Choice Of Second-line Therapy Research Articles

Insights from an Italian Delphi panel: exploring resistance to first-generation somatostatin receptor ligands and guiding second-line medical therapies in acromegaly management.

First-line medical therapy for acromegaly management includes first-generation somatostatin receptor ligands (fgSRLs), but resistance limits their use. Despite international guidelines, the choice of second-line therapy is debated. We aim to discuss resistance to fgSRLs, identify second-line therapy determinants and assess glycemia's impact to provide valuable insights for acromegaly management in clinical practice. A group of Italian endocrinologists expert in the pituitary field participated in a two-round Delphi panel between July and September 2023. The Delphi questionnaire encompassed a total of 75 statements categorized into three sections: resistance to fgSRLs therapy and predictors of response; determinants for the selection of second-line therapy; the role of glycemia in the therapeutic management. The statements were rated on a 6-point Likert scale. Fifty-nine (79%) statements reached a consensus. IGF-1 levels resulted central for evaluating resistance to fgSRLs, that should be defined considering also symptomatic clinical response, degree of tumor shrinkage and complications, using clinician- and patient-reported outcome tools available. Factors to be evaluated for the choice of second-line medical therapy are hyperglycemia-that should be managed as in non-acromegalic patients-tumor remnant, resistant headache and compliance. Costs do not represent a main determinant in the choice of second-line medical treatment. The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients.

The MAGIC Algorithm Probability Predicts Long-Term Outcomes and Treatment Response to Second-Line Therapy for Acute Gvhd

Introduction: Risk stratification approaches using clinical criteria or biomarkers in acute graft-versus-host disease (GVHD) have traditionally been implemented at diagnosis or initiation systemic treatment with corticosteroids. For patients who require second-line treatment, the significance of biomarkers at salvage therapy and the relationship between biomarker risk and choice of therapy are unknown. Methods: We studied adult patients who received second-line treatment for acute GVHD between January 2016 and December 2021 in the Mount Sinai Acute GVHD Consortium (MAGIC) database, which collects clinical data and longitudinal serum samples from allogeneic HCT recipients using a rigorous PRoBE study design. Exclusion criteria included relapse of underlying malignant disease prior to second-line therapy, missing response data, or missing serum sample. Serum samples collected from 7 days prior to 3 days after initiation of second-line therapy met criteria for biomarker analysis. The MAGIC algorithm probability (MAP) was calculated as a single value based on concentrations of ST2 and REG3α and was stratified at a threshold of 0.290 to define high MAP and low MAP groups. The primary objective evaluated the association between MAP and survival for patients receiving second-line therapy for acute GVHD. The key secondary objective was to investigate the MAP and choice of second-line systemic agent on Day 28 overall response rate (ORR) and survival. Results: In total, 316 adult patients received second-line treatment for acute GVHD; 149 patients (47%) were excluded for disease relapse (n=27), missing response data (n=48), or missing sample (n=74).Of the 167 evaluable patients, most had steroid-refractory acute GVHD (n=146, 87%), rather than steroid-dependent (n=8, 5%) or steroid-sensitive (n=14, 8%) disease. 62 patients received ruxolitinib while 102 received other systemic agents (best available therapy: BAT). Baseline clinical characteristics of the study population according to treatment choice were similar, except for donor type (Rux: MRD 15%, MUD 74%, haplo 11%; BAT: MRD 30%, MUD 67%, haplo 3%; P=0.014) and median days from corticosteroids to second-line treatment (Rux: 18, BAT: 12; P=0.02).In total, 81 patients had high MAPs and 86 patients had low MAPs, with similar distribution in each treatment cohort (P=0.53). For the entire cohort, the median follow-up for survivors was 22 months (range, 1.5-27).The MAP separated patients into 2 groups (high vs low) with significantly different mortality (NRM at 2 years, 76% vs 29%, P<.0001) and survival (OS at 2 years, 12% vs 63%, P<.0001). Patients who received ruxolitinib as second-line therapy had lower mortality (NRM at 2 years, 35% vs 60%, P<.002) and improved survival (OS at 2 years, 51% vs 32%, P<.008), compared to those who received other systemic agents. However, the outcomes of patients with high MAP were poor, regardless of second-line treatment choice ( Figure 1A). The MAP (low vs high), time from corticosteroids to second-line treatment (≥14 days vs < 14 days), GVHD grade at second-line (0-2 vs 3-4), and choice of second-line therapy (Rux vs BAT) were all significant (P<0.05) predictors of lower NRM and higher OS in multivariate analysis. The MAP also separated patients into 2 groups with significantly different D28 ORR (low: 49%, high: 30%, P<.0001). In agreement with prospective trials, ruxolitinib resulted in higher D28 response rates compared to other systemic therapies (ORR 54.9% vs 30.5%, P=0.005), which was observed in both low MAP (ORR, 64.5% vs 38.5%, P=0.017) and high MAP cohorts (ORR, 42.9% vs 22.6%, P=0.06) ( Figure 1B). The MAP (low vs high), GVHD grade at second line (0-2 vs 3-4), and choice of second-line therapy (Rux vs BAT) were significant predictors (P<0.05) of higher D28 ORR in multivariate analysis. Conclusion: The MAP measured at the initiation of second-line systemic treatment for acute GVHD predicts NRM and OS, as well as treatment response. The outcomes of patients with high MAP are poor, regardless of second-line treatment choice, and the higher CR rate in low MAP patients may drive higher survival rates. Incorporation of MAP into clinical trials in this setting warrants investigation. The results also support the current use of ruxolitinib as second-line treatment for acute GVHD, particularly in patients with low MAP.

