Citations

AbstractIntroduction18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C‐Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET.MethodsFDG, early frames of PiB images, and relative PiB delivery rate constants (PiB‐R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross‐sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history.ResultsMetabolism and perfusion images were spatially correlated. Regional PiB‐R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity.DiscussionHypometabolism estimated by PiB‐R1 may provide a measure of brain perfusion without increasing radiation exposure.

Abstract Rationale Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00–7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

TPS3624 Background: To improve survival for patients with mCRC, efforts are needed to identify and treat actionable genomic alterations. HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC. HER2 functions as an oncogenic driver and a mediator of EGFR antibody (Ab) resistance. Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ (HER2 IHC 3+ or HER2 amplified) mCRC, there are no HER2-directed therapies approved for these patients. Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2, currently being developed to treat metastatic breast cancer. In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition. Methods: This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC. Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal Ab. Patients must have HER2+ disease by IHC, FISH, or NGS. Prior treatment with anti-HER2 targeting therapy is excluded. The primary objective is to assess the objective response rate for the combination. Secondary objectives are to evaluate the efficacy (PFS, OS, clinical benefit rate), safety, and tolerability of the combination. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA. Subjects will receive tucatinib at a dose of 300mg by mouth daily, and trastuzumab will be administered every 3 weeks (8 mg/kg IV day 1 of cycle 1, then 6 mg/kg IV Q3 weeks). Response will be assessed every 3 cycles (9 weeks) per RECIST version 1.1. Both agents will be provided by the study. This study was initiated in February 2017. Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United (ACCRU) network. Clinical trial information: NCT03043313.

3511 Background: CALGB 80405 was a randomized Ph3 trial showing no OS or PFS difference in mCRC pts treated with Bevacizumab (BV) or Cetuximab (Cet) in the first line. A Nanostring platform was used to determine the CMS classification of 392 KRAS wt (codon 12 and 13) primary tumors and correlated it with OS and PFS in patients enrolled in 80405. Methods: CMS for 392 of 431tumors were defined using a custom CRC Nanostring panel (39 CMS classification not possible). Stratified Cox proportional hazard model was used to evaluate the effect of CMS classification stratified by prior radiation, prior chemotherapy, adjusting for age, sex, race, primary in place, liver met only, and sidedness. Results: We found CMS1 (14%), CMS2 (47%), CMS3 (2%), CMS4 (29%), NonConsensus (8%). Results are shown in Table 1. Patients with CMS1 who received BV had significantly longer OS than those who received Cet (HR 0.47, 95% CI [0.24, 0.92]). Patients with CMS2 who received BV tended to have shorter OS than those who received Cet (HR 1.41, CI [0.95, 2.08]). Conclusions: Our data suggest that CMS is associated with OS and PFS in first line therapy in mCRC patients. Preliminary data suggest that certain CMS may be associated with efficacy of Bev and Cet based chemotherapy. CMS classification should be explored as a stratification factor in future trials. Support: U10CA180821, U10CA180830, U10CA180882 Clinical trial information: NCT00265850. [Table: see text]

3504 Background: CALGB 80405 was a randomized phase III trial that found no difference in OS in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet). Primary tumor DNA from 361 pts, including KRAS mutant (mut) pts, has been profiled for somatic gene mutations/ML/MSI to discover molecular markers of OS. Methods: Mutations in 11 genes were determined by PCR, MSI by microsatellite analysis, and ML by next-generation sequencing (FoundationOne). Cox proportional hazard models are used, stratified by prior XRT and +/- adjuvant chemotherapy; adjusted by age, race, gender, synchronous vs. metachronous, liver metastases, sidedness, all RAS. Results: BRAF: Mut pts had shorter OS than wild-type (wt) pts (HR 1.92, 95% CI 1.34,2.75; p<0.001); HR 1.65 (1.09,2.50) after adjusting for sidedness (p 0.022). In mut pts longer OS is observed in Bev arm vs. Cet arm (p 0.041); in wt pts no arm difference is observed (p 0.291, table). MSI: OS does not differ between MSI-H and MSI-S pts (HR 0.78 [0.40, 1.52], p 0.450). In MSI-H pts longer OS is observed in Bev arm vs. Cet arm (p 0.002); in MSI-S pts no difference is observed (p 0.305, table). ML: Hypermutated MSI-H pts are excluded. In a subset of 205 pts, pts with ML>5 (N=93) have longer OS than pts with ML≤5 (N=112) (HR 0.65 [0.42,1.00], p 0.048). In Bev arm higher ML confers longer OS than lower ML (HR 0.85 [0.80,0.96], p 0.004); in Cet arm no difference is observed (HR 0.99 [0.90,1.09], p 0.862). Conclusions: BRAF is a strong negative prognostic factor in mCRC, even when sidedness is taken into account. ML is a novel marker for further evaluation. The effect of Bev and Cet in either BRAF mut or MSI-H pts should be tested in larger datasets. Updated results from more screened samples will be presented. [Table: see text]

