Citations

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]

249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.

174 Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]

237 Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.

Purpose To compare the risks of serious health outcomes among hematopoietic cell transplantation (HCT) survivors versus a matched population of patients with cancer who did not undergo HCT, where the primary difference may be exposure to HCT. Methods Two-year HCT survivors treated at a comprehensive cancer center from 1992 through 2009 who were Washington State residents (n = 1,792; 52% allogeneic and 90% hematologic malignancies) were frequency matched by demographic characteristics and underlying cancer diagnosis (as applicable) to non-HCT 2-year cancer survivors, using the state cancer registry (n = 5,455) and the general population (n = 16,340) using driver’s license files. Late outcomes for all three cohorts were ascertained from the state hospital discharge and death registries; subsequent cancers were ascertained from the state cancer registry. Results After median follow-up of 7.1 years, HCT survivors experienced significantly greater rates of hospitalization compared with matched non-HCT cancer survivors (280 v 173 episodes per 1,000 person-years, P < .001) and greater all-cause mortality (hazard ratio [HR], 1.1; 95% CI, 1.01 to 1.3). HCT survivors had more hospitalizations or death with infections (10-year cumulative incidence, 31% v 22%; HR, 1.4; 95% CI, 1.3 to 1.6) and respiratory complications (cumulative incidence, 27% v 20%; HR, 1.4; 95% CI, 1.2 to 1.5). Risks of digestive, skin, and musculoskeletal complications also were greater among HCT versus non-HCT cancer survivors. The two groups had similar risks of circulatory complications and second cancers. Both HCT and non-HCT cancer survivors had significantly greater 10-year cumulative incidences of all major organ-system outcomes versus the general population. Conclusion History of HCT was associated with late morbidity and mortality among cancer survivors. In particular, clinicians who care for HCT survivors should be aware of their high rates of late respiratory and infectious complications.

111 Background: Trastuzumab in combination with chemotherapy is recommended for advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2) overexpression. Despite this recommendation, an informal pilot survey suggested that many oncologists do not include HER2 testing as part of routine practice to identify patients most likely to benefit from adding trastuzumab to chemotherapy. Methods: An interactive online educational activity was developed to provide expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer. Pre- and post-education surveys were administered as part of the activity to measure changes in participant competence. In addition, 3 months after completing the educational activity, participants were sent another follow-up survey by email to assess changes in practice. Results: To date, pre-and post-education surveys have been obtained for 122 oncologists and 3-month follow-up surveys obtained from 14 oncologists. In the pre-education survey, only 46% said they were testing all of their patients with advanced gastric or GE cancer for HER2 overexpression. However, immediately after participating in the educational intervention, this proportion increased to 93%. Importantly, a follow-up survey indicated that HER2 testing of all patients with advanced gastric or GE cancer was now part of routine practice for 79% of those surveyed. A final analysis of pre- and post-education and 3-month follow-up surveys will be presented. Conclusions: Expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer provided through an interactive online educational intervention substantially improved oncologist competence and practice patterns.

Background Lower extremity peripheral arterial disease (PAD) is a common medical condition causing substantial morbidity. Limited data exist on whether discrepancies in PAD prevalence exist between the lower extremities using resting ankle-brachial indices (ABIs) and postexercise pressures. Objective We predicted the prevalence of PAD between the lower extremities. Methods and Results Consecutive patients who had undergone a noninvasive arterial lower extremity study at Mayo Clinic, Rochester, MN, between January 1996 and December 2012 with suspected PAD were retrospectively reviewed. We identified 12,312 consecutive patients who underwent an arterial lower extremity and an exercise treadmill study. Prevalence of PAD was assessed at rest and after exercise using two criteria: a resting ABI ≤ 0.90 and a postexercise pressure decrease of > 30 mm Hg. Mean age was 67 ± 12 years and there were 4,780 (39%) women studied. At rest, we found a higher prevalence of PAD on the left extremity (27.4%) compared with the right (24.6%) (p < 0.0001). After exercise, we found a higher prevalence of PAD on the right extremity (25.1%) compared with the left (19.0%) (p < 0.0001). These discrepancies between the prevalence of PAD at rest and after exercise were present in women and men. Conclusion Using validated criteria of a resting ABI of ≤ 0.90 and postexercise ankle pressure decrease > 30 mm Hg, our results suggest that there is a significantly higher prevalence of PAD in the left lower extremity at rest, in contrast to a greater prevalence of abnormal postexercise testing in the right lower extremity. The reason(s) of these discrepancies remain to be studied.