Second-line Treatment Regimens Research Articles

811P - Second-line palliative systemic treatment for synchronous metastatic esophagogastric cancer: A population-based study

BackgroundMetastatic esophagogastric cancer patients can be treated with paclitaxel/ramucirumab, or another taxane, or an irinotecan-containing regimen in second line. The aim of this study was to explore the real-world use of second-line palliative systemic treatment in esophagogastric cancer and to compare treatment regimens in terms of overall survival (OS) and time to failure of second-line treatment (TTF). MethodsSynchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010-2015) were selected from the nationwide Netherlands Cancer Registry. Systemic treatment was considered second line if a drug group was used that essentially differed from first-line treatment, irrespective of reason for switch of treatment. Thus, a switch from capecitabine/oxaliplatin (CapOx) to docetaxel was considered second line, while CapOx to i.v. 5-fluorouracil (5-FU)/oxaliplatin was not. OS and TTF were calculated from start of second-line treatment until date of death, or progression/failure of treatment, and analyzed using Kaplan Meier curves with logrank test. ResultsSecond-line systemic treatment was applied in 344 (20%) of the 1712 patients that received first-line systemic treatment in 2010-2015, of which 96% had adenocarcinoma and 4% squamous cell carcinoma. In the total cohort, 38 different second-line systemic treatment regimens were administered. Monotherapy with a taxane (31%), paclitaxel/ramucirumab (13%), carboplatin/paclitaxel (10%), trastuzumab-containing regimens (7%), fluoropyrimidine/platinum doublets (7%), irinotecan (6%), and 5-FU/irinotecan (6%) were most frequently used regimens. In patients that received second-line treatment, median OS was 5.2 (IQR 2.7, 8.6) and TTF 2.8 (IQR 1.5, 5.0) months. Median OS was 3.9 (IQR 2.3, 6.4) months in patients treated with second-line taxane monotherapy (n=108), and 5.4 (IQR 2.3, 9.7) months in patients treated with paclitaxel/ramucirumab (n=45, p=0.188). ConclusionsAccording to real-world evidence, 20% of synchronous metastatic esophagogastric cancer patients treated with first-line systemic therapy receive second-line systemic treatment, most frequently consisting of a taxane with or without ramucirumab. Legal entity responsible for the studyThe authors. FundingLilly. DisclosureR.H.A. Verhoeven: Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS. N. Haj Mohammad: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. J. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies: Servier; Advisory / Consultancy: Shire. T. Van Voorthuizen: Non-remunerated activity/ies: Astellas; Non-remunerated activity/ies: Ipsen; Non-remunerated activity/ies: Roche; Non-remunerated activity/ies: Bayer. M. van Oijen: Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Roche. H.W.M. van Laarhoven: Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Treatment of Helicobacter pylori in Special Patient Populations.

Helicobacter pylori infection can lead to gastritis, gastric and duodenal ulcers, and gastric cancer. Consequently, complete eradication is the goal of therapy. First-line therapy for H.pylori infection includes clarithromycin triple therapy (clarithromycin, proton pump inhibitor [PPI], and amoxicillin or metronidazole), bismuth quadruple therapy (bismuth salt, PPI, tetracycline, and metronidazole or amoxicillin), or concomitant therapy (clarithromycin, PPI, amoxicillin, and metronidazole). However, many patients have relative contraindications to the antibiotics included in these regimens, making therapy selection difficult. Furthermore, failure of initial therapy makes selection of second-line therapy challenging due to concerns for potential resistance to agents included in the initial regimen. This review discusses H.pylori microbiology, including antibiotic resistance, and summarizes the existing evidence for first- and second-line treatment regimens that may be considered for special populations such as patients with penicillin allergies, patients with or at risk for QTc-interval prolongation, and patients who are pregnant, breastfeeding, or elderly.

Gemcitabine, cisplatin, prednisone, and thalidomide for relapse and refractory peripheral T-cell lymphoma: a retrospective study from China.

BackgroundPeripheral T-cell lymphoma (PTCL) is often prone to relapse and progression even after formal first-line treatment, and there is no standard regimen for second-line treatment. What is more, the activity of thalidomide against this type of lymphoma is unknown.PurposeThe objective of this study was to evaluate the efficacy and safety of GDPT regimen in the treatment of relapsed/refractory peripheral T-cell lymphoma.Patients and methodsIn this retrospective study, gemcitabine, cisplatin, prednisone, and thalidomide (GDPT) combination regimen was used as salvage protocol for PTCL that failed in first-line treatment for 29 patients and it was scheduled to give 6 cycles of GDPT therapy in order to better evaluate the efficacy unless there was evidence of disease progression, unacceptable toxicities, or refusal by the patient.ResultsAfter a total of 106 cycles of GDPT regimen were administered, the result showed that the disease control rate (DCR) achieved 82.8% and overall response rate (ORR) reached 69.0% with 34.5% complete remission (CR) and 34.5% partial remission (PR). The median progression-free survival (PFS) was 10.0 months (95% CI 6.6–13.4) and median OS was 28.0 months (95% CI 19.2–36.8). And the 1-year PFS rate and 1-year OS rate were 43.6% and 64.6%, respectively. Both hematologic and non-hematologic toxicities were moderate and well tolerated. There was no treatment-related death.ConclusionThalidomide in combination with gemcitabine, cisplatin, prednisone regimen is a new promising approach to treating patients with relapse and refractory PTCL.

Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus

IntroductionMetastatic renal cell cancer (mRCC) patients have a median overall survival (mOS) of approximately 28 months. Until recently, mammalian target of rapamycin (mTOR) inhibition with everolimus was the standard second-line treatment regimen for mRCC patients, improving median progression-free survival (mPFS). Treatment with everolimus supports the expansion of immunosuppressive regulatory T cells (Tregs), which exert a negative effect on antitumor immune responses. In a phase 1 dose-escalation study, we have recently demonstrated that a low dose of 50 mg oral cyclophosphamide once daily can be safely combined with everolimus in mRCC patients and prevents the everolimus-induced increase in Tregs.Materials and methodsIn a multicenter phase 2 study, performed in patients with mRCC not amenable to or progressive on a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor (TKI) containing treatment regimen, we assessed whether the addition of this metronomic dosing schedule of cyclophosphamide to therapy with everolimus could result in an improvement of progression-free survival (PFS) after 4 months of treatment.ResultsThough results from this study confirmed that combination treatment effectively lowered circulating levels of Tregs, addition of cyclophosphamide did not improve the PFS rate at 4 months. For this reason, the study was abrogated at the predefined interim analysis.ConclusionAlthough the comprehensive immunomonitoring analysis performed in this study provides relevant information for the design of future immunotherapeutic approaches, the addition of metronomic cyclophosphamide to mRCC patients receiving everolimus cannot be recommended.

Antituberculosis Drugs Resistance and Treatment Outcomes Among Retreatment Patients in Guinea: A Five-Year Retrospective Cohort Study

Tuberculosis (TB) is a global outbreak whose drug resistance is a constant threat. This study aimed at describing anti-TB drugs resistance and treatment outcomes among retreatment TB patients in Guinea between 2008 and 2012. We conducted a retrospective cohort study with a sample of 558 patients aged of at least 10, who were admitted for TB retreatment and who were tested for anti-TB drugs susceptibility during the study period. Overall, 3187 retreatment TB patients were recorded from January 1, 2008 to December 31, 2012 in Guinea, of which 558 (17.5%) performed susceptibility testing to anti-TB drugs. We found overall resistance in 417 cases (74.7%) including 356 (85.4%) of multidrug resistance (MDR), 29 (6.9%) of monoresistance (isoniazid 2.9%, streptomycin 2.9%, rifampicin 0.9%, ethambutol 0.2%) and 32 (7.7% of polydrug resistance (isoniazid + streptomycin 4.3%, rifampicin + streptomycin 1.4%, isoniazid + ethambutol + streptomycin 1.0%, rifampicin + ethambutol + streptomycin 1.0%). Most of the patients (84.6%) with anti-TB drugs resistance were under 45 and labourers were mostly represented (27.8%) including drivers in majority (37.9%). MDR-TB incidence rate increased by 12.2% between 2008 (65.6%) and 2012 (77.8%), and the annual cure rate decreased gradually from 60.0% in 2009 to 45.7% in 2012. Among MDR-TB patients (n= 356), only 112 (31.5%) benefited from second-line treatment regimen, of which, 51.7% were cured, 6.3% completed treatment, 24.1% died, 6.3% were lost to follow-up and 11.6% were not evaluated. The cure rate was higher in HIV-negative patients (55.3%) than in those who were HIV-positive (35.3%) and the death rate was the highest (41.2%) in HIV-positive patients. Overall, treatment success rate was 58.0%. This study revealed a low rate of performing drug susceptibility testing, the gradual increase of the incidence of MDR-TB each year and the gradual decrease of cure rate from year to year. Besides, anti-TB drugs resistance concerned mostly drivers in our context. Prospective studies are needed for a deep understanding of the factors associated with these persistent challenges.

Twenty years of rifampicin resistance surveillance in Bangladesh: periodic vs. continuous monitoring.

To analyse 20 years of tuberculosis (TB) drug resistance surveillance, comparing conventional periodic random drug resistance surveys with continuous monitoring, in Damien Foundation-supported districts of Bangladesh. Retrospective study of data on TB drug resistance from five periodic surveys among newly registered patients vs. continuous monitoring of retreatment patients from 1996 to 2016. Periodic surveys and continuous monitoring showed similar trends in rifampicin (RMP) resistance; with all smear-positives registered as denominator, prevalence in new cases was found to be at approximately the same level as incidence in retreatment cases. Changes in trends observed using continuous monitoring preceded those detected in periodic surveys by a few years. The accurate interpretation of trend changes requires detailed knowledge of changes in treatment regimens, referral criteria, testing methods and operational factors. Low rates of resistance to RMP, isoniazid and the fluoroquinolones were maintained over the two decades, indicating excellent TB programme performance, including highly active standard first- and second-line treatment regimens. Continuous monitoring is feasible, but requires rigorous application of referral guidelines and data maintenance. Contrary to random surveys, continuous monitoring provides early indications of programme performance, essential for individual patient management, and is more efficient and cost-effective.