Drug-survival profiling of second-line biologic therapy in rheumatoid arthritis: Choice of another tumour necrosis factor inhibitor or a biologic of different mode of action?

To assess the best choice of second-line therapy between tumour necrosis factor-inhibitor (TNFi) and biologics of different-mode-of-action (BDMA-rituximab/tocilizumab/abatacept) in rheumatoid arthritis (RA) by evaluating drug-survival following discontinuation of the first-line TNFi. This retrospective drug-survival study was performed across two different hospitals by conventional-statistics and machine-learning approach. From a total of 435 patients, 213 (48.9%; TNFi = 122, BDMA = 91) discontinued their second-line biologic {median drug-survival: TNFi, 27 months [95% confidence interval (95%CI) 22-32] vs BDMA, 37 months (95%CI 32-52)}. As a second-line biologic, BDMA was likely to reduce the risk of treatment-discontinuation [hazard-ratio (HR) 0.63, 95%CI 0.48-0.83] compared to TNFi, but only in seropositive-patients (HR 0.52, 95%CI 0.38-0.73), not in seronegative-RA. Drug-survival benefit of BDMA over TNFi was not observed if the seropositive-patients were previously exposed to monoclonal-TNFi (HR 0.77, 95%CI 0.49-1.22) versus soluble-TNFi (etanercept/biosimilars) or if the first-line TNFi was terminated within 23.9 months of initiation (HR 0.97, 95%CI 0.56-1.68). BDMA, as a second-line biologic, is more likely to be sustained in seropositive-patients, particularly without prior exposure to monoclonal-TNFi. The drug-survival benefit of BDMA was not observed in seronegative-patients or if the first-line TNFi was stopped within 2 years.

Clinical Features, Treatment, and Outcome of Pediatric Steroid Refractory Acute Graft-Versus-Host Disease: A Multicenter Study

Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a severe complication in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to assess clinical course and outcomes of pediatric SR-aGvHD. We performed a retrospective nationwide multicenter cohort study in the Netherlands. All patients aged 0 to 18 years who underwent transplantation between 2010 and 2020 with SR-aGvHD were included. For each patient, weekly clinical aGvHD grade and stage, immunosuppressive treatment and clinical outcomes were collected. The primary study endpoint was the clinical course of SR-aGvHD over time. As a secondary outcome, factors influencing overall survival and SR-aGvHD remission were identified using a multistate Cox model. 20% of transplanted children developed grade II-IV aGvHD, of which 51% (n = 81) was SR-aGvHD. In these patients, second-line therapy was started at a median of 8 days after initial aGvHD-diagnosis. Forty-nine percent of SR-aGvHD patients received 3 or more lines of therapy. One year after start of second-line therapy, 34 patients (42%) were alive and in remission of aGvHD, 14 patients (17%) had persistent GvHD, and 33 patients (41%) had died. SR-aGvHD remission rate was lower in cord blood graft recipients than in bone marrow (BM) or peripheral blood stem cell (PBSC) recipients (hazard ratio [HR] = 0.51, 0.27-0.94, P = .031). Older age was associated with higher mortality (HR = 2.62, 1.04-6.60, P = .04, fourth quartile [aged 13.9-17.9] versus first quartile [aged 0.175-3.01]). In BM/PBSC recipients older age was also associated with lower remission rates (HR = 0.9, 0.83-0.96, P = .004). Underlying diagnosis, donor matching or choice of second-line therapy were not associated with outcome. Respiratory insufficiency caused by pulmonary GvHD was a prominent cause of death (26% of deceased). Our study demonstrates that SR-aGvHD confers a high mortality risk in pediatric HSCT. Older age and use of CB grafts are associated with an unfavorable outcome. Multicenter studies investigating novel treatment strategies to prevent pediatric SR-aGvHD and inclusion of children in ongoing trials, together with timely initiation of second-line interventions are pivotal to further reduce GvHD-related mortality.

