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C.K. Liam
Moderator of
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MO13 - SCLC I (ID 118)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 11
- Moderators:C.K. Liam, E.S. Santos
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO13.01 - Disease control rate at 8 weeks predicts subsequent survival in platinum-treated extensive stage small cell lung cancer (ES-SCLC): a patient level analysis of SWOG trials (ID 967)
10:30 - 12:00 | Author(s): P. Lara, J. Moon, M. Redman, K. Kelly, J. Allen, B. Gitlitz, P. Mack, D. Gandara
- Abstract
- Presentation
Background
Disease control rate (DCR) – the sum of partial (PR) and complete response (CR) plus stable disease (SD) – is a significant predictor of subsequent survival following platinum-based chemotherapy in patients with advanced non-small cell lung cancer (Lara, et al. JCO 2008). We evaluated whether this observation is also relevant in patients with platinum-treated ES-SCLC on investigational systemic therapy.Methods
Updated patient-level data from recent SWOG trials in 2[nd] and/or 3[rd] line ES-SCLC (S0802: topotecan + aflibercept; S0435: sorafenib; and S0327: PS-341) were pooled. Landmark analysis was performed among patients still alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors (including age, sex, platinum sensitivity status, number of prior chemo, weight loss, and LDH, among others) with DCR was assessed using logistic regression. A Cox proportional hazards model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors.Results
319 patients were included: median age = 63 years; male sex = 51%; PS 1 = 68%; weight loss > 5% = 29%; > 2 prior chemo = 16%; and elevated LDH = 43%. Only 8 patients had PR by RECIST for an overall response rate of 2.5%. Disease control at 8 weeks was observed in 74 patients (8 PR + 64 SD), for a DCR of 23.2%. Bivariate analysis of OS from the 8-week landmark revealed that only DCR (Hazard Ratio [HR] 0.53, p<0.0001) and elevated LDH (HR 1.69, p=0.001) were significantly associated with OS. Multivariable analysis showed that only DCR remained as an independent predictor of subsequent survival from the 8-week landmark (HR=0.58, p=0.002).Conclusion
In this large 2[nd]- and 3[rd]-line ES-SCLC database, DCR at 8 weeks was found to be the strongest predictor of subsequent survival in patients receiving investigational therapy. Thus, DCR at 8 weeks should be considered for use as a surrogate clinical trial endpoint to screen for drug activity against ES-SCLC. These results have critical implications in the design of future prospective trials in ES-SCLC.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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MO13.02 - Age as a prognostic factor in small cell lung cancer. A pooled analysis of randomized clinical trials from the Manchester lung cancer group (MLCG) and the UK Medical Research Council Clinical Trials Unit (MRC CTU). (ID 2270)
10:30 - 12:00 | Author(s): P. Wheatley-Price, E. Sabri, L. Ashcroft, S. White, P. Lorigan, N. Thatcher, F. Blackhall
- Abstract
- Presentation
Background
About 40% of all cases of small cell lung cancer (SCLC) occur in the over 70 year age group (70+), and 10% in patients aged over 80 years. A SEER database reports decreasing SCLC 5-year survival with age (7.1%, 3.9% and 2.2% in the <70, 70-79 and 80+ age groups, respectively). However age has been inconsistently reported as a prognostic factor in SCLC trials. Recently a series of randomized trials of chemotherapy (CT) in SCLC were pooled to analyze the prognostic impact of patient sex (Wheatley-Price et al, Annals of Oncology 2009). We used the same dataset to investigate the impact of age.Methods
Five randomized phase II and III CT trials, performed by the MLCG and MRC CTU between 1993 and 2005, were pooled for analysis (one study from the previous analysis was excluded as it did not contain elderly patients). One trial investigated a dose-dense approach and 4 trials compared CT regimens. The primary endpoints were overall survival (OS) in limited stage (LS) and extensive stage (ES) and the rates of haematological and non-haematological toxicity.Results