3503 Background: 80405 found no OS or Progression Free Survival (PFS) difference when bevacizumab (BV) or cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in All RAS wild type (wt) mCRC pts. There was a significant 1° side by biologic interaction (P int: OS = 0.008, PFS = 0.001) favoring pts with left-sided (L) 1°. Analyses of 1° tumors beyond All RAS includes Consensus Molecular Subtype (CMS), BRAF and MSI. (CMS results - see Lenz et al; BRAF -see Innocenti et al) We asked whether 1° tumor location - L vs right (R) - is an independent prognostic marker when these other molecular features are considered. Methods: We used a Cox proportional hazard model stratified by prior XRT and +/- adjuvant chemo; adjusted for age, gender, synchronous vs metachronous, CMS, MSI and BRAF status. Pts with transverse (T) tumors were excluded in this analysis. Results: Sidedness was determined in 782 pts (L - 472; R - 256; T -54). Molecular data from 728 pts (with L - and R-sided 1°s) was available as follows: KRAS -- 291, NRAS -393, BRAF - 393, MSI - 378, CMS - 533. L vs R mOS: 32.9 v 19.6 months (mo) (p < 0.0001). See Table for OS results in All RAS / BRAF wt and BRAF mutant (mut) pts. Sidedness (R vs L) is an independent prognostic marker even after adjusting for all these molecular features: HR = 1.392 (1.032, 1.878), p = 0.031. Conclusions: Primary tumor location is an independent prognostic factor when adjusted for age, gender, synchronous/metachronous, CMS, MSI and BRAF status. We are exploring clinical variables such as tumor burden, metastatic sites and measurability of disease in an attempt to explain the impact of sidedness. Support: U10CA188021, U10CA180882. Eli Lilly and Co, Genentech/Roche, Pfizer, Sanofi. Clinical trial information: NCT002655850. [Table: see text]

AbstractBackgroundGenetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine. We have previously found that in a postcesarean section cohort, the rate of hydromorphone formation was dependent on the genotype of CYP2D6 and that plasma hydromorphone, not hydrocodone, was predictive of pain relief.MethodBlood was obtained from a postcesarean cohort that were surveyed for pain response and common side effects. Plasma samples were genotyped for CYP3A4/5, and their hydrocodone concentrations were measured by LC-MS. R statistical software was used to check for differences in the outcomes due to CYP3A4/5 and CYP2D6, and a multivariate regression model was fit to determine factors associated with pain score.ResultsTwo-way ANOVA between CYP3A4/A5 and CYP2D6 phenotypes revealed that the former variants did not have a statistical significance on the outcomes, and only CYP2D6 phenotypes had a significant effect on total dosage (P = 0.041). Furthermore, a 3-way ANOVA analysis showed that CYP2D6 (P = 0.036) had a predictive effect on plasma hydromorphone concentrations, and CYP3A4/A5 did not have any effect on the measured outcomes.ConclusionsWith respect to total dosages in a cesarean section population, these results confirm that CYP2D6 phenotypes are predictors for plasma hydromorphone concentration and pain relief, but CYP3A4/A5 phenotypes have no influence on pain relief or on side effects.