Addition Of Monoclonal Antibody Research Articles

Innovative Approaches to the Management of Acute Lymphoblastic Leukemia Across the Age Spectrum.

Adults compose nearly half of all patients diagnosed with acute lymphoblastic leukemia (ALL) and historically have had poor survival compared with pediatric patients. Recently approved therapies, such as monoclonal antibodies, CAR T-cell constructs, and next-generation tyrosine kinase inhibitors, have improved survival in relapsed and refractory ALL, and studies are now examining incorporating these treatments and others into the upfront setting. In adolescent and young adult patients, use of pediatric-based regimens has already improved survival compared with historical controls, and the addition of monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may further enhance this survival benefit. In older adults, approaches have centered on minimizing conventional chemotherapy to decrease toxicity by incorporating monoclonal antibodies and other novel therapies to increase efficacy. With the addition of tyrosine kinase inhibitors to chemotherapy for patients with Philadelphia chromosome-positive ALL, survival of this once poor-prognosis ALL subtype now approaches or exceeds outcomes of other subtypes of adult ALL. Further refinements in the backbone treatment regimen and optimal consolidation approaches will likely improve survival further. Although allogeneic hematopoietic stem cell transplant was previously routinely used as consolidation for adults with ALL, incorporation of measurable residual disease and other risk stratification strategies has enabled better identification of patients who will benefit from allogeneic hematopoietic stem cell transplant. Ongoing clinical trials investigating these approaches will continue the evolution of treatment approaches for adults with ALL, with further improvement in outcomes anticipated.

Staffing and Capacity Planning for SARS-CoV-2 Monoclonal Antibody Infusion Facilities: A Performance Estimation Calculator Based on Discrete-Event Simulations.

BackgroundThe COVID-19 pandemic has significantly stressed healthcare systems. The addition of monoclonal antibody (mAb) infusions, which prevent severe disease and reduce hospitalizations, to the repertoire of COVID-19 countermeasures offers the opportunity to reduce system stress but requires strategic planning and use of novel approaches. Our objective was to develop a web-based decision-support tool to help existing and future mAb infusion facilities make better and more informed staffing and capacity decisions.Materials and MethodsUsing real-world observations from three medical centers operating with federal field team support, we developed a discrete-event simulation model and performed simulation experiments to assess performance of mAb infusion sites under different conditions.Results162,000 scenarios were evaluated by simulations. Our analyses revealed that it was more effective to add check-in staff than to add additional nurses for middle-to-large size sites with ≥2 infusion nurses; that scheduled appointments performed better than walk-ins when patient load was not high; and that reducing infusion time was particularly impactful when load on resources was only slightly above manageable levels.DiscussionPhysical capacity, check-in staff, and infusion time were as important as nurses for mAb sites. Health systems can effectively operate an infusion center under different conditions to provide mAb therapeutics even with relatively low investments in physical resources and staff.ConclusionSimulations of mAb infusion sites were used to create a capacity planning tool to optimize resource utility and allocation in constrained pandemic conditions, and more efficiently treat COVID-19 patients at existing and future mAb infusion sites.

Addition of Astatine-211-Labeled Anti-CD45 Antibody to TBI as Conditioning for DLA-Identical Marrow Transplantation: A Novel Strategy to Overcome Graft Rejection in a Canine Presensitization Model: “Radioimmunotherapy to Overcome Transfusion-Induced Sensitization”

