistant to the first test drug, it will be re-biopsied to see if another targeted therapy might be effective and to understand the basis for resistance to the initial treatment. By studying multiple agents at the same time, a higher proportion of patients will be eligible for the trial, and efficient progress can be made in the assessment of clinical benefit.
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MS28.03 - Biomarkers (ID 1975)
15:00 - 15:20 | Author(s): F.R. Hirsch
- Abstract
- Presentation
Abstract not provided
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MS28.04 - Drug Development and Drug Approval (ID 1976)
15:20 - 15:40 | Author(s): R. Gaynor
- Abstract
- Presentation
Abstract:
Over the past decade, there have been rapid advances in cancer drug discovery and development. Much of this progress has resulted from a better understanding of the genetic changes in cancer and the development of agents that target the underlying biology of disease. In addition, an improved understanding of the immune system and cancer has resulted in the development of immune checkpoint inhibitors that have profound clinical activity in many tumors. Finally, the role of the tumor microenvironment in the regulation of tumor growth, metastatic spread, and modulation of the immune system is an area of intense investigation[1]. This enhanced understanding of the complex biology of cancer, and novel drugs against these new targets, have ushered in an exciting era in drug development leading to important new drug approvals[2]. An increasingly important aspect in both clinical development and drug approval is the incorporation of biomarkers and companion diagnostics to select patients more likely to benefit from specific therapies[3]. In lung cancer, the utilization of companion diagnostics has been key in the clinical development of TKIs directed at a variety of EGFR mutations and ALK alterations[4,5,6]. Other biomarker tests have been used to identify genes such as BRAF and ROS1 in order to develop clinical trials to test approved targeted agents with activity in patients with these molecular alterations[7]. Ongoing clinical studies exemplified by the Lung Master Protocol and NCI Match Protocol are utilizing biomarker panel strategies, including next generation sequencing (NGS), to identify patients with specific mutations in lung and other cancers respectively[4]. The use of NGS to characterize molecular alterations is also becoming more common to characterize patients’ tumors in both the academic and community settings. Immunohistochemistry assays continue to be a mainstay for understanding tumor biology and are also being utilized to quantitate markers such as PDL-1 expression in tumor immune cells in order to identify patients who are more likely to respond to immune checkpoint inhibitors[8]. In addition, analysis of biomarkers in liquid biopsies (e.g. plasma, spinal fluid) are being analyzed to provide supplemental information and/or to obviate the need for ongoing tumor biopsies during therapy[9]. Clinical development based on patient subset will increasingly be the norm, rather than the exception, in oncology. Rather than exclusively utilizing histology to screen patients for clinical trials, the use of basket trials to identify and treat patients of various histologies with agents targeted to similar molecular alterations is an approach which is increasingly being utilized[10]. In addition, retrospective analyses are being conducted to understand underlying molecular abnormalities of patients with exceptional responses to existing therapies and to use the information to design future clinical trials. One of the major challenges in clinical development is tumor heterogeneity and drug resistance. To prevent or overcome the development of drug resistance, combination therapies to target specific pathways are being explored. One such example is the use of BRAF and MEK inhibitors in the treatment of metastatic melanoma[11]. Many clinical studies in lung cancer are now incorporating mandatory tumor biopsies during the course of EGFR and ALK inhibitor therapy to identify evolving genetic changes in tumors during therapy in order to incorporate second and third generation TKIs. New mechanisms to facilitate the drug review and approval processes are underway[12]. One such mechanism is the Breakthrough Therapy (BT) Program. Breakthrough Therapy is intended to expedite the development and review of drugs for serious or life threatening conditions. Designation of a drug as a BT is based on preliminary clinical evidence that demonstrates that a new drug may have substantial improvement over available therapy and facilitates ongoing communication between the sponsor and the FDA to streamline the drug development process. Accelerated approval has been developed by the FDA for speeding the development and approval of promising therapies to treat serious disease that provides a meaningful therapeutic benefit over available therapy. Accelerated approval is based on an improvement in patient benefit utilizing surrogates of survival that are reasonably able to predict clinical benefit. The accelerated approval mechanism has been essential in facilitating new drug approvals of promising therapies. In addition, fast track designation is an FDA program intended to facilitate the development and expedite the review of drugs to treat serious medical conditions. This program allows sponsors to facilitate the review process for drug approval by having ongoing FDA interactions and utilizing a rolling review of submissions. Given the importance of biomarker-directed therapy, an additional critical component of the regulatory landscape is the review and approval of companion diagnostics at the same time as specific drug approvals. The drug-diagnostic co-development model is becoming increasingly common in oncology as biomarker-driven patient selection is required for many of the new targeted and immune therapies. Thus, an evolution in both the clinical development paradigm and the regulatory landscape is occurring based on the discovery and development of more effective, biomarker-directed targeted agents and novel immune checkpoint inhibitors.REFERENCES 1. Hanahan, D. and Weinberg, RA. Cell 2011; 144: 646-674. 2. Wolford, JE. and Tewari, KS. Future Onc. 2015; 11: 1931-1945. 3. Shen, T., Hans Pajaro-Van de Stradt, S., Yeat, NC., et al. Front in Genet. 2015; 6:215 in press. 4. Morgensztern, D., Campo, MJ., Dahlberg, S., et al. J. Thor. Onc. 2015; 10: S1-S63. 5. Somasundarsm, A., Socinski, MA., and Burns, TF. Informa 2014; 15: 2693-2707. 6. Kwak EL, Bang Y-J, Camidge DR, et al. N Engl J Med. 2010; 18: 1693-1703. 7. Camidge, DR., Pao, W., and Sequist, LV. Nature Rev. Clin. Onc. 2014; 11: 473-481. 8. Carbognin, L., Pilotto, S., Milella, M., et al. PLOS ONE 2015; 10:1371 in press. 9. Francis, G. and Stein, S. Int. J. Mol. Sci. 2015; 16: 14122-14142. 10. Catenacci, DVT. Mol. Onc. 2015; 9: 967-996. 11. Long, GV., Stroyakovskiy, D., Gogas, H., et al. NEJM 2014; 371: 1877-1888. 12. Kesselheim, AS. and Darrow, JJ. Clin. Pharm. & Ther. 2015; 97: 29-36.