Are All Anti-Angiogenic Drugs the Same in the Treatment of Second-Line Metastatic Colorectal Cancer? Expert Opinion on Clinical Practice.

Targeting tumor-driven angiogenesis is an effective strategy in the management of metastatic colorectal cancer (mCRC); however, the choice of second-line therapy is complicated by the availability of several drugs, the occurrence of resistance and the lack of validated prognostic and predictive biomarkers. This review examines the use of angiogenesis-targeted therapies for the second-line management of mCRC patients. Mechanisms of resistance and anti-placental growth factor agents are discussed, and the role of aflibercept, a recombinant fusion protein consisting of portions of human vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2, is highlighted. The novel mechanism of action of aflibercept makes it a useful second-line agent in mCRC patients progressing after oxaliplatin-based chemotherapy, as well as in those with resistance after bevacizumab.

FP05.01 Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Choice of Second-line Therapy

FP05.01 Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Choice of Second-line Therapy

Diagnosis and treatment of autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

Decision Aid to Support Shared Decision Making in Pediatric Refractory Immune Thrombocytopenia

Background: Immune thrombocytopenia (ITP) is characterized by isolated low platelet count in the absence of other etiologies for thrombocytopenia. Despite published guidelines (Neunert, Blood Adv 2019), controversy exists in the management of patients with pediatric refractory ITP. Data on second-line treatment approaches is limited and no randomized controlled trials exist for this patient group. A comparative-effectiveness trial demonstrated variation in prescribing practices, with parental or patient preference involved in decision making in 55% of cases (Grace, Am J Hematol, 2018). Despite this data, no qualitative studies have been done to explore the patient experience. We aim for the first time to explore thematic areas surrounding rationale for treatment choice for patients with refractory ITP from the patient/parent point of view, as a first step to creating a decision aid. Our goal is that this aid will inform individuals with regards to options, encourage engagement of patients in decision, and assist patients with processing their preferences so they can make choices reflective of their values. Methods: Purposeful sampling identified participants locally from Columbia University Medical Center as well as nationally through the Platelet Disorder Support Association. Focus groups were conducted with an average of 5-7 parents of children with ITP in each group, and each lasting approximately 90 minutes. A written guide with open-ended questions was created to elicit participant opinions and foster guided discussion between them, illuminating particular concepts and permitting researchers to gain an understanding of patient experiences in the context of their own lives. Focus groups were audio recorded and transcribed. The de-identified transcripts were uploaded into Dedoose, a qualitative software. A thematic analysis was conducted to identify the nature, strength and prevalence of key concepts. Results: Three major themes were identified with regards to treatment choice for second line therapy: 'Experiences with Treatment Decision Making', 'Factors Important in Decision Making', and 'Concept of Remission'. Excerpts demonstrating findings from each theme, as well as some of the variability amongst participants' opinions, are shown in Table 1. With regards to experiences with treatment decision making, many parents expressed that they felt their hematologist presented the options with adequate descriptions of risks and benefits, though the extent to which parents seem to feel included in the decision was not consistent. Often, even if presented with options, parents did not view themselves as critical decision makers and some patients still reported not feeling well-educated about options. Additionally, many participants reported that they went through a "trial and error" process with regards to different second-line therapies, with no notable or specific conversations defining any one person's experience. Discussion: The data collected suggests that parents of children with refractory ITP have strong ideas about communications around their treatment options. The factors important to decision making appeared consistent between participants, and would provide valuable input in the ultimate decision making tool and also be important to capture in future research trials of different agents. Of interest, the concept of remission came up frequently, and did not have the meaning that the research team expected. Participants noted that the term had a negative connotation, and meant only that there was a possibility of the disease returning. They felt that the term gave a false sense of relief, because their disease was unlikely to be truly cured. This was emphasized as a value in treatment selection. The information provided by these focus groups indicates that physicians' views on choosing therapies "based on patient preference" are not completely aligned with the patient experience. Additional focus group work, creation of a patient decision-aid, and inclusion of patient relevant outcomes in research will hopefully close this gap. We ultimately hope to create a clinical decision aid developed from input of these focus groups in order to increase patient understanding of their options, improve targeted treatment effects with regards to patient-related outcomes of importance, and help to guide management decisions. Disclosures Neunert: Platelet Disorder Support Association: Research Funding.

