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A. Hossain
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OA24 - Radiotherapy of Lung Cancer: Recent Developments (ID 411)
- Event: WCLC 2016
- Type: Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:K. Dieckmann, S. Rieken
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 1
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OA24.01 - Radiotherapy Quality Assurance of Concurrent Chemoradiotherapy in PROCLAIM Phase III Trial (ID 4274)
14:20 - 15:50 | Author(s): A. Hossain
- Abstract
- Presentation
Background:
Trials of chemoradiotherapy for different tumors, including lung cancer, have shown a correlation between protocol deviations and adverse outcomes. Radiation quality assurance (RTQA) was mandated for all patients treated in the PROCLAIM (NCT00686959) trial evaluating two different chemoradiotherapy regimens.
Methods:
The study was open to accrual between 2008-2012. Planned chemoradiotherapy dose was 60-66 Gy in daily 2 Gy fractions. Quality was assessed through review of radiation treatment plans and monitoring of protocol violations. Review of the radiation plan was mandated for all patients; prior to radiation start for the first enrolled patient at each site. Real-time review was performed randomly in 20% of additional patients with nonreal-time review performed for the remainder. Parameters assessed for major violations per protocol included: <95% of planned total volume (PTV) received by 93% of prescribed dose; >1 cm[3] contiguous volume within or outside the PTV received >115% of prescribed dose; V~20~ (volume of lung receiving ≥20 Gy) >38%; and maximum point dose to spinal cord of >48 Gy. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kapan-Meier methodology and groups were compared by log-rank test and Cox proportional hazard modeling.
Results:
Of 598 patients randomized in 126 investigational sites, 554 received study assigned chemoradiotherapy. The median dose delivered was 66 Gy, with 92.6% of patients receiving planned chemoradiotherapy dose (60-66 Gy). A total of 40 patients, enrolled at twenty-eight sites had major RTQA violations. Seven sites enrolled ≥2 patients with major violations. Patients with major violations has a higher incidence of Stage IIIB disease (70.0% vs. 50.6%) and larger tumors (median planned PTV=653 vs. 523cc) than patients with no violations. Patients treated at sites with ≥2 patients with violations (n=86), had a lower median OS (median 21.1 vs. 29.8 months; HR 1.442) and median PFS (median 7.3 vs. 11.3 months; HR 1.345) than patients at sites where none had violations.
Conclusion:
Major chemoradiotherapy protocol violations were uncommon in the PROCLAIM study, which may be a reflection of the mandatory RTQA. Protocol violations were more frequent in patients with Stage IIIB and larger tumors, which generally require more complex chemoradiotherapy plans. The observation of discrepant outcomes at centres with multiple major RTQA violations is hypothesis-generating but should be interpreted with caution due to the small number of patients.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-012 - Phase 2 Study of Abemaciclib + Pembrolizumab in KRAS Mutation, PD-L1+, Stage IV Non-Small Cell or Squamous Cell Lung Cancer (ID 3762)
14:30 - 15:45 | Author(s): A. Hossain
- Abstract
Background:
Stage IV non-small cell lung cancer (NSCLC) harboring KRAS mutations remains a treatment challenge. Abemaciclib, a small molecular inhibitor of both cyclin-dependent kinase (CDK) 4 and CDK6, demonstrated acceptable safety, tolerability, and single-agent activity for patients with different tumors, including NSCLC. Preclinical evidence suggests a lethal interaction between CDK4 inhibition in lung cells and KRAS oncogenes. Pembrolizumab, a humanized monoclonal antibody against PD-1 protein, is approved in the US for patients with metastatic PD-L1+ NSCLC. Both compounds demonstrated manageable toxicities. We thus aim to study the combination of abemaciclib and pembrolizumab in pretreated patients with NSCLC.
