- Email: [email protected]
A Phase 1 Trial of X-396, a Novel ALK Inhibitor, in Patients With Advanced Solid Tumors
S52
International Journal of Radiation Oncology Biology Physics
Author Disclosure: S. Patel: None. W.F. Mourad: None. L. Patel: None. R. Young: None. R. Kabarriti: None. M. Bernstein: None. J. Glanzman: None. K. Mani: None. T. Santiago: None. N. Ohri: None. L. Hong: None. R. Yaparpalvi: None. P. LaSala: None. S. Kalnicki: None. M.K. Garg: None.
Results: Twenty patients met the requirements for chart review: female, NSCLC, and the presence of an EML4-ALK. Of these 20 cases, 16 included imaging of the pelvis by computed tomography as part of workup for systemic disease; 1 patient had prior hysterectomy-oophorectomy and was excluded. Five of 15 charts with pelvic imaging were notable for ovarian enlargement or mass. Two of these women underwent therapeutic intervention directed at their ovarian masses, tissue from 1 of these women demonstrated ALK positive NSCLC. Conclusions: The finding of adnexal abnormalities in one-third of female clinic patients with NSCLC harboring an ALK rearrangement is compelling. Metastases to the adnexa in female patients with ALK positive NSCLC should be a consideration during work-up for systemic disease. Author Disclosure: A.H. West: None. S.D. Yamada: None. H. MacMahon: None. S.M. Ali: A. Employee; Foundation Medicine. M. Stock; Foundation Medicine. R.V. Lukas: None. R. Salgia: None.
209 Local Treatment Improves Survival in NSCLC Patients With Synchronous Brain Oligometastases Metastatic Non-Small Cell Lung Cancer G. Guo, P. Lambert, N. Ahmed, G. Schroeder, D. Fewer, H. Quon, and S. Loewen; Cancercare Manitoba, Winnipeg, MB, Canada Purpose/Objective(s): Oligometastatic non-small cell lung cancer (NSCLC) patients with brain only involvement may benefit from aggressive local therapies. We retrospectively reviewed outcomes in patients who received locally ablative treatment in brain with or without aggressive thoracic therapy (ATT) defined as surgery and/or radiation therapy 40 Gy. Materials/Methods: The Gamma Knife patient database was reviewed for NSCLC patients treated in 2005-2012, and meeting the following criteria: 1-4 brain metastases with no extracranial metastatic sites, performance ECOG 0-2, brain metastases identified within 2 months of cancer diagnosis, stereotactic radiosurgery (SRS) and/or surgical metastectomy +/- whole brain radiation therapy (WBRT) within 3 months of cancer diagnosis, and nodal staging N2. Primary endpoints were median overall survival (OS) and time to progression (TTP). Results: Fifty-three patients met eligibility criteria. All patients received SRS, and 6 had surgical metastectomy for additional brain lesions. Fourteen patients (26%) received WBRT. Nearly half of the patients (49%) had more than one brain metastasis, and most patients had T1/2 (66%) and N2 (47%) staging. Half of the patients received thoracic surgery or radiation 40 Gy (51%), and a majority of patients (62%) received systemic chemotherapy. Fifteen patients had no local thoracic treatment and 11 had thoracic radiation therapy < 40 Gy. Median OS and TTP were 17.0 months and 13.1 months, respectively, with a median follow-up of 17.2 months (3.6-73 months). ATT was the sole significant predictor of improved OS (HR 0.346, 95% CI 0.19-0.64, P<.001). Conclusions: NSCLC patients with brain only oligometastases who received locally aggressive treatment in brain and thorax appear to have better outcomes than patients who received ablative therapy to brain only and palliative radiation therapy or no local therapy to the thorax. Chemotherapy use did not improve patient survival in our patient cohort. A larger sample population is required to identify additional predictive factors for survival and validate our findings. Author Disclosure: G. Guo: None. P. Lambert: None. N. Ahmed: None. G. Schroeder: None. D. Fewer: None. H. Quon: None. S. Loewen: None.