In a canine model of presensitization using donor blood transfusions, 100% of historical control dogs receiving 9.2 Gy total body irradiation (TBI) conditioning before dog leukocyte antigen (DLA)-identical marrow grafts had graft rejection. In this presensitization model, we investigated whether the addition of monoclonal antibody (mAb)-based targeted radioimmunotherapy (RIT) with astatine-211 (211At) to TBI could overcome graft rejection. 211At is an alpha-particle-emitting isotope that has a short path length, very high energy, and a short t½ of 7.2 hours, which allowed targeting radiation to the T cells responsible for graft rejection. Normal canine recipients were given three preceding transfusions of unirradiated whole blood on days -24, -17, and -10 before transplant from their DLA-identical marrow donors. 211At-anti-CD45 mAb was administered on day -3, and TBI followed by marrow grafts on day 0. Six of the 7 dogs (86%) achieved sustained engraftment as assessed by 100% donor chimerism in mononuclear cells, granulocytes, and CD3+ T cells. One dog receiving the lowest CD34+ cell content (0.35×106 cells/kg) rejected the graft. There were no late rejections in dogs followed up to 1 year. Graft-versus-host disease was seen in one dog. 211At-anti-CD45 mAb in combination with TBI as conditioning was successful in abrogating graft rejection in 86% of dogs in this presensitization model. 211At-anti-CD45 mAb conditioning with TBI may serve as a novel promising strategy to overcome graft rejection in heavily transfused patients with red cell disorders.

Survival analysis of colorectal cancer patients treated with first-line modified FOLFOX6 with or without bolus fluorouracil.

35 Background: The combination of oxaliplatin, bolus 5-FU (b5FU), infusional 5-FU (5-FUCI), and leucovorin (LV) is the preferred first line treatment option for mCRC. This study evaluates the impact of b5FU on survival in first line therapy for mCRC patients treated with mFOLFOX6. Methods: This was a retrospective chart review of patients ≥ 18 years old with mCRC receiving palliative first line mFOLFOX6 chemotherapy with or without b5FU/ LV from January 1, 2010 through June 1, 2019 at Winship Cancer Institute, Emory University. Data collection included the following: demographics (age, race, gender), disease characteristics (tumor sidedness), microsatellite status, KRAS status, BRAF status, addition of monoclonal antibodies (bevacizumab, panitumumab), ECOG PS, grade 3/4 neutropenic events, addition of growth factors, and treatment delays. The primary endpoint was PFS. The multivariable Cox proportional hazards model for PFS and OS was performed with selected covariates of interest. Results: A total of 252 patients with mCRC met the inclusion criteria. Median follow-up time was 2.4 years. 161 patients (64%) received mFOLFOX6 with b5FU/LV and 91 patients (36%) received mFOLFOX6 with no b5FU/LV. More cycles were delivered in the b5FU group as compared to the non-b5FU group (mean, 4.8 v. 3.8 cycles, respectively; p < 0.001). There were no differences in grade 3 and 4 neutropenic events between groups. Growth factor usage was numerically higher in the bolus group though not significantly different (p = 0.06). No difference was observed in treatment delays between groups (p = 0.83). There was no statistical difference in PFS between treatment groups (1.1 years in the b5FU/LV group v. 0.8 years (95% CI, 0.6-1.0) in the no 5-FU/LV bolus group; p = 0.076). The median OS was 2.5 years in the b5FU/LV group compared to 1.8 years in the no b5FU/LV group (p = 0.012). On univariate analysis, tumor sidedness and performance status were significantly different between groups. On multivariate analysis, none of the variables were significantly different between groups. Conclusions: The omission of the b5FU/LV from mFOLFOX6 does not significantly impact PFS, toxicity or treatment delays. However, OS is significantly shorter when the b5FU/LV is omitted suggesting the clinical importance of maintaining bolus administration with 5-FUCI in the first line palliative treatment of mCRC.

Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5.

The triple-negative breast tumor boundary is made of aligned, linear collagen. The pro-oncogenic impact of linear collagen is well established; however, its mechanism of formation is unknown. An in vitro analogue of the tumor border is created by a co-culture of MDA-MB-231 cells, adipose derived stem cells, and dermal fibroblasts. Decellularization of this co-culture after seven days reveals an extracellular matrix that is linear in fashion, high in pro-oncogenic collagen type VI, and able to promote invasion of reseeded cells. Further investigation revealed linear collagen VI is produced by fibroblasts in response to a paracrine co-culture of adipose derived stem cells and MDA-MB-231, which together secrete high levels of the chemokine CCL5. The addition of monoclonal antibody against CCL5 to the co-culture results in an unorganized matrix with dramatically decreased collagen VI. Importantly, reseeded cells do not exhibit pro-oncogenic behavior. These data illustrate a cellular mechanism, which creates linear extracellular matrix (ECM) in vitro, and highlight a potential role of CCL5 for building striated tumor collagen in vivo.

