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9051 Background: Patients (pts) with resectable stage IB (≥4cm)-IIIA non-small-cell lung cancer (NSCLC) derive modest overall survival benefit with neoadjuvant or postoperative adjuvant chemotherapy. Neoadjuvant therapy can speed the discovery of promising regimens by using pathologic response as a surrogate for OS. Major pathologic response (MPR), defined as < 10% viable tumor, was strongly associated with improved OS. PD-(L)1 checkpoint inhibitors in combination with chemotherapy are standard of care in advanced NSCLC. We hypothesize that the addition of N to neoadjuvant CP or CG will increase the MPR rate compared to historical controls. Methods: This is an investigator-initiated trial for pts with newly diagnosed AJCC 8th stage IB (≥4cm)-IIIA squamous or non-squamous EGFR/ALK WT NSCLC with a plan to have surgery. Pts receive 3 courses of N 360mg IV q 3w added to C 75mg/m2 IV q 3w plus P 500 mg/m2 IV q 3wks or G 1250mg/m2 IV d1, d8 with surgery 3 wks after the last dose. The primary objective is MPR. To estimate pathologic response, the resected pathology specimens are cut >1 section/cm. Using the Aperio Digital scanning system©, slides were imaged, and then annotated by at least 2 pathologists for viable tumor vs. treatment effect with respective areas then automatically calculated and percentage of viable tumor calculated. Our primary endpoint will be reached if 10/34 (29%) planned pts have at least an MPR. Results: From 6/2018-8/2019, 13 pts were enrolled all of whom had surgery. Median age was 69 (49-80), 38% women, 31% nonsquamous, 54% stage IIIA, and 77% PD-L1 positive (≥1%, SP263). Pre-surgical grade 3 toxicity occurred in 2/13 pts, one of whom was changed to carboplatin for courses 2 and 3. Grade 3 toxicities were neutropenia (2/13), anemia (1/13), and renal (1/13). One pt. developed hypothyroidism 4 mos after surgery. One pt died 6 weeks after surgery from complications unrelated to study drugs. Our primary endpoint was met; 11/13 (85%), had at least an MPR with 6/13 (46%) and 5/13 (38%) having an MPR and pCR respectively. Radiologic response rate was 46% (PR 5, CR 1). Pts with either PD-L1+ or PD-L1- had MPRs. With a median follow-up of 10 months there are no recurrences. Conclusions: The combination of nivolumab added to platinum doublets was well tolerated. The primary endpoint of MPR in at least 10/34 pts was surpassed with MPR or pCR in 11/13 pts post-surgery. MPR was seen independent of PD-L1 score. Exploratory outcomes assessing markers of immune bias in tumor tissue and plasma are in process. Clinical trial information: NCT03366766.

222 Background: Non-small cell lung cancer (NSCLC) accounts for 25% of all cancer deaths with 5-year survival of 6%. Recent scientific advances in molecular based treatments and immunotherapy and insurers’ emphasis on patient-centered care is changing patient care. This study sought to incorporate patients’ perceptions, goals, and preferences into treatment planning. Methods: After provider education and using electronic care planning software (CPS), a pilot of 50 patients with advanced NSCLC from two academic centers completed tablet-based surveys addressing treatment goals, decision-making preferences, and interest in clinical trials. Results were shared with the provider during the visit. Once treatment was selected, the CPS generated a personalized care management plan. Results: Participants were mean age 65 (range 41-86), 52% female, and 78% white. 60% (12/20) Stage IV patients believed that their cancer was curable. 62% (31/50) were not interested in clinical trial participation. 48% (24/50) wanted to share treatment decision making; 34% (12/50) wanted to make the final decision after seriously considering the doctor’s opinion; 6% (3/ 50) wanted the provider to make the final decision but consider their opinion, and 10% (5/50) wanted to leave all decisions to the provider. Conclusions: Patient perception of curability and decision-making preferences were important domains identified by personalized-care management planning in this Lung Cancer pilot study. Pre-visit CPS use provided the opportunity for the provider to address treatment intent and decision-making at the point-of-care. Academic centers generally expect their patients to have strong interest in clinical trials; Investigation for the reasons for disinterest warrants further exploration.

17 Background: Most patients with non-small cell lung cancer (NSCLC) have advanced disease at diagnosis and are older with median age 72 years. Evidence-based treatment (EBT) selection requires availability of molecular testing (MT) results at time of treatment decision and geriatric assessment (GA) helps determine a patient’s ability to tolerate therapy. This study describes practice patterns and evidence based treatment selections of providers managing older patients with NSCLC. Methods: After provider education and using care planning software (CPS), 50 patients with advanced NSCLC from two academic centers completed surveys regarding treatment goals and decision-making preferences, and patients ≥ 65 completed a modified GA that included activities of daily living and comorbidity assessment. Once treatment was selected, a personalized care plan was generated. Comparison treatment data from 17 community patients was obtained. Results: Participants were mean age 65, 52% female, and 78% white. Of 28 stage IV patients, 79% had MT and results available at time of treatment decision, and 100% met EBT guidelines. The community cohort had 47% testing, 29% results available, and 65% met guidelines. GA results in 24 patients were 46% frail, 29% intermediate fit, and 25% fit. Two patients (8%) were frail and had a plan change due to GA results. Conclusions: Obtaining timely MT results remains challenging. Continued strategies to ensure MT and timely results should be explored, including quality assurance monitoring given the increasing importance of MT in treatment selection. GA was less impactful in this setting, likely due to later stage patients, presumed frailty, and treatment goal being palliation. We believe GA would have greater impact in early stage NSCLC where aggressive treatments are offered with curative intent.