210 Unique Pattern of Metastasis to the Adnexa in ALK Rearranged Non-Small Cell Lung Cancer Metastatic Non-Small Cell Lung Cancer A.H. West,1 S.D. Yamada,1 H. MacMahon,1 S.M. Ali,2 R.V. Lukas,1 and R. Salgia1; 1University of Chicago Medicine, Chicago, IL, 2 Foundation Medicine, Cambridge, MA Purpose/Objective(s): NSCLC most commonly metastasizes to the brain, bone, liver, and adrenal glands. Recent observation of stage IV ALK rearranged NSCLC metastatic to the adnexa in our clinic led to the current study to estimate the frequency of metastasis to the female reproductive system. Materials/Methods: A retrospective chart review of female patients with stage IV ALK rearranged NSCLC was performed. Relevant charts were reviewed for pelvic imaging notable for ovarian, adnexal, or pelvic mass or enlargement.
211 A Phase 1 Trial of X-396, a Novel ALK Inhibitor, in Patients With Advanced Solid Tumors Novel Therapies/Experimental Therapies L. Horn,1 G. Blumenscheine,2 H.A. Wakelee,3 T.H. Arkenau,4 G. Dukart,5 K. Harrow,5 C. Liang,5 J.J. Gibbons,5 C.M. Lovly,1 and J.R. Infante6; 1 Vanderbilt Ingram Cancer Center, Nashville, TN, 2University of Texas MD Anderson Cancer Center, Houston, TX, 3Stanford Clinical Cancer Center, San Francisco, CA, 4Sarah Cannon Research Institute, London, United Kingdom, 5Xcovery Holding Company, West Palm Beach, FL, 6Sarah Cannon Research Institute, Nashville, TN Purpose/Objective(s): X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with significant antitumor activity in both ALK TKI naive and crizotinib-resistant models of ALK fusion-positive NSCLC. Materials/Methods: In this multicenter phase 1 study, patients with advanced solid tumors were enrolled and given X-396 on a continuous 28day schedule. This initially used an accelerated titration scheme with doubling of the dose until the first drug-related toxicity of grade 2 or DLT, followed by a classic 3+3 escalation design. The starting dose was 25 mg once daily without food, with dose escalations up to 250 mg daily. At selected dose levels, study drug was administered with food. All pts were assessed for adverse events (AEs) using CTCAE, version 4.0, response to therapy was assessed using RECIST 1.1, and pharmacokinetics (PK) was measured. Results: As of the April 10, 2014 cutoff, 35 patients enrolled (27 NSCLC, 4 H&N, 1 breast, 1 small cell lung cancer, and 2 colorectal cancer patients). Of 27 NSCLC patients enrolled, 24 were adenocarcinoma and 3 were squamous cell histology; 18 were ALK+ - 5 crizotinib naı¨ve (28%) and 13 crizotinib resistant (72%). Median age was 57 (range 30-74), 17 female and 18 male, 14 ECOG PS 0 and 21 PS 1. The most common drugrelated AEs include rash (31%, G1-3), nausea (31%, G1), vomiting (29%, G1-2), fatigue (26%, G1-2), and edema (17%, G1-2). Grade 3/4 treatmentrelated AEs were rash (2 patients), edema (1 patient). X-396 exhibited linear PK at doses 25 to 250 mg. At 200 mg QD, the t1/2 is w23 hours, and the trough level (w300 nM) is sufficient to inhibit most crizotinibresistant mutations in vitro. Food decreased absorption by w 20%. To date, 22 patients are evaluable for response; PR 32% and SD 23%; median duration of treatment 10.25+ weeks. Among 11 evaluable ALK+ NSCLC cases, response rate 55% and SD 18%; median duration of treatment 16 + weeks. Responses occurred in crizotinib-naı¨ve and crizotinib-treated patients. CNS responses have been observed in 2 patients, 1 crizotinib-naı¨ve, and 1 crizotinib-resistant. Although the maximum tolerated dose was not officially reached, 225 mg daily was considered the appropriate dose for further evaluation in the expansion cohorts. Conclusions: X-396 is generally well-tolerated at doses up to 225 mg daily. X-396 induces responses in both crizotinib-naı¨ve and crizotinibresistant ALK+ NSCLC patients. Enrollment is ongoing in the ALK positive paired biopsy expansion cohort with or without food. Author Disclosure: L. Horn: E. Research Grant; Astellas. F. Honoraria; Boehringer Ingelheim. G. Consultant; Bayer (uncompensated), Xcovery
Volume 90 Number 5S Supplement 2014
Poster Presentations
S53
(uncompensated). K. Advisory Board; Bristol Myers Squibb, Clovis, Helix Bio, PUMA (uncompensated). G. Blumenscheine: None. H.A. Wakelee: None. T.H. Arkenau: A. Employee; Sarah Cannon Research Institute. G. Dukart: G. Consultant; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. K. Harrow: A. Employee; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. C. Liang: A. Employee; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. S. Leadership; Xcovery Holding Company. J.J. Gibbons: A. Employee; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. S. Leadership; Xcovery Holding Company. C.M. Lovly: F. Honoraria; Qiagen, Abbott Molecular. K. Advisory Board; Pfizer. J.R. Infante: None.