In total 1439 patients were included, of whom 45% were female and 36% had ES disease. The median age was 63 years (range 30-88), and 343 (24%) were 70+, and only 33 (2%) were 80+. Anthracycline-based CT was given in 61%, versus platinum-based CT in 38% of patients. More patients in the younger group had a good performance status (ECOG 0-1, Karnofsky 80-100); 65% versus 39% (p=0.0007). Baseline hyponatremia was present in 35% and did not differ by age group. Overall, median OS was significantly longer in younger patients in univariate analysis (9.3 months versus 7.4 months; HR 0.79, 95% CI 0.66-0.95, p=0.01). By disease stage, median OS in LS patients was significantly longer in younger patients (HR 0.88, 95% CI 0.79-0.99, p=0.04), and a similar effect was observed in ES (HR 0.75, 95% CI 0.55-1.01, p=0.06). However in multivariate analysis (age, stage, sex, hyponatremia, anemia), factors significantly associated with longer survival were LS, female sex, good PS and absence of hyponatremia, but younger age was no longer prognostic (HR 0.96, 95% CI 0.86-1.08, p=0.52). The elderly were more likely to experience grade 3 or 4 leucopenia (52% versus 40%, p=0.0035), neutropenia (36% versus 31%, p=0.045) and thrombocytopenia (34% versus 22%, p=0.0003), but less likely to experience grade 3 or 4 emesis (8% versus 14%, p=0.022) or mucositis (5% versus 11%, p=0.021). There were no differences in infection rates or blood transfusion rates, although the elderly required more platelet transfusions (p<0.0001). The dose intensity (total number of CT cycles delivered divided by the planned number of cycles) was higher in the younger group (p<0.0001).Conclusion
In a large pooled analysis of CT trials in SCLC, age was not a prognostic factor for survival. However the elderly experienced higher rates of grade 3 and 4 hematological toxicity. Further analysis is ongoing.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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MO13.03 - Duration of Thoracic Radiotherapy with Concurrent Chemotherapy is Important for Outcome of Patients with Limited-Stage Small Cell Lung Cancer (L-SCLC) (ID 2834)
10:30 - 12:00 | Author(s): R. Komaki, P. Allen, X. Wei, D.R. Daniel, J.V. Heymach, J.W. Welsh, M.S. O'Reilly, O. Takahashi, S.H. Lin, J.D. Cox
- Abstract
- Presentation
Background
A previous Intergroup study of L-SCLC showed that accelerated hyperfractionated thoracic radiotherapy (TRT) given over 3 weeks with concurrent etoposide and cisplatin (EP) led to improved 5-year survival rates compared with daily TRT given over 5 weeks, albeit with higher rates of grade 3 acute esophagitis. We retrospectively compared the efficacy and toxicity of TRT with concurrent EP for L-SCLC given in <6 weeks (Group A) versus >6 weeks (Group B).Methods
A total of 577 patients with cytotogically or histologically biopsy proven L-SCLC (staged by chest/upper abdominal CT and brain MRI) received TRT+EP at a single institution in 1985‒2009. Group A received 45 Gy in 30 fractions over 3 weeks (BED=52) or 28 fractions over 5 weeks (BED=43) or 61.2 Gy in 34 fractions over 5 weeks (BED=72). Group B received a median 60 Gy in 6 weeks (BED=72). Cone-down fields were used routinely. Complete responders received prophylactic cranial irradiation (PCI). Kaplan-Meier analysis was used to estimate survival, with log-rank tests used to compare survival curves; p values ≤0.05 were taken to indicate signifiance. Cox regression analysis was used for univariate and multivariate analyses and toxicity was graded according to CTCAE v2.0.Results
The median follow-up time for patients alive at the time of analysis was 32 months (range 1.2‒222 months); median age was 62 years (range 27–95); and 87% had Karnofsky Performance Status (KPS) scores of ≥80. Group A contained 503 patients and group B had 74. The groups did not differ in KPS, age, smoking history, or receipt of PCI. Group A was more likely to have received concurrent chemoTRT than sequential chemoTRT (p<0.001). At 5 years, the overall survival (OS) rates were 26.1% for group A vs. 14.1% for group B (p=0.077); disease free-survival (DFS) rates were 31.6% (group A) vs. 13.5% (group B) (p=0.008); local-regional control (LRC) rates were 55.1% (A) vs. 36.2% (B) (p=0.077); and distant metastasis-free survival (DMFS) rates were 40.8% (A) vs. 20.0% (B) (p=0.008). No differences were found in rates of grade ≥3 acute esophagitis (17% group A vs.18% group B) or pneumonitis (4% group A vs. 3% group B). Group B had a higher rate of grade ≥3 lung fibrosis (10% group A vs. 22% group B, p=0.01). Multivariate analysis showed that factors influencing worse DFS were receiving TRT in more than 6 weeks (HR=1.46, p=0.008) and receipt of sequential rather than concurrent chemoTRT (HR=1.51, p=0.001); age <62 years (HR=0.99, p< 0.039) and receipt of PCI (HR=0.77, p=0.015) were associated with better DFS.Conclusion
TRT given with concurrent EP over periods longer than 6 weeks led to lower rates of DFS, worse local and distant disease control, and higher rates of severe lung fibrosis. Factors associated with better DFS were younger age, concurrent chemoTRT, and use of PCI. Rates of acute grade ≥3 esophagitis and pneumonitis were low in both groups. Final recommendations await the results of an ongoing prospective randomized trial.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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MO13.04 - <strong>A Phase II Trial of second line Pazopanib in Small Cell Lung Cancer (SCLC) patients: Preliminary results in patients with sensitive disease</strong> (ID 2095)
