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H.A. Wakelee
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MS03 - The Cutting Edge of Molecularly Targeted Therapy (ID 20)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Medical Oncology
- Presentations: 3
- Moderators:N. Saijo, H.A. Wakelee
- Coordinates: 10/28/2013, 14:00 - 15:30, Plenary Hall, Ground Level
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MS03.1 - Novel Targets in Small Cell Cancer (ID 467)
14:00 - 15:30 | Author(s): R. Thomas
- Abstract
- Presentation
Abstract
I will discuss recent results from genomic sequencing studies on small cell lung cancer. In particular, results related to possible therapeutic opportunities will be a focus of my talk.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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MS03.2 - Novel Targets in Squamous Cancer (ID 468)
14:00 - 15:30 | Author(s): P. Hammerman
- Abstract
- Presentation
Abstract
Lung squamous cell carcinoma (lung SqCC) is the second most common histology of non-small cell lung cancer (NSCLC). While the treatment of lung adenocarcinoma has developed substantially over the past decade due to the discovery of a host of therapeutic biomarkers progress in lung SqCC has been more modest. However, large scale genomic studies of lung SqCC as well as early biomarker directed trials suggest that treatment options are likely to improve in the near future for lung SqCC given the rapid expansion in our knowledge of the molecular basis of this disease. There is now an opportunity for substantial improvement in outcomes for patients with lung SqCC and my presentation will focus on the opportunities and challenges that face our community as we try to make progress in treating this disease. Here, I will discuss several recent studies which have defined the genomic landscape of lung SqCC in multiple patient cohorts and discuss the results of these studies in contrast to lung adenocarcinoma. I will review the predictive and prognostic biomarkers identified to date for lung SqCC and present pre-clinical and early clinical data on several therapeutic biomarkers with an emphasis on Fibroblast Growth Factor Receptor alterations. I will note clinical trials in progress and those which are likely to begin soon as well as diagnostic testing for patients with lung SqCC. I will also discuss pre-clinical data which have shed light on the development of lung SqCCs and discuss opportunities for further development in this field.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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MS03.3 - Novel Targets in Adenocarcinoma (ID 469)
14:00 - 15:30 | Author(s): M. Meyerson
- Abstract
- Presentation
Abstract not provided
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O16 - NSCLC - Targeted Therapies III (ID 115)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 8
- Moderators:H.A. Wakelee, L. Crino
- Coordinates: 10/29/2013, 10:30 - 12:00, Parkside Auditorium, Level 1
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O16.01 - Impact of tumor burden on the overall survival analysis of the LUME-Lung 1 study: a randomized, double-blind phase 3 trial of nintedanib (BIBF 1120) + docetaxel in NSCLC patients progressing after first-line chemotherapy (ID 3284)
10:30 - 12:00 | Author(s): M. Reck, S. Novello, A. Mellemgaard, S. Orlov, R. Kaiser, J. Barrueco, B. Gaschler-Markefski, J. Douillard
- Abstract
- Presentation
Background
Nintedanib is an orally available potent anti-angiogenic agent inhibiting the isoforms of VEGFR, PDGFR and FGFR. LUME-Lung 1 is a placebo-controlled phase 3 trial of nintedanib + docetaxel in second-line NSCLC patients.Methods
Patients with stage IIIB/IV or recurrent NSCLC after failure of first-line chemotherapy were stratified by histology, ECOG PS, prior bevacizumab and brain metastases, and were randomised to nintedanib 200 mg bid + docetaxel 75 mg/m[2] q21d (n=655), or placebo + docetaxel (n=659). The primary endpoint was centrally reviewed PFS after 714 events. The key secondary endpoint was OS after 1,121 events. Predefined sensitivity analyses used baseline sum of longest diameters of target lesions (SLD) and stratification factors, as covariates in the Cox model.Results
The study met its primary endpoint demonstrating a statistically significant improvement in PFS that translated into a 21% reduction in the risk of progression in patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 months), regardless of histology (adenocarcinoma HR 0.77, CI: 0.62, 0.96; p=0.0193; squamous HR 0.77, CI: 0.62, 0.96; p=0.0200). OS was significantly prolonged in adenocarcinoma patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.83; CI: 0.70, 0.99; p=0.0359; median 12.6 vs 10.3 months) but not in squamous cell carcinoma patients (HR 1.01; CI: 0.85, 1.21; p=0.8908; median 8.6 vs 8.7 months). The intent-to-treat (ITT) analysis of OS in all study patients showed a 1-month improvement that did not reach statistical significance (HR 0.94; CI 0.83, 1.05; p=0.272; median 10.1 vs 9.1 months). When adjusted for SLD, however, a significant OS benefit was seen for the ITT population (HR 0.88; CI: 0.78, 0.99; p=0.0365). Further analyses showed that the impact of SLD was reflected in the squamous cell carcinoma population (HR 0.92; CI: 0.77, 1.10; p=0.3649), with the greatest impact observed for squamous cell carcinoma patients with a large SLD. An impact of SLD was also seen in adenocarcinoma patients but to a lesser extent (HR 0.81; CI:0.69, 0.97; p=0.0186), as compared with the squamous cell carcinoma population. The most common AEs reported for the ITT population were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis.Conclusion