Abstract 4141: EWS-FLI regulates mitotic kinesins in Ewing sarcoma family of tumors

Abstract The current situation faced by children and young adults diagnosed with Ewing sarcoma family of tumors (ESFT), the second most common pediatric bone malignancy in the U.S., is bleak. Although the oncogenic phenotype and master regulator of ESFT is driven by an underlying pathognomonic chromosomal translocation (EWS-Ets), therapeutic targeting of this molecular Achilles' heel has been notoriously challenging. For pediatric patients with progressive (refractory) or recurrent ESFT, the overall survival continues to remain poor. To date, no established second-line (salvage) treatment regimen exists for these pediatric sarcoma patients. The failure to improve the overall survival for these patients highlights the need to better understand the molecular points of vulnerability of these diseases, which can be translated into novel treatment strategies. To address this challenge, we have identified KIF11, KIF15 and TPX2, part of the cellular mitotic machinery, as druggable downstream targets of EWS-Ets in ESFT. Our recent studies sought to identify drugs that reverse a gene expression profile similar to the pattern obtained by the silencing of EWS/FLI1 via RNAi approaches (siEWS/FLI1) (Pessetto et al., 2017). This work identified KIF15 (gene rank #1, p=0.00005) and its potential binding partner TPX2 (gene rank #14, p=0.01830) as significantly downregulated genes within this signature. These genes encode KIF15 and TPX2, which are postulated to play a compensatory role in resistance to KIF11 inhibitors in the clinic. We found that KIF11, KIF15 and TPX2 proteins are abundantly expressed in ESFT cell lines as compared with benign controls (7.7-, 5.5-, and 8.5-fold, respectively). We also discovered that RNAi-mediated downregulation of KIF15 increases sensitivity of ESFT cell lines to treatment with KIF11 inhibitors (KIF11i). We have for the first time, shown that silencing EWS-FLI1 (the most common EWS-Ets translocation), in ESFT cells decreases KIF11, KIF15 and TPX2 promoter activity by 99%, 97%, and 87%, respectively. We propose that this activity is a function of EWS-FLI1-mediated E2Fs; EWS-FLI1 disrupts the E2F-regulated proliferation balance such that the suppressive E2F4 transcription factor is displaced by the activating E2F3. Our data show that E2F3 is enriched at KIF15 (8.9-fold) and TPX2 (2.9-fold) promoters. Further, when EWS-FLI1 is siRNA depleted, enrichment at the KIF15 and TPX2 promoters is lost (3.9-fold or 2.6-fold decrease, respectively). These data strongly suggest that aberrant expression of the genes encoding these proteins is controlled by oncogenic EWS-FLI1. Taken together, we have demonstrated that KIF11, KIF15 and TPX2 are aberrantly expressed in ESFT and are putative therapeutic targets. Our ongoing work includes development of KIF11/KIF11/TPX2 axis-targeting compounds toward the goal of implementing pharmacologic approaches to provide new therapies for children diagnosed with these deadly diseases. Citation Format: Rebecca J. Wates, Yan Ma, Jennifer Crow, Glenson Samuel, Andrew K. Godwin. EWS-FLI regulates mitotic kinesins in Ewing sarcoma family of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4141.

Economic Evaluation of Dapagliflozin vs. Other Oral Hypoglycemic Drugs in China via Idealized Model

Objective: To analyze and compare economic values of cardiovascular benefits from dapagliflozin to the ones from other oral hypoglycemic drugs in China using the idealized model. Methods: An idealized model for type 2 diabetes in China with an assumed number of cases (n=2000) was established. Half of cases (Dapa group; n=1000) are treated with 10 mg of dapagliflozin and another half (Other hypoglycemic drug group; n=1000) are treated with other oral hypoglycemic drugs as monotherapy. Cardiovascular benefits resulting from the CVD-REAL study were used as the evaluation criteria for predictions of cardiovascular events. Information about the direct economic loss brought by cardiovascular events reported in relevant literatures from 20to the present (Data source including the Web of Science, PubMed, Google scholar, Wanfangdata, CNKI and Cqvip) was collected as the standard for cost calculation. Results: Compared with other oral hypoglycemic drugs, the application of dapagliflozin allows each type 2 diabetic patient to save an average of 14279.57 CNY on cardiovascular events annually in China. The annual per capita treatment cost for patients receiving dapagliflozin in the control of blood glucose and cardiovascular events was 66.98% of that of patients in the first and second-line treatment regimens, and was 65.83% of that of patients in the second-line treatment regimen. Conclusions: Based on this idealized model, dapagliflozin is expected to save 33.02% of annual cost on hyperglycemia control and cardiovascular complications in patients with type 2 diabetes compared to patients treated with the first and second-line treatment regimens and to save 34.17% of annual cost compared to patients treated with the second-line treatment regimen in China. Disclosure J. Zheng: None. L. Long: Employee; Self; AstraZeneca. Z. Ye: Employee; Self; AstraZeneca. L. Chen: None.