10:30 - 12:00 | Author(s): A. Kotsakis, N. Kentepozidis, V. Karavasilis, I. Varthalitis, S. Peroukidis, N. Ziras, H. Res, D. Mavroudis, V. Georgoulias, S. Agelaki
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- Presentation
Background
Pazopanib, a small molecule competitive inhibitor of the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Microvessel density and VEGF expression in SCLC tumor samples correlate with development of metastases and poor prognosis. A phase II trial of pazopanib in SCLC patients who have relapsed after, or have refractory disease to front-line chemotherapy was conducted.Methods
This is a two-cohort, non-randomized, two-stage phase II study. Patients with sensitive (cohort A) and resistant/refractory (cohort B) histologically confirmed SCLC are enrolled onto the study. An interim analysis has been planned after enrolment of 19 patients in each cohort. Eligible patients have to have measurable disease (RESIST) and ECOG performance status (PS) 0-2. Up to 1 prior regimen (cisplatin/etoposide) for extended disease is allowed. Treatment consists of daily pazopanib 800 mg given p.o.q28 days, until disease progression. The primary endpoint is progression-free rate with a planned sample size of 39 eligible patients per cohort.Results
We present the first interim analysis in cohort A. 19 eligible patients have been enrolled with a median age of 67 years (range 46-77); male 16; PS 0, 10 pts; PS 1, 9 pts. Four patients had only local relapse. Four (21%) partial responses and 8 (42%) stable disease were documented which is translated in a disease control rate (DCR) of 63% (95% CI: 41.5- 85%). The median PFS was 4.3 months and the estimated 1-year survival 58%. Grade 4 neutropenia and diarrhea occurted in 1 patient each; other grade 3 adverse events were fatigue (n=2), nausea (n=1); grade 2 hypertransaminasemia occurred in 2 patients, grade 1 hemorrhage (epistaxis) in 3 and hypertension in 2. No deaths related to the study drug were observed.Conclusion
These preliminary results show that pazopanib is an active and well tolerated drug in patients with sensitive SCLC. Recruitment in both cohorts is ongoing. A biomarker analysis is planned.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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MO13.05 - DISCUSSANT (ID 3962)
10:30 - 12:00 | Author(s): M. Millward
- Abstract
- Presentation
Abstract not provided
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MO13.06 - Prophylactic Cranial Irradiation for patients with Small Cell Lung Cancer with 30 Gy in 10 fractions - analysis of efficacy and subset analysis of neurocognitive impairment. (ID 1310)
10:30 - 12:00 | Author(s): S. Saha, A.G. Dastidar, S. Chattopadhyay, P. Chattopadhyay
- Abstract
- Presentation
Background
Prophylactic cranial irradiation (PCI) plays crucial role to prevent brain metastasis for small cell lung cancer (SCLC) patients – both limited stage (LS) or extensive (ES) – who respond to initial therapy. For better quality-adjusted life expectancy and to avoid neurointellectual impairment (NIP), optimum dose and fractionation for PCI needs to be explored, with due consideration to coexisting medical comorbidities that might enhance the adverse events, specially neurocognitive functions. Aim of the study was to find the safety and efficacy of PCI with the dose of 30 Gy/ 10 fractions and to analyze its impact on NIP with special focus on any possible influence of these medical comorbidities.Methods
This is an on-going single arm multicentric trial initiated in November 2010 where both LS- as well as ES-SCLC patients who responded to initial therapy and were not having any visceral metastasis are offered PCI for a dose of 30 Gy in 10 fractions with CT-based planning. All patients received Platinum + Etoposide for 6 cycles. LS-SCLC patients received, in addition, concomitant thoracic radiation after 2 cycles of chemotherapy. To minimize neuro-psychological impairment, at least 2 weeks gap is given before PCI and after completion of all chemotherapy to avoid entry of more chemotherapeutic agent into brain parenchyma by way of radiation induced permeability alterations. All relevant medical comorbidities (Diabetes, Hyperlipidimia, previous history of CVA) are recorded. Neuropsychological screening measure of immediate and delayed verbal memory by using Hopkins Verbal Learning Test - Revised (HVLT - R), assessment of cognitive function using Mini-Mental Status Examination (MMSE) and Instrumental Activities of Daily Living (IADL) questionnaires are applied before initiation of PCI and on follow up .Results