Multiple Myeloma :Trends in Consulting Fees and Drug Utilization

Introduction Per the National Cancer Institute epidemiological data, the incidence of multiple myeloma has not changed significantly over the past decade. Mortality from myeloma has not changed significantly between 2007-2016 with an estimated 5-year survival of 55.2 % between 2009-2015. The treatment of multiple myeloma has improved significantly over the past decade with the approval of several new drugs. In the recent IFM trial, the 4-year overall survival in a select group of myeloma patients was 82% when treated with bortezomib, lenalidomide and dexamethasone followed by autologous stem cell transplant and maintenance therapy. These numbers may further improve with approval of monoclonal antibodies and several new drugs in clinical trials. The cost of healthcare has been growing consistently for the past several years. Per CMS data, healthcare spending grew 3.7% in 2017 reaching $3.5 trillion, or $10,739 per person. National health spending is projected to grow at a rate of 5.5% per year from 2018-2027 reaching nearly $6.0 trillion. Health share of the GDP is expected to rise from 17.9% to 19.4%. Pharmaceutical costs have been rising consistently over the past several years with cancer therapies being some of the costliest. Most new cancer therapy costs more than $100,000 per year with the triplet combinations for myeloma costing upwards of $200,000 per year. Methods Our goal was to evaluate the utilization of the newer drugs approved for myeloma by the Medicare population and assess the economic burden of growing drug prices on the health care system. We queried the national CMS database from 2013-2017 to obtain information on Medicare payments made, number of providers making claims and consulting fees for bortezomib, carfilzomib, daratumumab, elotuzumab, ixazomib, lenalidomide, panobinostat and pomalidomide. Results Between 2013-2017 there has been a significant increase in the annual Medicare payments made for myeloma drugs. The amount of payments has tripled between 2013-2017. The number of claims made and providers making those claims have increased. There has also been an exponential increase in consulting fees paid by various pharmaceutical companies to promote prescription of the aforementioned drugs. The amount of money paid in consultation has nearly quadrupled since 2013. Results are consolidated in Table 1 and Figure 1. Discussion This past decade has been an exciting period in cancer research and drug approvals, with myeloma being one of the many malignancies benefitting from this progress. This was made possible by the collaboration between pharmaceutical companies and academic institutions. With the need for continuous combination therapy in multiple myeloma along with increasing prices of existing drugs and high upfront market prices for newly approved drugs, there is significant financial burden placed on the healthcare system. Based on the published literature substitution of carfilzomib for bortezomib or addition of monoclonal antibodies in induction would double cost. Some of these drug approvals are based solely on surrogate endpoints of overall response rates and progression free survival benefit of few months. This is without proven overall survival data while harboring significant toxicity. Conclusion: With pharmaceutical companies spending millions of dollars for drug development there has been a trend towards higher drug pricing. These companies also pay large amounts of consulting fees to physicians dedicated to aggressively market these newly approved drugs which are priced higher than existing therapy. Some of the current cancer guidelines include authors who have financial conflicts of interest and receive consulting fees from pharmaceutical companies. It would be interesting to investigate the correlation between the consulting fees and its effect on prescription patterns. Even the cancer care guidelines do not consider the cost effectiveness of equally effective regimens. There has been a push from various pioneers in the field to incorporate value-based recommends into their guidelines. Given the trajectory of rising costs within our healthcare system, it is imperative for all physicians to be mindful of value-based care while seeking therapy options that provide true benefit to their vulnerable patient populations. Disclosures No relevant conflicts of interest to declare.

Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials

ABSTRACTIntroduction: The addition of monoclonal antibody (mAb) epidermal growth factor receptor (EGFR) inhibitors to classic chemotherapy doublet backbones has improved survival of metastatic colorectal cancer (mCRC). However, the role of triple-drug chemotherapy regimens in combination with an anti-EGFR mAb inhibitor is not yet clear.Areas covered: The activity of triple-drug chemotherapy regimens when combined with an anti-EGFR mAb in mCRC patients is examined. We describe the overall safety and tolerability profiles based on a literature review of all published phase I and II clinical trials in this setting. Drug exposure, tumor mutational status, and metastases resectability are discussed. A review of PubMed and abstracts of major oncology congresses from 2009 to 2018, with MeSH and full-text search terms for clinical trials of anti-EGFR for ‘metastatic’ or ‘advanced’ ‘colorectal cancer/adenocarcinoma’ was implemented. Only English language publications were included.Expert opinion: Efficacy data from phase II trials are promising, but the safety profiles are not as encouraging; the development of severe diarrhea and acneiform rash limit the drug exposure that is critical for improved outcomes. Phase II studies of these triplet chemotherapy/anti-EGFR mAb combinations have focused on conversion therapy in liver-limited disease or in the first-line setting in advanced disease. The identification of biomarkers of response and toxicity may support the use of personalized medicine and more precise design of phase III trials.Trial registration: ClinicalTrials.gov identifier: NCT03231722.Trial registration: ClinicalTrials.gov identifier: NCT02980510.Trial registration: ClinicalTrials.gov identifier: NCT01442935.Trial registration: ClinicalTrials.gov identifier: NCT02063529.Trial registration: ClinicalTrials.gov identifier: NCT01802645.Trial registration: ClinicalTrials.gov identifier: NCT02515734.

Are 4-Drug Regimens Here to Stay? Role in Induction and Salvage Therapies.

With 10 novel therapies approved across the decade, the multiple myeloma (MM) treatment paradigm continues to evolve in breadth and complexity. The current gestalt of the day has been the emergence of data to support 3-drug combinations over their 2-drug counterparts. Current guidelines and consensus statements support this approach. With the recent incorporation of monoclonal antibodies into the fray of myeloma therapy, we have begun to ask what the roles of 4-drug combinations are in both the upfront and the relapsed and refractory settings. The recent approval of daratumumab in combination with bortezomib, melphalan, and prednisone (Dara-VMP/ALCYONE) supports the role of quadruplet therapy in some patients with newly diagnosed disease who do not plan to proceed toward autologous transplant. There are a number of ongoing studies evaluating this type of strategy in both transplant-eligible and non-transplant-eligible newly diagnosed MM patients and in relapsed and refractory MM patients. Many of these seek to enhance standard-of-care treatments with the addition of monoclonal antibodies. We evaluate the historical and current data supporting the role of quadruplet- versus triplet-based therapies in MM.

Impact of Delayed Addition of Anti-EGFR Monoclonal Antibodies on the Outcome of First-Line Therapy in Metastatic Colorectal Cancer Patients: a Retrospective Registry-Based Analysis.

The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results. To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens. Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle. Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2months (95% confidence interval [CI] 10.9-13.5), and the median overall survival (OS) was 33.5months (95% CI 27.6-39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5-14.3) and 30.6months (95% CI 25.2-36.1) for cohort A, 9.7 (95% CI 9.1-10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8-13.2) and 37.9months (95% CI 28.6-47.3) for cohort C, respectively. Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