9567 Background: The relationship between immunosuppressants and immunotherapy (IO) is an active area of research. Here we study the impact of pre-treatment steroid use on the completion of ipilimumab (ipi) therapy. Methods: This population-based study identified patients diagnosed with melanoma and treated with ipi (brand name Yervoy) in 2010-2014 from the linked Surveillance, Epidemiology and End Result-Medicare files. “Completion of IO on time” was defined as receiving 4 cycles of IO within 90 days. Otherwise, the patients were considered to have delayed or incomplete IO. The frequencies of patients completing each dose, up to 4 doses were tabulated. Exact Clopper-Pearson 95% confidence intervals (CI) were computed for prevalence estimates. A crude relative risk (RR) for completing IO was calculated. Results: We identified 1,205 melanoma patients treated with ipi with a median age of 71 years. Among 709 patients with no pre-treatment steroids, 35.7% had completed 4th dose of IO, compared to 20.3% of patients who received pre-treatment steroids within 1 month of IO (Table). In these patients, having no exposure to steroids in the year prior to initiating IO was associated with a 28% increased probability of completing the IO regimen (RR=1.28, 95% CI: 1.07-1.53). Conclusions: This large scale real-world study demonstrated both the overall completion rate of ipi in melanoma patients as well as the negative impact of pre-treatment steroids on rate of treatment completion. Further studies on treatment outcomes associated with pre-IO steroids use are warranted. [Table: see text]

e13118 Background: Immune checkpoint inhibitors (ICIs), especially ipilimumab (ipi) and nivolumab (nivo), have received approvals from the U.S. Food and Drug Administration for the treatment of multiple tumor types. These medications have shown great promise in the treatment of several malignancies but are associated with immune-related adverse events. This study was undertaken to better understand the patterns of adverse events following different ICIs. Methods: We used the World Health Organization (WHO) Vigiaccess Database, the largest adverse events reporting database, to identify, summarize, and report adverse drug events (AE) attributed to ipi and nivo. The database contains reports for ipi beginning in 2008 and for nivo beginning in 2012. We manually extracted the data from the database and conducted Chi-square tests to examine the difference in occurrence of AEs in various organ systems between patients receiving ipi and nivo. The five most common organ systems affected by AE associated with ipi and nivo were identified. Results: AEs were reported in 15,504 ipi users and 21,306 nivo users. Ipi users reported significantly higher AEs in gastrointestinal system compared to nivo users (p < 0.0001). Conversely, nivo users reported significantly higher AEs in respiratory disorders (p < 0.0001), skin and subcutaneous tissue organ systems (p = 0.0001), and neoplasms benign, malignant and unspecified (p < 0.0001) compared to ipi users. Conclusions: To our knowledge this is the largest study on reported AEs following ipi and nivo. The patterns of treatment-related AEs differed significantly for these two immune checkpoint inhibitor therapies. Further studies are required to guide treatment selection.[Table: see text]

6016 Background: Discordant radiographic responses are described in other tumor types in response to immunotherapy with response at some anatomic sites and progression in others. Here we determined the frequency of discordant treatment effects (TE) in HNSCC patients treated with immunotherapy in the context of a neoadjuvant trial. Methods: 23 Patients with resectable primary HNSCC were 1:1 randomized to receive nivolumab (240 mg IV Q 2 weeks x 2) or nivolumab and tadalafil 10 mg daily. Surgery was performed 4 weeks after the first nivolumab infusion. Resection specimens were graded histopathologically by two pathologists. Areas exhibiting TE (defined by fibrosis with chronic inflammation, foamy macrophage reaction and multinucleated giant cells) were expressed relative to the total tumor area. This was assessed in the primary tumor and all lymph nodes (LN). Each primary lesion and individual LN was defined as a) no response 0%TE, b) minimal response 1-19%TE, c) response 20-99% or d) complete response 100%. Concordance was defined if primary lesion and LNs were in the same ordinal data set. Results: 11/23 (48%) of subjects experienced concordant ΤΕ in the primary tumor and LNs. Within this cohort, 3 patients had a complete pathologic response both at the primary site and LNs. In contrast, 12/23 patients (52%) revealed discordant ΤΕ between the primary tumor sites (average of 17% TE) and involved LNs (average of 62% TE), (p= 0.018; signed rank test). Interestingly, in the discordant group, TE effects in LNs were invariably greater than in primary lesions. In 5 of 11 patients with multiple involved LN, the TE varied between nodes. This included patients with adjacent LNs demonstrating 0% and 100% TE in the same level. Systemic and local immune parameters as they relate to concordant and discordant TEs in individual patients will be presented including a type 1 immune bias. Conclusions: Early histologic evaluation of TE in patients with HNSCC receiving immunotherapy demonstrate a wide variety of response between the primary tumor and LNs. Further investigations will lend insight into complex interactions of cancer cells with the microenvironment. Clinical trial information: NCT03238365.

