Michael P. Chu

Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial

Importance Capecitabine is an oral cytotoxic chemotherapeutic commonly used across cancer subtypes. As with other oral medications though, it may suffer from drug interactions that could impair its absorption. Objective To determine if gastric acid suppressants such as proton pump inhibitors (PPIs) may impair capecitabine efficacy. Design, Setting, and Participants This secondary analysis of TRIO-013, a phase III randomized trial, compares capecitabine and oxaliplatin (CapeOx) with or without lapatinib in 545 patients with ERBB2/HER2-positive metastatic gastroesophageal cancer (GEC); patients were randomized 1:1 between CapeOx with or without lapatinib. Proton pump inhibitor use was identified by medication records. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with PPIs vs patients who were not. Specific subgroups were accounted for, such as younger age (<60 years), Asian ethnicity, female sex, and disease stage (metastatic/advanced) in multivariate Cox proportional hazards modeling. The TRIO-013 trial accrued and randomized patients between June 2008 and January 2012; this analysis took place in January 2014. Interventions Patients were divided based on PPI exposure. Main Outcomes and Measures Primary study outcome was PFS and OS between patients treated with PPIs vs patients who were not. Secondary outcomes included disease response rates and toxicities. Results Of the 545 patients with GEC (median age, 60 years; 406 men [74%]) included in the study, 229 received PPIs (42.0%) and were evenly distributed between arms. In the placebo arm, PPI-treated patients had poorer median PFS, 4.2 vs 5.7 months (hazard ratio [HR], 1.55; 95% CI, 1.29-1.81, P < .001); OS, 9.2 vs 11.3 months (HR, 1.34; 95% CI, 1.06-1.62; P = .04); and disease control rate (83% vs 72%; P = .02) vs patients not treated with PPIs. In multivariate analysis considering age, race, disease stage, and sex, PPI-treated patients had poorer PFS (HR, 1.68; 95% CI, 1.42-1.94; P < .001) and OS (HR, 1.41; 95% CI, 1.11-1.71; P = .001). In patients treated with CapeOx and lapatinib, PPIs had less effect on PFS (HR, 1.08; P = .54) and OS (HR, 1.26; P = .10); however, multivariate analysis in this group demonstrated a significant difference in OS (HR, 1.38; 95% CI, 1.06-1.66; P = .03). Conclusions and Relevance Proton pump inhibitors negatively effected capecitabine efficacy by possibly raising gastric pH levels, leading to altered dissolution and absorption. These results are consistent with previous erlotinib and sunitinib studies. Whether PPIs affected lapatinib is unclear given concurrent capecitabine. Given capecitabine’s prevalence in treatment breast cancer and colon cancer, further studies are under way. Trial Registration clinicaltrials.gov Identifier: NCT00680901

Does gastric acid suppression affect sunitinib efficacy in patients with advanced or metastatic renal cell cancer

Introduction: Renal cell cancer is a chemotherapy-insensitive cancer treated by vascular endothelial growth factor receptor antagonists. Recently, a question has arisen on whether there is an interaction between tyrosine kinase inhibitors, such as sunitinib, and acid suppressing agents. Methods: A retrospective chart review was conducted for patients at two tertiary care centers who received sunitinib between 1 January 2006 and 31 March 2013. Using electronic systems and a province-wide electronic health records database, medication dispensing records were obtained. A univariate Cox’s proportional hazard model determined if acid suppression had effects on progression-free survival and overall survival. Results: Of 383 patient charts reviewed, 231 were included in the study. Patients on intermittent acid suppression, lost to follow-up or received sunitinib for less than one week were excluded from the study. The median age of the study population was 65. Patients who received no acid suppression (n = 186) had a median progression-free survival of 23.6 weeks (95% CI, 19.0–31.9 weeks) and patients who received continuous acid suppression (n = 45) had a median progression-free survival of 18.9 weeks (95% CI, 11.0–23.7 p = 0.04). A median overall survival of 62.4 weeks (95% CI, 42.0–82.7 weeks) was observed in the group with no acid suppression, while a median overall survival of 40.9 weeks (95% CI, 26.1–74.4 weeks) was observed in the continuous acid suppression group (p = 0.02). Conclusion: There was a significant difference in progression-free survival and overall survival between the acid suppressed and no acid suppression groups. Further research is required to confirm this potential interaction.