Severe adverse events impact overall survival and costs in elderly patients with advanced non-small cell lung cancer on second-line therapy

ObjectivesElderly patients with advanced non-small lung cancer (aNSCLC) represent a high-risk patient population due to disease burden, comorbidities, and performance status, particularly after progressing on first-line therapy. Among elderly patients who receive second-line therapy, treatment related toxicities can have substantial impact on both clinical and economic outcomes. This study assessed the impact of severe adverse events (AEs) during second-line therapy on overall survival (OS) and all-cause heathcare costs in elderly with aNSCLC. Materials and methodsPatients with aNSCLC aged ≥65 years who initiated second-line chemotherapy/targeted therapy were identified in the SEER-Medicare database (2007–2011). Fifty-seven AEs were identified by literature review and consultation with two oncologists. Severe AEs were defined as AEs that required a hospitalization and were operationalized based on AE diagnosis(es) recorded during hospitalizations. OS post-second-line initiation and healthcare costs during second-line were compared between patients with and without severe AEs. ResultsAmong 3967 patients initiating second-line therapy, 1624 (41%) had ≥1 severe AE, where hypertension (26%), anemia (24%), and pneumonia (23%) were most commonly reported. Patients with and without severe AEs had similar demographic and cancer characteristics at diagnosis and similar second-line treatment regimens, but patients with severe AEs had more comorbidities at second-line initiation. Median OS was lower in patients with versus without severe AEs (6 vs. 11 months). After multivariate adjustment, hazard of death was more than twice higher in patients with versus without severe AEs (adjusted hazard ratio [HR] 2.31, 95% CI 2.16–2.47). Healthcare costs were more than twice higher in patients with versus without severe AEs ($16,135 vs. $7559 per-patient-per-month). ConclusionSevere AEs among elderly patients with aNSCLC treated with second-line chemotherapy/targeted therapy were found to be associated with decreased OS and increased healthcare costs. Results suggest a potential link between severe AEs in second-line treated aNSCLC elderly and patient survival and economic burden to the healthcare system.

Clinical outcome of multidrug-resistant tuberculosis patients receiving standardized second-line treatment regimen in China

ObjectivesThe aim of this study was to retrospectively analyze the clinical outcome and the risk factors associated with poor outcome of MDR-TB patients receiving standardized second-line treatment regimen in China. MethodsBetween January 2008 and December 2010, a total of 12,100 clinical diagnosed TB cases at high risk of drug-resistant TB (DR-TB) were enrolled in this study. Routine follow-up tests were conducted every month during the 6-month intensive phase, and every two months during the 18-month continuation phase. ResultsOn the basis of phenotypical drug susceptibility test (DST) results, 2322 MDR-TB patients were confirmed, of which 1542 further received standardized second-line anti-TB regimen. The treatment success rate was 47.6% (734/1542): 688 patients (44.6%) were cured and 46 (3.0%) completed treatment. The percentage of cases with favorable outcome in previously untreated patients (57.6%) was significantly higher than that in treatment-experienced patients (46.1%, OR: 1.58, 95% CI: 1.17–2.14). In addition, a significant lower percentage of male MDR-TB cases with favorable outcome (45.8%) was observed using female MDR-TB cases as a reference (52.0%, OR: 1.31, 95% CI: 1.03–1.60). The proportion of MDR-TB cases with favorable outcome was significantly decreased in older age groups. ConclusionsIn conclusion, our data demonstrate that less than half of these patients receiving standardized second-line treatment regimen meet the definition of successful treatment during a 3-year period in China. More attention should be paid to the MDR-TB population at high-risk of poor clinical outcome, including male, elderly age, and those who have received prior treatment.

Pharmacotherapeutic Management of Pediatric Lymphoma.

Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) comprise approximately 15% of all childhood malignancies. Cure rates for both lymphoma entities have evolved tremendously during the last couple of decades, raising the 5-year survival rates to almost 100% for HL and to 85% for NHL. The mainstay therapy for both malignancies is still chemotherapy-with different regimens recommended for different types of disease. In HL, combined modality treatment, i.e., chemotherapy followed by radiotherapy, has long been the standard regimen. In order to reduce long-term side effects, such as second malignancies, most major pediatric HL consortia have studied response-based radiotherapy reduction strategies over the last 3 decades. For recurrent disease, high-dose chemotherapy followed by an autologous or an allogeneic hematopoietic stem-cell transplant is an option. No targeted agents have yet gained regulatory approval for use in pediatric patients with lymphoma. For adult lymphoma patients, the CD20 antibody rituximab and the CD30 antibody-drug conjugate brentuximab vedotin are targeted agents used regularly in first- and second-line treatment regimens. More recently, immune checkpoint inhibitors, phosphatidyl-inositol-3-kinase inhibitors, and Bruton's tyrosine kinase inhibitors appear to be very promising new treatment options in adult lymphoma. Here, we discuss the current experience with these types of agents in pediatric lymphoma patients.

Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh.

ABSTRACTPyrazinamide (PZA) is a frontline antituberculosis (anti-TB) drug used in both first- and second-line treatment regimens. However, due to complex laboratory requirements, the PZA susceptibility test is rarely performed, leading to a scarcity of data on susceptibility to PZA. Bangladesh is a country with a burden of high rates of both TB and multidrug-resistant TB (MDR-TB), but to our knowledge, published data on rates of PZA susceptibility (PZAs), especially among MDR-TB patients, are limited. We aimed to analyze the PZA susceptibility patterns of Mycobacterium tuberculosis isolates from MDR-TB patients and to correlate the pncA mutation with PZA resistance in Bangladesh. A total of 169 confirmed MDR M. tuberculosis isolates from a pool of specimens collected in a nationwide surveillance study were included in this analysis. All the isolates were tested for phenotypic PZA susceptibility in Bactec mycobacterial growth indicator tube (MGIT) culture medium, and the pncA gene was sequenced. We also correlated different types of clinical information and treatment outcomes with PZA susceptibility. We found that 45% of isolates were phenotypically PZA resistant. Sequencing of the pncA gene revealed a high concordance (82.2%) between the pncA gene sequence and the phenotypic assay results. A total of 64 different mutations were found, and 9 isolates harbored multiple mutations. We detected 27 new pncA mutations. We did not find any significant correlation between the different clinical categories, the genetic lineage, or treatment outcome group and PZA susceptibility. Considering the turnaround time, sequencing would be the more feasible option to determine PZA susceptibility, and further studies to investigate the MIC of PZA should be conducted to determine an effective dose of the drug.

Macular Edema in Uveitis - Steroids or VEGF Inhibitors?

Macular edema in uveitis patients is certainly the most frequent complication leading to a permanent and irreversible reduction in vision during the course of the disease. Thanks to optical coherence tomography (OCT) technology and fluorescein angiography (FAG), significantly more macular edemas are detected. Macular edema can be found in various uveitis varieties and can show different clinical patterns. All macular edema should be treated. Macular edema with active inflammation usually reacts very well to general uveitis treatment. In the case of eyes without visible inflammation, however, the response to such therapy is usually less effective. According to the latest treatment recommendations, dexamethasone implants should be used as the first intravitreal therapy. Vascular endothelial growth factor inhibitors (VEGF inhibitors) are second-line treatment regimens. The choice of therapy is, therefore, primarily based on the degree of inflammation and the individual complications, such as glaucoma, lens situation or previous increase in IOP after steroid administration. These individual complications may allow using VEGF inhibitors as first line treatment. An improvement in the macular edema can be achieved with both groups of active substances.

Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial

Weekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer. We did a randomised, open-label, non-inferiority, phase 3 trial at 72 institutions in Japan. Patients aged 20 years or older with advanced gastric adenocarcinoma refractory to a fluoropyrimidine-containing first-line chemotherapy regimen, with progressive disease or a relapse fewer than 24 weeks after the final dose of adjuvant chemotherapy were randomly assigned (1:1:1) to receive intravenous nab-paclitaxel (260 mg/m2) every 3 weeks (on day 1 of a 21-day cycle), weekly nab-paclitaxel (100 mg/m2, on days 1, 8, and 15 of a 28-day cycle), or weekly solvent-based paclitaxel (80 mg/m2, on days 1, 8, and 15 of a 28-day cycle). Randomisation was done with the minimisation method, with stratification for previous use of docetaxel, presence of peritoneal metastases, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, with a non-inferiority margin of 1·25 for the hazard ratio. This trial is registered with Japan Pharmaceutical Information Center Clinical Trial, number JapicCTI-132059, and has been completed. Between March 13, 2013, and May 14, 2015, 741 patients were randomly assigned to nab-paclitaxel every 3 weeks (n=247), weekly nab-paclitaxel (n=246), or weekly solvent-based paclitaxel (n=248). Median follow-up for overall survival was 9·99 months (IQR 6·05-15·05). Median overall survival was 10·3 months (95% CI 8·7-11·4) in the group that received in the nab-paclitaxel every 3 weeks, 11·1 months (9·9-13·0) in the weekly nab-paclitaxel group, and 10·9 months (9·4-11·8) in the weekly solvent-based paclitaxel group. Weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0·97, 97·5% CI 0·76-1·23; non-inferiority one-sided p=0·0085), whereas nab-paclitaxel every 3 weeks was not non-inferior to solvent-based paclitaxel (1·06, 95% CI 0·87-1·31; non-inferiority one-sided p=0·062). The main grade 3 or worse adverse drug reactions were neutropenia (158 [65%] of 244 patients in the group that received nab-paclitaxel every 3 weeks vs 99 [41%] of 241 patients in the weekly nab-paclitaxel group vs 71 [29%] of 243 patients in the weekly solvent-based paclitaxel group), peripheral sensory neuropathy (49 [20%] vs six [2%] vs six [2%]), and febrile neutropenia (30 [12%] vs seven [3%] vs two [1%]). Hypersensitivity reactions were less frequent with nab-paclitaxel every 3 weeks (two [1%] patients) and weekly nab-paclitaxel (three [1%] patients) than with weekly solvent-based paclitaxel (13 [5%] patients). Four treatment-related deaths were reported overall (pneumonia in one patient in the group that received nab-paclitaxel every 3 weeks, febrile neutropenia/pneumonia in one patient, and septic shock in one patient in the weekly nab-paclitaxel group, and respiratory disease/interstitial lung disease in one patient in the weekly solvent-based paclitaxel group). As the trial showed that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel in terms of overall survival, the advantages of the nab-paclitaxel formulation make it a potential regimen for second-line treatment of gastric cancer. Taiho Pharmaceutical.