6070 Background: Standard cisplatin-based chemoradiotherapy for LA SCCHN is associated with toxicity and less than desirable survival in high-risk patients (pts). The combination of the anti-PD1 antibody nivolumab (nivo) and the anti-CTLA-4 antibody ipilimumab (ipi) has been effective in melanoma and renal cell carcinoma and is under investigation in other solid tumors including SCCHN. Combining RT and immunotherapy (IO) has a strong preclinical rationale and is being evaluated in the clinic. This pilot trial combines IO and RT to build upon these observations. Methods: We enrolled previously untreated high-risk pts with AJCC 7th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, larynx. HPV+ OP tumors were T4, or N2c or N3 by AJCC 7th edition criteria. Nivo 3 mg/kg was administered every 2 weeks IV x 17 doses and ipi 1 mg/kg every 6 weeks x 6 doses beginning 2 weeks before IMRT 2 Gy/fraction/day given to total dose 70 Gy. The primary safety endpoint was acute in-field toxicity. Exploratory correlative studies include tumor PD-L1 expression, tumor immune bias, and exosome quantity and composition. The total sample size is 24 pts with 12 enrolled in the first stage and 12 in the expansion cohort. Results: A planned safety analysis was performed in the first 12 pts (8 OP; 1 hypopharynx; 3 larynx). No acute grade (G) 4 or dose-limiting toxicities were seen. Acute G 3 in-field toxicity occurred during RT in 50% of pts: dysphagia (4 pts), mucositis (3), odynophagia (2), hoarseness (1), dermatitis (1). 50% of pts had immune-related toxicity at any time. 3 pts discontinued treatment at > 3 months post RT: 1 for an immune-related cause (G 3 colitis that resolved with steroids), and 2 for non-immune-related causes (1 G 5 bleeding due to carotid rupture secondary to an in-field ulcer at 4 months post RT in a pt with complete response and 1 G 3 OP ulcer resolving with hyperbaric oxygen). 1 pt with a laryngeal primary developed a solitary lung metastasis vs new primary 6 months post RT. 10 of 12 pts are alive with no evidence of disease (follow up 7.2-18.4 months). Conclusions: Preliminary results with this non-platinum-containing RT plus IO regimen are encouraging. Longer follow-up is needed for assessment of late effects and efficacy. Enrollment is ongoing in the expansion cohort. This study is supported by BMS. Clinical trial information: NCT03162731.

TPS8582Background: For patients (pts) with stage IB (≥4cm)-IIIA Non-small-cell lung cancer (NSCLC), multi-modality therapy yields a modest improvement in 5 year post-surgical overall survival (OS),...

Purpose To investigate the feasibility of combining concomitant boost accelerated radiation with docetaxel and cisplatin and assess the regimen's toxicity, locoregional control rate, and survival in patients with locally advanced head and neck cancer (HNSCC). Patients and Methods Patients with stage III-IV HNSCC were eligible. Phase I included two schedules of docetaxel and cisplatin: arm 1, once per week during weeks 1 to 4; arm 2, every 21 days for weeks 1 and 4. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (concomitant boost). Results Twenty patients were enrolled in phase I. The arm 1 maximum-tolerated dose (MTD) was defined at docetaxel 15 mg/m2 and cisplatin 20 mg/m2 based on prolonged mucositis in 29% of patients. The initial dose level in arm 2 was above the MTD. In total, 52 patients were treated using the arm 1 regimen in phase II. Acute toxicity included grade 3 mucositis and dermatitis in 81% and 44% of patients. The 2-year locoregional control rate was 71%. The 2-year progression-free and overall survival rates were 61% and 65%. Median survival was 37.8 months. Late effects included feeding tube dependence in 17% of patients alive and free of disease. Conclusion Locoregional control, survival, and acute toxicity with this regimen were comparable with other trials utilizing taxanes and/or platins and concomitant conventional or altered fractionation radiation. Our data suggest that chemotherapy added to concomitant boost fractionation may increase rates of long-term feeding tube dependence. Phase III trials are needed to assess the contribution of concomitant boost fractionation to chemoradiotherapy.

3054Background: Imatinib mesylate can induce rapid tumor regression, inhibit tumor immunosuppressive mechanisms, and release large amounts of antigenic debris from tumor cell death with subsequent ...

2550Background: BPM 31510 targets the metabolic machinery of cancer cells to reverse the Warburg effect. The current study evaluates BPM 31510 as a 6-day continuous infusion as a single agent and i...

11057Background: Pazopanib is approved for treatment of advanced soft tissue sarcomas; however, all patients ultimately develop resistance to therapy. The mechanisms of resistance can include activ...

11019 Background: With the paradigm shift to precision medicine, we hypothesized that matching patients to therapy based on molecular profile could significantly improve outcomes. Methods: Archival...

105 Background: Although BRAF inhibitors have demonstrated efficacy, resistance develops in most pts. We hypothesized that BRAF inhibitor vemurafenib, in combination with carboplatin and paclitaxel...

2539 Background: BPM 31510 is a small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative...

9624 Background: Limited data exist about sleep quality (SQ) in patients (pts) on phase 1 clinical trials. Poor SQ is often not captured as an adverse event (AE) and its association with fatigue, o...

TPS2617 Background: Cancer cells deficient in BRCA1/2 and other components of the homologous recombination repair pathway are selectively sensitive to the double stranded DNA breaks whose repairs a...

3511 Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are poor prognostic markers and are associated with a low response to the combinat...

4072 Background: CC is an aggressive disease with a dismal prognosis and no clear therapy in the refractory setting. Mek inhibition and anti-angiogenic therapies have shown modest activity in advan...

2597 Background: Although C and D both demonstrate activity resistance can develop. Preclinical studies demonstrated that activation of MET requires c-SRC. We hypothesized that a c-SRC inhibitor (D...

2584 Background: Preclinical models suggest synergistic anticancer activity of histone deacetylase (HDAC) and mTOR inhibitors by reducing activity of AKT/mTOR and HDAC. Methods: This is a phase I s...

3608 Background: We initiated a prospective, institution-wide study to determine whether genomic testing with a 409-gene panel in solid tumors can identify new actionable genomic information (beyon...

