Citations

TPS5093 Background: Globally, docetaxel remains the standard of care for metastatic CRPC; however, its use may be delayed until pts develop symptoms. The presence of infiltrating leukocytes in CRPC tumors suggests a natural antitumor immune response is occurring. This is supported by an overall survival (OS) benefit reported in men with asymptomatic or minimally symptomatic metastatic CRPC who received sipuleucel-T. Ipi, a monoclonal antibody that binds CTLA-4, augments antitumoral activity of cytotoxic immune cells. Ipi demonstrated OS benefit in two phase III trials for advanced melanoma, with side effects that were managed using product-specific treatment guidelines. In phase I/II trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostate-specific antigen [PSA] declines and RECIST response) with a similar toxicity profile to that observed in melanoma. This global (149 sites in 24 countries) phase III study (ClinicalTrials.gov identifier: NCT01057810) evaluates Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The study is designed to detect a 9.3-month median difference (HR=0.7) in OS with 90% power and 0.05 two-sided significance. Pts are randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo as induction therapy. Eligible pts will receive maintenance therapy of blinded study drug every 12 weeks. The accrual goal is 600 pts randomized. Clinical trial information: NCT01057810. [Table: see text] [Table: see text]

TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.

8037 Background: Advances in the treatment of MM have greatly improved clinical outcomes for patients (pts). SPM occurrence has been observed in early and late stage MM as well as with increasing age. US SEER Cancer Registry reports a background incidence rate of SPM 2.1/100 person-yrs (PY) among persons ≥ 65 yrs of age. However, incidence of SPM in MM pts and the relationship to therapy still warrants further exploration. Methods: Connect MM is a US-based observational registry designed to characterize pts with newly diagnosed MM from 266 US sites. Initiated in Sep 2009, patient data were collected at baseline and each subsequent quarter with a standardized form. On Dec 14, 2011, Connect MM reached full enrollment at 1,500 pts. Results: As of Jan 13, 2012, preliminary retrospective SPM data is available for 1015 pts. Median age was 67 yrs, 56.8% male, and median follow-up was 10.6 mo (0.03-24.9 mo). 12 pts (7 male) with median age of 68.5 yrs developed SPM. Median time to SPM was 8.5 mo (0.8-17.7 mo) after treatment initiation. 11 invasive SPM were observed - 4 hematological (heme): 1 AML, 1 MDS, 1 CMML and 1 DLBCL, and 7 solid: 2 melanoma skin, 1 bronchus, 1 breast, 1 prostate, 1 tonsil, and 1 gastric carcinoid. Also, 1 pt had non-melanoma skin cancer (NMSC), and 1 pt with invasive skin cancer also had NMSC. Of the 4 pts developing heme SPM, 3 had bortezomib (BORT), 1 had thalidomide (THAL), 1 had lenalidomide (LEN), 2 had melphalan (MEL), and all 4 pts had steroids. Of the 7 pts who developed solid tumor SPM, 5 had BORT, 5 had LEN, 2 had doxorubicin, 1 had MEL, 5 had steroids, 1 had irradiation, and 1 had not received MM treatment. 2 pts with prior history of invasive malignancy developed solid tumor SPM (1 pt also developed NMSC).1 pt who received irradiation developed NMSC. Early overall incidence of invasive SPM was 1.21/100 PY (95% CI 0.60, 2.16) for all pts and 1.20/100 PY (95% CI 0.44,2.62) for pts ≥ 65 yrs of age. Conclusions: This preliminary analysis shows that SPM occurred at an expected rate in this disease specific registry of patients with NDMM and appeared to occur irrespective of MM treatment administered. Incidence rates of SPM may increase over time as patients receive transplantation and alkylators. Prospective observation will continue.