Other; MM is an equity holder in Foundation Medicine. K. Wong: None. P. Hammerman: G. Consultant; P.S.H. reports consulting fees from ARIAD.
212
Purpose/Objective(s): Lung tumors treated with fractionated radiation respond variably during the course of treatment. While adaptive radiation protocols are being investigated, which tumor and treatment characteristics most influence tumor shrinkage and how this influences outcome is unknown. Materials/Methods: Lung cancer patients treated with fractionated radiation with daily cone beam CT (CB-CT) from 2009-2012 were retrospectively analyzed. Tumor and nodal volumes were contoured on 3 CB-CT scans (Day 1, Day 1 of Week 4, and final day of treatment), and on the 6-8 week post-tx follow-up CT. Tumor (T stage, size, histology) and treatment (total dose, dose/fraction, and use of chemotherapy) characteristics were evaluated for their impact on volume change over time using a linear mixed effects model. Using the log rank statistic, a greater than 60% (median volume change) reduction in tumor volume was assessed for its influence on median local failuredfree survival (LFFS), regional, locoregional (LRFFS), distant (DFFS), progression-free survival, and overall survival (OS). Results: One hundred fifty-nine patients with stage I, II, III, and IV treated in 12%, 11%, 62%, and 15% respectively (89% NSCLC, 11% SCLC). The median dose and fraction size was 70 Gy (range 45-74 Gy) and 2 Gy per fraction (range 1.5-2.7) with 44 patients (28%) receiving > 2 Gy per fraction. Chemotherapy was delivered in 87% of stage III patients (concurrently in 78%). The average shrinkage among the primary tumor and lymph nodes from the Day 1 CBCT to the week 4 CBCT was 25% and 13% with corresponding values for the planning CT and first follow-up scan of 56% and 49%. Among tumor and treatment covariates, only initial tumor volume and use of concurrent chemotherapy influenced the rate of volume reduction over time in the linear mixed effects model. Histology (including SCLC) did not influence tumor shrinkage. At a median followup of 11 months, a primary volume reduction of greater than 40% (median change across all subjects) at the week 4 CBCT (Responders) conferred a 2 year overall survival advantage of 60% vs 36% (PZ.021) relative to those below the median volume change (Non-Responders). Similarly, improved survival was noted for patients with a 60% reduction at the first post treatment scan, 58% vs 28% (PZ.004). Primary responder status was not found to influence the rate of LF, LRFFS, or DFFS. Conclusions: Our study has implications in patient selection for adaptive radiation protocols. Larger tumors treated with concurrent chemoradiation therapy experience the greatest shrinkage. Volume reduction is associated with improved survival meaning patients without significant reduction might be candidates for treatment intensification. Author Disclosure: J.M. Kilburn: None. J.T. Lucas: None. M.H. Soike: None. D. Ayala-Peacock: None. J.G. Kuremsy: None. A. Blackstock: None. W.H. Hinson: None. A.A. Miller: None. W.J. Petty: None. M.T. Munley: None. J.J. Urbanic: None.