320 Background: Pancreatic cancer is a disease that generally presents in advanced stage and is nearly fatal in all cases. In 2011, we reported our experience with pancreatic cancer patients enrolled on phase 1 clinical trials from 2004-2009. At the time, gemcitabine and erlotinib were the only US FDA approved drugs for pancreatic cancer. Median overall survival from presentation in the phase 1 clinic was 5 months. After an additional 5 years of progress, we queried the impact of novel cancer therapeutics, evolving molecular profiling, and targeted therapy on pancreatic cancer patient outcomes in the phase 1 setting. Methods: A retrospective review of advanced pancreatic adenocarcinoma patients from the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, was conducted for patients treated from 1/2009 to 1/2014. Statistical analyses utilized the Kaplan-Meier method. Results: A total of 90 patients were identified in 50 trials reviewed. Median age was 62 years (40-84), 57% were male, and 40% had stage IV disease at presentation. Median documented PS was 1 (range 0-3). The median time from diagnosis to treatment on a phase I protocol was 15 months (0.2-119). Patients were treated with an average of 4 prior regimens prior to Phase 1 referral (0-10) with 8% having undergone >5 treatments. The median overall survival from the first phase I treatment was 5.2 months, 95% CI = (4.4-6.3) and the 1 year overall survival from the first phase 1 treatment was 15% (9%- 25%). The median duration on regimen with best phase I response was 1.9 months (0.2-21.3). Of 88 evaluable, the best responses were PR in 1 patient and SD (> 6 months) in 5 patients. Although 47 patients had biomarker profiling performed and 61 patients were treated with targeted therapy alone or in combination with cytotoxic therapy, only 6 patients (5 PD, 1 SD currently on protocol) were placed on trials based on biomarker testing results. Conclusions: Pancreatic cancer remains a difficult disease to treat with poor outcome. Referral to phase 1 occurs late in the disease course. Biomarker based therapies may be more successful with more stringent patient selection and when referred earlier or used prior to cytotoxic treatment.

605 Background: Advanced relapsed colorectal adenocarcinoma (CRC) is emerging as a cancer not with a singular phenotype but rather as a multitude of ‘diseases’ subdivided based on its molecular genotype. Given the heterogeneity in outcomes of CRC patients on targeted therapy clinical trials, we sought to identify a unique molecular subset within this disease. Methods: To that end, we identified advanced CRC patients in our Phase I clinic on whom adequate tissue was available for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: We identified 51 patients with advanced relapsed CRC (26 male, 25 female; median age 54 years; 49 colonic primary lesion, 4 rectum primary). Overall, 44 (86%) harbored a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 40 pts, 78%). Of these 44 patients, half (n=22, 50%) had ≥1 concurrent mutation affecting the PI3K/AKT/MTOR pathway, most commonly PIK3CA in 11 patients (4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K). Furthermore, 20 of these 22 pts with both Wnt and PI3K pathway mutations also demonstrated a concomitant MAPK pathway abnormality, most commonly KRAS (n=16) and 3 BRAF (V600E, G466R, D594G). Overall 20 of 51 (39%) patients had coexisting mutations implicated in all three signaling pathways (Wnt, PI3K, and MAPK). Conclusions: Three prominent pathways linked to the continuum of development and progression of cancer (Wnt, MAPK, PI3K) occur frequently in concurrence in patients with advanced CRC, thereby highlighting the role for an innovative therapeutic combination targeting all three pathways.

e22082 Background: Biomarkers associated with efficacy of HER2-directed treatments are lacking. We evaluated HER2 ECD levels and HER2 SNPs in patients treated on a clinical trial of combination tra...

2563 Background: Besides its selective activity to induce autophagy and caspase-independent apoptosis in argininosuccinate synthetase (ASS)-deficient cancer cells, ADI-PEG20 (pegylated arginine dei...

TPS2639 Background: Preclinical models have shown that concurrent inhibition of the mammalian target of rapamycin (mTOR) pathway signaling cooperates with epidermal growth factor (EGFR)/vascular en...

e13521 Background: Genomic profiling is increasingly used in the management of patients with cancer. We used “precision medicine” with genomic profiling to treat patients referred to our Phase I Clinical Trials Program. Methods: Genomic analysis of patients referred from 9/07 to 10/13 was performed in a CLIA-certified lab. Patients with tumor alterations were treated with matched targeted therapy (MTT), when available. Results: Of 3,745 patients, 2,089 (55.8%) had ≥1 alteration (actionable, 1,740): KRAS 20%; PTEN 16%; PI3K 11%; BRAF 10%; NRAS 8%; EGFR 4%; and CKIT 2%; 1,187 patients were treated (median age, 58 yrs; women, 61%): MTT: 673 (56.7%); non-matched therapy (NMT): 514 (43.3%). Results are shown in Table. The clinical benefit (CB) rates in patients with PI3K/AKT/mTOR pathway alterations treated with MTT by tumor type were: breast 40% (18/45); gynecologic 33% (20/60); head and neck 24% (6/25); colorectal 3% (1/32); and other 33% (18/54) (p=.006). The CB rates in patients with RAS/RAF/MEK pathway al...

10595 Background: Therapeutic options are limited for advanced sarcomas. Search for molecular alterations could lead to identification of novel therapies for refractory sarcoma patients. Rarity pos...

e22154 Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify futur...

e22139 Background: Cell-free (cf) DNA from the plasma of cancer patients offers an easily obtainable source of biologic material for analysis and monitoring of molecular aberrations. Novel technolo...

