Primary Non-responders Research Articles

P055 Vedolizumab Treatment Persistence up to 5 Years: Post hoc Analysis in Vedolizumab-Naïve Patients From the GEMINI Long-Term Safety Study

BACKGROUND: Vedolizumab (VDZ) is a gut-selective, humanized monoclonal antibody approved for moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Although VDZ efficacy and safety are well established, there are limited publications on longer-term (>3 years) treatment persistence. This study evaluated VDZ treatment persistence for up to 5 years in a GEMINI long-term safety (LTS) VDZ de novo cohort. METHODS: All patients in GEMINI LTS (NCT00790933) were treated with VDZ every 4 weeks. A post hoc analysis of data from patients not previously treated with VDZ before Week 0 of GEMINI LTS (de novo cohort) was conducted, with VDZ treatment persistence assessed using Kaplan-Meier survival analysis. Treatment discontinuations due to adverse events (AEs) or lack of efficacy were considered for the analysis; discontinuations due to protocol deviation, patient withdrawal, or loss to follow-up were censored. Treatment persistence analyses were further stratified by Week 12 treatment response (primary response/nonresponder), prior anti-tumor necrosis factor (anti-TNF) failure (Yes/No), type of anti-TNF failure (primary/secondary nonresponse), and concomitant therapy (corticosteroids, 5-aminosalicylates, immunomodulators, or their combinations) at baseline (Yes/No); a log-rank test assessed statistical differences between subgroups. RESULTS: The GEMINI LTS de novo cohort included 421 patients (UC 190; CD 231) with a mean disease duration of 8.7 (UC) and 10.6 (CD) years, 6.0 mean partial Mayo score (UC) and 11.1 mean Harvey-Bradshaw Index; 61% of patients with UC and 74% with CD had prior anti-TNF failure. Up to 5 years follow-up, 276 patients (66%) total discontinued VDZ: 16% with UC and 17% with CD due to AEs, and 24% with UC and 33% with CD due to lack of efficacy. Survival probabilities for VDZ treatment persistence at 54 months were 53% for UC and 41% for CD. These VDZ 54-month survival probabilities were higher in patients with VDZ treatment response at Week 12 vs without (UC, 60% vs 26%, respectively, P < 0.0001; CD, 42% vs 35%, respectively, P = 0.001) and in patients without prior anti-TNF failure vs with (UC, 63% vs 47%, respectively, P = 0.046; CD, 47% vs 42%, respectively, P = 0.016). Among patients with baseline anti-TNF failure, survival probabilities for VDZ treatment persistence at 54 months were higher in UC patients who were secondary nonresponders vs those who were primary nonresponders (65% vs 15%, respectively, P < 0.0001); this difference was not observed in CD patients (44% vs 40%, respectively, P = 0.573). There were no differences in survival probabilities of continuing VDZ at 54 months among patients with UC or CD who initiated VDZ therapy with vs without any concomitant medications. CONCLUSION(S): More than half of patients with UC and 4 of every 10 patients with CD persisted on VDZ for 54 months. Treatment persistence rates in UC and CD cohorts were significantly higher in Week 12 responders and patients without prior anti-TNF failure, whereas there were no differences in persistence rates with baseline use of concomitant medications. Vedolizumab discontinuation rates due to AEs were low. These findings from GEMINI LTS support the longer-term effectiveness and safety of VDZ in patients with moderately to severely active UC and CD.

Serum γ-globulin and albumin concentrations predict secondary loss of response to anti-TNFα in inflammatory bowel disease patients.

Loss of response to anti-TNFα treatment occurs frequently in IBD- patients. We evaluatedthe predictive value of serum albumin and γ-globulin concentrations for treatment failure. Prospectively, all patients treated for the first time with either infliximab or adalimumab for IBD between 2007 and 2018 were included. All patients were tested for serum albumin and γ-globulin concentrations and were followed up until June 2018. 128 patients (95 Crohn's disease, 67 females, age 40.1 ± 13.7 years) were included in the study. 81patients (63.3%) received infliximab and 47 (36.7%) adalimumab first line. Eight patients (6.3%) were primary non-responders, 50 patients (39.0%) showed a sustained clinical remission and 70 patients (54.7%) developed a secondary loss of response. Meantime to develop secondary loss of response was 24.5 ± 20.5 months. Albumin serum concentrations in the clinical response group were significantly higher than in the secondary loss of response group (39.8 ± 5.7 g/L vs. 35.0 ± 5.4 g/L). γ-globulin serum concentrations in the sustained response group were significantly lower than in the secondary loss of response group (11.8 ± 2.8 g/L vs. 14.7 ± 4.5 g/L). Hypoalbuminemia and hypergammaglobulinemia were associated with the loss of response. Immunosuppressant co-medication in patients with high γ-globulin serum concentrations reduced the risk of secondary loss of response. Low albumin and increased γ-globulin serum concentrations are strongly associated with a higher risk for loss of response to an anti-TNFα treatment. Increased serum γ-globulin concentrations may have a higher risk to produce anti-drug antibodies or a different phenotype of disease less responsive to anti-TNFα treatment.