Result of first 38 patients receiving PCI (LS- SCLC = 28, ES-SCLC = 10) with minimum duration of follow up of 18 months is being presented. Brain metastasis, in spite of PCI was faced by 0/28 of LS and 1/10 of ES-SCLC. Median duration of survival was 8.5 months for ES and 14 months for LS-SCLC. 1/10 ES-SCLC and 16/28 LS-SCLC lived one year. Corresponding data for 18 months is 0/10 and 4/28 respectively. MMSE deterioration was noted in 12/38 patients. Subset analysis of these 12 patients revealed 8/12 are having long standing diabetes and another 2/12 had both diabetes and hyperlipidimia. HVLT decline in immediate recall (13/38) was in 10/12 patients having MMSE deterioration and 9 out of these 12 had delayed recall deterioration also. So NIP (as evidenced by HVLT) was found in 10/14 diabetic patients receiving PCI, contrary to 3/24 non-diabetics (P = 0.0004).Conclusion
30Gy/ 10 fractions is an effective PCI protocol for both LS and ES – SCLC. But patients with medical comorbidities, specially long standing Diabetes (and may be hyperlipidaemia) are more prone to develop impairment of neurocognitive functions (possibly due to presence of cerebral microinfarcts and lacunar infarcts) and deserve special attention and should be treated possibly with lower dose / fraction size less than 3 Gy. Further study with more patient accrual is required to arrive at a definite conclusion.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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MO13.07 - Survival of small cell lung cancer patients undergoing lung resection in England 1998-2009 (ID 1691)
10:30 - 12:00 | Author(s): M. Luchtenborg, S.P. Riaz, E. Lim, R. Page, D.R. Baldwin, E. Jakobsen, P. Vedsted, M. Lind, M.D. Peake, A. Mellemgaard, J. Spicer, L. Lang-Lazdunski, H. Moller
- Abstract
- Presentation
Background
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC) except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected small cell lung cancer is limited but this is widely offered.Methods
Data on 359,873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC; non-SCLC [NSCLC]) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socio-economic status.Results
The survival of 465 resected SCLC patients was lower than resected NSCLC patients (five-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 “elective” SCLC where the diagnosis was most likely known before resection than for the subgroup of 267 “incidental” cases, where the SCLC diagnosis was likely to have been made after resection.Conclusion
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. SCLC patients treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected SCLC 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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MO13.08 - A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high grade pulmonary neuroendocrine carcinona (Large cell neuroendocrine carcinoma and small cell lung cancer) (ID 1562)
10:30 - 12:00 | Author(s): H. Kenmotsu, S. Niho, T. Ito, Y. Ishikawa, M. Noguchi, H. Tada, I. Sekine, S. Watanabe, M. Yoshimura, N. Yamamoto, F. Oshita, K. Kubota, K. Nagai
- Abstract
- Presentation
Background
Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.Methods
Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.Results
Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.Conclusion
The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.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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MO13.09 - Small cell lung cancer in daily practice; SCOT registry (Small cell lung Cancer treatment and OuTcome) (ID 2300)
10:30 - 12:00 | Author(s): P.E. Postmus, E. Quoix, A. Ardizzioni, T. Le Chevalier, P. Garrido, A. Raillard, P. Rabier, S. Lavigne, C. Deville, J. Fletcher, F. Sapunar, F. Mehmud
- Abstract
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Background
The SCOT registry is an international, multicenter, observational registry of newly diagnosed patients with SCLC. The treatment plan remained the responsibility of the patient’s physician and data collected in this registry reflect a "real world" approach for the diagnosis and treatment of patients with SCLC.Methods
56 centers included 507 evaluable patients between 10[th] of November 2009 to 18[th] of August 2010. Participating countries are from Western Europe, Eastern Europe and Korea. Data has been entered into an electronic CRF via the internet.Results