3516 Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are considered poor prognostic markers, and

2576 Background: VEGF inhibition-mediated tumor hypoxia promotes invasive growth by transcriptional activation of hypoxia-induced factors mediated by tumor hypoxia. Accordingly, we conducted this p...

3607 Background: This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapy in order to explore the concept of clonal evolution by evaluating the impact o...

2606 Background: Activation of the PI3K/AKT/mTOR pathway has a key role in breast cancer development and therapeutic resistance. Next generation sequencing (NGS) has expanded our understanding of t...

407 Background: c-MET is a tyrosine kinase receptor involved in cancer growth, migration, development of metastasis and angiogenesis. Deregulation of this gene has been associated with poor prognosis and resistance to treatment in prostate, bladder and renal cell cancer (RCC). Methods: Patients with GU malignancies referred to the phase I clinic were evaluated for the presence of c-MET mutation and amplification. Their outcomes on protocols containing c-METinhibitors were also analyzed. Results: c-MET amplification was detected in 7 out of 97 (7.2%) patients (4/27 renal, 1/18 urothelial and 2/12 adrenocortical carcinoma), while c-MET mutation/variant in 3 out of 53 (5.7%) patients (2/20 renal and 1/15 prostate cancer). No demographic characteristics were associated with either c-MET abnormalities, but patients tested positive for either mutation or amplification had a higher number of metastatic sites (median number of sites of 4 versus 3 for wild type patients). Median overall survival from phase I consult was 4.4 and 10.6 months for patients with and without a c-MET alteration, respectively. Twenty-nine (25%) patients were treated under a protocol containing a c-MET inhibitor. Overall 6 (21%) patients had a partial response (all prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (0.4-19.7) for all treated patients. No responses were detected in patients with a c-MET genetic abnormality or treated with a specific c-MET inhibitor as a single agent. Conclusions: c-MET mutation and amplification are present in different GU malignancies conferring a worse prognosis for patients referred to the phase I program. We observed activity of c-MET inhibitors for patients without c-MET genetic abnormalities and when c-MET inhibition was combined with other targets/drugs.

263 Background: The PRONOUNCE trial was a phase III, randomized, open-label U.S. study comparing pemetrexed (PemC) with bevacizumab (PCB) in the treatment of advanced chemo-naive nonsquamous non-small cell lung cancer (NS-NSCLC). The primary endpoint of improved PFS without grade 4 toxicity for PemC over PCB was not met. There were no differences in PFS or OS. This analysis was conducted to estimate differences in costs of treatment and related patient care between the groups to inform evidence-based treatment decision making. Methods: A cost-minimization analysis was performed using data from the PRONOUNCE trial and publically available U.S. unit costs. Drug costs modeled included induction, maintenance, and subsequent therapies. Other estimated medical costs were drug administration, concomitant medications, and treatment of grade 3/4 toxicities. A probabilistic sensitivity analysis (PSA) was conducted to model joint uncertainty associated with model parameters. Results: The average cost of treatment with PemC was $4,689 less than PCB ($30,334 vs $35,024). Drug acquisition and administration costs were less in all modeled settings (induction, maintenance, and subsequent lines) for PemC. Costs associated with concomitant medications and grade 3/4 toxicities were similar ($13,286 vs $13,738). PemC was cost saving in 99% of 10,000 PSA iterations. Conclusions: Based on the PRONOUNCE trial and model results, PemC may present a similarly effective but less costly treatment option for patients in the United States compared with PCB. While treatment decision making should consider the overall safety profile and patient preferences, this study provides estimates of the costs of treatment of these two therapeutic options. The analysis was based on clinical trial data; therefore, the results may not be generalizable to all patients. [Table: see text]

LBA8003 Background: PemC and PCB are regimens used for first-line treatment of advanced NS-NSCLC. The primary objective was to compare progression-free survival without Grade 4 toxicity (G4PFS) between two vs three drug regimen arms. Methods: Patients ≥18 years, Stage IV NS NSCLC, AJCC (v7.0), and ECOG PS 0/1 were enrolled. Patients were randomized (1:1); received 4 cycles of induction (PemC: Pem, 500 mg/m2 and C, AUC = 6; PCB: P, 200 mg/m2, C, AUC = 6, and B, 15 mg/kg) followed by Pem (PemC Arm) or B (PCB Arm) maintenance therapy in the absence of progressive disease or discontinuation. Secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The study was powered for G4PFS; assuming hazard ratio (HR) of 0.75; there was 80% power to detect superiority of PemC over PCB with a 2-sided type I error of 0.10. Efficacy data were analyzed by intent-to-treat principle using the log-rank test for time-to-event variables, and an exact test for ORR and DCR. Safety data were evaluated using CTCAE v3 for patients who received ≥1 dose of study treatment. Results: Patients were randomized to PemC (N = 182) or PCB (N = 179). Baseline factors were balanced between arms: median age 66/66 years; % female 42/42; % PS=0, 47/47; % stage IV M1a 29/30; for PemC vs PCB, median G4PFS (months) was 3.91/2.86 (HR = 0.85, 90% CI 0.7, 1.04, p = 0.176); PFS and OS had HR = 1.06 (95% CI 0.84, 1.35), p = 0.610, and HR = 1.07 (95% CI 0.83, 1.36), p = 0.616, respectively. The ORR (%) 23.6/ 27.4 and DCR (%) 59.9/57.0 were for PemC vs PCB, respectively. Significantly more drug-related grade 3/4 anemia (18.7% vs 5.4%), and thrombocytopenia (24.0% vs 9.6%) were seen on PemC; significantly more grade 3/4 neutropenia (48.8% vs 24.6%) and grade 1/2 alopecia (28.3 % vs 8.2%) were seen on PCB. Conclusions: PemC was not superior to PCB in G4PFS; no difference in PFS or OS was observed for the two- vs three-drug regimens. There were no unexpected toxicities; the toxicity profiles demonstrated distinctions by arm, and both regimens demonstrated tolerability. Clinical trial information: NCT00948675.