Profile of Tofacitinib in the Treatment of Ulcerative Colitis: An Evidence-Based Review of Recent Data.

Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25–50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.

Clinical outcomes for ibrutinib in relapsed or refractory mantle cell lymphoma in real-world experience.

Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis‐related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty‐three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression‐free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high‐risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo‐HSCT.

Defining response to TNF-inhibitors in rheumatoid arthritis: the negative impact of anti-TNF cycling and the need for a personalized medicine approach to identify primary non-responders

Current guidelines recommend treating rheumatoid arthritis (RA) patients to reach low disease activity or remission, however, most biologic-naive RA patients fail to reach treatment targets on their first biologic therapy. Approximately 90% of biologic-naive RA patients receive a tumor necrosis factor alpha inhibitor (anti-TNF) as their first biologic treatment, even though several alternative mechanism of action (MOA) therapies are approved as first-line options. After 3 months of therapy, patients may remain on anti-TNF therapy even if they fail to achieve the treatment target, mainly due to formulary structures. This means patients have to endure a second and even a third ineffective anti-TNF—called anti-TNF cycling—before changing MOA. This significantly delays patients from reaching their treatment targets. All anti-TNF drugs target the same molecular and inflammatory pathways; thus, it is not surprising that most patients who are primary non-responders to their initial anti-TNF therapy fail to achieve their treatment targets when cycled through alternative anti-TNFs. This suggests that primary non-responders should be switched to an alternative MOA therapy rather than enduring anti-TNF cycling. Avoiding anti-TNF cycling would prevent disease progression and improve quality of life for RA patients who are primary non-responders to anti-TNFs. The development of a personalized medicine approach to identify primary non-responders to anti-TNFs prior to treatment would allow significantly more patients to reach their treatment target by treating them with alternative MOA therapies as first-line therapies.

Salvage therapy versus upfront autologous stem cell transplantation in multiple myeloma patients with progressive disease after first-line induction therapy

It is a matter of debate whether myeloma patients with progressive disease (PD) after induction should receive salvage therapy or proceed directly to autologous stem cell transplantation. We performed a retrospective analysis of 1599 patients treated between 1991 and 2016 at the University Hospital of Heidelberg and other centers. Deepening of response through salvage therapy did not lead to better progression-free or overall survival (PD versus salvage therapy patients: HR = 0.71, 95% CI [0.28, 1.80], p = 0.5 and HR = 0.77, 95% CI [0.30, 1.95], p = 0.6, respectively), neither in patients treated with novel agents (HR = 0.66, 95% CI [0.23, 1.85], p = 0.4 and HR = 0.76, 95% CI [0.27, 2.15], p = 0.6) nor older regimens (HR = 0.86, 95% CI [0.36, 2.07], p = 0.7 and HR = 0.8, 95% CI [0.34, 1.91], p = 0.6). Therefore, primary nonresponders might benefit from a direct transplant rather than salvage induction, although the analyzed salvage therapy cohort was small (n = 23) and cytogenetics was not included in the multivariable analysis.

P045 Do Levels Matter? Maintaining Anti-TNF Class After Secondary Loss of Response to Adalimumab in Inflammatory Bowel Disease