Therapeutic Options for "Slow go" Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is a disease of older patients, most of them suffering from significant comorbidities or functional limitations (so -called 'slow- go' patients). Unfortunately, clinical trials in chronic lymphocytic leukemia have until recently focused mainly on the subgroup of younger patients in good overall condition ('go- go' patients). Clinico- biological parameters, such as performance status, calculated creatinine clearance, the number and severity of comorbidities along with individual clinical assessment can help guide decisions relating to the objectives and ultimately the intensity of treatment. Two large randomized studies have recently demonstrated that the addition of monoclonal antibodies against CD20 (obinutuzumab, rituximab and ofatumumab) to chlorambucil in untreated 'slow- go' patients resulted in a significant increase in the number of complete remissions, progression-free survival and even overall survival (for obinutuzumab and rituximab) with an acceptable safety profile. Chemoimmunotherapy combining chlorambucil with anti-CD20 antibody is thus the new standard 1st line therapy in this group of patients. Treatment of relapsed/ refractory chronic lymphocytic leukemia in 'slow- go' patients is very difficult and specific data is sparse. In this indication, we have witnessed an extraordinary breakthrough by means of small oral inhibitors interfering with B -cell receptor downstream signaling pathways: ibrutinib, the Brutons tyrosine kinase inhibitor, and idelalisib, the inhibitor of phosphatidylinositol 3- kinase δ. Both drugs radically changed the approach to the treatment of relapsed/ refractory chronic lymphocytic leukemia; relatively mild toxicity also predetermines their use in elderly/ comorbid patients. Other treatment options for relapsed/ refractory chronic lymphocytic leukemia in this subgroup include alemtuzumab, ofatumumab, high-dose glucocorticoids + anti-CD20 antibodies, or bendamustine + rituximab regimen. This review summarizes current data regarding the treatment of elderly and comorbid patients with chronic lymphocytic leukemia.

Chemotherapy for Advanced-Stage Non-Small Cell Lung Cancer.

Use of platinum-based chemotherapy doublets is the standard of care for patients with advanced-stage non-small cell lung cancer, being associated with improved survival compared with best supportive care in fit patients with good performance status. Randomized studies showed that the addition of monoclonal antibodies against vascular endothelial growth factor receptor or epidermal growth factor receptor may increase the survival compared to chemotherapy alone. Patients with either advanced age or poor performance status can also benefit from chemotherapy. Docetaxel with or without ramucirumab, pemetrexed, and erlotinib are approved for previously treated patients. New treatment approaches are needed to improve the outcomes in this patient population.

Does the addition of targeted biological agents to first-line chemotherapy for advanced colorectal cancer increase complete response? A systematic review and meta-analysis.

The study assessed whether the addition of monoclonal antibodies (MoAbs) to first-line chemotherapy for advanced colorectal cancer (CRC) increases the complete response (CR) compared with controls. PubMed was reviewed for randomized clinical trials (RCTs) with approved MoAbs (bevacizumab, cetuximab and panitumumab) vs non-MoAbs as first-line therapy for patients with advanced CRC. The incidence and ratio of CR events were calculated in patients assigned to MoAbs compared with controls. A total of 3790 patients from nine RCTs were included for analysis. The overall incidence of CR in patients treated with MoAbs was 2.4% (95% CI: 1.7-3.3%) compared with 1.3% (95% CI: 0.8-2.2%) in controls. Comparison of the different types of MoAbs showed that the incidence of CR was higher for bevacizumab (3.1%, 95% CI: 2.1-4.3%) than for cetuximab (0.8%, 95% CI: 0.4-1.8%). The addition of MoAbs to chemotherapy significantly increased the OR of obtaining a CR compared with controls (OR=1.96; 95% CI: 1.12-3.46; P=0.02). No significant differences in the OR were observed in any of the subgroups. The CR is a rare event in advanced CRC; however, the addition of MoAbs to first-line chemotherapy significantly increases the curative rate of metastatic disease compared with controls.

Which is false: Oxaliplatin or fluoropyrimidine? An analysis of patients with KRAS wild‐type metastatic colorectal cancer treated with first‐line epidermal growth factor receptor monoclonal antibody

This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (hazard ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. A total of 1767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR = 0.88; 95% confidence interval (CI), 0.79-0.99; P = 0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14-1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR = 0.96; 95% CI, 0.85-1.08; P = 0.48). However, the differences in OS and PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P = 0.06; PFS, HR = 0.76; 95% CI, 0.65-0.86; P = 0.0002), and even OS was marginally significant, which was consistent with the subgroup analysis of cetuximab and panitumumab. EGFR mAbs combined with oxaliplatin and an infusional 5-FU regimen was associated with significantly improved RR, PFS and OS as first-line treatment in KRAS wild-type mCRC.