e13575 Background: Mucositis is a well-known side effect of mTOR inhibitor (temsirolimus) treatment of cancer patients, limiting the use of mTOR inhibitors. We investigated whether combination treatment of temsirolimus with another agent that was not known to cause mucositis would result in a higher or lower incidence of mucositis. We further investigated if there was an association between the severity of mucositis and tumor response to the temsirolimus-based combination treatment. Methods: This retrospective data review was approved by IRB and conducted in the department of Investigational Cancer Therapeutics at MD Anderson Cancer Center. We reviewed the electronic medical records of 87 patients who were enrolled in temsirolimus-based combination phase I trials (n=3), including physician notes from the date they enrolled on the study to the date they came off treatments. We first examined the incidence of mucositis during the course of study and its severity. We assessed patient response to the study treatment with severity of the mucositis. Results: The overall incidence of mucositis in the 3 temsirolimus-based combination trials was 46%, similar to the published data for the single agent of 41%. The grades of mucositis were: for grade 1 (n=14), grade 2 (n=17) and grade 3 (n=9). No grade 4 mucositis was observed. Neither gender nor ethnicity altered the incidence of mucositis. The median onset time was 14 days after the start of the studies. Of 87 patients, 20 responded to the study treatments with at least stable disease for longer than 6 months or a partial or complete response. The incidence of the mucositis was not associated with the response to temsirolimus-based treatment. Severity of mucositis did not correlate with response to the temsirolimus-based regimen. (grades 1/2 vs. ≥ grade 3; p=0.512). Conclusions: The incidence of mucositis did not increase significantly in patients who received a temsirolimus-based regimen compared to single-agent temsirolimus. Severity of mucositis did not correlate with tumor response to the temsirolimus-based regimen. Future study is warranted to optimize management for mTOR inhibitor-induced mucositis.

1051 Background: Matching molecular alterations in patients with breast cancer to targeted therapy may increase response rates. Methods: We analyzed 22 sequential breast cancer patients with next generation sequencing (NGS) profiling of their tumors profiling (FoundationOne) treated on Phase I trials at the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. Objectives included: (1) characterize molecular alterations including mutations, amplifications and deletions, (2) evaluate associations between molecular alterations and response to therapy. Results: Twenty-two breast cancer patients, all female with median age 56 years were included. Twenty-one of 22 of patients (95%) analyzed demonstrated at least one molecular alteration. Twenty-one of 22 patients were evaluable for response to therapy (1 patient had not yet reached restaging). Sixteen patients were treated on Phase I trials with targeted therapy that was either directly or indirectly associated with a molecular alteration. Seven of these 16 patients (44%) achieved stable disease (SD) ≥6 months/partial response (PR)/complete response (CR) including 3 patients with PR and 1 patient with CR. Examples of molecular alterations include: mutations in PIK3CA (8 patients), PIK3R1 (2 patients), PTEN (1 patient), cMET (1 patient), NF1 (one patient); amplifications in CCND1 (8 patients), FGFR1 (4 patients), MYC (3 patients), MCL1 (3 patients), IRS2 (2 patients) and CCNE1(1 patient). Conclusions: A majority of patients with advanced or metastatic breast cancer whose tumors underwent NGS profiling demonstrated molecular alterations. Of the 9 patients who had either SD≥6 months/PR/CR on Phase I treatment, 7 (78%) had molecular alterations, either directly or indirectly associated with therapy. Further investigation of larger cohorts of patients with NGS is ongoing.

2611 Background: Pathway crosstalk and emergence of drug resistance have limited the activity of targeted therapies, including anti-angiogenic agents and mTORC1 inhibitors. However, this vulnerability may be addressed by rationally combining targeted therapies to improve outcomes. We sought to determine the MTD/recommended phase II dose and define the pharmacokinetics (PK) of the combination of sorafenib (S), bevacizumab (B), and temsirolimus (T) in patients with advanced solid tumors. Methods: S was given once or twice daily, B was given intravenously every three weeks, and T was given intravenously weekly. Doses were escalated in a stair-step dose escalation with 6 planned dose levels (DL) in a standard 3+3 design. Responses were defined using RECIST 1.1. Results: To date, 51 patients have been enrolled. Three patients withdrew consent after only one dose. One dose-limiting toxicity (DLT) occurred at DL 5 (grade 4 fatigue, pain) and one DLT occurred at DL 6 (G3 headache). However, 5/6 patients required dose reduction on DL6 (G2 nausea, fatigue, hand/foot syndrome, rash). Thus, DL5 (B 10mg/kg, T 20mg, S 200mg twice daily) is being explored in dose expansion (N=10) and tumor expansion cohorts as the recommended phase II dose. The most common adverse events (>10%) were fatigue (69%; G3/4 6%), nausea (38%, G3/4 2%), pain (35%, G3/4 10%), thrombocytopenia (33%, G3/4 8%), mucositis (33%, 0%), constipation (29%, G3/4 0%), hand/foot syndrome (23%, G3/4 0%), rash (19%, G3/4 0%), hypertension (17%, 0%), neuropathy (17%, G3/4 0%), diarrhea (15%, G3/4 6%), vomiting (15%, G3/4 2%), headache (12%, G3/4 2%), and hypertriglyceridemia (10%, G3/4 2%). Of 34 patients evaluable for response, 4 had PR including ovarian (-57%, +6m), gastric (-46%, +5m), colorectal (-32%, +5 m), and thyroid (-31%, +6m) cancer. Eight patients had SD for greater than 4 months including ovarian (0%, +7m), colorectal (-5%, +8m), endometrial (-26%, +5m; -16%, +4m; -15%, +6m), leiomyosarcoma (-5%, +6m), squamous lung cancer (-6%, +6m), and triple negative breast (-15%, +4m) cancer. Conclusions: The combination of S, B, and T is well tolerated and demonstrates preliminary evidence of tumor activity in a variety of solid tumors. PK studies at the recommended phase II dose are ongoing. Clinical trial information: NCT01187199.