Nintedanib + docetaxel significantly reduced the risk of progression in NSCLC patients independent of histology. Adjustment for tumor burden, as represented by the SLD, led to a significant reduction in the risk of death. AEs were generally manageable with dose reductions and symptomatic treatment.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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O16.02 - Efficacy of standard care for second-line advanced non-small cell lung cancer (NSCLC) by <em>KRAS</em> mutation status: observations on MEK inhibitor enhancement of chemotherapy (ID 3329)
10:30 - 12:00 | Author(s): P.A. Jänne, D. Clemett, H. Mann, I. Smith
- Abstract
- Presentation
Background
KRAS mutations that activate the MEK/ERK pathway are found in 20–30% of NSCLC. Response to second-line therapies for advanced NSCLC may be different in the presence or absence of a KRAS mutation. MEK inhibitors are being developed in combination with cytotoxic chemotherapy for NSCLC, based on preclinical findings that MEK inhibition increases pro-apoptotic BIM levels, enhancing cytotoxic therapy, and that MEK inhibition reduces KRAS mutation-induced oncogenic drive. We reviewed available information from KRAS mutation-positive (KRAS+) and KRAS wild-type subsets in AstraZeneca clinical studies in second-line NSCLC and published data on MEK inhibitors. Our objective was to determine whether differential therapeutic activity is present in KRAS+ and KRAS wild-type populations and whether preclinical findings translate into enhanced tumour response.Methods
We reviewed data on objective clinical response in second-line NSCLC according to KRAS status in five randomised double-blind Phase II or III studies of gefitinib, vandetanib or selumetinib and three published studies of trametinib. Ninety-five percent confidence intervals (CI) around point estimates of objective response were calculated using exact (Clopper-Pearson) methods for a single proportion.Results
The studies involved 4466 patients receiving second- or later line treatment for advanced NSCLC. In total, 1286 patients received singlet chemotherapy (docetaxel or pemetrexed), including 429 with known tumour KRAS mutation status: 138 had KRAS+ and 291 had KRAS wild-type NSCLC. Additionally, 132 patients with known KRAS status received singlet chemotherapy plus a MEK inhibitor (selumetinib or trametinib): 91 with KRAS+ and 41 with KRAS wild-type NSCLC. Figure 1Conclusion
Our retrospective comparison suggests that second-line singlet chemotherapy response rates may be greater in KRAS wild-type than in KRAS+ NSCLC, and that MEK inhibition may enhance second-line chemotherapy activity in both KRAS+ and KRAS wild-type NSCLC. These observations support prospective validation of these results and further evaluation of MEK inhibitors plus chemotherapy in second-line KRAS unselected NSCLC.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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O16.03 - Cost-utility analysis of first-line treatment with erlotinib versus chemotherapy in EGFR-mutant advanced non-small-cell lung cancer (NSCLC): economic analysis of EURTAC trial (ID 1100)
10:30 - 12:00 | Author(s): A. Vergnenegre, R. Rosell, B. Massuti, P. Do, R. Corre, E. Felip, R. Palmero, R. Garcia-Gomez, F. De Marinis, M. Santarpia, E. Wright, C. Chouaid
- Abstract
- Presentation
Background
The impact of tyrosine kinase inhibitors (TKIs) in EGFR-mutant advanced NSCLC is poorly documented. Two studies (Jacob et al, ISPOR2010, Brown et al, Health Technol Assess, 2010) are based on modelisation and indirect comparisons. The present study reports a cost-utility analysis of a phase III randomized trial (EURTAC).Methods
A three state Markov model (first line PFS, second line PD and death) was built. Clinical data and resource assessment (drugs, drug administration, adverse events, second-line treatment) were collected from the trial. Utility values were derived from Nafees et al, as previously published (Vergnenegre et al. JTO 2011). Incremental cost-utility ratios (ICUR) were calculated for the first-line treatment and the overall strategy until death from the perspective of different countries (2013 actualized euros). Sensitivity analyses researched the main cost drivers.Results
The quality-adjusted life-years gained was 0.124 with erlotinib, which showed an improvement in the quality of life for these patients. Despite the extra treatment costs of second-line erlotinib in the chemotherapy arm, there was a cost benefit for erlotinib first, resulting in fewer patients receiving second-line pemetrexed along with other therapy. Cost gain in favor of first-line erlotinib was 8,918 Euros. The main results are depicted in Table1.