Is oxaliplatin a good partner for EGFR monoclonal antibodies as first-line treatment in KRAS wild-type metastatic colorectal cancer? A meta-analysis.

e14645 Background: This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Methods: Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (Hazard Ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. Results: A total of 1,767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR=0.88; 95% confidence interval (CI), 0.79 to 0.99; P=0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14 to 1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR=0.96; 95% CI, 0.85 to 1.08; P=0.48). However, the differences neither in OS nor in PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P=0.06; PFS, HR=0.76; 95% CI, 0.65 to 0.86; P=0.0002), and even OS was marginally significant. Conclusions: Oxaliplatin and infusional 5-FU regimen tends to be a better backbone combination with EGFR mAbs as first-line treatment in KRAS wild-type mCRC.

Effect of KRAS codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy. Results from a translational study of the AIO colorectal study group

BackgroundTo evaluate the value of KRAS codon 13 mutations in patients with advanced colorectal cancer (advanced CRC) treated with oxaliplatin and fluoropyrimidines.MethodsTumor specimens from 201 patients with advanced CRC from a randomized, phase III trial comparing oxaliplatin/5-FU vs. oxaliplatin/capecitabine were retrospectively analyzed for KRAS mutations. Mutation data were correlated to response data (Overall response rate, ORR), progression-free survival (PFS) and overall survival (OS).Results201 patients were analysed for KRAS mutation (61.2% males; mean age 64.2 ± 8.6 years). KRAS mutations were identified in 36.3% of tumors (28.8% in codon 12, 7.4% in codon 13). The ORR in codon 13 patients compared to codon 12 and wild type patients was significantly lower (p = 0.008). There was a tendency for a better overall survival in KRAS wild type patients compared to mutants (p = 0.085). PFS in all patients was not different in the three KRAS genetic groups (p = 0.72). However, we found a marked difference in PFS between patients with codon 12 and 13 mutant tumors treated with infusional 5-FU versus capecitabine based regimens.ConclusionsOur data suggest that the type of KRAS mutation may be of clinical relevance under oxaliplatin combination chemotherapies without the addition of monoclonal antibodies in particular when overall response rates are important.Trial registration number2002-04-017

Long-term follow-up (FU) of patients with durable complete response (DCR) after chemotherapy (CT) and trastuzumab (T) for HER2-altered (HER2+) metastatic breast cancer (MBC).

615 Background: Durable CT-induced complete response (DCR) of MBC is reported only anecdotally. The addition of monoclonal antibody T to conventional CT results in significant increase in response rates and prolonged survival for patients (pts) with HER2+ MBC. Though CRs are reported in most phase II and III clinical trials of CT+T, there is lack of data about clinical features and long-term outcome of these pts. Methods: We retrospectively reviewed all pts with HER2+ MBC treated at our Institutions with any CT+T and identified cases who achieved DCR. HER2 positivity was defined as 3+score at immunohistochemistry and/or amplification at FISH test. DCR was defined as a CR according to RECIST 1.0 criteria lasting >36 months. Results: We identified 13 pts with HER2+ MBC who met criteria for DCR following CT+T. Their characteristics are: median age: 56yrs (range 30-65), stage at diagnosis: M0 54%/M1 46%, histology: ductal 84%/mixed ductal-lobular 8%/unknown 8%, tumour grade: G3 54%/G2 23%/unknown 23%, oestrogen receptors (ER): neg 62%/pos 38%, sites of metastatic disease: liver only 54%/other visceral 15%/bone and soft tissues only 31%, chemotherapy regimen: taxane+carboplatin 54%/single-agent taxane 23%/docetaxel+lapatinib 15%, capecitabine 8%. Metastatic disease was biopsy-proven in 54% of pts. All pts received maintenance T. Median follow-up (FU) is 6.5 yrs (range 3.0-11.6). Median duration of T was 59 months (17-121). At database cut-off date 12 pts (92%) are alive. Five pts (38%) had disease relapse (3 on maintenance T, 2 after T discontinuation), 2 of whom had radical surgery. In 8 pts (62%) disease has not relapsed (characteristics: all 1st-line therapy, ER negative 75%, liver only distant disease 75%). Conclusions: This is the largest series to our knowledge analyzing long-term FU of HER2+ MBC pts with DCR following CT+T. DCR pts appear to have prolonged survival and a substantial subgroup of them have no further disease relapse. These pts are usually treated in the 1st-line setting, have more frequently ER-negative disease and liver-only metastases. We are currently investigating the molecular profile of this subset of pts.