2604 Background: Lenalidomide (immunomodulatory and antiangiogenic drug) and temsirolimus (mTOR inhibitor) are potentially synergistic (Raje N, Blood 2004;104(13):4188). We conducted a phase I study of the combination in patients with advanced cancers. Methods: During the escalation phase, lenalidomide (PO days 1-21) and temsirolimus (IV, Q weekly) were given at the following respective doses: level 1 (10 mg, 15mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). A “3+3” study design was used. The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Results: Forty- three patients were treated (median age: 58 (21-80) years; male/female: 26:17). The most common diagnoses were colorectal cancer (N=5), sarcoma (N=5) and adenoid cystic carcinoma (N=4). Overall, 121 cycles (median: 2) were administered. No dose limiting toxicities were observed. The maximum tested dose (level 4) was used for expansion. Grade 3-4 toxicity (all reversible) occurred in 19 (44%) patients: neutropenia (N=12), thrombocytopenia (N=6), and infection (N=1). Of 43 patients, 31 (72%) received anticoagulation prophylaxis. There were no thrombotic events. Of 36 patients who were evaluable for response, PR was noted in 1 (2.7%), and stable disease (SD) was noted in 17 (47%) patients (SD ≥6 months: 17%). Tumors with SD≥6 months were soft tissue sarcoma, 2/5 (40%), adenoid cystic carcinoma, 1/4 (25%), parotid ca, 1/2 (50%), adrenocortical ca 1/3 (33%), and neuroendocrine ca, 1/4 (25%) (Table). The median progression-free survival was 2.2 months (95% CI, 1.5-2.9) and overall survival was 7.8 months (95% CI, 5.1-10.6). Conclusions: Lenalidomide and temsirolimus combination was well tolerated and had antitumor activity in selected participants with advanced cancer. Clinical trial information: NCT01183663. [Table: see text]

LBA8003 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

e22086 Background: The prognostic significance of KRAS mutations varies by mutation type. We compared the outcomes of patients with different KRASmutations treated in phase I clinical trials. Methods: Patients with advanced cancer and KRAS mutation who were treated in the phase I program from 9/08 to 12/12 were analyzed. The presence and type of KRAS mutation in the patients’ tumor samples were assessed in a CLIA-certified laboratory using PCR, sequenom analysis or next-generation sequencing. We compared clinical outcomes according to type of mutation, tumor, and therapy. Results: KRAS mutations were identified in 365 patients (codon 12, n=278; codon 13, n = 49; other codon, n = 38). The median age was 59 yrs (range, 18-87); and 46% men. Of 365 patients, 260 had KRAS mutation alone; 105 patients had 130 additional aberrations: PI3KCA, n=45 (39%); p53, n=29 (25.2%); PTEN, n=22 (19%); other, n=34 (29%). Of 260 patients, 159 were treated and evaluable for response. Outcomes in patients with KRAS mutation alone or with KRAS and additional molecular aberrations are shown in the Table. Conclusions: Keeping in mind that the number of patients was small, our results demonstrate heterogeneity in outcomes of patients with KRAS mutations. Combination studies of MEK inhibitors with other drugs may have improved antitumor activity. [Table: see text]

11086 Background: Mutations in the BRAF gene provide actionable targets for cancer therapy in melanoma and other tumor types. Novel, fast, and accurate diagnostic systems are needed for further implementation of personalized therapy. Methods: The molecular diagnostics (MDx) prototype platform (Biocartis, Mechelen, Belgium) is a fully integrated real-time PCR-based system with high sensitivity (1% mutant in wild-type [wt] background) and fast turnaround time (< 90 minutes), which requires no sample preparation and

e13534 Background: Patients with metastatic cervical cancers have a poor prognosis and few effective therapies available. Thus, access to a phase I trial may provide a viable option. Methods: Outcomes of 54 consecutive patients with metastatic cervical cancers seen in a phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 12/31/2012 were reviewed in accordance with the MD Anderson IRB guidelines. Results: The 54 patients included Caucasians (n=34, 63%), Hispanics (n=9, 17%), African Americans (n=7, 13%), and others (n=4, 7%). Pathological diagnoses were squamous cell carcinoma (n=33, 60%), adenocarcinoma (n=12, 22%), adenosquamous (n=3, 6%), poorly differentiated carcinoma (n=2, 4%), small cell carcinoma (n=2, 4%), clear cell carcinoma (n=1, 2%), and melanoma (n=1, 2%). Initial staging was as follows: I (n=16, 30%), II (n=11, 20%), III (n=11, 20%), and IV (n=16, 30%). Prior treatment included surgery (n=23, 43%), radiotherapy (n=41, 76%), and systemic chemotherapy (n=54, 100%) including one regimen (n=30, 55%), two (n=15, 28%) and more (n=9, 17%). At their initial visit to the phase I clinic, the median age was 47 years. The majority of patients had ECOG PS 0-1 (n=45, 83%), and MDACC prognostic scores 0-1 (n=48, 89%). Almost all the 54 referred patients were enrolled into a phase I trial (n=52, 96%). Initial phase I trials these patients had received led to one CR, five PR, and 12 SD ≥ 6 months (CR/PR/SD≥6 months=35%). Of the patients who progressed on their first protocols, 11 patients (21%) were enrolled into a second protocol, leading to 36% of PR/SD≥6 months (n=4). Among those enrolled into a third (n=4) and a fourth (n=1) study, no CR/PR/SD≥6 months was achieved. The median overall survival in these 54 referred patients was 10.6 months. Among 36 patients who underwent molecular marker studies, 15 were found to harbor PIK3CA mutations and/or PTEN loss (42%) and achieved 60% of CR/PR/SD≥6 months (3 PR and 6 SD≥6 months). Conclusions: Aberrant PI3K pathway was frequently identified in advanced cervical cancers, and the high rate of CR/PR/SD≥6 months was observed in these patients treated under a phase I trial, suggesting that phase I trials, especially mutation matched regimens, may provide potential benefits to these patients.