2510 Background: Blocking the interaction between programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, and its ligand PD-L1 may enhance T-cell function. Here we describe the safety and activity from the first clinical study of BMS-936559 in patients (pts) with advanced solid tumors, further validating the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was given Q2 wk IV in a 6-wk cycle at doses of 0.3−10.0 mg/kg during dose escalation and/or cohort expansion; pts could receive up to 16 cycles (48 doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL, n=53), non-small-cell lung (NSCLC, n=50), colorectal (n=18), renal cell (RCC, n=17), ovarian (n=17), and pancreatic (n=7) cancer were treated. Median therapy duration was 11 wks (max 99 wks). Common related adverse events (rAEs; ≥5% pts) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs was 8.6%. AEs of special interest included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drug-related deaths. Clinical activity was observed in MEL, RCC, and NSCLC. Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting ≥1 yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data lock. Several pts had prolonged stable disease. Some pts had a persistent reduction in overall tumor burden in the presence of new lesions but were not categorized as responders. In NSCLC, ORs were observed irrespective of histology. Conclusions: BMS-936559 was active and generally well tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from anti-PD-1/BMS-936558 trials, this study concurrently validates the importance of the PD-1/PD-L1 pathway for cancer immunotherapy and supports further clinical development of anti-PD-1/PD-L1 directed therapy. [Table: see text]

1087 Background: EP is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. EP demonstrated a 29% overall response rate in patients with mBC, leading to a phase III global BEACON study in patients with mBC. CTCs in patient blood samples provide a minimally invasive approach to detect PD markers of drug activity. We developed quantitative multiplex immunofluorescent assays to measure target-specific PD biomarkers for EP in CTCs isolated pre- and post-treatment. Methods: Assays for Top1, Top2, g-H2Ax, Rad51, ABCG2, and Ki-67 were developed using control (0.1% DMSO) and drug-treated (SN38, 10 uM) tumor cell lines (HCT116, MCF7, A549, SKBr3) and PBMCs from healthy donors. The optimal antibody for each biomarker was then multiplexed in a panel with antibodies against cytokeratin, CD45 and DAPI for phenotypic identification of CTCs. For analysis of BEACON pts, serial 7.5 mL whole blood samples were drawn and shipped ambient to Apocell (Houston, TX) for further processing. PBMCs were separated and CTCs were isolated using ApoStream technology. CTCs were stained for PD markers and analyzed using an iCys laser scanning cytometer equipped with image analysis software. Results: Antibodies bound to tumor cells showed staining confined to the nucleus (Top1, Top2, g-H2AX, Ki-67) or membrane (ABCG2), exhibited defined peak separation from their isotype controls, and signal strength correlated with cellular expression of high and low levels of markers. To date, ~ 80% of BEACON pts consent to participate in the CTC sub-study. As of 30 Oct 2012, data from 167 pre-dose blood samples from BEACON pts were available. 99% of blood samples were successfully processed. 93% had detectable CTCs, yielding a median of 216 CTCs (range: 7.5-14816). Staining was positive for Top1, Top2, g-H2Ax, Rad51, ABCG2, and Ki-67 in 82%, 89%, 16%, 53%, 31%, 52% of samples, respectively. Conclusions: EP target-specific pharmacodynamic biomarkers can be reliably measured in CTCs isolated from patients participating in BEACON. Sample collection and analysis of pre- and post-treatment samples is ongoing. Clinical trial information: NCT01492101.

e18556 Background: Studies in the United States (US) have identified variation in incidence and survival of multiple myeloma (MM) patients of different races, and noted that MM is the most common hematologic cancer among African Americans. This analysis evaluated whether health-related quality of life (HRQOL) of patients in the US varies by race as they initiate treatment having been newly diagnosed with active, symptomatic MM. Methods: Data were collected in Connect MM, a prospective US observational registry begun in September 2009. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients at enrollment within 2 months of diagnosis. Patients completed the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Mean reported scores for BPI, EQ-5D and FACT-MM were analyzed by patient race. Statistical significance was ascertained by ANOVA using SAS 9.1. Results: Baseline HRQOL data were reported by 1144 patients (enrolled in 228 centers) of whom 82% were White, 13% Black, and 6% Other race. The cohorts did not differ statistically by ECOG status or by multiple myeloma stage (assessed by either the International Staging System or the Durie and Salmon system). Compared to non-Blacks, Black patients reported less anxiety/depression on the EQ-5D (p=0.030) and better emotional well-being on the FACT-MM (p=0.003). No other statistically significant differences were noted between cohorts on the BPI, other EQ-5D domains (mobility, self care, usual activities, pain/discomfort), or other FACT-MM domains (physical, social/family, functional, and MM-specific considerations). Conclusions: Initial results from the Connect MM Registry indicate that baseline HRQOL prior to initiation of treatment may vary by patient race with respect to emotional well-being, and specifically anxiety/depression. These results serve as a baseline reference for future analyses. As patients in the Connect MM Registry proceed through therapy, analyses should be conducted of patients by race, among other characteristics and factors, to determine whether it may be associated with subsequent clinical outcomes and HRQOL over time.

