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G. Liu
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MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:Y. Yatabe, R. Perez-Soler
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI05.13 - Treatment of EGFR/ALK-Driven Non-Small Cell Lung Cancer (NSCLC) Brain Metastases: Impact of First-Line Whole Brain Radiotherapy on Outcome (ID 1251)
17:55 - 18:00 | Author(s): G. Liu
- Abstract
- Presentation
Background:
Brain metastases (mets) in EGFR/ALK-driven NSCLC are common, and frequently pose treatment dilemmas. Effective systemic therapy with tyrosine kinase inhibitors (TKIs) controls extracranial disease in up to 70% of patients, but often radiotherapy is required for intracranial control. As whole brain radiation (WBRT) may be associated with neurocognitive toxicity, we aimed to evaluate the impact of molecularly targeted therapy and stereotactic radiotherapy (SRS) for EGFR/ALK-driven NSCLC on intracranial disease control with and without WBRT.
Methods:
This retrospective analysis included patients treated with EGFR/ALK-positive NSCLC at Princess Margaret Cancer Centre from 1998-2015, with brain mets at lung cancer diagnosis or during treatment/follow-up. Demographic data were collected from electronic patient records. Time to intracranial progression (TTIP) and overall survival (OS) were calculated from date of diagnosis of brain mets, using the cumulative incidence function and Kaplan-Meier methods respectively; differences between groups were tested with Gray’s or log-rank test.
Results:
From 1998-2015, 162 patients with brain mets from EGFR/ALK-driven NSCLC were identified: 138 in the EGFR cohort, 23 in the ALK cohort and one included in both cohorts for analysis, whose tumour carries both an EGFR mutation and ALK rearrangement. Table 1 contains clinical characteristics and treatment details. In the EGFR cohort, initial brain mets treatment consisted of systemic therapy alone in 19 patients (17 TKI, 2 chemotherapy), SRS +/- surgery in 27 patients and WBRT +/- SRS/surgery in 88 patients. 1-year intracranial progression rates were 26%, 32% and 12%, respectively, and median TTIP was 18, 16 and 40 months [p=0.12]. Median OS was 26, 27 and 34 months respectively [p=0.49]. In the ALK cohort, initial brain mets treatment consisted of systemic therapy alone in 4 patients (1 TKI, 3 chemotherapy), SRS/surgery alone for 4 patients and WBRT +/- SRS/surgery for 15 patients. 1-year intracranial progression rates were 50%, 50% and 13%, respectively, and median TTIP was 18, 14 and 69 months [p=0.028]. Median OS was 35 months, not reached and 51 months, respectively [p=0.75]. Multivariable analysis for the whole group showed that age [p=0.021], number of brain mets [p=0.012] and extracranial control [p=0.008] were significantly associated with OS, but not WBRT [p=0.61].
Conclusion:
In this cohort of patients with brain mets from EGFR/ALK-driven NSCLC, patients treated with WBRT trended to longer TTIP. Although not statistically significant, our data also show a trend towards longer survival in patients who received WBRT. These observations require further validation in this patient population.EGFR (N=139) ALK (N=24) Median Age (Range) 59(29-86) 53(31-77) Female Sex 93(67%) 15(62%) Ethnicity Asian Caucasian Other 58(42%) 63(45%) 18(13%) 7(29%) 13(54%) 4(17%) Smoking Never Smoker Former/Current Smoker Unknown 108(77%) 30(22%) 1(1%) 19(79%) 5(21%) 0 ECOG PS (Diagnosis) 0 1 2-4 66(48%) 67(48%) 6(4%) 7(29%) 14(58%) 3(13%) Brain Mets at Stage IV diagnosis 93(67%) 13(52%) Number of Brain Mets 1 2-4 5+ N/A 32(23%) 39(28%) 62(45%) 6(4%) 9(38%) 6(24%) 9(38%) 0 Symptomatic Brain Mets No Yes 78(56%) 61(44%) 16(67%) 8(33%) Initial Brain Mets treatment WBRT WBRT+SRS/Surgery SRS+/-Surgery Systemic Therapy None 71(51%) 17(12%) 27(19%) 19(14%) 5(4%) 13(54%) 3(12%) 4(17%) 4(17%) 0
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.12 - Genomic Profiling of Patient-Derived Xenografts Identify Passenger Aberrations Associated with Better Prognosis in Non-Small Cell Lung Cancer (ID 1735)
11:50 - 11:55 | Author(s): G. Liu
- Abstract
Background:
Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers, test novel therapeutics, and identify potential biomarkers, as they more accurately model human cancers than established tumor cell line cultures. However, uncertainty remains as to how well the genomic characteristics of patient non-small cell lung cancer (NSCLC) are recapitulated in these PDX models.