BACKGROUND: Anti-tumor necrosis factor (Anti-TNF) biologic therapies have evolved as a mainstay of treatment for inflammatory bowel disease (IBD). However, 10%–20% of patients are primary non-responders to anti-TNF in clinical series and up to 40% of patients lose response to treatment over time. Current guidelines suggest that treatment failure in the setting of adequate drug concentrations are due to mechanistic failure and should be switched out of the anti-TNF class. Our aim was to assess the efficacy of switching to infliximab, rather than changing out of class, in patients with secondary loss of response to adalimumab who had a therapeutic drug level. METHODS: A retrospective chart review identified patients with ulcerative colitis (UC) and Crohn's disease (CD) treated with adalimumab within the University of North Carolina Inflammatory Bowel Disease clinic between January 1, 2007 and December 31, 2017. Patients with a therapeutic adalimumab level and treatment failure and who were subsequently treated with infliximab were included in the study. RESULTS: There were a total of 16 patients with therapeutic adalimumab levels (>5 μg/mL) and no antibody formation with treatment failure. In this population, 11 of the patients had CD, 3 patients had inflammatory bowel disease undifferentiated (IBDU) and 2 had UC. Ileocolonic CD (45.5%) and penetrating disease (54.4%) were the most common phenotypes. All patients had secondary loss of response to adalimumab and 87.5% had been increased to weekly dosing. Mean adalimumab level was 9.8 ± 6.8 μg/mL prior to switching to infliximab. Thirteen patients (81.3%) achieved clinical response with infliximab at 14 weeks and of the 8 patients with endoscopic assessments, 100% achieved endoscopic remission (5 with UC/IBDU and 3 with CD). There were a total of 6 patients in a sensitivity analysis assessing therapeutic levels >7 μg/mL. All patients were female, however all other characteristics in this group were similar to those patients evaluated with a therapeutic threshold of 5 μg/mL, including the rate of clinical response at 14 weeks (83.3%). When compared to 28 patients with adalimumab levels <5 μg/mL, there was no significant difference in clinical response at 14 weeks (P = 0.692). CONCLUSION(S): Switching within class to infliximab after secondary loss of response to adalimumab with a therapeutic level achieved clinical remission at 14 weeks in 81.3% of patients, and appears to be an acceptable strategy in selected patients. Therapeutic drug levels alone are not predictive of clinical response to a second anti-TNF.

IL-12/23 in IBD: Making the Best Use of Available Evidence

Prof Ghosh presented data from the UNITI studies exploring ustekinumab in primary or secondary nonresponders to TNF agonists (UNITI-1) and conventional therapy failures (UNITI-2). The data demonstrate that ustekinumab shows higher efficacy in patients who have failed conventional therapy compared to those who have failed anti-TNF therapy. Further sub-studies showed similar efficacy for ustekinumab 90 mg every 8 weeks (q8w) and ustekinumab 90 mg every 12 weeks (q12w) subcutaneous (SC) regimens, except for in patients with high inflammatory burdens, who did better with q8w regimens. No new safety signals were identified for ustekinumab between Week 96 and Week 156, with overall rates of adverse events and serious adverse events being comparable to placebo. Rates of antibody formation remained low. Dr Raine described two case studies involving Crohn’s disease patients treated with ustekinumab. The first case described a female patient with luminal Crohn’s disease who had secondary nonresponse to an anti-TNF with signs of intestinal and systemic inflammation. The second case considered a patient with bio-naïve luminal Crohn’s disease who had a previous history of opportunistic infections (coughs, colds, and recurrent herpes simplex). Prof Armuzzi presented the results of the induction part of the UNIFI study, which randomised patients with moderate-to-severe ulcerative colitis (UC) to placebo, ustekinumab 130 mg, or a weight-tiered ustekinumab dose (˜6 mg/kg). Results showed clinical remission at Week 8 was 5.3% for placebo, 15.6% for ustekinumab 130 mg intravenous (IV) (p<0.001), and 15.5% for ustekinumab at ˜6 mg/kg IV (p<0.001). Furthermore, ustekinumab IV induced clinical response and endoscopic and mucosal healing, improved health related quality of life, and had an adverse event profile consistent with known safety profiles.

Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study

IntroductionRheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a...

Evaluation of combined biomarkers for tumor response to immunotherapy (I/O) in patients with advanced non-small cell lung cancer (NSCLC).

e14269 Background: Immune checkpoint inhibitors have revolutionized NSCLC treatment. At present, the only established predictive biomarker for I/O-therapy stratification are PD-L1 expression and MSI status. However, the expression of PD-L1 is limited by heterogeneous expression and even high expressors not always respond to I/O therapy. The aim of the study is to evaluate the value of combinations of positive (Tumor Mutational Burden, PD-L1) and negative (a.o. CD73 expression and inactivating STK11 mutations) predictive markers in patients (pts) with advanced NSCLC on I/O therapy. Methods: A retrospective study was performed on a cohort of 54 pts with advanced NSCLC that have been treated with I/O between 2015 and 2017. Pts were selected by the availability of tumor tissue and based on tumor response evaluated by RECIST v1.1 criteria: only patients with durable tumor response (CR,PR ≥ 6 months) and patients with no tumor response (PD as best response) were analyzed for biomarkers: hybrid capture NGS assay for TMB (New Oncology) including STK11 mutations and IHC tests for PD-L1, CD73 and VISTA. Adjusted Cox regression and ROC analysis will be performed to evaluate the predictive value of the different biomarkers. Results: 43/54 pts received nivolumab, 11/54 pembrolizumab in different therapy lines (from 1st to 6th line). 24 pts were defined as having a durable tumor response (median PFS 20 months, median OS not reached) 30 pts as primary progressors (median PFS 2 months, p > 0.0001), median OS 12 months, p > 0.0001). In 30/54 pts enough material was available for TMB testing. The median TMB-value is 11.42 mutations/Mb. In 13 durable responders median TMB-value was 13.28 mutations/Mb versus 11.00 mutations/Mb in 17 primary non-responders. Additional analyses of PD-L1, CD73, STK11 and VISTA will be presented at the meeting as well as correlative data of the parameters analyzed. Conclusions: Our results suggest that integrating several biomarkers including positive and negative predictive markers may correlate better with responses to I/O than PD-L1 and TMB alone.