Retreatment Patterns and Outcomes Among Patients with Relapsed Multiple Myeloma

Introduction: Clinical trials have suggested that retreatment with multiple myeloma (MM) therapy provides clinical benefit (Mohty 2012), however, little is known about real-world utilization and outcomes of retreatment. Information from this analysis will help to better understand the real-world impact of retreatment for management of first MM relapse.Methods: A retrospective claims analysis of commercial and Medicare Advantage patients aged 18 years in the Optum Research Database. To be included, patients had to have ≥ 2 medical claims ≥ 30 days apart with an MM diagnoses (ICD-9 =203.00) between 01 Jan 2009 and 31 Dec 2013 (study period); ≥ 2 lines of therapy and no evidence of hematopoietic cell transplant during the study period and data available for 1 year prior to index date and ≥ 6 months post index date. The date of the first claim of an NCCN recommended MM treatment during the study period was considered the index date. All MM treatments identified < 30 days of the index date were considered part of first line of therapy. An algorithm was developed for identifying subsequent lines of therapy. A new line of therapy was identified when there was a switch to a new agent < 180 days of discontinuation of the prior line of therapy or retreatment with the same treatment ≥ 180 days of discontinuation with previously used agents. Additionally, patients had to be treated for relapse MM defined according to lines of therapy when 1) there was an active line of therapy ≥ 60 days long and there was a gap of ≥ 180 days from the end of the line of active therapy to the start of the next line of active therapy or 2) there was a line of therapy ≥ 180 days long and a different treatment was started, with or without a 180-day gap between discontinuation of the prior line and start of the subsequent line of therapy . The data evaluated in the analysis included baseline demographics, Quan-Charlson comorbidity scores, line of therapy, and clinical outcomes, including treatment duration and overall survival. Data were analyzed using chi-square and t-tests to compare patients with retreatment vs. treatment with a different regimen for first relapse MM (i.e. second-line therapy).Results: A total of 252 patients (mean age: 70 yrs; 48% male) were identified as having second-line treatment for relapse MM; 90 patients (35.7%) were retreated with the same regimen and 162 (64.3%) patients were treated with a different regimen. Mean Quan-Charlson comorbidity scores were equal between the two groups (p=0.585). Among the retreatment group, 48.2% were treated with monotherapy for first-line, compared to 25.2% of the different regimen group (p-value < 0.001). Dexamethasone (dex) monotherapy, bortezomib plus dex, and lenalidomide plus dex were common regimens used in retreatment, see Figure 1. Lenalidomide plus dex was also commonly used as a different regimen for second-line treatment. Additionally, dex monotherapy was significantly less likely to be used as a new therapy compared to being used as retreatment for second-line therapy (p<0.05). Conversely, bortezomib plus lenalidomide plus dex was significantly more likely to be used as a new therapy compared to being used as retreatment for second-line treatment (p<0.05). The mean length of relapse line was 161 days in the retreatment group versus 212 days in the different regimen group (p-value 0.067). The incidence rate of death was 13 events (1.43 events per 10,000 person-days of follow-up) in the retreatment group versus 22 events (1.51 events per 10,000) in the different regimen group (p=0.895).Figure 1: Second-line Treatment Regimens among Patients who Received the Same Regimen (Retreatment) vs. a Different Regimen for the Treatment of First-Relapse MM\\sConclusions: In this analysis, approximately one-third of patients were retreated with the same treatments in first-line and second-line of therapy. Patients who were retreated with the same regimen tended to have shorter duration of second-line therapy. However, risk of death did not appear to differ between the two groups. This real-world analysis suggests that retreatment in second-line may affect the time to next treatment, but may not negatively impact the overall risk of death.Reference: Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and 'retreatment' approaches in the era of novel agents. Leukemia 2012; 26: 73-85. [Display omitted] DisclosuresLal:Optum: Employment. Chastek:Optum: Employment. Blauer-Peterson:Optum: Employment. Maiese:Janssen Scientific Affairs, LLC: Employment.