Methods:
PDXs were established by implantation of surgically resected NSCLC patient tumors into the subcutaneous or sub-renal capsule of non-obese diabetic severe combined immune deficient (NOD-SCID mice. Comprehensive genomic profiling including exome, gene copy number, DNA methylation and mRNA expression were conducted on 36 independent PDX models, their matched patient tumors and normal lung tissue. Publicly available cell line and TCGA data were used for comparison. Integrative analysis was performed to identify genomic alterations in PDXs that are associated with significant clinical outcomes in patients.
Results:
From 441 resected NSCLC tumors, 127 serially transplantable and stable PDX models were established. Among 264 NSCLC patients with at least 3-years follow-up, patients whose tumor formed stable PDXs (versus those who did not) showed significantly worse disease free (HR=3.12, 95% CI =2.02-4.83, P<0.0001) and overall survival (HR=4.08, 95% CI =2.16-7.73, P<0.0001), after multivariable adjustment for clinical pathological factors. Genomic and transcriptomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with published cell line data. In addition to known mutations, we found at least 16 non-synonymous somatic mutations in known oncogenes and tumor suppressors that have never been reported. All these mutations had higher observed variant allele frequency in PDXs compared to their matched patient tumors, suggesting that these were tumor sub-clones selected or enriched for growth in the PDXs. Tumor models characterized by a higher number of somatic alterations among 865 frequently altered genes were associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by higher alteration number; this was validated in the TCGA lung cancer dataset patients (HR=0.28, p=0.000022). These 865 genes were enriched for those encoding for proteins involved in cell adhesion and interactions with the extracellular matrix, and a quarter of the genomic alterations would putatively form neo-antigens implicating a potential role of immune response in the observed improved patient survival.
Conclusion:
PDXs are close preclinical models of patient tumors. Further investigations of passenger mutations may clarify their clinical impact on interactions between tumor cells, stroma, immune microenvironment and patient prognosis.
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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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MINI29.12 - 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): G. Liu
- 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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MS 03 - Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC? (ID 21)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
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MS03.03 - Where Are We with Defining Potential Biomarkers (ID 1858)
15:00 - 15:20 | Author(s): G. Liu
- Abstract
- Presentation
Abstract:
Angiogenesis-targeting drugs have been evaluated in a multitude of lung cancer settings, with variable results. Unlike other pathways, these drugs target host related pathways and host responses to lung tumors. Thus there is the potential for both host and tumor mechanisms to lead to variable responses to therapy. In the advent of precision medicine, there has been a concerted effort to evaluate whether there are known genetic and genomic, epigenomic, serologic, and tissue biomarkers of response or toxicity to both anti-angiogenesis monoclonal antibodies and small molecule inhibitors of the angiogenesis pathways. Such studies will be reviewed in detail. Nonetheless, the evaluation of such biomarkers has been challenging, as the relevant anti angiogenesis pathways are large, mechanisms of drug function are often incompletely understood, and tumor-stromal interactionsare particularly difficult to measure. There are currently no clear examples of biomarkers that can define the anti-angiogenesis drug responsive patient. However, this review will focus on both the key opportunities and challenges associated with defining potential biomarkers related to anti-angiogenesis drug therapy in lung cancer, and the current state of ths research. Biomarker development has mostly focused on the discovery of novel marekrs of the VEGF pathway. The roles of assessing magnitudes and directions of association must still be supplemented by the evaluation of test performance, namely biomarker discriminatory performance and calibration. The need to move biomaker association studies towards these other specific evaluations will help move the field of VEGF-related biomarker research forward.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.02 - Time to Progression and Post-Progression Survival in ALK+ Ceritinib-Treated NSCLC (ID 945)
16:56 - 17:07 | Author(s): G. Liu
- Abstract
- Presentation
Background:
There is strong interest in evaluating the outcomes of patients who have progressed after failing targeted agents. With different agents, the post-progression survival (PPS) may be either improved or shortened when a longer duration of time-to-progression (TTP) has been observed. This study evaluated the association between TTP and the duration of PPS among adult patients who received ceritinib for the treatment of advanced anaplastic lymphoma kinase-positive (ALK+) NSCLC.