10607 Background: p53 mutation is one of the most common mutations in human tumors and plays an important role in apoptosis, genomic stability and inhibition of angiogenesis. Methods: We retrospectively reviewed 121 consecutive patients (pts) with solid tumors referred to the Clinical Center for Targeted Therapy (Phase I program) who were tested for p53 mutation, and compared clinical characteristics and outcomes in p53 positive vs. wild-type (wt) pts. Results: Of the 121 tested pts, 65 (53.7%) were p53 mutation-positive. The presence of p53 mutation was not associated with sex and race. Tumors with p53 mutation metastasized more often to the liver (44 pts (67.7%) with mutated p53 vs. 26 pts (46.4%) with wt p53, p=0.0264); there was no difference in metastasis to the bones, lungs, brain, soft tissues and adrenals. p53 mutation also showed a trend toward an association with PTEN-loss (13 out of 43 (30%) with p53 mutated vs. 4 out of 37 (11%) with wt p53, p=0.053). Among pts with the p53 mutation, the best median progression-free survival (PFS) prior to phase I trial entry was 10.97 months (range 0.85–29.04 months) when the treatment regimen included bevacizumab and 4.37 months (range 0.92–14.98 months) when the treatment did not include bevacizumab (P=0.0046). Among patients with wt p53, there was no significant difference in PFS between bavacizumab-containing regimens and regimens without bevacizumab. The median OS from diagnosis was 7.7 years (95% CI 6.32–9.84 years) vs. 11.8 years (95% CI 10.37 years, not attained) for p53 mutant vs. wild-type disease (p = 0.03). Univariate analysis for OS from diagnosis showed that mutated p53, Hispanic race (vs. Caucasians) and the shorter time from diagnosis to metastasis were associated with a worse prognosis. Conclusions: Tumors with p53 mutation have a more aggressive clinical behavior, metastasize more to the liver and may have a higher rate of PTEN loss compared to tumors with wt p53; In addition, anti-angiogenic agents may be of therapeutic value in p53-mutated pts.

7543 Background: Although chemotherapy (chemo) may be effective in treating brain metastases from both small cell (SCLC) and non-small cell (NSCLC) lung cancer, ability to detect non-response early...

TPS290 Background: Pemetrexed plus carboplatin and paclitaxel plus carboplatin and bevacizumab are active regimens in the first-line treatment of patients with advanced NSCLC and nonsquamous histol...

e19069 Background: Early determination of therapeutic failure can potentially spare a pt ineffective and toxic treatment. We previously reported in a retrospective study the use of CT within 4 weeks of initiation of chemotherapy in advanced NSCLC to assess response and progression by RECIST (Bruzzi et al. JTO 2006). Here, we prospectively assess whether CT imaging after the first cycle of pemetrexed in advanced NSCLC has a role in evaluating response and management. Methods: We accrued pts with PS 2 or 3 advanced NSCLC receiving at least one dose of 1st or 2nd line pemetrexed. A repeat CT prior to a 2nd course was required. Pts with progression by RECIST were to come off study. CT scans were done using multislice CT technology (GE Lightspeed Plus), and images were reconstructed with slice thicknesses of 3.75mm or less. All images were reviewed using a PACs workstation (Stentor iSite) and measurements were done with electronic calipers. RECIST criteria: progression, an increase in the tumor's longest dimension by 20%, response, a decrease by 30%. Results: Thirty pts had a median age of 68 years (45 - 81). PS 2/3, 1st/2nd line, and F/M were 16/14, 17/13, and 12/18 respectively. Pts received 1–8 cycles (median 2). Twelve pts received only 1 course of whom 7 pts had f/u CTs at a median of 20 days (12–25) after 1st chemo dose. Of these pts, 5/7 had progression by RECIST and the other 2/7 pts had stable disease with 1 pt who came off due to serial PEs and 1 pt who opted off for reasons of travel. Two of the 5 pts who had progression by CT had no detectable change by CXR. Of 5/12 pts treated with only 1 course without f/u CT, 2 pts died, 2 pts had progression by CXR, and 1 pt stopped after treatment for pneumonia. All 18 pts receiving ≥2 cycles had a repeat CT prior to their 2nd course. Conclusions: The results of this prospective trial support earlier retrospective findings that short-term follow-up using CT in pts with advanced NSCLC can detect tumor progression and impact patient management. We will also present f/u CTs in pts who received ≥ 1course to determine whether early signs of progression predict later RECIST determined progression. [Table: see text]