Outcomes of infliximab dose escalation in patients with rheumatoid arthritis.

Dose escalation of infliximab in both primary and secondary nonresponders is widely reported; however, the usefulness of dose escalation has been disputed. The objective of this analysis is to evaluate trends in clinical efficacy following multiple infliximab dose escalations in patients with rheumatoid arthritis (RA). Patients enrolled in a US RA registry were included if they initiated infliximab at 3mg/kg every 8weeks, received ≥ 1 infliximab dose escalation within 12months of initiation, and had ≥ 1 visit following dose escalation. Trends in mean Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ) scores from visits following dose escalations were evaluated. In patients who received 2 or 3 dose escalations, the initial (1 or 2) dose escalations resulted in reduced mean CDAI scores, but subsequent escalations did not further reduce disease activity. In patients who received ≥ 4 dose escalations, mean CDAI scores did not further reduce disease activity over time. Mean HAQ scores were stable over time in patients who received 2 or 3 dose escalations. In patients who received ≥ 4 dose escalations, mean HAQ scores decreased following 1 dose escalation but progressively increased following subsequent dose escalations. Initial dose escalations (from 3mg/kg to the equivalent of approximately 5 to 7mg/kg) may be useful in controlling disease activity; however, there may be diminishing clinical benefit of further escalations, which can also increase the potential risk for infection and increase incremental drug costs. • Initial infliximab dose escalations (1 to 2) may be useful in lowering disease activity in patients with rheumatoid arthritis. • There does not appear to be a clinical benefit in infliximab dose escalations above the equivalent of 5 to 7 mg/kg.

Immune Determinants in the Acquisition and Maintenance of Antibody to Hepatitis B Surface Antigen in Adults After First-Time Hepatitis B Vaccination.

Global implementation of a birth‐dose hepatitis B (HB) vaccine has significantly reduced the prevalence of hepatitis B virus (HBV) carriers. Durable and sufficient titers of antibodies to hepatitis B surface antigen (anti‐HBs) are desirable for vaccinees to gain resistance to HBV exposure. However, the existence of primary nonresponders and vaccinees who lost anti‐HBs over time remains a challenge for the strategy of HBV elimination. We thus aim to clarify the mechanisms of acquisition and maintenance of vaccine‐induced anti‐HBs in healthy adults. We retrospectively analyzed the vaccination records of 3,755 first‐time HB‐vaccinated students and also traced the acquired antibody transition of 392 first‐time vaccinees for 10 consecutive years. To understand the cellular and humoral immune response, we prospectively examined peripheral blood from 47 healthy first‐time HB‐vaccinated students, 62 booster‐vaccinated health care workers, and 20 individuals who maintained their anti‐HBs. In responders, a significant increase of follicular helper T (Tfh) cells, activated plasmablasts, and plasma cells was observed in first‐time‐vaccinated but not booster‐vaccinated persons. We also discovered memory B cells and antibody‐secreting cells were more abundant in individuals who maintained anti‐HBs. According to vaccination records, higher anti‐HBs antibody titer acquisition was related to the longer term maintenance of anti‐HBs, the level of which was positively correlated with prevaccination levels of serum interferon‐γ and related chemokines. The second series of vaccination as a booster provided significantly higher anti‐HBs antibody titers compared to the initial series. Conclusion: Coordinated activation of Tfh and B‐cell lineages after HB vaccination is involved in the acquisition and maintenance of anti‐HBs. Our findings support the rationale of preconditioning the immune status of recipients to ensure durable vaccine responses.

Optimising infliximab induction dosing for patients with ulcerative colitis.