Sensitivity analyses will be presented at the meeting.First-line erlotinib First-line chemotherapy Average cost of first-line (euros 2013) Drugs 21,679 1030 Administration 329 4,455 Adverse events 546 2,686 Cost of post-first progression care 40,467 67,281 ICUR (erlotinib versus chemotherapy) ICUR France negative ICUR Spain negative ICUR Italy negative Conclusion
ICUR favored first-line erlotinib in EGFR-mutant patients with advanced NSCLC, which is the widely accepted treatment compared to chemotherapy. The cost-utility of the overall strategy remained beneficial in three different European countries. On behalf GFCP,GEPC and AIOT groupsOnly 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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O16.04 - DISCUSSANT (ID 3955)
10:30 - 12:00 | Author(s): J.C. Yang
- Abstract
- Presentation
Abstract not provided
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O16.05 - Efficacy, safety, and patient-reported outcomes (PROs) with crizotinib versus chemotherapy in Asian patients in a phase III study of previously treated advanced <em>ALK</em>-positive non-small cell lung cancer (NSCLC) (ID 2818)
10:30 - 12:00 | Author(s): M. Nishio, V. Hirsh, D. Kim, K.D. Wilner, A. Polli, A. Reisman, S. Iyer, F. Blackhall
- Abstract
- Presentation
Background
Crizotinib is a potent selective ATP-competitive ALK inhibitor demonstrating a high ORR in patients with advanced ALK-positive NSCLC. The main objective of the present post hoc analyses was to compare the impact of crizotinib on efficacy, safety, and PROs with that of standard second-line chemotherapy in a subgroup of patients of Asian ethnicity from the ongoing phase III study PROFILE 1007.Methods
Patients with stage IIIB/IV ALK-positive NSCLC who had received one prior platinum-based regimen were randomized to open-label crizotinib (250 mg PO BID) or chemotherapy (pemetrexed 500 mg/m[2] or docetaxel 75 mg/m[2], IV q3w). In these subgroup analyses, PFS and ORR based on independent radiologic review, OS, safety, and PROs were evaluated. PROs were assessed at baseline, on day 1 of each cycle, and at end of treatment using the validated cancer-specific questionnaire EORTC QLQ-C30 and its LC module QLQ-LC13. Time to deterioration (TTD) was defined as the time from randomization to the earliest time with a ≥10-point increase from baseline (worsening) in pain in chest, dyspnea, or cough. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms.Results
Of 347 patients randomized, 45% were of Asian ethnicity (crizotinib, n=79; chemotherapy, n=78 [pemetrexed, 50; docetaxel, 27; no treatment, 1]). At data cutoff (March 2012), 52 Asian patients (crizotinib, 41; chemotherapy, 11) were continuing on treatment. PFS was significantly longer with crizotinib than with chemotherapy (median 8.1 vs. 2.8 months; HR, 0.53; P=0003). The ORR on crizotinib (75%) was significantly higher than on chemotherapy (22%; P<0.0001). In an interim analysis, median OS had not yet been reached in the crizotinib arm and was 22.8 months in the chemotherapy arm (HR, 0.89; P=0.347, noting that in the overall study population, only 40% of planned events had occurred and 64% of patients in the chemotherapy arm subsequently received crizotinib in another study). The most common all-causality AEs with crizotinib were diarrhea (70%), vision disorder (68%), and nausea (66%) and with chemotherapy were decreased appetite (40%), nausea (39%), and fatigue (35%). Crizotinib treatment was associated with a significantly longer TTD in LC symptoms compared with chemotherapy (median 4.2 vs. 1.6 months; HR, 0.66; 95% CI, 0.44−0.98; P=0.037). A significantly greater improvement from baseline was observed with crizotinib for global QOL (P<0.05), cough (P<0.001), dyspnea (P<0.001), pain in arm or shoulder (P<0.001), pain in chest (P<0.001), pain in other parts (P<0.05), fatigue (P<0.05), insomnia (P<0.05), and pain (P<0.001). A significantly greater improvement was observed with crizotinib compared with chemotherapy for emotional functioning (P<0.05), physical functioning (P<0.05), hair loss (P<0.001), and sore mouth (P<0.05). A significantly greater deterioration was observed in the crizotinib arm for constipation (P<0.05) and diarrhea (P<0.001) compared with chemotherapy.Conclusion