NRF2 Is a Novel Oncogene and Biomarker of Therapeutic Resistance in Non-Small Cell Lung Cancer Novel Therapies/Experimental Therapies M. Abazeed,1 C. Xu,2 D. Adams,3 P. Tamayo,3 J. Loeffler,4 J. Suh,1 M. Meyerson,2 K. Wong,2 and P. Hammerman2; 1Cleveland Clinic Foundation, Cleveland, OH, 2Dana-Farber Cancer Institute, Boston, MA, 3 Broad Institute, Cambridge, MA, 4Massachusetts General Hospital, Boston, MA Purpose/Objectives(s): Radiation therapy is one of the mainstays of anticancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is not well defined. To accelerate discovery of genotype-directed radiation therapy, or precision radiotherapeutics, systematic approaches are needed to identify genetic features that confer radiotherapeutic resistance and target these features with small-molecule drugs. Materials/Methods: We developed a systematic high-throughput method for profiling radiation sensitivity and benchmarked this method against the conventional clonogenic survival assay. We combined results from this high-throughput assay with genomic parameters in cell lines from squamous cell lung carcinoma, which is standardly treated by radiation therapy, to identify parameters that predict radiation sensitivity. Results: We identified the frequent presence (32%) of mutations in NFE2L2 (encoding the antioxidant- and detoxification-inducing transcription factor, NRF2) and KEAP1, a NRF2 binding partner, in squamous cell lung cancer. These data were generated using whole-exome and directed sequencing of 176 squamous cell lung cancers (The Cancer Genome Atlas [TCGA]) and 20 lung squamous cancer cell lines, respectively. We showed that gain-of-function mutations in NFE2L2 make lung cancer cells confer resistance to radiation. NFE2L2 knockdown resulted in growth arrest and radiation sensitivity in cell lines with NFE2L2 mutation but not in wild type cell lines. An expression-based, in silico screen nominated inhibitors of PI3K as NFE2L2 antagonists. We showed that the selective PI3K inhibitor, NVP-BKM120, both decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1 mutant cells to radiation in a GSK-3b dependent manner. We developed transgenic mice expressing a gain-of-function NFE2L2 alleles. We bred the NFE2L2 transgenic with a strain expressing a conditional allele of TP53 and found that the mice developed lung carcinomas, implicating NFE2L2, for the first time, in lung oncogenesis. Analysis of TCGA data indicates that alterations in NFE2L2 and KEAP1 confer poorer overall survival (PZ.02). Conclusions: The integrative, high-throughput methods shown here for large-scale profiling of radiation survival and genomic features of solidtumor derived cell lines should facilitate tumor radiogenomics and the discovery of radiation sensitizers and protective agents. The potential clinical translation of these findings includes the development of NFE2L2 molecular diagnostics and the prospective validation of the first radiotherapeutic resistance biomarker in lung NSCLC. Author Disclosure: M. Abazeed: None. C. Xu: None. D. Adams: None. P. Tamayo: None. J. Loeffler: None. J. Suh: None. M. Meyerson: G. Consultant; MM is a consultant to Foundation Medicine. R. Ownership
213 Which Lung Tumors Shrink During Fractionated Radiation and How Does This Influence Outcome?: Appropriately Selecting Tumor and Treatment Characteristics for Adaptive Radiation Therapy Protocols Novel Therapies/Experimental Therapies J.M. Kilburn,1 J.T. Lucas,2 M.H. Soike,2 D. Ayala-Peacock,2 J.G. Kuremsy,2 A. Blackstock,2 W.H. Hinson,2 A.A. Miller,2 W.J. Petty,2 M.T. Munley,2 and J.J. Urbanic2; 1Wake Forest University School of Medicine, Winston-Salem, NC, 2Wake Forest Baptist Health, WinstonSalem, NC
214 Efficacy of MET Inhibitors in NSCLC With CBL Alterations Novel Therapies/Experimental Therapies Y.C. Tan,1 C. Rolle,1 L. Zhu,2 M.K. Srivastava,2 S. Sharma,2 and R. Salgia1; 1The University of Chicago, Chicago, IL, 2University of California Los Angeles, Los Angeles, CA
International Journal of Radiation Oncology Biology Physics
Author Disclosure: S. Patel: None. W.F. Mourad: None. L. Patel: None. R. Young: None. R. Kabarriti: None. M. Bernstein: None. J. Glanzman: None. K. Mani: None. T. Santiago: None. N. Ohri: None. L. Hong: None. R. Yaparpalvi: None. P. LaSala: None. S. Kalnicki: None. M.K. Garg: None.
