Citations

LBA2 Background: Docetaxel (D) improves OS of men with mPrCa who have progressed on androgen deprivation therapy (ADT). We aimed to assess the benefit of upfront chemohormonal therapy for metastatic PrCa. Methods: 1:1 randomization to ADT alone or ADT + D dosed 75mg/m2 every 3 weeks for 6 cycles within 4 month (mos) of starting ADT. Stratification factors: high volume (HV) vs. low volume (LV) disease (HV: visceral metastases and/or 4 or more bone metastases); anti-androgen use beyond 30 days; Age ≥70 vs. < 70 years; ECOG PS 0-1 vs. 2; Prior adjuvant ADT > 12 vs. ≤ 12 mos; FDA approved drug for delaying skeletal related events. Key eligibility criteria: suitable organ and neurological function for D; adjuvant ADT ≤ 24 mos and no progression within 12 mos of adjuvant ADT. OS was the primary endpoint and the study was powered to assess for a 33.3% improvement in median OS (80% power and 1-sided alpha=2.5%). Projected median OS for ADT alone: HV-33 mos; LV-67 mos. Results: 790 men were accrued from 7/28/06 to 11/21/2012: ADT N=393; ADT + D: N=397; balanced for demographic, stratification and disease factors. Median age: 63 years (range: 36 to 91); 98% ECOG PS 0 or 1; 89% Caucasian; 24% prior radiotherapy, 24% prior prostatectomy; HV 64% on ADT and 67% on ADT + D. Data released after 4th interim analysis in Sept 2013 when O’Brien Fleming upper boundary was crossed with 53.1% information. This report reflects 1/16/2014 data with median follow-up of 29 mos with 137 deaths on ADT alone vs. 104 deaths on ADT+D. ADT+D: Grade (G) 3/4 Neutropenic fever: 4%/2%; G3 neuropathy: 1% sensory, 1% motor; 1 death due to treatment (no deaths due to treatment on ADT). Efficacy data is in the table below. After disease progression, 123 pts on ADT alone and 45 pts on ADT + D received docetaxel. Conclusions: ADT + D improves OS over ADT alone in men with HV mPrCa. Longer follow-up is needed for men with LV mPrCa. Clinical trial information: NCT00309985. [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.

CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012). Methods: We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m2 daily for 5 days in 28-day cycles (or DTIC 1000 mg/m2 q21 days) for patients (pts) with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS) and response rate (RR). Select pts underwent tumor biopsies at baseline and after 14 (+/- 3 days) of sel. Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6 (p=0.1). Randomization was stratified by mut (Gq vs G11), M stage and number of prior therapies (tx). Tumor assessment occurred every 4 weeks (wks) for 8 wks and then every 8 wks using RECIST 1.1. Pts receiving TMZ who progressed could receive sel (TMZ→sel). Results: 80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZ→sel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%. Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented. Clinical trial information: NCT01143402.

653 Background: Next-generation sequencing often reveals potentially actionable molecular alterations; however, data on approved targeted therapies in non-indicated tumors are limited. MyPathway (NCT02091141) evaluates agents targeting the HER2, EGFR, BRAF, or Hedgehog (Hh) pathways in tumors for which these therapies are not currently indicated. Here, we present early response data for patients with GI tumors. Methods: Eligible patients had metastatic tumors with potentially actionable genomic alterations, identified by a CLIA-certified lab, and progression on standard therapy. Based on the identified alteration, patients received standard doses of trastuzumab + pertuzumab (HER2), erlotinib (EGFR), vemurafenib (BRAF), or vismodegib (Hh). Response was evaluated by the investigator using RECIST v1.1. Results: As of Aug 21, 2015, 96 patients had enrolled, 36 of whom (38%) had GI tumors with the following alterations: HER2 (n=28 [22 amplifications, 5 activating mutations, 1 both]), BRAF (n=4), Hh (n=2 [2 PTCH-1 mutations]), and EGFR (n=2). Patients had a median of 4 (range, 1–8) prior lines of therapy. Tumor types and interim best response data are shown below. Among all evaluable patients with GI tumors (n=26), 5 have had a PR to targeted therapy (duration 3–10+ months). Conclusions: Targetable molecular alterations were found in a variety of GI tumors, resulting in clinical benefit from targeted treatments that would not have otherwise been realized. These early results support this molecular testing strategy. Accrual to the trial continues; based on activity observed, the HER2-positive colorectal cancer cohort will be expanded to ≥30 patients. Additional data will be presented at the meeting. Clinical trial information: NCT02091141. [Table: see text]