Integrating HIV-1 Pharmacogenomics into the Universal Coverage Health- Care System in Thailand: From Scientific Evidence to Policy

In addition to the direct effect adverse drug reactions (ADRs) have on increased morbidity and mortality, their indirect impact on antiretroviral adherence and subsequent drug resistance is a major problem for HIV health services in a resource-limited setting. ADR is a major factor contributing to the interruption of antiretroviral intake in patients with good adherence to highly active antiretroviral therapy (ART). Antiretroviral non-adherence results in viral drug resistance, which derails antiretroviral effectiveness and causes higher costs for complicated treatment regimens; a burden that is more significant in resource-limited countries. Moreover, the costlier second-line treatment regimens (2-9 times higher in price than first-line regimens) are unaffordable for individual or government agencies in developing countries. This situation forms the basis for development of a pharmacogenomics initiative in Thailand, with special focus on HIV. The first target is to improve the prescription algorithm by personalizing the initial drug regimen; increasing the regimens efficacy; and simultaneously avoiding ADR. The ultimate aim of this initiative is to minimize the cost of ART for the public health system by incorporating research findings. Integrating HIV-1 pharmacogenetic screening tests into Thailand’s universal health-care system is a major challenge for the future and, if successfully implemented, they will eventually benefit both individuals and society.

Real-world treatment patterns, comorbidities, and disease-related complications in patients with multiple myeloma in the United States

Objectives:To describe multiple myeloma (MM) treatment patterns and comorbidities over time in the US.Research design and methods:Study patients were newly diagnosed with MM (ICD-9-CM 203.0x) between 1 July 2006 and 31 March 2014 and had ≥6 months of data prior to the initial MM diagnosis in MarketScan Research Databases. Patients were followed until inpatient death or the end of data. First-line, second-line, and third-line treatment regimens were identified following diagnosis and were described over time based upon the start date of the first line of therapy (2006–2007, 2008–2014, 2013–2014). Comorbid conditions and disease-related complications were examined during the 6 months prior to the line of therapy start dates.Results:A total of 24,507 MM patients were examined (mean age: 65.2 years, 54.1% male, mean follow-up: 23 months, 16.2% transplant). Across all lines of therapy, the proportion of patients on thalidomide-based regimens decreased over time. In the first line, bortezomib-based regimens became more common from 2006–2007 to 2008–2014 (2006–2007: 17.0%, 2008–2014: 44.3%, 2013–2014: 49.4%). In the second line, lenalidomide- and bortezomib-based regimens were the most common (2013–2014: lenalidomide: 28.9%, bortezomib: 26.2%). The combination regimen of lenalidomide + bortezomib became more common in the first and second lines. In the third line, carfilzomib- and/or pomalidomide-based regimens were 37.0% in 2013–2014. Skeletal-related events, hypertension, anemia, and chronic kidney disease were the most prevalent comorbidities and disease-related complications. During the 6 months prior to each line of therapy, the prevalence of the majority of the comorbidities and complications increased as patients progressed to higher lines of therapy.Conclusions:MM treatment patterns have been dynamic over time. Comorbid conditions and myeloma-related complications increase as patients progress and may worsen MM patients’ prognoses over time. Combination regimens such as lenalidomide + bortezomib are more widely used as first- and second-line therapy. Newly approved agents (carfilzomib, pomalidomide) are the prevailing treatments in the third line and are under further investigation for earlier lines of therapy.

Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance.

Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

Abstract A15: Humanized anti-hepatocyte growth factor (HGF) antibody, suppresses innate irinotecan resistance induced by fibroblast-derived HGF in colon cancer cells

Abstract Background and Purpose: Preclinical and clinical findings indicate that multiple tumor micro-environmental factors, including growth factors, protect solid tumors from therapeutic interventions. Experimental evidence has clarified some of the resistance mechanisms, which have led to the development of innovative approaches to treat cancer. Irinotecan is a semi-synthetic derivative of camptothecin, originally isolated from the Chinese/Tibetan ornamental tree Camptothecaacuminata. It is a key component of the first- and second-line treatment regimens for metastatic colorectal cancer (CRC). Study of irinotecan has demonstrated that its efficacy to treat cancer is superior to that of the best supportive care. However, de novo or acquired clinical resistance to camptothecins still exists expecting new target. The hepatocyte growth factor (HGF)/c-Met signaling system is known to be implicated in the development and progression of CRC, but the relationship between the expressions of HGF or c-MET and clinicopathologic feature remains controversial. We hypothesized that HGF from cancer-associated fibroblast (CAF) is related to innate irinotecan resistance. Therefore, HGF deprivation using neutralizing antibody is promising strategy to overcome irinotecan resistance induced by HGF in CRC. Results: We postulated that innate drug resistance might be caused at least in part by factors secreted by the tumor stromal cells. We measured the levels of mRNA and secreted protein of HGF by real-time PCR and ELISA in fibroblast and CRC cell lines. The mRNA level of HGF was significantly higher in fibroblast than CRC cell lines. Also, secreted HGF was not detected in conditioned media (CM) from CRC cell, but was detected in CM from fibroblast. Fibroblast-conditioned media rescued CRC from irinotecan, indicating that the rescue was due to a factor secreted by the fibroblasts. We determined whether fibroblast derived HGF increases irinotecan resistance through MET-dependent pathway. Fibroblast-derived conditioned media led to activation of MET receptors in CRC. The siHGF transfection abrogated such MET activation. To test whether HGF directly contributes to the effect on enhancing irinotecan resistance in CRC, anti-HGF antibodies were added to the CM to neutralize the HGF activity. We found that anti-HGF antibodies suppressed irinotecan resistance. Taken together, our findings suggest that the fibroblast derived HGF may play a general role in cancer cell survival and targeting HGF may represent a novel strategy for the treatment of CRC. To examine the possible induction of irinotecan resistance by fibroblast derived HGF and the efficacy of combined treatment with humanized anti-HGF antibody and irinotecan in vivo, we generated xenograft in NOD/SCID mice inoculating HCT-116 human colon cancer cells subcutaneously with or without fibroblast. We found that the combination of irinotecan and humanized anti-HGF antibody induced marked suppression of tumor development. These results suggest that HGF produced by fibroblast induces irinotecan resistance, and that humanized anti-HGF antibody abrogates such resistance in vivo. Conclusion: We identified HGF as an important determinant of resistance against irinotecan in CRC. Humanized anti-HGF antibody overcomes irinotecan resistance. These results demonstrate new options toward the early diagnosis of chemoresistance and suggest novel chemotherapy combining with anti-HGF antibody to prevent or significantly delay the onset of therapy resistance. These observations open new avenues toward the diagnosis of chemoresistance tumors and therapies targeting HGF over-expressing cancers. Citation Format: Jong Kyu Woo, Ju-Hee Kang, Keumju Shin, Seong-Won Song, Jung Ju Kim, Sang-Jin Lee, Seung Hyun Oh. Humanized anti-hepatocyte growth factor (HGF) antibody, suppresses innate irinotecan resistance induced by fibroblast-derived HGF in colon cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A15.