Results: Twenty patients met the requirements for chart review: female, NSCLC, and the presence of an EML4-ALK. Of these 20 cases, 16 included imaging of the pelvis by computed tomography as part of workup for systemic disease; 1 patient had prior hysterectomy-oophorectomy and was excluded. Five of 15 charts with pelvic imaging were notable for ovarian enlargement or mass. Two of these women underwent therapeutic intervention directed at their ovarian masses, tissue from 1 of these women demonstrated ALK positive NSCLC. Conclusions: The finding of adnexal abnormalities in one-third of female clinic patients with NSCLC harboring an ALK rearrangement is compelling. Metastases to the adnexa in female patients with ALK positive NSCLC should be a consideration during work-up for systemic disease. Author Disclosure: A.H. West: None. S.D. Yamada: None. H. MacMahon: None. S.M. Ali: A. Employee; Foundation Medicine. M. Stock; Foundation Medicine. R.V. Lukas: None. R. Salgia: None.
209 Local Treatment Improves Survival in NSCLC Patients With Synchronous Brain Oligometastases Metastatic Non-Small Cell Lung Cancer G. Guo, P. Lambert, N. Ahmed, G. Schroeder, D. Fewer, H. Quon, and S. Loewen; Cancercare Manitoba, Winnipeg, MB, Canada Purpose/Objective(s): Oligometastatic non-small cell lung cancer (NSCLC) patients with brain only involvement may benefit from aggressive local therapies. We retrospectively reviewed outcomes in patients who received locally ablative treatment in brain with or without aggressive thoracic therapy (ATT) defined as surgery and/or radiation therapy 40 Gy. Materials/Methods: The Gamma Knife patient database was reviewed for NSCLC patients treated in 2005-2012, and meeting the following criteria: 1-4 brain metastases with no extracranial metastatic sites, performance ECOG 0-2, brain metastases identified within 2 months of cancer diagnosis, stereotactic radiosurgery (SRS) and/or surgical metastectomy +/- whole brain radiation therapy (WBRT) within 3 months of cancer diagnosis, and nodal staging N2. Primary endpoints were median overall survival (OS) and time to progression (TTP). Results: Fifty-three patients met eligibility criteria. All patients received SRS, and 6 had surgical metastectomy for additional brain lesions. Fourteen patients (26%) received WBRT. Nearly half of the patients (49%) had more than one brain metastasis, and most patients had T1/2 (66%) and N2 (47%) staging. Half of the patients received thoracic surgery or radiation 40 Gy (51%), and a majority of patients (62%) received systemic chemotherapy. Fifteen patients had no local thoracic treatment and 11 had thoracic radiation therapy < 40 Gy. Median OS and TTP were 17.0 months and 13.1 months, respectively, with a median follow-up of 17.2 months (3.6-73 months). ATT was the sole significant predictor of improved OS (HR 0.346, 95% CI 0.19-0.64, P<.001). Conclusions: NSCLC patients with brain only oligometastases who received locally aggressive treatment in brain and thorax appear to have better outcomes than patients who received ablative therapy to brain only and palliative radiation therapy or no local therapy to the thorax. Chemotherapy use did not improve patient survival in our patient cohort. A larger sample population is required to identify additional predictive factors for survival and validate our findings. Author Disclosure: G. Guo: None. P. Lambert: None. N. Ahmed: None. G. Schroeder: None. D. Fewer: None. H. Quon: None. S. Loewen: None.