What Next After Metformin? Thinking Beyond Glycaemia: Are SGLT2 Inhibitors the Answer?

The prevalence of type 2 diabetes continues to increase, along with a proliferation of glucose-lowering treatment options. There is universal agreement in the clinical community for the use of metformin as the first-line glucose-lowering therapy for the majority of patients. However, controversy exists regarding the choice of second-line therapy once metformin is no longer effective. The most recent treatment consensus focuses on the presence of cardiovascular disease, heart failure or kidney disease as a determinant of therapy choice. The majority of patients in routine practice, however, do not fall into such categories. Heart failure and kidney disease represent significant clinical and cost considerations in patients with type 2 diabetes and have a close pathophysiological association. Recent data has illustrated that sodium-glucose transporter 2 (SGLT2) inhibitor therapy can reduce the burden of heart failure and the progression of renal disease across a wide range of patients including those with and without established disease, supported by an increased understanding of the mechanistic effects of these agents. Furthermore, there is growing evidence to illustrate the overall safety profile of this class of agents and support the benefit–risk profile of SGLT2 inhibitors as a preferred option following metformin monotherapy failure, with respect to both kidney disease progression and heart failure outcomes.

Treatment patterns and associated factors in 14 668 people with type 2 diabetes initiating a second-line therapy: Results from the global DISCOVER study programme.

AimTo evaluate treatment data from DISCOVER (NCT02322762 and NCT02226822), a global, prospective, observational study programme of patients with type 2 diabetes initiating a second‐line glucose‐lowering therapy.Materials and MethodsData were collected using a standardized case report form. First‐ and second‐line treatments were assessed in 14 668 patients from 37 countries across six regions. Among patients prescribed first‐line metformin monotherapy, Firth logistic regression models were used to assess factors associated with second‐line treatment choices.ResultsThe most common first‐line therapies were metformin monotherapy (57.9%) and combinations of metformin with a sulphonylurea (14.6%). The most common second‐line therapies were combinations of metformin with other agents (72.2%), including dipeptidyl peptidase‐4 (DPP‐4) inhibitors (25.1%) or sulphonylureas (21.3%). Among patients prescribed first‐line metformin monotherapy, the most common second‐line therapies were combinations of metformin with a DPP‐4 inhibitor [32.8%; across‐region range (ARR): 2.4%‐51.3%] or a sulphonylurea (30.0%; ARR: 18.3%‐63.6%); only a few patients received combinations of metformin with sodium‐glucose co‐transporter‐2 inhibitors (6.7%; ARR: 0.0%‐10.8%) or glucagon‐like peptide‐1 receptor agonists (1.9%; ARR: 0.1%‐4.5%). Both clinical and non‐medical factors were associated with choice of second‐line therapy after metformin monotherapy.ConclusionsFewer patients than expected received metformin monotherapy at first line, and the use of newer therapies at second line was uncommon in some regions of the world. Patients' socioeconomic status was associated with treatment patterns, suggesting that therapy choices are influenced by cost and access.

Outcomes of Follicular Lymphoma (FL) with Early Progression (EP): Does Choice of Second Line Therapy Impact the Course of Disease?