Consistent with previously reported results in the overall study population, crizotinib treatment showed significantly greater improvement in PFS, ORR, patient-reported LC symptoms, and global QOL compared with chemotherapy in a subgroup of patients of Asian ethnicity with previously treated advanced ALK-positive NSCLC, confirming the utility of crizotinib in this patient population.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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O16.06 - A phase 1 dose escalation study of a new ALK inhibitor, CH5424802/RO5424802, in ALK+ Non-Small Cell Lung Cancer (NSCLC) patients who have failed crizotinib (AF-002JG/NP28761, NCT01588028). (ID 1661)
10:30 - 12:00 | Author(s): S. Gadgeel, S. Ou, A.A. Chiappori, G. Riely, R. Lee, L. Garcia, J. Sato, S. Yokoyama, T. Tanaka, L. Gandhi
- Abstract
- Presentation
Background
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated following chromosomal translocation in 3-7% of non-small cell lung cancer (NSCLC). These patients usually respond to the ALK inhibitor crizotinib with a median duration of response around 10 months. CH5424802 is a more potent and specific ALK inhibitor that is being studied as a treatment for NSCLC patients with ALK gene rearrangement.Methods
A phase 1 dose escalation study of CH5424802 was performed using 3+3 study design in NSCLC patients who failed crizotinib. The primary endpoint was dose limiting toxicity, and the secondary endpoints were efficacy, safety and pharmacokinetic (PK) analyses. Key eligibility criteria include prior progression on crizotinib, ECOG 0-2, adequate organ functions, confirmed ALK-rearrangement by an FDA approved test. Patients with symptomatic CNS metastases required treatment before participating. CH5424802 was administered orally at doses of 300, 460, 600, 760 and 900 mg BID until lack of clinical benefits. Intensive PK sampling was performed. Efficacy was assessed by RECIST criteria v1.1. Toxicities were evaluated by CTCAE v4.0.Results
37 NSCLC patients who have failed crizotinib and chemotherapy were enrolled in the study from 6 US sites from May 2012 to May 2013. No DLTs were observed up to the highest dose tested (900 mg BID). Only 1 patient required dose modification due to grade 2 fatigue. The most common AEs were fatigue, CPK increase, myalgia, cough, ALT increased, peripheral edema and rash. Grade 3/4 AEs include GGT increase (n=3), neutrophil decrease (n=2), hypophosphatemia, hyperglycemia, syncope, renal failure and pericardial effusion (n=1 each), but no grade 3 nausea, vomit, diarrhea, edema were reported. Preliminary efficacy was observed with PR 48% and SD 34% by investigator assessment amongst the 30 evaluable patients (See Figure of Waterfall plot). Median progression-free survival has not been reached with 27 patients (73%) remaining on study as of June 10, 2013 (median duration 85 days, range 39-347+ days). CNS activity was observed and described in the companion abstract by Ou et al. CH5424802 single dose half-life was approximately 22 hr, AUC was dose-dependent from 300 to 600 mg BID following multiple doses with a potential plateau at doses higher than 600 mg BID based on available data.Figure 1Conclusion
CH5424802 is a well-tolerated ALK inhibitor with no DLTs observed up to the highest dose tested in this study. Promising anti-tumor activity was observed in patients who have failed crizotinib.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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O16.07 - Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028). (ID 1668)
10:30 - 12:00 | Author(s): S.I. Ou, S. Gadgeel, A.A. Chiappori, L. Gandhi, M. Azada, L. Garcia, I. Takaya, S. Yokoyama, T. Kamei, T. Tanaka, R. Lee, G. Riely
- Abstract
- Presentation
Background
Disease progression in brain occurs in ~50% ALK-rearranged NSCLC patients treated with crizotinib. This is likely due in part to low penetration of crizotinib into CNS. CH5424802 is a new ALK inhibitor that is effective in patients who have ALK re-arrangement. Preclinical studies in CNS implantation models suggest a promising anti-tumor activity of CH5424802 against CNS lesions. This report describes CNS activity observed in an ongoing phase I/II clinical trial.Methods