210 Unique Pattern of Metastasis to the Adnexa in ALK Rearranged Non-Small Cell Lung Cancer Metastatic Non-Small Cell Lung Cancer A.H. West,1 S.D. Yamada,1 H. MacMahon,1 S.M. Ali,2 R.V. Lukas,1 and R. Salgia1; 1University of Chicago Medicine, Chicago, IL, 2 Foundation Medicine, Cambridge, MA Purpose/Objective(s): NSCLC most commonly metastasizes to the brain, bone, liver, and adrenal glands. Recent observation of stage IV ALK rearranged NSCLC metastatic to the adnexa in our clinic led to the current study to estimate the frequency of metastasis to the female reproductive system. Materials/Methods: A retrospective chart review of female patients with stage IV ALK rearranged NSCLC was performed. Relevant charts were reviewed for pelvic imaging notable for ovarian, adnexal, or pelvic mass or enlargement.
211 A Phase 1 Trial of X-396, a Novel ALK Inhibitor, in Patients With Advanced Solid Tumors Novel Therapies/Experimental Therapies L. Horn,1 G. Blumenscheine,2 H.A. Wakelee,3 T.H. Arkenau,4 G. Dukart,5 K. Harrow,5 C. Liang,5 J.J. Gibbons,5 C.M. Lovly,1 and J.R. Infante6; 1 Vanderbilt Ingram Cancer Center, Nashville, TN, 2University of Texas MD Anderson Cancer Center, Houston, TX, 3Stanford Clinical Cancer Center, San Francisco, CA, 4Sarah Cannon Research Institute, London, United Kingdom, 5Xcovery Holding Company, West Palm Beach, FL, 6Sarah Cannon Research Institute, Nashville, TN Purpose/Objective(s): X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with significant antitumor activity in both ALK TKI naive and crizotinib-resistant models of ALK fusion-positive NSCLC. Materials/Methods: In this multicenter phase 1 study, patients with advanced solid tumors were enrolled and given X-396 on a continuous 28day schedule. This initially used an accelerated titration scheme with doubling of the dose until the first drug-related toxicity of grade 2 or DLT, followed by a classic 3+3 escalation design. The starting dose was 25 mg once daily without food, with dose escalations up to 250 mg daily. At selected dose levels, study drug was administered with food. All pts were assessed for adverse events (AEs) using CTCAE, version 4.0, response to therapy was assessed using RECIST 1.1, and pharmacokinetics (PK) was measured. Results: As of the April 10, 2014 cutoff, 35 patients enrolled (27 NSCLC, 4 H&N, 1 breast, 1 small cell lung cancer, and 2 colorectal cancer patients). Of 27 NSCLC patients enrolled, 24 were adenocarcinoma and 3 were squamous cell histology; 18 were ALK+ - 5 crizotinib naı¨ve (28%) and 13 crizotinib resistant (72%). Median age was 57 (range 30-74), 17 female and 18 male, 14 ECOG PS 0 and 21 PS 1. The most common drugrelated AEs include rash (31%, G1-3), nausea (31%, G1), vomiting (29%, G1-2), fatigue (26%, G1-2), and edema (17%, G1-2). Grade 3/4 treatmentrelated AEs were rash (2 patients), edema (1 patient). X-396 exhibited linear PK at doses 25 to 250 mg. At 200 mg QD, the t1/2 is w23 hours, and the trough level (w300 nM) is sufficient to inhibit most crizotinibresistant mutations in vitro. Food decreased absorption by w 20%. To date, 22 patients are evaluable for response; PR 32% and SD 23%; median duration of treatment 10.25+ weeks. Among 11 evaluable ALK+ NSCLC cases, response rate 55% and SD 18%; median duration of treatment 16 + weeks. Responses occurred in crizotinib-naı¨ve and crizotinib-treated patients. CNS responses have been observed in 2 patients, 1 crizotinib-naı¨ve, and 1 crizotinib-resistant. Although the maximum tolerated dose was not officially reached, 225 mg daily was considered the appropriate dose for further evaluation in the expansion cohorts. Conclusions: X-396 is generally well-tolerated at doses up to 225 mg daily. X-396 induces responses in both crizotinib-naı¨ve and crizotinibresistant ALK+ NSCLC patients. Enrollment is ongoing in the ALK positive paired biopsy expansion cohort with or without food. Author Disclosure: L. Horn: E. Research Grant; Astellas. F. Honoraria; Boehringer Ingelheim. G. Consultant; Bayer (uncompensated), Xcovery
Volume 90 Number 5S Supplement 2014
Poster Presentations
S53
(uncompensated). K. Advisory Board; Bristol Myers Squibb, Clovis, Helix Bio, PUMA (uncompensated). G. Blumenscheine: None. H.A. Wakelee: None. T.H. Arkenau: A. Employee; Sarah Cannon Research Institute. G. Dukart: G. Consultant; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. K. Harrow: A. Employee; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. C. Liang: A. Employee; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. S. Leadership; Xcovery Holding Company. J.J. Gibbons: A. Employee; Xcovery Holding Company. M. Stock; Xcovery Holding Company. N. Stock Options; Xcovery Holding Company. S. Leadership; Xcovery Holding Company. C.M. Lovly: F. Honoraria; Qiagen, Abbott Molecular. K. Advisory Board; Pfizer. J.R. Infante: None.