Skeletal muscle density is an independent predictor of diffuse large B‐cell lymphoma outcomes treated with rituximab‐based chemoimmunotherapy

While much cancer research focuses on tumours and their microenvironment, malignancies cause widespread physiologic changes. Cancer and treatment‐related sarcopenia, measured with quantitative imaging or as a decrease in overall body mass, are indicative of poor prognosis in elderly diffuse large B‐cell lymphoma (DLBCL) patients, skeletal muscle radiodensity (SMD) may be a better prognostic marker. SMD, a measure of muscle radiation attenuation on CT imaging, is more prognostic than sarcopenia or International Prognostic Index (IPI) scores in follicular lymphoma and multiple solid organ malignancies. Low SMD appears to correlate with fat accumulation in muscle and is associated with inflammation. This study set out to examine SMDs prognostic ability in DLBCL.

MS4A4A: a novel cell surface marker for M2 macrophages and plasma cells

MS4A4A is a member of the membrane‐spanning, four domain family, subfamily A (MS4A) that includes CD20 (MS4A1), FcRβ (MS4A2) and Htm4 (MS4A3). Like the first three members of this family, transcription of MS4A4A appears to be limited to hematopoietic cells. To evaluate expression of the MS4A4A protein in hematopoietic cell lineages and subsets we generated monoclonal antibodies against extracellular epitopes for use in flow cytometry. In human peripheral blood we found that MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. In vitro differentiation of monocytes demonstrated that MS4A4A is expressed in immature but not activated dendritic cells, and in macrophages generated in the presence of interleukin‐4 (‘alternatively activated’ or M2 macrophages) but not by interferon‐γ and lipopolysaccharide (‘classically’ activated or M1 macrophages). MS4A4A was expressed in the U937 monocytic cell line only after differentiation. In normal bone marrow, MS4A4A was expressed in mature monocytes but was undetected, or detected at only a low level, in myeloid/monocytic precursors, as well as their malignant counterparts in patients with various subtypes of myeloid leukemia. Although MS4A4A was not expressed in healthy B lymphocytes, it was highly expressed in normal plasma cells, CD138+ cells from multiple myeloma patients, and bone marrow B cells from a patient with mantle cell lymphoma. These findings suggest immunotherapeutic potential for MS4A4A antibodies in targeting alternatively activated macrophages such as tumor‐associated macrophages, and in the treatment of multiple myeloma and mantle cell lymphoma.

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Malignant cells cultured in three-dimensional (3D) models have been found to be phenotypically and biochemically different from their counterparts cultured conventionally. Since most of these studies employed solid tumor types, how 3D culture affects multiple myeloma (MM) cells is not well understood. Here, we compared MM cells (U266 and RPMI8226) in a 3D culture model with those in conventional culture. While the conventionally cultured cells were present in single cells or small clusters, MM-3D cells grew in large spheroids. We discovered that STAT3 was the pathway that was more activated in 3D in both cell lines. The active form of STAT3 (phospho-STAT3 or pSTAT3), which was absent in MM cells cultured conventionally, became detectable after 1–2 days in 3D culture. This elevated pSTAT3 level was dependent on the 3D environment, since it disappeared after transferring to conventional culture. STAT3 inhibition using a pharmacological agent, Stattic, significantly decreased the cell viability of MM cells and sensitized them to bortezomib in 3D culture. Using an oligonucleotide array, we found that 3D culture significantly increased the expression of several known STAT3 downstream genes implicated in oncogenesis. Since most primary MM tumors are naturally STAT3-active, studies of MM in 3D culture can generate results that are more representative of the disease.