A phase I dose escalation study of CH5424802 was performed in ALK-rearranged NSCLC who have failed crizotinib. Patients received oral CH5424802 doses ranging from 300 to 900 mg BID. All patients had head CT/MRI and body CT scans at baseline, and every 6 weeks after initiation of treatment if baseline scans are positive for brain metastasis. Brain lesions without prior radiation were used to assess CNS response based on modified RECIST criteria. Simultaneous collection of cerebrospinal fluid (CSF) and plasma PK samples in selective patients is ongoing to evaluate CSF/plasma CH5424802 ratios to correlate with clinical activity in brain metastasis.Results
As of June 6, 2013, 37 patients were enrolled in the phase I study, and 31 of them were evaluable for efficacy. Preliminary overall response rate (ORR) is ~48% (15/31) in evaluable patients. 16 had brain metastases at baseline, and 2 had no prior brain irradiation but all had documented CNS progression prior to study treatment. These 16 patients received CH5424802 at 300mg (n=2), 460mg (n=2), 600mg (n=5), 760mg (n=3), and 900mg (n=4) BID. The median duration of follow-up of these 16 patients was 130+ days, with the longest being 347+ days. Activity against CNS lesions was observed as early as the first scan (3[rd] week). The preliminary CNS response is highly promising as shown in the representative scans below. Enrollment is still ongoing and CNS progression-free survival (PFS) will be presented. Currently 2 patients had simultaneous CSF and plasma levels of CH5424802, and the CSF/plasma ratios will be reported to evaluate any correlation between CSF/plasma ratios and the observed clinical activity of CH5424802 in brain metastasis.Figure 1Conclusion
CH5424802 demonstrates consistent and rapid clinical activity in brain metastases in ALK+ NSCLC patients who progressed on crizitinib. Within 3-6 weeks of treatment, CH5424802 dramatically shrinks brain lesions that progressed on crizotinib. CH5424802 could potentially replace or delay the need of brain radiation in ALK-positive NSCLC 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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O16.08 - DISCUSSANT (ID 3956)
10:30 - 12:00 | Author(s): D..R. Camidge
- Abstract
- Presentation
Abstract not provided
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Author of
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MO03 - Thymic Malignancies (ID 123)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:F. Detterbeck, M. Okumura
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO03.11 - DISCUSSANT (ID 3975)
10:30 - 12:00 | Author(s): H.A. Wakelee
- Abstract
- Presentation
Abstract not provided
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P1.24 - Poster Session 1 - Clinical Care (ID 146)
- Event: WCLC 2013
- Type: Poster Session
- Track: Supportive Care
- Presentations: 2
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.24-008 - Are patients' needs being met after-hours? An evaluation of phone calls made after hours for patients with thoracic malignancies. (ID 873)
09:30 - 16:30 | Author(s): H.A. Wakelee
- Abstract
Background
Understanding phone calls that patients with lung cancer make after hours is important as it represents an opportunity to provide improved care for patients and their caregivers. Furthermore, better understanding of after- hours phone calls can help to influence ways to reduce healthcare spending. Therefore, we sought to evaluate the nature of after-hours calls initiated by patients and their caregivers to the thoracic oncology clinic from the hours of 5pm-8am and on weekends.Methods
The study is a retrospective analysis of 4 months of outpatient phone calls made to the Stanford Cancer Institute during the weekends and hours of 5pm until 8am on weekdays. On-call after-hours physicians documented who made the call, chief complaint, age, gender and the advice given. Phone calls were excluded from analysis if there was missing information regarding reason for call or advice given. Differences in proportions were analyzed by Fisher's exact test. A two-sided p value <0.05 was considered significant.Results