Other; MM is an equity holder in Foundation Medicine. K. Wong: None. P. Hammerman: G. Consultant; P.S.H. reports consulting fees from ARIAD.
212
Purpose/Objective(s): Lung tumors treated with fractionated radiation respond variably during the course of treatment. While adaptive radiation protocols are being investigated, which tumor and treatment characteristics most influence tumor shrinkage and how this influences outcome is unknown. Materials/Methods: Lung cancer patients treated with fractionated radiation with daily cone beam CT (CB-CT) from 2009-2012 were retrospectively analyzed. Tumor and nodal volumes were contoured on 3 CB-CT scans (Day 1, Day 1 of Week 4, and final day of treatment), and on the 6-8 week post-tx follow-up CT. Tumor (T stage, size, histology) and treatment (total dose, dose/fraction, and use of chemotherapy) characteristics were evaluated for their impact on volume change over time using a linear mixed effects model. Using the log rank statistic, a greater than 60% (median volume change) reduction in tumor volume was assessed for its influence on median local failuredfree survival (LFFS), regional, locoregional (LRFFS), distant (DFFS), progression-free survival, and overall survival (OS). Results: One hundred fifty-nine patients with stage I, II, III, and IV treated in 12%, 11%, 62%, and 15% respectively (89% NSCLC, 11% SCLC). The median dose and fraction size was 70 Gy (range 45-74 Gy) and 2 Gy per fraction (range 1.5-2.7) with 44 patients (28%) receiving > 2 Gy per fraction. Chemotherapy was delivered in 87% of stage III patients (concurrently in 78%). The average shrinkage among the primary tumor and lymph nodes from the Day 1 CBCT to the week 4 CBCT was 25% and 13% with corresponding values for the planning CT and first follow-up scan of 56% and 49%. Among tumor and treatment covariates, only initial tumor volume and use of concurrent chemotherapy influenced the rate of volume reduction over time in the linear mixed effects model. Histology (including SCLC) did not influence tumor shrinkage. At a median followup of 11 months, a primary volume reduction of greater than 40% (median change across all subjects) at the week 4 CBCT (Responders) conferred a 2 year overall survival advantage of 60% vs 36% (PZ.021) relative to those below the median volume change (Non-Responders). Similarly, improved survival was noted for patients with a 60% reduction at the first post treatment scan, 58% vs 28% (PZ.004). Primary responder status was not found to influence the rate of LF, LRFFS, or DFFS. Conclusions: Our study has implications in patient selection for adaptive radiation protocols. Larger tumors treated with concurrent chemoradiation therapy experience the greatest shrinkage. Volume reduction is associated with improved survival meaning patients without significant reduction might be candidates for treatment intensification. Author Disclosure: J.M. Kilburn: None. J.T. Lucas: None. M.H. Soike: None. D. Ayala-Peacock: None. J.G. Kuremsy: None. A. Blackstock: None. W.H. Hinson: None. A.A. Miller: None. W.J. Petty: None. M.T. Munley: None. J.J. Urbanic: None.
