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J. Spicer
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MO09 - Mesothelioma I (ID 120)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track:
- Presentations: 1
- Moderators:K. Suzuki, S.G. Armato III
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 204 A+B, Level 2
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MO09.02 - A Randomised Phase II trial of Pegylated Arginine Deiminase in patients with Malignant Pleural Mesothelioma (ID 1355)
16:15 - 17:45 | Author(s): J. Spicer
- Abstract
- Presentation
Background
Preclinically, arginine deprivation has shown activity as a novel antimetabolite strategy for MPM patients who are deficient for the rate-limiting enzyme in arginine biosynthesis argininosuccinate synthetase (ASS1). Here, we examine the efficacy and safety of the arginine-lowering agent ADI-PEG20 (Polaris Group, San Diego, US) among patients with MPM.Methods
We performed a multicentre randomised phase II clinical trial, based on patients with good performance status (0 or 1), non-resectable disease, ASS1-deficient MPM, and measurable disease. Patients were randomized 1:2 to receive best supportive care (BSC) or BSC+ADI-PEG20, stratified by: gender, histology (sarcomatoid versus non-sarcomatoid), prior treatment (chemonaive or previous platinum combination therapy), and centre. The primary endpoint, progression-free survival (PFS), is assessed by modified RECIST, and secondary endpoints include overall survival, tumor response rate, and toxicity. Translational endpoints included measurement of plasma arginine, citrulline and ADI-PEG20 antibody levels, assessment of metabolic response by [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and ASS1 methylation status using Illumina’s 450K DNA methylation array. The target sample size was estimated to detect a PFS hazard ratio of 0.60. [Trial funded by Cancer Research UK].Results
ASS1 deficiency was detected in 98 of 214 patients (46%) of which 68 were randomized on the trial (44 ADI-PEG20+BSC and 24 BSC alone). 66 patients have progressed so far (42 ADI-PEG20+BSC vs. 24 BSC alone), and 32 patients were alive (23 ADI-PEG20+BSC vs. 9 BSC alone). The hazard ratio for PFS was 0.53 (95%, CI 0.31 to 0.90, p=0.02) with a median PFS of 98 days for patients randomized to ADI-PEG20+BSC compared with 59 days for patients receiving BSC alone. ADI-PEG20 toxicity in patients with MPM has been consistent with previous trials of ADI-PEG20 in melanoma and liver cancer: commonly skin injection site reactions (grade 1-2), infrequent episodes of neutropenia (range: grade 1-4), anaphylactoid reactions (2 patients with grade 3 episodes) and serum sickness (1 patient). The best response by modified RECIST was stable disease. Metabolic responses (in 39 evaluable ADI-treated patients) were as follows: 46% with partial response (18/39), 31% with stable disease (12/39), 15% progressive metabolic disease (6/39) and 8% mixed metabolic response (3/39) by FDG-PET assessment. There was a significant difference between IHC assessed ASS1-negative and ASS1-positive patients and the methylation status of the ASS1 gene (p=0.025).Conclusion
ADI-PEG20 is generally well tolerated and shows evidence of clinically significant activity in patients selected for arginine-dependent MPM demonstrating differential methylation of ASS1. Arginine deprivation may have a role in the future management of MPM either alone or in combination with selected therapies.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 - SCLC I (ID 118)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:C.K. Liam, E.S. Santos
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO13.07 - Survival of small cell lung cancer patients undergoing lung resection in England 1998-2009 (ID 1691)
10:30 - 12:00 | Author(s): J. Spicer
- 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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O03 - NSCLC - Targeted Therapies I (ID 113)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:J. Ross, J.C. Yang
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
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O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)