There were a total of 271 phone calls made after hours by patients with lung cancer, however after exclusions, there were 215 phone calls for analysis. The majority of phone calls occurred between the hours of 5pm and 11pm (n = 157; 73%) followed by daytime calls made during the weekend (n = 37; 17%). A majority of the phone calls were made by the patient (50%) with a slightly lower proportion made by a family member (46%). The majority of the patients who called were in their 50’s (29%) and female (54%). A high proportion of patients called for more than one chief complaint (30%) although almost all patients complained of more than one symptom on review of systems (95%). The main symptoms patients called for were cough (28%) followed by shortness of breath (27%). Of the phone calls made, 62% (133) were referred to the emergency room. Of those patients referred to the emergency department, 77% (103/133) resulted in a hospital admission.Conclusion
Most after-hours phone calls from patients with lung cancer are related to symptoms. A large proportion of patients who were referred to the emergency department subsequently required an admission. Future studies should evaluate whether there are ways to improve patient triage after hours and improve symptom control to prevent hospitalizations for these patient populations. -
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P1.24-048 - Stage 1 results of a 2-stage phase II trial of single agent amrubicin in patients with previously treated thymic malignancies (ID 3175)
09:30 - 16:30 | Author(s): H.A. Wakelee
- Abstract
Background
There are limited treatment options for patient with advanced thymic malignancies and the utility of many of the available chemotherapies is restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). We designed this study to look at single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, in patients with advanced thymic malignancies.Methods
Eligible patients have confirmed thymic malignancy (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapeutic regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles. The study is a Simon 2-stage design based on a null hypothesis of a true response rate <5%, with 90% power to detect a 20% true response rate and a plan to accrue 12 evaluable patients in stage 1, then if at least 1 response is seen, to add 25 additional evaluable patients in stage 2 for a total of 39 patients.Results
Enrollment was initiated in July 2011. Here, we report on the first 12 patients, all enrolled at Stanford University over a 19-month period. Of the first 12 patients enrolled, 11 were dosed. All were pre-treated (5 with prior anthracycline). There were 5 women and 7 men; age range of 30-67 years old; 6 were of Asian ethnicity, 5 were non-Hispanic White and 1 was Hispanic. After enrollment of the first 8 patients, of whom 3 were hospitalized with febrile neutropenia (FN) (38%), the study was amended to a starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. Other than FN in the 3 patients mentioned above, G4 thrombocytopenia in 1 patient, and treatment-related G3 fatigue in 2 patients, other toxicities were generally mild and well tolerated. No significant changes in LVEF have been noted on serial echocardiograms. Of the 11 treated patients, there were 3 partial responses (2 T and 1 TC), 7 with stable disease for at least 4 cycles, and 1 with progressive disease (PD) after 2 cycles (TC). Of the 11 treated patients, only 1 patient, with PD after C2, has stopped before completing 6 cycles, and 5 to date have tolerated >10 cycles (with others still on treatment who may receive >10 cycles), with 15 cycles as the highest number to date.Conclusion
Amrubicin, at 35 mg/m[2] IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with a 27% RR in the first 11 treated patients. This exceeded the threshold for proceeding to step 2 and the study will now continue to a total of 39 patients and has expanded to other sites including Indiana University.