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ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:B.C. Cho, P. Lara Jr.
- Coordinates: 9/08/2015, 14:15 - 15:45, Four Seasons Ballroom F1+F2
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ED07.03 - Lung Master Protocol in Squamous Cell Lung Cancer (Lung-MAP, S1400) (ID 1800)
15:00 - 15:20 | Author(s): M. Redman
- Abstract
- Presentation
Abstract:
In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.
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MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:R. Feld, R. Dziadziuszko
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI17.02 - SWOG 0709: Randomized Phase II Trial of Erlotinib vs. Erlotinib plus Carboplatin/Paclitaxel in Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC) and Impaired Performance Status (PS2) as Selected by Serum Proteomics (ID 658)
16:55 - 17:00 | Author(s): M. Redman
- Abstract
- Presentation
Background:
Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, erlotinib in PS 2 pts yielded progression-free (PFS) and overall survival (OS) of 2.1 and 5 months respectively. In a trial of erlotinib versus carboplatin/paclitaxel in PS2 pts (Lilenbaum, JCO 2008), PFS for erlotinib and chemotherapy were 1.9 and 3.5 months, respectively. Early reports suggested a potential role for serum proteomics in predicting erlotinib benefit beyond that of EGFR mutational status. We therefore conducted a prospective trial of erlotinib +/- chemotherapy in NSCLC pts with PS2 enriched by serum proteomics (Veristrat assay).
Methods:
Metastatic NSCLC pts with PS2, acceptable end-organ function, and “good” classification by serum proteomics were randomized to either Arm A (erlotinib 150 mg orally QD) or Arm B (erlotinib 150 mg orally QD on days 2-16 plus carboplatin AUC 5 IV day 1 and paclitaxel 200 mg/m2 IV day 1 x 4 cycles, followed by erlotinib 150 mg orally QD). Cycle length was 3 weeks. Arm B agents were “pharmacodynamically separated” to mitigate potential antagonism. The arm with superior observed median PFS would be selected for further evaluation, but only if ≥ 3 months. A sample size of 98 pts was based on a variety of assumed PFS probabilities for each arm. The trial was prematurely closed after the FDA determined midway through accrual that an IDE application was required for the proteomics assay; however SWOG had limited resources available for such filing.
Results:
Of 156 pts screened, 83 (59%) were classified as “good” by serum proteomics. 59 of 83 pts (60%) met trial eligibility and were randomized. Treatment-related grade 4 adverse events were seen in 2 pts in Arm A (thrombosis, hypomagnesemia) and 5 pts in Arm B (neutropenia -5, febrile neutropenia-1, leukopenia -1), with no treatment related deaths. Figure 1
Conclusion:
In Zubrod PS2 pts with advanced NSCLC and “good” classification by serum preoteomics, pharmacodynamically-separated erlotinib plus chemotherapy had better observed median PFS/OS versus erlotinib alone and surpassed the protocol-specified benchmark of PFS >= 3 months required for further study. Updated data will be presented.
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MINI 29 - Meta Analyses and Trial Conduct (ID 156)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:D. Morgensztern, M. Redman
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2a-3b
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MINI29.10 - Discussant for MINI29.06, MINI29.07, MINI29.08 (ID 3386)
19:20 - 19:30 | Author(s): M. Redman
- Abstract
- Presentation
Abstract not provided
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MS 28 - Future Clinical Trials (ID 46)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Other
- Presentations: 1
- Moderators:S. Mandrekar, M. Redman
- Coordinates: 9/09/2015, 14:15 - 15:45, 205+207
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MS28.01 - Trial Designs (ID 1973)
14:20 - 14:40 | Author(s): M. Redman
- Abstract
- Presentation
Abstract not provided
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MTE 02 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (Ticketed Session) (ID 54)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Advocacy
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 07:00 - 08:00, 105
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MTE02.01 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (ID 1979)
07:00 - 07:30 | Author(s): M. Redman
- Abstract
- Presentation
Abstract:
The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2
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PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mok, F.R. Hirsch
- Coordinates: 9/09/2015, 10:45 - 12:15, Plenary Hall (Bellco Theatre)
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PLEN04.01 - A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): SWOG S0819 (ID 3612)
10:45 - 10:57 | Author(s): M. Redman
- Abstract
- Presentation
Background:
This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.
Methods:
Results:
Conclusion:
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