NRF2 Is a Novel Oncogene and Biomarker of Therapeutic Resistance in Non-Small Cell Lung Cancer Novel Therapies/Experimental Therapies M. Abazeed,1 C. Xu,2 D. Adams,3 P. Tamayo,3 J. Loeffler,4 J. Suh,1 M. Meyerson,2 K. Wong,2 and P. Hammerman2; 1Cleveland Clinic Foundation, Cleveland, OH, 2Dana-Farber Cancer Institute, Boston, MA, 3 Broad Institute, Cambridge, MA, 4Massachusetts General Hospital, Boston, MA Purpose/Objectives(s): Radiation therapy is one of the mainstays of anticancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is not well defined. To accelerate discovery of genotype-directed radiation therapy, or precision radiotherapeutics, systematic approaches are needed to identify genetic features that confer radiotherapeutic resistance and target these features with small-molecule drugs. Materials/Methods: We developed a systematic high-throughput method for profiling radiation sensitivity and benchmarked this method against the conventional clonogenic survival assay. We combined results from this high-throughput assay with genomic parameters in cell lines from squamous cell lung carcinoma, which is standardly treated by radiation therapy, to identify parameters that predict radiation sensitivity. Results: We identified the frequent presence (32%) of mutations in NFE2L2 (encoding the antioxidant- and detoxification-inducing transcription factor, NRF2) and KEAP1, a NRF2 binding partner, in squamous cell lung cancer. These data were generated using whole-exome and directed sequencing of 176 squamous cell lung cancers (The Cancer Genome Atlas [TCGA]) and 20 lung squamous cancer cell lines, respectively. We showed that gain-of-function mutations in NFE2L2 make lung cancer cells confer resistance to radiation. NFE2L2 knockdown resulted in growth arrest and radiation sensitivity in cell lines with NFE2L2 mutation but not in wild type cell lines. An expression-based, in silico screen nominated inhibitors of PI3K as NFE2L2 antagonists. We showed that the selective PI3K inhibitor, NVP-BKM120, both decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1 mutant cells to radiation in a GSK-3b dependent manner. We developed transgenic mice expressing a gain-of-function NFE2L2 alleles. We bred the NFE2L2 transgenic with a strain expressing a conditional allele of TP53 and found that the mice developed lung carcinomas, implicating NFE2L2, for the first time, in lung oncogenesis. Analysis of TCGA data indicates that alterations in NFE2L2 and KEAP1 confer poorer overall survival (PZ.02). Conclusions: The integrative, high-throughput methods shown here for large-scale profiling of radiation survival and genomic features of solidtumor derived cell lines should facilitate tumor radiogenomics and the discovery of radiation sensitizers and protective agents. The potential clinical translation of these findings includes the development of NFE2L2 molecular diagnostics and the prospective validation of the first radiotherapeutic resistance biomarker in lung NSCLC. Author Disclosure: M. Abazeed: None. C. Xu: None. D. Adams: None. P. Tamayo: None. J. Loeffler: None. J. Suh: None. M. Meyerson: G. Consultant; MM is a consultant to Foundation Medicine. R. Ownership
213 Which Lung Tumors Shrink During Fractionated Radiation and How Does This Influence Outcome?: Appropriately Selecting Tumor and Treatment Characteristics for Adaptive Radiation Therapy Protocols Novel Therapies/Experimental Therapies J.M. Kilburn,1 J.T. Lucas,2 M.H. Soike,2 D. Ayala-Peacock,2 J.G. Kuremsy,2 A. Blackstock,2 W.H. Hinson,2 A.A. Miller,2 W.J. Petty,2 M.T. Munley,2 and J.J. Urbanic2; 1Wake Forest University School of Medicine, Winston-Salem, NC, 2Wake Forest Baptist Health, WinstonSalem, NC
214 Efficacy of MET Inhibitors in NSCLC With CBL Alterations Novel Therapies/Experimental Therapies Y.C. Tan,1 C. Rolle,1 L. Zhu,2 M.K. Srivastava,2 S. Sharma,2 and R. Salgia1; 1The University of Chicago, Chicago, IL, 2University of California Los Angeles, Los Angeles, CA