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P2.15 - Poster Session 2 - Thymoma (ID 191)
- Event: WCLC 2013
- Type: Poster Session
- Track: Thymoma & Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.15-003 - Gli1, Notch1 and CTNNB1 Expression by Automated Quantitative Immunofluorescence (AQUA) in a Thymic Malignancy Tissue Microarray (TMA) (ID 778)
09:30 - 16:30 | Author(s): H.A. Wakelee
- Abstract
Background
Thymoma is a rare malignancy, with a paucity of data on its biology and on the role of targeted therapeutics. Wnt, notch and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to both thymus and T-cell development. AQUAnalysis[®] is a digital image analysis software that continuously measures multiplexed protein expression and has the potential to overcome limitations of small sample sizes and tissue heterogeneity in the tumor microenvironment. We analyzed a thymoma TMA for gli1, notch1 and CTNNB1 (β-Catenin) expression by AQUA[®] as surrogate markers of activity of the sonic hedgehog, notch and wnt pathways, respectively. We hypothesized this preclinical screen may provide rationale for attacking these pathways with targeted therapeutics in thymoma.Methods
A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Gli1, notch1 and CTNNB1 expression were assayed using quantitative fluorescent immunohistochemistry at the Tom Baker Cancer Center (Alberta, Canada). The TMA was stained with anti-gli1 rabbit mAb (monoclonal antibody), clone EPR4523 (Epitomics, Burlingame, CA, USA); anti-Notch1 rabbit mAb, clone EP1238Y (Epitomics, Burlingame, CA, USA); and anti-beta-catenin mouse mAb, clone β-Catenin-1 (Dako Mississauga, ON, Canada) using a Dako autostainer. To isolate expression of these stem-cell pathway proteins separately in the tumor and the lymphocytes, the TMA was also stained with anti-pan-cytokeratin guinea pig mAb (Acris, San Diego, CA, USA); anti-vimentin rat mAb, clone 280618 (R&D Systems, Minneapolis, MN, USA); and anti-CD45 rabbit mAb, clone EP322Y (Epitomics, Burlingame, CA, USA). Automated image acquisition was performed using an Aperio Scanscope FL (Aperio Inc., Vista, CA, USA). Images were then analyzed using the AQUAnalysis® program, version 2.3.4.1. A tumor-specific mask and a tumor cytoplasmic mask were generated to distinguish thymoma cells from surrounding stromal tissue by thresholding the pan-cytokeratin images to identify pan-cytokeratin positive cells as tumor cells and define the tumor cytoplasm. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Two-tailed t-tests were used to compare the differences between thymic tumor and benign control tissue. ANOVA and Dunnett’s t-test was used to compare differences in gli1, notch1, and CTNNB1 expression by WHO histology.Results
Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Masaoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). No difference in gli1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 396 vs. 418, p=0.66) or notch1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumors and controls. In a subset analysis, we found no significant differences by WHO histology compared to controls.Conclusion
AQUA® was used to help overcome limitations of analyzing protein expression in histologically heterogeneous thymic tumors with small sample sizes. We found no clinically or statistically significant increased expression of gli1, notch1, and CTNNB1 in thymoma compared to benign thymic tissue. Thus, this study provides no evidence for upregulation of the sonic hedgehog, notch or wnt pathways in thymic tumors.
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P3.01 - Poster Session 3 - Cancer Biology (ID 147)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.01-007 - Energy metabolism in lung adenocarcinoma (ID 2557)
09:30 - 16:30 | Author(s): H.A. Wakelee
- Abstract
Background
Cancer cells have defects in regulatory circuits governing proliferation and homeostasis. Consequently, cell metabolism is altered to meet the demand for accelerated, deregulated growth. Metabolic perturbations arising from malignant transformation have not been well characterized in human lung cancers in situ. The most well known metabolic derangement(s) in tumors is that of enhanced glycolysis and a decrease in mitochondrial oxidative phosphorylation. We wanted to characterize this phenomenon more accurately in human lung adenocarcinomas by metabolomic profiling.Methods
We performed metabolomic analysis of matched pairs of solid, non-small cell lung adenocarcinomas and normal lung tissue from 25 surgically resected patients. Metabolites were extracted by a methanol-chloroform-water technique. The resulting extracts were divided into multiple fractions. Ultrahigh performance liquid chromatography/ mass spectrometry coupled with tandem mass spectrometry and gas chromatography/ mass spectrometry experiments were conducted. Agilent MassHunter Qualitative software was utilized. The Molecular Feature Extractor was utilized to find features in raw data files. Extracted peaks were retention time aligned using Mass Profiler Professional and unique features detected by least squares analysis. The Agilent version of the Metlin database was utilized to identify metabolites. Matched pairs t-test identified biochemicals significantly altered between tumor and normal specimens. The false discovery rate method assessed for significance; p-value ≤ 0.05 and q-value < 0.10.Results