Methods:
This open-label phase 2 study will evaluate safety and preliminary efficacy of abemaciclib 150 mg given orally every 12 hours on a continuous schedule on days 1-21 in combination with intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle to patients in 1 of 3 disease cohorts: KRAS mutation, PD-L1+, stage IV NSCLC (Part A); stage IV NSCLC with squamous histology (Part B); or hormone receptor+, HER2- metastatic breast cancer (Part C). Total target accrual is approximately 75 patients (25 per cohort). Only the 2 NSCLC cohorts will be presented here. Patients eligible for Part A have a confirmed KRAS mutation, PD-L1+ expression score of ≥1%, and are chemotherapy-naïve for metastatic NSCLC. Part B includes patients with predominately squamous NSCLC who have received 1 prior platinum-based chemotherapy for advanced NSCLC. Patients must provide tumor tissue before and after treatment (cycle 3, day 1); have measurable disease, adequate organ function, an ECOG PS ≤1, and a life expectancy ≥12 weeks; and be ≥18 years of age and able to swallow oral medications. The primary objective is to characterize the safety profile of abemaciclib plus pembrolizumab. Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), characterization of pharmacokinetics, and health outcomes. Patients who receive any study drug will be included in the analyses. Analyses of ORR, DCR, DoR, and PFS will be evaluated according to RECIST v.1.1 and irRECIST. Time-to-event variables will be estimated by Kaplan-Meier methodology. An interim analysis of safety and preliminary efficacy may occur after all patients have completed (or discontinued from) approximately 24 weeks of treatment. The final OS analysis will occur based on data collected for approximately 12 months after the last patient receives treatment.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-102 - Safety and Tolerability of Abemaciclib Combined with LY3023414 or with Pembrolizumab in Patients with Stage IV NSCLC (ID 4625)
14:30 - 15:45 | Author(s): A. Hossain
- Abstract
Background:
Currently, treatment options are limited for patients with advanced and/or metastatic NSCLC particularly after initial treatment. In a prior phase 1 study, abemaciclib, a CDK4 & 6 inhibitor, demonstrated single-agent anti-tumor activity when dosed orally on a continuous schedule, with an acceptable safety profile in patients with previously treated metastatic NSCLC (NCT01394016). PI3kinase is an escape pathway after CDK inhibition in tumor models and aberrant immunity is a hallmark of cancer, providing the rationales to combine abemaciclib with PI3K and with checkpoint inhibitors. An ongoing Phase 1b multicenter, open-label, 3+3 dose-escalation trial with an expansion phase is investigating abemaciclib in combination with multiple single-agent options in metastatic NSCLC (NCT02079636). Here we report preliminary results for two arms of the study.
Methods:
In Part D, abemaciclib was administered orally on a continuous schedule every 12 hours (q12h) in combination with the PI3K/mTOR inhibitor, LY3023414, at 100, 150, or 200 mg q12h. In Part E, abemaciclib was administered in combination with the anti-PD-1 antibody, pembrolizumab (200 mg I.V. infusion q3 weeks). Patients with late stage NSCLC and 1-3 prior therapies without central nervous system metastasis were treated until disease progression or other discontinuation criteria were met. Primary endpoints for each cohort included safety/tolerability and identification of the recommended phase 2 dose. Safety assessments followed the Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0). Parts D and E began enrolling patients on April 13, 2015 and April 29, 2016, respectively.
Results:
As of August 24, 2016, Parts D and E escalation included, respectively, 22 [male (64%)/Caucasian (77%)/stage IV (91%)/adenocarcinoma (91%)] and 6 patients [male (33%)/Caucasian (100%)/stage IV (67%)/adenocarcinoma (100%)]. ECOG PS was ≤1 in both cohorts. In Part D, 1 patient on dose level-2 (DL-2) experienced a dose limiting toxicity (DLT) (G4 thrombocytopenia). Evaluation of additional dose levels is ongoing. Seventeen patients (77%) experienced ≥1 treatment-related emergent adverse event (TRAE). Common TRAEs were nausea (50%), diarrhea (50%), vomiting (36%), fatigue (32%), and decreased appetite (27%). In Part E, no DLTs or deaths occurred in the two dosing cohorts evaluated. Four patients (67%) experienced ≥1 TRAE with 75% G1/2. Common TRAEs included fatigue (50%), diarrhea and proteinuria, (33%, each).
Conclusion:
The majority of previously treated advanced/metastatic NSCLC patients administered abemaciclib with LY3023414 or with pembrolizumab had manageable and tolerable adverse events, similar to those of the single agents.