Background: The spectrum of FL varies from an indolent disease course spanning decades to early transformation and death. Longitudinal studies have identified a subset of high risk patients (pts) who progress within 24 months of frontline therapy. It is still unclear how best to treat these patients and as yet, there is no standard 2nd line therapy for FL. Given the multitude of treatments available and the heterogenous disease course, it is challenging to compare outcomes of 2nd line therapy. It is unclear if the efficacy of second-line therapy in FL is influenced by the type of therapy, disease biology (early vs. late progression) or both. We conducted a single institute, retrospective study to determine the clinical benefit of 2nd line therapy in FL and to evaluate if any particular type of therapy was associated with improved outcomes in FL patients with early progression (EP).Methods: All patients with relapsed/refractory FL treated at our Institute between 1990 and 2014 were included. Patients were included if they received anti-CD20 monoclonal antibody (mAb)-based therapy in the first-line setting and completed both, first-line and second-line therapy at our Institution. Demographic, clinical, pathological and outcomes data was collected by retrospective chart review. Clinical endpoints included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). Treatments were divided in two groups for comparison: immunotherapy alone (anti-CD20 mAb) (IT) or chemo-immunotherapy (CIT). Differences in clinical outcomes were analyzed between FL patients with early progression after 1st line therapy (EP, i.e. progression ≤ 2yrs) vs. FL with late relapse (LP, i.e. progression > 2yrs). Comparisons were made using the Mann-Whitney U and Person chi-square tests as appropriate. Survival outcomes were assessed using standard Kaplan-Meier methods. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05.Results: A total of 537 newly diagnosed FL pts were identified of which 291 pts received 1st line therapy at our Institute. IT or CIT was given to 19.6% and 80.4% pts respectively. IT treated pts were older (median age: 61y vs 57y, p=0.033) and had lower FLIPI scores (1.5 vs 2.1, p<0.001) than CIT treated pts. Disease progression requiring 2nd line therapy was observed in 108 of 291 pts (36.4%) , 64 (59.3%) of which had EP vs 44 (40.7%) had LP. Baseline characteristics including age, gender and FLIPI scores were similar between EP and LP groups. ORR to 2nd line therapy was similar between EP and LP pts (64.3 vs. 78%, P=0.53). After a median follow up of 89.5 months (mo), the PFS, TTNT and OS of pts requiring 2nd line therapy was 14.3 mo, 17.5 mo and 92.9 mo respectively. Pts with EP had a significantly lower PFS (6.6 vs 32.8 mo, p <0.001) and TTNT (11.7 vs 36.2 mo, p <0.001) compared to LP pts with no difference in OS (77 vs 132 mo, p=0.36) [Figure 1]. Among pts with EP receiving 2nd line therapy, there were no differences between IT and CIT in terms of PFS (9.3 vs 6.4 mo, P=0.50) or TTNT (15 vs 11.6 mo, P=0.59). The OS was better in IT vs CIT (NR vs 47.6 mo, p=0.036) but has to be interpreted in the context of most pts (except one) in each group going on to receive subsequent therapies [Figure 2]. Of interest, the ORR of 2nd line therapy among pts with LP was excellent regardless of the use of IT or CIT (90.4 vs 100%, P=0.07). Moreover, in pts with LP, there were no difference in PFS (29.4 vs 32.8 mo, p=0.83), TTNT (102 vs 36.2 mo, p=0.96) and OS (132 vs 93 mo, p=0.34) based on the choice of 2nd line therapy (IT or CIT) [Figure 3].Conclusion: FL pts with LR have excellent outcomes to 2nd line therapy and treatment selection could be determined by the agent(s) toxicity profile. In contrast, EP predicts poor clinical outcomes with short duration of response to standard IT or CIT. Therapeutic approaches incorporating clinically available targeted agents (i.e. immunomodulatory agents of B-cell receptor signaling inhibitors) or novel agents in the context of clinical trials, may provide a more effective disease control in this subgroup. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Management of Resistance to First-Line Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor Therapy.

A decade after the discovery of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (EML4-ALK) rearrangements in non-small cell lung cancer (NSCLC), several inhibitors have gained regulatory approval, and their sequential use has deferred platinum-based chemotherapy to later lines of therapy. Nevertheless, although most ALK-driven tumors dramatically respond to ALK TKIs , all patients ultimately develop drug-resistant disease. Analysis of post-progression biopsy samples has provided invaluable insight into the mechanisms of resistance, now informing on subsequent therapeutic strategies. In particular, the identification of secondary ALK mutations, which are a common mechanism of resistance to both first-generation and to an even larger extent to second-generation ALK TKIs, may shape a personalized optimal treatment strategy beyond the current first-line choice. Alectinib has now become a preferred treatment option in the first line of therapy, and extrapolation of data obtained from post-progression samples after second-line next-generation ALK TKIs suggests that acquired resistance is likely to be mediated in more than half of patients by ALK resistance mutations. Nevertheless, clinical and preclinical evidence suggests that multiple resistance mechanisms may co-exist at different levels in the same TKI-resistant patient. Newer ALK tyrosine kinase inhibitors (TKIs) overcome some resistance mutations through higher exposure and potency, and generally present greater CNS activity, but are unlikely to overcome resistance mediated through separate oncogenic pathway activations, or epithelial to mesenchymal transition (EMT) and small cell lung cancer (SCLC) transformation. Furthermore, while resistance mutations can be detected through commonly available sequencing methods, the identification of other mechanisms of resistance is much less straightforward in the clinic. We hypothesize that the ALK resistance mutation status will likely be crucially important in the choice of second-line therapy after a second-generation TKI. Emerging clinical data also refines the optimal placing of PD-1- and PD-L1-directed immunotherapy in the treatment sequence.