Based on known library standards to identify biochemicals, our global metabolomic profiling found 204 overexpressed and 42 underexpressed metabolites in tumors relative to normal lung (p< 0.05). We observed altered metabolite levels in lung tumors that mapped to not one, but two glucose utilization pathways. Glucose-6-P (2.7-fold), fructose-6-P (2.6-fold), fructose-1,6-bisP (6.9-fold), lactate (2.7-fold), and NAD[+] (1.4-fold) were significantly upregulated in tumors consistent with an aerobic glycolysis (i.e. Warburg) biosignature, the major source of ATP. Concurrently, pentose phosphate pathway (PPP) metabolites were upregulated in tumors: ribulose-5-P (2.6-fold), ribulose (3.6-fold), ribitol (4.6-fold), ribose (4-fold), and sedoheptulose-7-P (3-fold). Our data reveals evidence of multiple active pathways to explain glucose utilization in lung adenocarcinomas. The PPP is important to protect against oxidative stress as it serves to generate NADPH, and is a key anabolic pathway of nucleotide synthesis by generating the ribose-5-P backbone for proliferating cells. Observing both pathways simultaneously in lung adenocarcinomas suggests they are coupled to give tumors a growth advantage over normal tissue. Consistent with this, we observed an overall increasing nucleotide biosynthesis signature in tumors: multiple metabolites (range 2 to 17-fold) in purine and pyrimidine pathways were significantly elevated.Conclusion
Metabolomic analysis identified a unique glucose energetic biosignature in lung tumors that is more complex that just a single process/ pathway. Our results suggest a specific strategy to target lung adenocarcinomas by exploiting their high glucose uptake.
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P3.24 - Poster Session 3 - Supportive Care (ID 160)
- Event: WCLC 2013
- Type: Poster Session
- Track: Supportive Care
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.24-049 - Palliative Care and Anti-Cancer Care Integration: Description of three models of care delivery at a tertiary medical center (ID 3182)
09:30 - 16:30 | Author(s): H.A. Wakelee
- Abstract
Background
The American Society of Clinical Oncology issued a Provisional Clinical Opinion on the integration of palliative care (PC) with anti-cancer care which states, “Based upon strong evidence from a phase III RCT, patients with metastatic non-small-cell lung cancer should be offered concurrent palliative care and standard oncologic care at time of initial diagnosis.” There is both a national shortage of PC providers, as well as a lack of guidelines on the best operational ways to integrate PC into oncologic care. Here we describe different models of palliative care integration into anti-cancer care models performed at the Stanford Cancer Institute.Methods
Three methods of PC integration into oncology care at Stanford Hospital and Clinics, a tertiary medical center, are being tested. These include a low resource model using a social work (SW) only intervention for advance care planning and goals of care, as well as two high resource models using an MD, advance nurse practitioner, and social worker. The first high resource model is concurrent care with joint PC and oncology visits, and the second is a traditional model of separate PC and oncology visits. Observations around successes and barriers within these various models, as well as resources needed, will be described. Data evaluated include volume, referral patterns, advance care planning, symptom assessment, and resource utilization.Results
The SW only intervention was run as a pilot in thoracic oncology. Resources required for appropriate implementation included information technology (IT) for appropriate cohort identification, operations support, data management support, and team cooperation from the physician and nursing team. Process outcomes measured included % of patients seen by SW within 3 visits, documentation of advance care planning within the medical record, and co-signature of advance care planning documentation by the physician. The joint visit model utilized a high resource team (physician, nurse practitioner, and social worker) which was present concurrently with the oncology visit for advance care planning and symptom management. In addition to the resources required for the SW only intervention, this model also included a care coordinator for visit coordination. Process outcomes measured included lead time to arrange for the joint visit and documentation of advance care planning. End outcomes included discharge to hospice, hospital utilization patterns, and effective symptom management. Other outcomes included volume and number of referring providers. Our third model was a traditional clinic visit with the PC team only, not coordinated with the oncology team. Resources and outcomes were the same as for the joint visit model. A total of 529 consults were seen in the first year. 61% were seen in a traditional clinic model and 39% were seen in the concurrent model. Volume of consults have increased over time. There were 10 consults per month in January of 2012. Currently over 100 consults are seen per month.Conclusion
Appropriate integration of PC into oncology care for thoracic oncology patients is still under investigation. Here we describe the strengths and weaknesses of three separate models of integration of PC with oncology care at an academic medical center.