Burkholderia pseudomallei-induced cell fusion in U937 macrophages can be inhibited by monoclonal antibodies against host cell surface molecules

Burkholderia pseudomallei induces the formation of multinucleated giant cells in cell monolayers. After infection of human macrophage-like U937 cells with B. pseudomallei, addition of monoclonal antibodies against integrin-associated protein (CD47), E-selectin (CD62E), a fusion regulatory protein (CD98), and E-cadherin (CD324) suppressed multinucleated giant cells in a concentration-dependent manner while monoclonal antibodies against other surface molecules did not inhibit fusion despite binding to the cell surface. Flow cytometric analysis showed increased expression of CD47 and CD98, but not CD62E and CD324, upon B. pseudomallei infection. Our data suggest the involvement of specific cellular factors in the process of B. pseudomallei-induced fusion.

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

Introduction: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity.Areas covered: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing.Expert opinion: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.

Clostridium difficile: moving beyond antimicrobial therapy

Background New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. Methods Objective To assess the ability of monoclonal antibodies directed against two toxins of C.difficile to prevent recurrence of disease. Design Randomized, double-blind, placebo-controlled study Setting 30 medical centers in the United States and Canada Subjects 200 subjects with diarrhea and a positive stool toxin assay for C.difficile being treating with metronidazole or vancomycin Intervention Antibodies administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight Outcomes The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. Results Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P < 0.001). The absolute risk reduction (ARR) was 16%, yielded a number needed to treat (NNT) of 5.5. The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P = 0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P = 0.09). Conclusions The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298 [ClinicalTrials.gov].)

The Factor VIIIa C2 Domain (Residues 2228–2240) Interacts with the Factor IXa Gla Domain in the Factor Xase Complex

Factor VIIIa functions as a cofactor for factor IXa in the phospholipid surface-dependent activation of factor X. Both the C2 domain of factor VIIIa and the Gla domain of factor IXa are involved in phospholipid binding and are required for the activation of factor X. In this study, we have examined the close relationship between these domains in the factor Xase complex. Enzyme-linked immunosorbent assay-based and surface plasmon resonance-based assays in the absence of phospholipid showed that Glu-Gly-Arg active site-modified factor IXa bound to immobilized recombinant C2 domain (rC2) dose-dependently (Kd = 108 nm). This binding ability was optimal under physiological conditions. A monoclonal antibody against the Gla domain of factor IXa inhibited binding by approximately 95%, and Gla domainless factor IXa failed to bind to rC2. The addition of monoclonal antibody or rC2 with factor VIIIa inhibited factor IXa-catalyzed factor X activation in the absence of phospholipid. Inhibition was not evident, however, in similar experiments in the absence of factor VIIIa, indicating that the C2 domain interacted with the Gla domain of factor IXa. A fragment designated C2-(2182-2259), derived from V8 protease-cleaved rC2, bound to Glu-Gly-Arg active site-modified factor IXa. Competitive assays, using overlapping synthetic peptides encompassing residues 2182-2259, demonstrated that peptide 2228-2240 significantly inhibited both this binding and factor Xa generation, independently of phospholipid. Our results indicated that residues 2228-2240 in the factor VIIIa C2 domain constitutes an interactive site for the Gla domain of factor IXa. The findings provide the first evidence for an essential role for this interaction in factor Xase assembly.