1 Background: To determine whether the efficacy of a hypofractionated (H) schedule is no worse than a conventional (C) schedule in men with low-risk prostate cancer. Methods: From April 2006 to December 2009, one thousand one hundred fifteen men with low-risk prostate cancer (clinical stage T1-2a, Gleason ≤ 6, PSA < 10) were randomly assigned 1:1 to a conventional (C) schedule (73.8 Gy in 41 fractions over 8.2 weeks) or to a hypofractionated (H) schedule (70 Gy in 28 fractions over 5.6 weeks). The trial was designed to establish with 90% power and alpha = 0.05 that (H) results in 5-year disease-free survival (DFS) that is not lower than (C) by more than 7% (hazard ratio (HR) < 1.52). Secondary endpoints include freedom from biochemical recurrence (FFBR) and overall survival. At the third planned interim analysis (July 2015), the NRG Oncology Data Monitoring Committee recommended that the results of the trial be reported. Results: One thousand one hundred and one protocol eligible men were randomized: 547 to C and 554 to H. Median follow-up is 5.9 years. Baseline characteristics are not different according to treatment arm. At the time of analysis 185 DFS events have been observed; 99 in the C arm and 86 in the H arm. The estimated 7-year disease-free survival is 75.6% (95% CI 70.3, 80.1) in the C arm and 81.8% (77.5, 85.3) in the H arm. The DFS HR (C/H) is 0.85 (0.64, 1.14). Comparison of biochemical recurrence (HR = 0.77, (0.51, 1.17)) and overall survival (HR = 0.95, (0.65, 1.41)) also met protocol non-inferiority criteria. Grade ≥ 3 GI toxicity is 3.0% (C) vs. 4.6% (H), Relative risk (RR) for H vs. C 1.53, (95% CI 0.86, 2.83); grade ≥ 3 GU toxicity is 4.5% (C) vs. 6.4% (H), RR = 1.43 (0.86,2.37). Conclusions: In men with low-risk prostate cancer, 70 Gy in 28 fractions over 5.6 weeks is non-inferior to 73.8 Gy in 41 fractions over 8.2 weeks. Clinical trial information: NCT00331773.

300 Background: The National Radiation Oncology Registry (NROR) is developing an IT infrastructure to support the efficient collection, aggregation, and analysis of data concerning cancer patients treated with radiotherapy across the United States. Methods: Detailed requirements were developed to emphasize the following distinguishing goals for the system: 1) streamline the process of data collection by minimizing manual data entry; 2) support the collection of patient-reported outcomes (PROs) and their linkage with clinician-observed outcomes; 3) facilitate data integration within the NROR and between the NROR and other registries; 4) allow for evolution of the system in response to new learning; and 5) promote sustainability and ongoing improvement through an open standard of interoperability. Results: An innovative technical architecture has been designed to meet the goals described. The system maximizes efficiency through automated extraction and electronic transfer of data from radiation oncology information systems. PROs are collected directly from patients via a web-based portal and linked to data submitted from participating institutions. A data dictionary has been developed based on national standards and controlled vocabularies to facilitate data integration. Contemporary forms-based database technology is used in combination with traditional relational technology to permit both flexible evolution of the system and efficient data analysis. A unique “gateway” architecture and open transmission standard makes it possible for commercial products to interoperate with the registry in the future. Conclusions: The NROR prototype system will be launched later this year to collect data for a pilot registry of prostate cancer patients. Its performance and usability will be important factors in the success of the pilot. If effective, the platform will support the expansion of the NROR to benefit patients, clinicians, researchers, payors, device manufacturers, and policy-makers by capturing reliable, population-based information on radiation treatment delivery and health outcomes.

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.

LBA500 Background: The primary endpoint of NSABP B-35, a phase III trial comparing 1 mg/day anastrozole to 20 mg/day tamoxifen, each given for 5 years, was breast cancer-free interval (BCFI), defined as the time from randomization to any breast cancer (BC) event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS. Methods: Postmenopausal women with ER-receptor or PgR-receptor positive (by IHC analysis) DCIS and no invasive BC who had undergone a lumpectomy with clear resection margins were randomly assigned to receive either 20 mg/day tam or 1 mg/day A (blinded) for 5 years. Stratification was by age (<60 v ≥60). Results: From 1/6/2003 to 6/15/2006, 3,104 pts were entered and randomized (1552 in groups tam and A each). As of 2/28/15, follow-up information was available on 3,083 pts for OS and on 3,077 pts for all other disease-free endpoints, with mean time of follow-up of 8.6 years. There were 198 BCFI events, 114 in the tam group and 84 in the A group (HR, 0.73; p=0.03). 10-year point estimates for BCFI were 89.2% for tam and 93.5% for A. A significant time-by-treatment interaction (p=0.02) indicated that the effect was not evident until later in the study. There was a significant interaction between treatment and age group (p=0.04); benefit of A is only in women <60 years old. As to secondary endpoints, there were 495 DFS events, 260 in the tam group and 235 in the A group (HR, 0.89; p=0.21). 10-year point estimates for DFS were 77.9% for tam and 82.7% for A. There were 186 deaths, 88 in the tam group and 98 in the A group (HR, 1.11; p=0.48). 10-year point estimates for OS were 92.1% for tam, 92.5% for A. There were 8 deaths due to breast cancer in the tam group and 5 in the A group. There were 63 cases of invasive breast cancer in the tam group and 39 in the A group (HR, 0.61; p=0.02). There was a non-significant trend for a reduction in breast second primary cancers with A (HR, 0.68; p=0.07). Conclusions: Anastrozole provided a significant improvement compared to tamoxifen for BCFI, which was seen later in the study, primarily in women <60 years. Support: CA12027, 37377, 69651, 69974; 180868, 180822, 189867 196067, 114732; AstraZeneca Pharmaceuticals LP. Clinical trial information: NCT00053898.