Trabectedin in Ovarian Cancer: is it now a Standard of Care?

In patients with recurrent ovarian cancer, the choice of second-line therapy is complex. Several factors have to be considered, such as platinum-free interval (PFI), residual toxicity from the previous treatments, BRCA1/2 gene mutation status. Trebectedin is a minor groove DNA binder derived from a marine organism that has shown efficacy in different settings in ovarian cancer therapy. It has been approved in the treatment of partially platinum sensitive (PPS) (PFI between 6 and 12 months) relapsed ovarian cancer according to the statistically significant progression-free survival (7.3 versus 5.8 months) and overall survival (22.2 versus 18.9 months) benefit compared with single-agent pegylated liposomal doxorubicin (PLD) in the OVA 301 phase III trial. This drug has been shown to prolong the time to first subsequent treatment and improve the efficacy of further platinum-based chemotherapy. The role of trabectedin/PLD followed by platinum combination compared with the reverse sequence in PPS is actually in evaluation in the INOVATYON phase III study, which will clarify the best sequence to be adopted in this setting. Trabectedin has been shown to be active in patient carriers of BRCA mutations, probably for its mechanism of action directly affecting DNA and it is actually tested as a single agent in some phase III trials in BRCA mutated and BRCAness ovarian cancer patients. Trabectedin is also active on the immune system. There is, therefore, the rational for new trials of a combination with immune checkpoint inhibitors.

Second-line chemotherapy for patients with advanced gastric cancer.

The first choice for treating patients with metastatic gastric cancer is chemotherapy, and combination therapy with fluorouracil, platinum, and trastuzumab has been established as the standard first-line chemotherapy. For further improvement of treatment outcomes, it is important to develop second- and third-line chemotherapy. In the first decade of this century, irinotecan and taxanes, cytotoxic agents, and various molecular targeted agents began to be developed as second-line therapy. Treatment with paclitaxcel weekly in combination with ramucirumab targeting vascular endothelial growth factor receptor2 has become the first choice for second-line therapy. Immune checkpoint inhibitors are now being developed, and the current treatment strategies for advanced gastric cancer may undergo major changes in the future. This review summarizes the transitions and future prospects of clinical developments for second-line therapy in patients with advanced gastric cancer.

Sequential treatment in patients with metastatic pancreatic neuroendocrine tumors after progression on first-line therapy.

426 Background: Pancreatic neuroendocrine tumors (pNETs) are rare malignancies with an age-adjusted annual incidence of 0.32/100,000, with metastatic disease at diagnosis occurring in 64%. Patients with advanced disease are considered for surgery/ablative therapy (SG) or systemic therapy (ST), including chemo- and targeted therapy, somatostatin analogues, and peptide receptor radiotherapy (PRRT). Optimal sequence of therapy is unknown and we sought to characterize sequential treatment patterns in patients with metastatic pNETs and overall survival (OS). Methods: Patients diagnosed with metastatic pNETs referred to the BC Cancer Agency between 2000-2013 and received more than one line of therapy were reviewed. Results: Of 151 patients, 81 received one line of therapy while 45 patients received &gt;1 treatment. Median age was 55.1 years (IQR 47.4-64.8) and 23 (51%) were male. Sites of metastases included liver (n=33), lymph nodes (n=5), lung (n=1), peritoneum (n=2), and bone (n=5). Median time to start of therapy was 1.5 months (IQR 0.4-3.0). First-line SG was associated with increased OS compared to first-line ST (88.9 vs. 38.2 months; p=0.004). There was no difference in OS between patients receiving second-line SG or ST, measured from start of second-line therapy. Second-line chemotherapy was associated with decreased PFS compared to alternate treatments, both after first-line chemotherapy (0.7 vs. 5.8 months; p=0.002) and after other treatments (4.8 vs. 16.7 months; p=0.002). Median length of follow-up was 48.3 months. Conclusions: We present the sequential treatment patterns of patients with metastatic pNETs. Results confirm the primary role of SG, reserving ST for secondary therapy. Upon progression, choice of second-line therapy was not prognostic and may be chosen based on disease and patient characteristics. [Table: see text]

Patterns of Care in Patients with Metastatic Renal Cell Carcinoma Among a U.S. Payer Population with Commercial or Medicare Advantage Membership.