Mean age was 65.4 years, 73% of the patients were male, mean BMI was 25.5 Kg/m2. Smoking status showed 50% were current and 46% former smokers. The most common symptoms at presentation (>25%) were cough, dyspnea, weight loss and fatigue. Patients presented with an ECOG status of 0 (24%; 33% for limited disease (LD) and 19% for extensive disease (ED)), ECOG 1 (52%), ECOG 2 (19%) and ECOG 3 (5%). Histology was small cell carcinoma in 98% of patients and 66% presented with extensive disease. Chemotherapy alone was given to 59% of patients in the first 6 months of treatment. 58% of patients had one line of therapy, 26% had 2 lines, 11% had 3 lines of therapy and 4% had 4 lines or more. The agents most commonly used in each line of therapy are below: Table 1: Chemotherapy agents by line of therapy in SCOT (% within the treatments of the line)
67 % of patients with LD received chemo + thoracic radiotherapy. PCI in the first 6 months was given in 26% of patients (LD 34% ED 22%). Best overall response at 6 months in patients with combined chemoradiotherapy was PR=51%, CR=22%, SD=16%, PD=11%. Median overall survival (OS) was 10.6 months [95%CI 9.6, 12.1] with 17.8mo for limited disease and 8.7mo for extended disease. Western Europe and Korea showed OS of 11.5mo and 11.3mo respectively whereas in Eastern European median OS was 9.1 months.AGENT/LINE FIRST SECOND THIRD > 3 Platinum/Etoposide 90.7 26.8 14.5 10.5 Topotecan 0.2 25.7 20.2 2.3 Taxanes 2.1 9.3 21.7 26.3 Cyclophosphamide 3.9 10.9 11.6 15.8 Cyclo/Vincristine 3.9 12.0 11.6 15.8 Vinorelbine 0.2 1.1 2.9 2.3 Gemcitabine 0.0 2.2 0.0 6.8 Conclusion
This observational study captured real world data of the current treatment paradigm of SCLC. Patients are commonly treated with etoposide/platinum or chemoradiotherapy as first line. The combination of platinum and etoposide remains by far the first choice of chemotherapy in 1[st] line and often at relapse, followed by topotecan starting from second line and beyond. Details on patterns of disease, treatment and efficacy by region and smoking status plus medical resource utilisation will be available at the meeting.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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MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)
10:30 - 12:00 | Author(s): M.C. Pietanza, A. Varghese, H. Won, N. Rekhtman, L. Wang, W.D. Travis, P.K. Paik, G.J. Riely, M.F. Zakowski, M. Ladanyi, M.F. Berger, M.G. Kris, L.M. Krug
- Abstract
- Presentation
Background
Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.Methods
Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.Results
For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).Conclusion
As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.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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MO13.11 - DISCUSSANT (ID 3963)
10:30 - 12:00 | Author(s): M.M.E. O'Brien
- Abstract
- Presentation
Abstract not provided
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Author of
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PC02 - EGFR as a Target in Early Stage Disease (ID 71)
- Event: WCLC 2013
- Type: Pro/Con Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:N. Pavlakis, J.S. Lee
- Coordinates: 10/29/2013, 14:00 - 15:30, Parkside Auditorium, Level 1
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PC02.3 - Con: Patients with EGFR Mutations Should Not Receive Adjuvant EGFR TKIs (ID 630)
14:00 - 15:30 | Author(s): C.K. Liam
- Abstract
- Presentation
Abstract
Adjuvant therapies are required to prevent disease recurrence and improve patient survival after surgery in early stage (stage I–IIIA) non-small cell lung cancer (NSCLC). In advanced disease, patients whose tumours have activating EGFR mutations have an approximately 60%-75% response rate to EGFR tyrosine kinase inhibitors (TKIs) treatment as first-line therapy and a progression-free survival that is significantly superior to standard chemotherapy. Although adjuvant TKI therapy is an appealing treatment strategy, can the remarkable efficacy of EGFR TKI in advanced EGFR-mutant NSCLC be extrapolated to stage I-IIIA disease? While adjuvant cisplatin-based chemotherapy prolongs survival with just 3-4 months of treatment, no trial to date has studied the value of a few months of adjuvant EGFR TKI. The phase III BR.19 trial by the National Cancer Institute of Canada designed to study 1,160 patients with fully resected stage IB, II and IIIA NSCLC randomised to receive 2 years of adjuvant gefitinib at 250 mg daily or 2 years of adjuvant placebo was greatly underpowered because enrolment was stopped prematurely when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in a patient population not enriched for the presence of EGFR mutations with