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A. Tsao



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    MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO14.11 - Safety of hemithoracic pleural intensity-modulated radiation therapy (IMRT) for malignant pleural mesothelioma (MPM) in the multimodality setting: interim analysis of a phase II study. (ID 2802)

      10:30 - 12:00  |  Author(s): A. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      Pleurectomy/decortication (P/D) is increasingly used for the surgical management of MPM. The presence of the remaining ipsilateral lung poses a challenge when delivering adjuvant radiation therapy, as the risk for radiation pneumonitis (RP) is high. We developed an IMRT technique targeting the entire pleura of the involved hemithorax, with promising early results. Here, we present the interim results of a prospective phase II study to determine the safety and toxicity profile of pleural IMRT following induction chemotherapy and P/D.

      Methods
      Twenty-nine patients with locally advanced MPM have been enrolled to date. All patients received up to four cycles of pemetrexed/platinum chemotherapy. P/D was performed for all resectable patients. Sequential hemithoracic pleural IMRT was then administered with the intent of achieving a total planned dose of 50.4Gy in 28 fractions, as previously described (Rosenzweig et al., IJROBP 2012). All patients were simulated with a 4D-CT scan. A PET scan for image fusion and radiation planning was available for all patients. A Simon two-stage design was applied. A safety analysis after the first 9 patients led to the identification of only one case with ≥grade 3 RP in the first 3 months. The cohort was therefore expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint is the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids are typically initiated for ≥grade 2 RP.

      Results
      To date, 21 out of 29 patients total are evaluable. The median follow-up is 10 months. The median age at diagnosis is 66 years (range 38-79). Median KPS was 90% (range 70-90%). Three patients had sarcomatoid, 3 had biphasic and 23 had epithelioid MPM. All patients received chemotherapy. Eight patients (28%) had a partial response, nine patients (38%) progressed, and all others had stable disease. Twenty-four patients (83%) underwent surgical exploration. Five patients underwent an extended P/D or P/D, 11 had a partial P/D, and 8 were found to be unresectable. Eight patients were removed from the study prior to receiving IMRT (7 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). To date, nineteen patients have completed IMRT [median dose 4680cGy (range 4500 to 5040cGy)]; one patient had distant disease progression after 16 fractions; one patient is currently on treatment. Five patients experienced grade 2 RP that was successfully controlled with steroids. One patient experienced grade 3 RP requiring supplemental oxygen, but quickly improved after steroid initiation. Other commonly observed ≥grade 2 radiation-related toxicities included fatigue (37%), dyspnea (47%), nausea (42%), esophagitis (26%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.

      Conclusion
      Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this ongoing phase II study. Early intervention with steroids is effective in controlling RP. This novel radiation technique has great promise as a component of lung-sparing multi-modality therapy in locally advanced MPM.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.06 - BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1949)

      16:15 - 17:45  |  Author(s): A. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need, while a personalized medicine approach is increasingly adopted in NSCLC guided by tumor molecular profiling. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies (ClinicalTrials.gov NCT01248247).

      Methods
      This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in NSCLC pts that failed at least 1 prior line of therapy. Patients are adaptively randomized to 4 arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS mutation status while predictive biomarkers are being developed by means of gene expression profiling, targeted next generation sequencing and protein expression. EGFR sensitizing mutations and EML4/ALK translocation in pts that are erlotinib and crizotinib naïve are exclusion criteria, while erlotinib resistant patients are excluded from erlotinib monotherapy. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers follows a rigorous, internally and externally reviewed statistical analysis that follows a training, testing methodology with validation in stage 2 of the trial. All Stage 1 and 2 randomization biomarker assays are CLIA-certified.

      Results
      286 pts have been enrolled, 236 biopsies performed,172 pts randomized, and 167 pts treated. 144 pts are evaluable for the 8-week DCR endpoint. Within the randomized pts group KRAS mutation rate is 22.8%, and EGFR mutation rate 14.8%, while 36.3% patients have been previously treated with erlotinib. Treatment is well tolerated with no unanticipated toxicity.

      Conclusion
      Accrual updates, demographics, and further details will be presented at the meeting. (Supported by NCI R01CA155196-01A1)

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-010 - Physical Targeting of Locally Advanced Non-Small Cell Lung Cancer (NSCLC): Proton Therapy (ID 1020)

      09:30 - 16:30  |  Author(s): A. Tsao

      • Abstract

      Background
      Radiation therapy is a critical element in the potentially curative treatment of locally advanced NSCLC. Important developments have permitted more precise and effective physical targeting with radiations, an important complement to molecular targeting with drugs. Proton beam therapy (PBT) represents the most advanced physical targeting available thus far. A review of our experiences with proton therapy for NSCLC may serve as a benchmark for technically advanced radiation therapy.

      Methods
      Patients were enrolled on a protocol to investigate normal tissue effects of proton therapy between 2006 and December, 2010. Patients were excluded if they did not received concurrent chemotherapy, were treated on a phase II study of high dose PBT (JY Chang, PI) or were part of a randomized trial of PBT vs. intensity modulated radiation therapy (IMRT) (Z Liao, PI). They were evaluated before treatment with positron emission tomography (PET) and contrast enhanced computed tomography (CT), studies that were also used for planning treatment. Consultation with thoracic surgeons assured they were not candidates for resection. The mediastinal lymph nodes stations were evaluated with mediastinoscopy and/or fiberoptic bronchoscopy with ultrasound. Treatment planning consistently included motion management with 4D CT simulation and creation of an internal target volume (ITV). Patients were assessed for failure patterns and survival as well as normal tissue effects. Kaplan Meier estimates and Cox regression analysis were used to calculate survival outcomes.

      Results
      Of the 178 patients enrolled, the median age at diagnosis was 69 yrs (range 37.8 yrs to 94.9 yrs). KPS ranged from 60 to 100, median 80. 43% of patients had squamous carcinoma, and 57% had non-squamous histology. Stage distribution was 15% stage II, 65% III, 5% IV, 15% postoperative recurrence. The median tumor volume was 59 cc (range 4-753 cc) and the median total tumor dose was 74 Gy(RBE). Median follow-up time for living patients was 34.6 mos. Median survival was 32.7 mos. Three year survival rate was 46.5% (49.8% for squamous, 42.1% for non-squamous. Local failure at 3 years was 36.4% for squamous and 48.9% for non-squamous tumors. Distant metastasis-free survival at 3 years was 44.5% for squamous and 55.8% for non-squamous cell histology. Multivariate analysis found age, squamous histology and tumor size adversely affected survival.

      Conclusion
      Prognostic factors with PBT and concurrent chemotherapy are similar to those seen in series of patients treated with x-irradiation. Favorable median and 3 year survival rates with this relatively large data set suggest superior outcomes with PBT and quite possibly a new platform for physical targeting upon which to build chemical and molecular targeting strategies.