Abstract 4525: The impact of chemoimmunotherapy dose intensity in diffuse large b-cell lymphoma

Introduction Chemotherapy dose intensity (DI) impacts outcomes across tumor subtypes. In diffuse large B-cell lymphoma (DLBCL), DI played a large role prior to rituximab, but is still a subject of investigation. Research into intensifying treatment for poorer prognostic lymphoma subtypes has yielded dose-adjusted EPOCH-R where etoposide is added to standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Though, R-CHOP given every 14 vs. 21 days has not been found to improve survival, this study examines if delays in treatment or reductions in R-CHOP21 DI impact patient outcomes. Methods In this single institution review, DLBCL patients (pts) treated with first-line R-CHOP between 2004 and 2010 were included. After factoring in covariates such as revised International Prognostic Index (R-IPI) and gender, pts were compared by DI (ratio of actual total dose received vs. prescribed dose) of cyclophosphamide, doxorubicin, and treatment duration as a whole for their impact on progression-free (PFS) and overall survival (OS). Results Of 232 pts identified, 224 were included in final review. Median age and ECOG performance status was 62 years and 1, respectively. Majority had stage IV disease (46%). 124 patients were male with pts evenly distributed between R-IPI 0-1 (low, 28%), 2 (low-intermediate, 21%), 3 (high-intermediate, 26%), and 4-5 (high, 25%). A median DI of both cyclophosphamide and doxorubicin was 97%. 118 pts had >/ = 1 week delay during treatment duration. Cutpoint analysis found that DI was more important at 85% for both cyclophosphamide and doxorubicin. Median PFS for patients who received / = 85% cyclophosphamide DI was 27.2 vs. 55.0 months (hazard ratio [HR] 2.48, p = 0.03). Similarly, median OS was 41.8 months vs. not reached (HR 2.79 p = 0.02), respectively. PFS and OS for doxorubicin was similar at 27.6 vs. 53.7 months (HR 2.25, p = 0.04) and 40.9 months vs. not reached (HR 2.54, p = 0.02), respectively. Actual treatment durations that differed Conclusions While intensifying R-CHOP by shortening cycles to every 14 days has not been beneficial, this study suggests that delays and dose reductions in R-CHOP21 substantially impact outcomes. In doing so, it highlights that maintaining pts on schedule is important and that more accurate methods of determining appropriate chemotherapeutic doses may affect both survival and toxicity. Although it is our standard to only use growth factor support with delays it may be beneficial to starting all patients up front on growth factor support. Citation Format: Michael P. Chu, Sunita Ghosh, Andrew Belch, Neil S. Chua, Amelie Fontaine, Randeep Sangha, Robert Turner, Christopher Venner, Vickie Baracos, Michael B. Sawyer. The impact of chemoimmunotherapy dose intensity in diffuse large b-cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4525. doi:10.1158/1538-7445.AM2015-4525