6122 Background: Clinicians and investigators commonly use ECOG PS and clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multi-faceted construct that comprehensively looks at the pt perspective on disease and well-being. Because limited data exist on the relationships between PS, fatigue, and HRQOL for CLL pts, we examined the associations between these measures, and 3 validated HRQOL instruments: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, and Brief Fatigue Inventory (BFI). Methods: Data were collected in CONNECT CLL, a prospective US observational registry initiated in 2010. Patient demographics and clinical characteristics were provided by clinicians. Patient HRQOL was self-reported at enrollment using the FACT-Leu, EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and clinician-reported fatigue (yes, no). Differences in HRQOL scores were assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 148 community, 10 academic, and 3 government centers. ECOG PS was available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS severity and was worse in pts with fatigue (all p<0.0001). All FACT-Leu domains except social/family were worse in pts with fatigue and those with higher ECOG PS. Mean EQ-5D pain/discomfort, mobility, self care and usual activities domain scores worsened in severity as ECOG worsened and for pts with fatigue (all p<0.011). BFI data indicated that global fatigue, fatigue severity and fatigue-related interference worsened by ECOG severity and were associated with clinician-reported fatigue (all p<0.0001). Conclusions: Initial CONNECT CLL results confirm that HRQOL worsens with worsening ECOG PS and was worse among pts with fatigue, especially in physical/functioning domains, pain/discomfort, and mobility. These results indicate that baseline ECOG PS and physician-rated fatigue are rapid assessments that predict robust measures of HRQOL. Future analyses are planned to examine how HRQOL, ECOG PS and fatigue change over time with changes in treatment and CLL disease status.

4033 Background: HCC is a major health problem across the world. The global HCC BRIDGE study is the first global, large-scale, observational study to document the real-world experience of HCC patients from diagnosis to death. Methods: This longitudinal cohort study (started March 2009) includes HCC patients newly diagnosed between January 2005 and June 2011 and treated at major medical centers, with data collected retrospectively and prospectively as recorded in patient charts. Full patient enrollment is expected at the end of January 2012. Results: At the time of the first interim analysis (July 2011), 12,442 treated HCC patients were enrolled at 42 sites in Asia (n=8909, 72% [China: n=6295, 71%; Japan: n=295, 3%]), Europe (n=2040, 16%) and North America 1493 (n=1493, 12%). Mean age was 57 years; 82% were male. The predominant risk factor was HBV in Asia (76%) and HCV in Europe (48%), North America (45%) and Japan (69%). Most patients were diagnosed without surveillance (Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In Asia, Europe and North America, the predominant BCLC stage at diagnosis was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded treatments in Asia, Europe and North America were resection (31%, 15%, 21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 8%). Treatments ever used (2005–2011) in Asia, Europe and North America were resection (33%, 17%, 24%), transplantation (2%, 6%, 12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 37%) and systemic therapy (9%, 20%, 21%). These results will be updated with data from the full study population (approx. 19,000 patients), and preliminary survival data will be presented. Conclusions: As the largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE study provides valuable insights into global HCC disease characteristics and patient management. Based on prior analyses, differences in risk factors among regions confirm well-known trends, while other observed differences (e.g., treatment variations) may be related to country- and site-specific practices and patient characteristics.

AbstractImmune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PAX1deficiency causes a syndromic form of SCID by altering differentiation of thymic epithelial cells and other pharyngeal pouch tissues.