Several systemic therapies are now approved for first- and second-line treatment of metastatic renal cell carcinoma (mRCC). Although the National Comprehensive Cancer Network (NCCN) guidelines offer physicians evidence-based recommendations for therapy, there are few real-world studies to help inform the utilization of these agents in clinical practice. To (a) describe the patterns of use associated with systemic therapies for mRCC among Humana members in the United States diagnosed with mRCC, (b) assess consistency with the NCCN guidelines for treatment, and (c) to describe the initial first-line therapy regimen by prescriber specialty and site of care. This was a retrospective study using Humana's claims database of commercially insured patients and patients insured by the Medicare Advantage Prescription Drug plan. The study period was from January 1, 2007, to December 31, 2013. Patients with mRCC were identified by ICD-9-CM codes 189.0/189.1 and 196.xx to 199.xx; all patients were between 18 and 89 years of age, had received systemic therapy for their disease, and were followed up for 180 days. Outcome measures included choice of initial systemic therapy, starting and ending doses, first-line treatment persistence and compliance, and choice of second-line therapy. Persistence was measured using time to discontinuation of first-line therapy and proportion of days covered (PDC; the ratio of [total days of drug available minus days of supply of last prescription] to [last prescription date minus first prescription date]). Compliance was measured using the medication possession ratio (MPR; the ratio of [total days supply minus days supply of last prescription] to [last prescription date minus first prescription date]). A total of 649 patients met all inclusion criteria; 109 were insured by commercial plans and 540 were insured by Medicare. The mean ± SD age of patients was 68.6 ± 9.4 years, and 68.6% were male; Medicare patients were older than commercial patients (71.7 ± 7.4 vs. 56.6 ± 9.1 years, respectively; P < 0.001). The most common comorbidities among the patient population were hypertension, hyperlipidemia, diabetes, and heart disease. The majority of patients (68.6%) received an oral tyrosine kinase inhibitor (TKI) as their first line of therapy: 43.9% received sunitinib, 14.0% received sorafenib, 10.0% received pazopanib, and 0.6% received axitinib. Mean ± SD time to discontinuation of first-line TKI treatment was 169.1 ± 29.5 days with sunitinib, 160.3 ± 41.1 days with pazopanib, and 160.1 ± 41.4 days with sorafenib. Other first-line therapies included inhibitors of mammalian target of rapamycin (mTOR) (19.7%) and the antivascular endothelial growth factor agent bevacizumab (9.4%). Among patients receiving mTOR inhibitors, 14.8% were started on temsirolimus and 4.9% were started on everolimus. The median starting and ending doses were the same for each drug except for sunitinib. Mean ± SD times to discontinuation of temsirolimus, everolimus, and bevacizumab were 171.8 ± 26.2, 137.0 ± 62.2, and 150.8 ± 56.0 days, respectively. Persistence on first-line regimen as measured by PDC was high (PDC ≥ 80%) for 89% of oral therapies and 77% of injectable therapies; first-line compliance was high (MPR ≥ 80%) for 77% of oral therapies and 68% of injectables. Among patients who received second-line therapy, the most common regimen was everolimus (29.2%), followed by bevacizumab (19.8%), temsirolimus (15.6%), and sunitinib (13.6%). Specialty codes obtained from the database provider identified internal medicine specialists and oncologists as the most common prescribers of TKIs and mTOR inhibitors. Patterns of use were similar for each of the prescribed systemic treatments for mRCC, and the majority of patients were highly persistent and compliant with first-line therapies. Time to treatment discontinuation was slightly longer with oral agents compared with injectable drugs.

Trastuzumab emtansine associated nodular regenerative hyperplasia: A case report and review of literature

Abstract Background Trastuzumab emtansine (T-DM1), a novel drug-antibody conjugate, has shown promising activity in HER2-positive breast cancer and is the recommended agent of choice for second line therapy for advanced HER 2-positive breast cancer. Elevations in transaminase levels have been reported in up to 40% of patients treated with T-DM1 on phase I-III clinical studies. More serious hepatotoxicity can also result from this drug-antibody conjugate, but has been infrequently described in the literature. Case Presentation Here we report a 73 year old female with previously untreated metastatic HER 2-positive breast cancer who developed nodular regenerative hyperplasia and noncirrhotic portal hypertension while on treatment with single agent T-DM1. Liver biopsy demonstrated nodular regenerative hyperplasia, bile duct injury, and portal fibrosis. Conclusion A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. Abdominal imaging, liver biopsy, and prompt discontinuation of T-DM1 is recommended for patients with signs or symptoms of liver injury.