10:30 - 12:00 | Author(s): J. Spicer
- Abstract
- Presentation
Background
Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).Methods
We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.Results
Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.Conclusion
Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.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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O14 - Radiotherapy - Toxicity and Clinical Trials (ID 105)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Radiation Oncology + Radiotherapy
- Presentations: 1
- Moderators:G. Pratt, S.K. Vinod
- Coordinates: 10/29/2013, 10:30 - 12:00, Parkside Ballroom A, Level 1
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O14.07 - IDEAL CRT: Isotoxic Dose Escalation and Acceleration in Lung Cancer ChemoRadiotherapy - a phase I/II trial of concurrent chemoradiation with dose-escalated radiotherapy in patients with stage II or stage III Non-Small Cell Lung Cancer. (ID 1368)
10:30 - 12:00 | Author(s): J. Spicer
- Abstract
- Presentation
Background
The IDEAL-CRT trial uses an individual patient approach to radiotherapy (RT) dose escalation, escalating the dose within a fixed overall treatment time, 6 weeks, by increasing dose per fraction. Isotoxic RT is based on the calculated risk of RT-pneumonitis (RTPN), RT dose being escalated so that all patients are exposed to the same RTPN risk. We investigated the feasibility and safety of individualised, isotoxic dose escalation for once daily RT delivered in 30 once-daily fractions with concurrent chemotherapy.Methods
Eligibility; NSCLC stage II/III, PS 0/1, FEV~1~ (≥40% predicted or ≥1L), DCLO (≥40% predicted). A radiobiological model was used to individualize RT dose-prescription – selecting a dose which, in 30# once daily for 6 weeks, is associated with a 10% risk of grade 3+ RTPN, but limiting prescribed doses to between 63Gy - 73Gy (2Gy dose equivalent α:β=10, 63.5Gy-86Gy). Dose constraints were fixed for spinal cord, heart, brachial plexus. In Arm 1, initially the maximum dose to 1cc oesophageal did not exceed 63Gy. Arm 2 comprised patients in whom oesophageal dose rather than lung dose limited the prescription dose: the oesophageal dose was raised from 65Gy to 68Gy, 71Gy and 73Gy in consecutive cohorts, the prescribed dose lying between 63Gy and 73Gy and being the highest consistent with the oesophageal limit. Dose escalation was determined using a 6+6 design. Dose limiting toxicity (DLT) was defined as Grade 3+ oesophagitis. MTD was determined if grade 3+ oesophagitis >42% (>5/12). Two cycles of Cisplatin-Vinorelbine chemotherapy given concurrently during RT. All contouring and dosimetry on planning CT scans was centrally reviewed. IMRT was introduced in November 2012. Primary endpoints: oesophagitis and RTPN. Serial pulmonary function tests and ECGs performed. Efficacy endpoints: overall survival (OS), progression free survival (PFS), and tumour response.Results
Between October 2010 and February 2013, 84 patients recruited (9 UK centres), 49 patients Arm 1, 35 patients Arm 2 (13 at 65Gy, 12 at 68Gy, 10 at 71Gy; none at 73Gy as the 73Gy upper prescription dose limit was only rarely associated with an oesophageal dose higher than 71Gy). Median follow up was 11 months (range 2,24); median age 66 years (range 43-84); 74% male; 39%/60% WHO 0/1; 30% adenocarcinoma, 54% squamous. Mean GTV 121cc (range 14-602cc). Mean prescribed dose for patients completing RT (n=80) 67.6Gy (range 63-73Gy) in Arm 1 and 70.1 Gy (63-73) in Arm 2. Mean 1cc-oesophageal-dose in Arm 1 55.5Gy (range 14.2-68.0Gy). In Arm 1 grade 3+ oesophagitis was 6% (3/49). In Arm 2, Grade 3+ oesophagitis was 17% (2/12) at 68Gy; no Grade 3+ oesophagitis in 65Gy (0/12) and 71Gy (0/10) cohorts. Grade 3+ RTPN 2% (1/49) in Arm 1 and 6% (2/35) in Arm 2. 1 year OS and PFS rates were 92% and 74% respectively.Conclusion
Isotoxic RT dose escalation was safe and feasible. The MTD for oesophagus was not reached. Acceleration of the IDEAL-CRT schedule to five weeks is under investigation in a second study, currently recruiting.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.