Abstract 4628: Acid suppression therapy impairs sunitinib efficacy in renal cell cancer (RCC)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Sunitinib, a tyrosine kinase inhibitor (TKI), is standard therapy in metastatic RCC (mRCC). Developing side effects may be a marker of sufficient treatment doses. But as an oral drug, a potential issue is pH-dependent absorption. Recent evidence suggests TKI plasma levels can be altered by concomitant use of acid suppression therapy. Given gastroesophageal reflux disease (GERD) is a side effect of sunitinib and has high prevalence, this study aims to determine if coadministration of acid suppression therapy and sunitinib affected clinical outcomes in mRCC. Methods: mRCC patients treated with sunitinib between two cancer centres from 2007 to 2013 were retrospectively reviewed. Patients were excluded if they received ≤ 1 week of treatment. Aside from demographics and histologic subtype, Memorial Sloan Kettering Cancer Center (MSKCC) and Heng prognostic scores were calculated. Sunitinib dose reductions were noted to divide patients into those that received 50 mg, 37.5 mg, or 25 mg. Patients were identified as receiving acid suppression if their pharmacy records included a proton pump inhibitor (PPI). Patients were considered taking these medications concomitantly if dates for PPI overlapped their sunitinib prescription by ≥ 20% of treatment duration. Progression free survival (PFS) and overall survival (OS) were primary endpoints. Results: Of 383 mRCC patients identified, 379 were eligible for review. Median age was 62.7 years, 276 male, and 103 female. 286 had clear-cell histology and 93 non-clear cell. 47 patients were identified as continuously taking concomitant PPI, 146 intermittently, and 186 none at all. Median PFS for continuous, intermittent and no-PPI therapy groups were 4.3 months, 15.0 months, and 5.4 months, respectively (p<0.0001). OS for the three groups were 9.3 months, 34.3 months, and 12.1 months, respectively (p<0.0001). In multivariate analysis considering age, gender, histologic subtype, prior nephrectomy, and Heng score, Cox proportional hazards ratios for PFS and OS between continuous and no-PPI therapy groups were 2.08 (95% CI 1.43-3.05, p=0.0002) and 2.06 (95% CI 1.37-3.11, p=0.0006), respectively. Switching Heng for MSKCC score found similar hazards ratios of 2.06 (95% CI 1.41-3.01, p= 0.0002) and 2.09 (95% CI 1.39-3.14, p=0.0004), respectively. Our study found a trend to improved PFS and OS for those requiring a dose reduction (p=0.08). Effects of PPI therapy were still significant considering dose reductions. Conclusion: This large population based study demonstrates sunitinib outcomes are affected by gastric acidity. Results lend further support that PPI therapy can alter TKI absorption; particularly as the intermittent PPI therapy group performed best suggesting that these patients were likely placed on PPI due to sunitinib toxicity. Consequently, they were effectively dose reduced using PPIs rather than decreasing administration dosage. Citation Format: Michael P. Chu, Vincent Ha, Margaret Ngo, Sunita Ghosh, Carole R. Chambers, Michael B. Sawyer. Acid suppression therapy impairs sunitinib efficacy in renal cell cancer (RCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4628. doi:10.1158/1538-7445.AM2014-4628

620PDPROTON PUMP INHIBITOR (PPIS) THERAPY MAY IMPAIR CAPECITABINE (CAPE) EFFICACY IN METASTATIC GASTROESOPHAGEAL CANCER (GEC), RESULTS FROM THE TRIO-013/LOGIC TRIAL

ABSTRACT Aim: Cape is used to treat GI and other malignancies. Oral drug absorption often relies on pH-dependent solubility. Many GEC patients (pts) take PPIs for symptom control, which increases gastric pH and PPIs have been shown to impact other anti-cancer drug activity. TRIO-013 is a phase III randomized trial of cape + oxaliplatin (CapeOx) with lapatinib or placebo in HER2-positive metastatic GEC. Outcomes in both arms were comparable with modern GEC studies, but adding lapatinib did not improve progression free (PFS) or overall survival (OS). This ad hoc study analysed PPI effects in both arms. Methods: Study data were reviewed. PPI use was documented by medication records. Given reported improvement on survival in younger ( Results: 545 pts were randomized 1:1 between CapeOx + lapatinib or placebo. 229 pts received PPIs (42.0%), split evenly between arms. High cape dose intensity was maintained in both arms and yet CapeOX toxicity was lower than expected. In placebo arm, PPI pts had poorer median PFS, 4.2 vs. 5.7 mo (hazard ratio [HR] 1.55, 95% CI 1.29-1.81, p = 0.0008); and OS, 9.2 vs. 11.3 mo (HR 1.34, 95% CI 1.04-1.64, p = 0.04) vs. no-PPI pts. In multivariate analysis considering age, race, stage, and gender, PPI-pts had poorer PFS (HR 1.64, 95% CI 1.38-1.90, p = 0.0002) and OS (HR 1.39, 95% CI 1.09-1.69, p = 0.03). In the lapatinib arm, PPIs had less effect on PFS (HR 1.08, p = 0.54) and OS (HR 1.26, p = 0.10). However in multivariate analysis, there was a significant difference in OS (HR 1.36, 95% CI 1.06-1.66, p = 0.03). Conclusions: PPIs negatively impacted cape efficacy possibly by raising gastric pH leading to altered cape solubility and absorption. These results are consistent with erlotinib and sunitinib studies. Whether PPIs affected lapatinib is unclear given concurrent cape use. Given capes prevalence in breast and colon cancer, further studies are underway. Disclosure: Y.J. Huang and S. Khan-Wasti: is an employee of GSK. All other authors have declared no conflicts of interest.