Chronic Inflammatory Demyelinating Polyneuropathy in Children: A Review of Clinical Characteristics and Recommendations for Treatment

Context: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is an acquired and autoimmune neuropathy, characterized by a chronic, rapidly progressive, symmetric weakness. In children, abnormal gait is as a first symptom of muscle weakness. Evidence Acquisition: The diagnosis of CIDP is on the basis of clinical characteristics, electrodiagnostic that shows the severity of the disease, lumbar puncture and spine magnetic resonance imaging (MRI). Results: The first-line treatments in childhood CIDP are intravenous immunoglobulin (IVIG), corticosteroids, and plasmapheresis. Response to first-line therapies is usually satisfactory; nevertheless, recommendations regarding the choice of second-line therapy can only be prepared on the basis of the existing practice described in some of the case reports. Conclusions: This review demonstrated the clinical presentation, diagnosis, and treatment of childhood CIDP.

709P - Single-Agent or Doublets As Second-Line Chemotherapy After Folfirinox in Patients with Locally Advanced or Metastatic Pancreatic Cancer

ABSTRACT Aim: FOLFIRINOX represents an active regimen in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) patients (pts) with good performance status (PS). Currently, there are no accepted standard regimens in second-line therapy for patients with disease progression and data about efficacy of chemotherapy after FOLFIRINOX failure are lacking. Methods: We retrospectively investigated clinical and laboratory characteristics (including blood count, LDH, CEA and CA19.9) of PDAC pts treated between June 2011 and April 2014 in four Italian institutions with either doublet or single agent as second-line therapy after FOLFIRINOX failure. Survival estimates were quantified using Kaplan Meier curves, and differences between groups were compared with the log-rank test. Results: Among 96 pts treated with FOLFIRINOX as first-line chemotherapy, 50 pts received second-line treatment (52%). Median age at diagnosis was 60 years (range 36-76); 66 pts were males (72%). PDAC was locally advanced in 15 (30%) and metastatic in 35 pts (70%). Patients who received second line single agent (gemcitabine, docetaxel or nab-paclitaxel) or doublets (gemcitabine with either abraxane, capecitabine, cisplatin or docetaxel) were 24 (48%) and 26 (52%), respectively. According to RECIST criteria, 2 pts achieved PR (4%), 10 (20%) SD for ≥9 wks and 38 (76%) PD. Median progression-free survival (PFS) was 2.7 months and median overall survival (OS) was 3.4 months. No differences were found in terms of OS (5.0 vs 3.1, p = 0.489) or PFS (4.0 vs 2.7 p = 0.182) between patients treated with single-agent or doublets as second-line. At multivariate analysis, ECOG ≥ 2 was the only independent prognostic factor for worst OS (p = 0.002) and PFS (p = 0.020). Conclusions: Our findings suggest that the choice of second line therapy in patients treated with first-line FOLFIRINOX should be carefully evaluated. ECOG ≥ 2 was significantly associated with poor prognosis, while pre-treatment CA 19-9, LDH, Hb, neutrophil and platelet counts were not prognostic factors for OS, although these data should be confirmed in perspective studies. Disclosure: All authors have declared no conflicts of interest.

The choice of second-line therapy in steroid-resistant immune thrombocytopenia: role of platelet kinetics in a single-centre long-term study.

Splenectomy is a time-honoured well established approach for patients with steroid-resistant immune thrombocytopenia (ITP). However, due to the more recent availability of therapeutic options alternative to splenectomy, such as rituximab and agonists of the thrombopoietin-receptor, the choice of second-line therapy is challenging. Platelet kinetics has been widely used to predict response to splenectomy. We describe the outcome of 70 chronic ITP patients who performed a platelet kinetic study after failure of front-line corticosteroids and subsequently underwent open splenectomy. After a median follow-up from surgery of 20 years, 62 (88.5%) patients responded to splenectomy and 9 patients (13%) relapsed. Achieving a complete response (CR) significantly predicted a higher probability long-term stable response. The pattern of platelet sequestration was predominantly splenic in 52 patients (74%), predominantly hepatic in 12 patients (17%), and diffuse in 6 (9%). Patients with nonsplenic (diffuse and hepatic) sequestration showed significantly lower overall responses compared to patients with splenic captation (P = 0.002). A nonsplenic sequestration significantly correlated with lower CR rate and, among CR patients, predicted an increased risk of relapse. Also, the probability of stable responses in nonsplenic uptake patients was substantially lower than in patients with splenic uptake (85% vs. 50%, P = 0.0083). Platelet life span and platelet turnover did not correlate with response and relapse rate. Overall, splenic sequestration was able to predict not only a better quality, but also a higher durability of the responses. However, it should be enphasized that the response rate and duration of response even in patients with nonsplenic uptake were similar or even superior to those reported in patients treated with rituximab as first option.