Evaluation of the efficiency of combination palliative treatment in patients with metastatic clear-cell renal cell carcinoma

Background. Experience with combination treatment, i.e. systemic therapy in combination with palliative surgery, in the treatment of metastatic kidney cancer is very rarely described in world literature. Objective: to evaluate the efficiency of combination treatment in combination with palliative cytoreductive surgery and targeted therapy and to define optimal indications for combination treatment. Subjects and methods . Data on 47 patients with metastatic renal cell carcinoma (mRCC) who received systemic (targeted) therapy in combination or after incomplete cytoreduction (iCR) were analyzed in this retrospective study. The proportion of men and women was 72.3 % and 27.7 %, respectively; their ratio was 2.6:1. All the patients (100%) underwent surgical treatment as nephrectomy or kidney resection for primary tumor. In the patients who had received radical treatment in different periods, the median relapse-free survival was 25.3 (0-187) months; the mean follow-up duration in the study was 33.2 (27.4–39.0) months. Out of the histological characteristics of a primary tumor, its Fuhrman grade was studied. Prior to initiation of mRCC therapy, Memorial Sloan Kettering Cancer Center (MSKCC) prognosis groups were assessed; the patients were divided into good (n = 9 (19.1 %)), interim (n = 28 (59.6 %)), and bad (n = 10 (21.3 %)) prognosis groups. Their total somatic status was separately rated using the ECOG scale: 0, (n = 10 (21.3%)), 1 (n = 24 (51.1 %)), and 2, (n = 13 (27.6 %)). The sites of metastases were as follows: the lung (n = 29), bones (n = 18), adrenals (n = 11), recurrence in the removed kidney bed (n = 10), and liver (n = 10). Multiple organ involvements were detected in 22 (46.8 %) patients. There were more than 5 metastases in one organ in 18 (40.0 %) patients and only 15 (33.3 %) were found to have a single focus in one organ. Whether iCR might be used as a separate line treatment was studied. A comparative analysis was made between 2 groups of patients with mRCC: 1) 20 patients who underwent iCR and 2) 27 patients who received systemic therapy (immunotherapy (n = 12), sorafenib (n = 8), and sunitinib (n = 7)). The control points were estimation of overall survival (OS), optimal indications for iCR in patients with mRCC, and time to progression (TTP) during first- and second-line systemic treatment. Resuts. The median OS duration in Group 1 was longer: 46 months versus 31 months (p = 0.09). TTP was comparable: 9 and 6 months, respectively. Comparison of first-line systemic treatment showed that the median TTP was twice longer (13 and 17 months in the targeted (sorafenib and sunitinib) therapy group than that in the cytokine therapy group (6 months) (p = 0.0174). TTP during second-line therapy was 10 months. Median OS after immunotherapy, sorafenib and sunitinib therapy demonstrated no differences and was 34.2, 36.5, and 39.2 months (р = 0.8). Conclusion. This investigation suggests that the comprehensive approach in effective in treating mRCC. iRC may be used as an individual treatment in a certain patient group. However, survival rates in the examined group of patients can be increased only when targeted drugs are necessarily used in both first- and second-line treatment regimens. In spite of the metastatic pattern of RCC, the treatment algorithm for these patients should estimate the possibilities of using palliative cytoreductive treatment since its use may provide a median TTP of as many as 9 months. Just the same, over 30-month survival rates may be obtained when the latter is used in combination with systemic treatment.