inoperable stage III NSCLC. EGFR mutation status was tested post-hoc in two thirds of 537 patients enrolled. There was no overall survival (OS) benefit for adjuvant gefitinib over placebo (HR 1.58; 95% CI, 0.83 - 3.0; P = 0.16) in 76 patients with EGFR mutant tumours. Despite an underpowered study, the negative finding should caution us about recommending adjuvant EGFR TKI therapy outside of a protocol setting. The phase III Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) compares 2 years of adjuvant erlotinib, at 150 mg orally per day, to 2 years of placebo following complete resection of stage I-IIIA NSCLC in 945 patients who were selected based on having either EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by FISH. At the 2009 ASCO meeting, the RADIANT investigators presented the results of the biomarker analyses from the first 655 patients enrolled which showed an EGFR mutation-positive rate of 12%, which suggests that in the final result there will be approximately 38 EGFR mutation-positive patients on the placebo arm and about 76 on the erlotinib arm. This study is unlikely to provide sufficient power to a draw a firm conclusion about genotype-directed adjuvant therapy for patients with EGFR mutations. Investigators from the Memorial-Sloan Kettering Cancer Center reported a retrospective series of 167 patients at their centre with resected stages I-III NSCLC which were EGFR mutation-positive, among whom 32% received adjuvant EGFR TKI therapy. An improved 2-year disease-free survival (DFS) was observed in patients who received adjuvant TKI therapy compared to those who did not (89% vs 72%) (HR, 0.53; 95% CI, 0.28 - 1.03; P = 0.06). A trend toward more favorable 2-year OS in recipients of EGFR TKI therapy was also seen (96% vs 90%; HR 0.62, CI 0.26-1.51, P = 0.296). When the number of patients with resected EGFR mutant lung cancers was increased to 222, the same investigators in a more recent publication, showed treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, DFS HR 0.43 (95% CI: 0.26-0.72, P = 0.001), and a trend toward improved OS. The phase II SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) trial is a single-arm, prospective study of two years of adjuvant erlotinib in 100 patients with resected, state IA to IIIA EGFR mutation positive NSCLC. Preliminary results presented at the 2012 ASCO meeting for the first 36 patients showed a DFS of 94% compared to a historical control of 70% with a median follow-up of 2.7 months. The answer provided by the SELECT trial is also unlikely to be definitive. The phase II/III Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) trial by the French Collaborative Intergroup compares 4 cycles of standard cisplatin/pemetrexed (CP) adjuvant chemotherapy (arm A, n = 74) with customised adjuvant treatment (arm B, n = 76) based on EGFR and ERCC1 status in patients with completely resected stage IIA, IIB or IIIA (non-N2) (6[th] TNM edition) nonsquamous NSCLC. In the experimental arm, EGFR mutated patients received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. EGFR mutation was identified in only 10 patients (3 in arm A, 7 in arm B). All 7 patients with EGFR mutation in arm B received erlotinib for a median duration of 276 days. The phase III was cancelled due to the unexpected unreliability of the ERCC1 immunohistochemistry read-out. Two randomised studies comparing gefitinib 250 mg daily for 2 years with adjuvant chemotherapy (4 cycles of cisplatin/vinorelbine) in patients with surgically resected stage IIA, IIB and IIIA EGFR mutation-positive adenocarcinoma are ongoing in Japan and in China (ADJUVANT CTONG 1104). In conclusion, it remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, and it is premature to recommend adjuvant EGFR TKI therapy outside well-designed clinical trials as there is currently no conclusive data on its role in early- and locally advanced NSCLC harbouring EGFR mutations. Given the consistent development of acquired resistance to EGFR TKI therapy in patients with metastatic NSCLC, there is good reason to question whether it is advisable to use EGFR TKI for adjuvant therapy in patients who have no evidence of disease and who can develop resistance to an otherwise effective treatment. Furthermore, the optimal duration of adjuvant therapy is yet to be defined and it is unknown whether EGFR TKI is merely by suppressing the growth of residual disease after surgery rather than eradicating minimal residual disease. Given the fact that adjuvant therapy needs to be given post-operatively for a prolonged period, the quality of life of patients while on therapy and the financial cost involved also need to be considered.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