Methods:
Patients experiencing disease progression during two single-arm, open-label, Phase I and II trials of ceritinib (ASCEND-1 [ClinicalTrials.gov Identifier: NCT01283516] and ASCEND-2 [ClinicalTrials.gov Identifier: NCT01685060]) were included in this analysis. For uniformity, all patients analyzed had received crizotinib prior to ceritinib. TTP after the initiation of ceritinib was studied as a predictor for the length of subsequent PPS using Cox proportional hazards models. Adjustments were made for patients’ baseline characteristics, including age, body mass index, gender, race, Eastern Cooperative Oncology Group (ECOG) performance score, number of prior regimens, tumor histology, and presence of brain metastases. A Kaplan-Meier analysis for PPS was performed stratified by shorter (< 6 months) versus longer TTP (≥ 6 months). As a secondary descriptive analysis, associations were quantified between the duration of TTP and the duration of survival (OS) measured as the sum of TTP and PPS.
Results:
Of 181 patients who experienced disease progression during study follow-up, 94% received at least one chemotherapy prior to baseline, 75% had an ECOG performance score greater than zero at screening, and 79 died during subsequent follow-up. In an unadjusted model, each 3 months of longer TTP was associated with a 24% lower hazard of death following progression (hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.60-0.96). Results were similar after adjusting for baseline characteristics (HR: 0.77, 95% CI: 0.61-0.97). Patients with TTP ≥ 6 months experienced significantly longer PPS compared to those with TTP < 6 months (median: 9.8 vs. 6.5 months, log-rank p-value < 0.01). This positive relationship between TTP and PPS translated into the duration of OS: each 3 months of longer TTP was associated with a 58% lower hazard of death after adjusting for baseline characteristics (HR: 0.42, 95% CI: 0.32-0.54). Median OS was not reached for patients with TTP ≥ 6 months and was 10.3 months for patients with TTP < 6 months.
Conclusion:
A longer duration of TTP after treatment with ceritinib was significantly associated with both longer duration of PPS and longer OS.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-044 - EGFR and ALK Status Influence Health Utility and Global Quality of Life Scores in Patients with Metastatic Lung Cancer (ID 1613)
09:30 - 09:30 | Author(s): G. Liu
- Abstract
Background:
EGFR mutations and EML4-ALK rearrangements play important roles in prognosis and response to treatment. While extending survival is a main goal of treatment, improving symptoms, well-being, and quality of life is an equally important priority.
Methods:
At Princess Margaret Cancer Centre, a cross-sectional study evaluated 224 outpatients with metastatic lung cancer who completed demographic and EQ5D-3L questionnaires generating health utility scores (HUS, 0-1) and a visual analogue scale (VAS) slider (0-100). Patients rated their ECOG performance status (0-4), and described their health over the last month from 1 (excellent) to 5 (poor). Results were correlated with clinical and demographic data. Our objective was to compare HUS and global quality of life by mutational status. Patients with EGFR mutations and ALK rearrangements were enriched through targeted enrolment, while patients with neither alteration were selected randomly from the same outpatient clinics.
Results:
94 patients (42%) had an EGFR mutation, 23 (10%) an ALK rearrangement and 107 (48%) had neither (“wildtype”) in their tumor. Participation rate was 87%. Characteristics of the populations were as expected, with higher rates of never smokers in patients with EGFR or ALK alterations (p<0.0001), greater proportion of Asians (p=0.0004), and higher proportion of adenocarcinoma (p<0.0001). Current systemic treatment differed among groups, as the majority of patients with driver mutations were receiving targeted agents at the time of assessment (77% EGFR and 65% ALK vs 7% wildtype). Conversely, wildtype patients were more likely on chemotherapy (6% vs 17% vs 38%) or not on treatment (17% vs 17% vs 47%, p<0.0001). Patients filled questionnaires on average 25 months after initial diagnosis of lung cancer. Patients with EGFR mutations (97%) or ALK rearrangements (100%) were more often ECOG performance status 0-1 at the time of diagnosis of stage IV disease than wildtype individuals (86%, p=0.02). For quality of life analysis, we regrouped the patients with EGFR/ALK alterations (n=117). Their mean HUS was better than for wildtype patients (0.80 vs 0.71, p=0.0003), their mean VAS slider was higher (66.9 vs 60.8, p=0.0381) and their mean self-rated ECOG scores was better (0.90 vs 1.26, p=0.022).
Conclusion:
In a clinical population, patients with metastatic lung cancer harboring EGFR and ALK alterations report superior HUS and global quality of life scores when compared with patients without these molecular changes, during the course of their therapy. This is reflected in higher proportion of patients on active therapy, particularly with molecularly targeted agents, and with improved self-reported performance scores. Health utility values used in economic analyses of metastatic lung cancer patients in clinical practice should be specific for different mutations.