The therapeutic failure of infliximab therapy in patients with ulcerative colitis remains a challenge even 2 decades after its approval. Therapeutic drug monitoring (TDM) has shown value during maintenance therapy, but induction therapy has still not been explored. Patients may be primary nonresponders or underexposed with the standard dosing regimen. We aimed to: (i) develop a population pharmacokinetic-pharmacodynamic model; (ii) identify the best exposure metric that predicts mucosal healing; and (iii) build an exposure-response (ER) model to demonstrate model-based dose finding during induction therapy with infliximab. Data were retrospectively collected from a clinical database. A total of 583 samples, from 204 patients, was used to develop a population pharmacokinetic model to generate exposure metrics for subsequent ER modelling. A subset of 159 patients was used to develop a logistic regression ER model, describing the relationship between infliximab exposure and ordered transitions between Mayo endoscopic subscore (MES) 3, 2 and ≤1 (baseline to post-induction). A 1-compartment population pharmacokinetic model with interindividual and interoccasion variability was found to fit the data best. Covariates influencing exposure were C-reactive protein, albumin, baseline MES, fat-free mass, concomitant corticosteroid use and pancolitis. The cumulative area under the infliximab concentration-time curve until endoscopy (CAUCendoscopy ) was found to be the best exposure metric for predicting mucosal healing (baseline MES >1 and post-induction MES ≤1). The model predicted that 70% of patients will attain mucosal healing with infliximab administered at days 0, 14 and 42 and a target CAUCendoscopy of 3752mg/L*day at day 84. TDM-based dose individualisation targeting CAUCendoscopy has the potential to improve the effectiveness of infliximab during induction therapy.

Immunogenicity is not the driving force of treatment failure in vedolizumab-treated inflammatory bowel disease patients.

The pivotal GEMINI trials reported low immunogenicity of vedolizumab. However, anti-vedolizumab antibodies (AVA) are frequently underestimated because most assays are not drug-tolerant and unable to detect antidrug antibodies while there is drug in the circulation. This study aimed to explore which antidrug antibody assay is best suited to detect AVA and investigated immunogenicity of vedolizumab in inflammatory bowel disease (IBD) patients discontinuing vedolizumab therapy. A drug-tolerant affinity capture elution (ACE) assay was developed for the measurement of AVA in the presence of vedolizumab and compared with the previously established drug-resistant and drug-sensitive assays. Vedolizumab and AVA were measured at week 6, at the last infusion, and 12-20weeks after treatment discontinuation in a cohort of 40 vedolizumab-treated IBD patients who stopped treatment due to primary non-response, loss of response, or adverse events. The drug-tolerant ACE assay could detect AVA in samples that the drug-resistant and drug-sensitive assays were unable to. Using the drug-tolerant ACE assay, 3 (8%) out of 40 vedolizumab-treated IBD patients who discontinued therapy were AVA positive at week 6, whereas no AVA were detected at the last infusion nor after treatment discontinuation. Primary non-responders had numerically lower median vedolizumab concentrations at week 6 compared with patients with loss of response (20.3 vs 30.7μg/mL, respectively, P=0.0570). Immunogenicity of vedolizumab is not the driving force of treatment failure, and AVA do not increase upon treatment discontinuation in vedolizumab-treated IBD patients. Underexposure during induction might partially be responsible for primary non-response.

Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma

BackgroundIsolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP.MethodBetween 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68 second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien–Dindo).ResultsThe results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p = 0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93 months (p = 0.02).ConclusionAs a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.

Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors.

Checkpoint inhibitors act by blocking physiologic mechanisms coopted by tumor cells to evade immune surveillance, restoring the immune system’s ability to identify and kill malignant cells. These therapies have dramatically improved outcomes in multiple tumor types with durable responses in many patients, leading to FDA approval first in advanced melanoma, then in many other malignancies. However, as experience with checkpoint inhibitors has grown, populations of patients who are primary nonresponders or develop secondary resistance have been the majority of cases, even in melanoma. Mechanisms of resistance include those inherent to the tumor microenvironment, the tumor cells themselves, and the function of the patient’s native immune cells. This review will discuss resistance to checkpoint inhibitors in melanoma as well as possible methods to restore sensitivity.

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Introduction: The association between infliximab (IFX) and fecal calprotectin (FC) levels on one hand, and the clinical and endoscopic response of patients with inflammatory bowel disease on the other, is well established. Objective and Methods: To investigate the association between inflammatory biochemical parameters and serum concentrations of IFX during induction treatment with a primary nonresponse in a prospective cohort of Crohn’s disease (CD) patients. Results: Of the 35 patients included, 8 (22.8%) had primary nonresponse at the end of induction. Induction IFX levels were lower among primary nonresponders at weeks 6 and 14 (week 6: median IFX level 7.3 vs. 11.2 μg/mL, respectively, p = 0.090; week 14: median IFX level 1.5 vs. 4.7 μg/mL, respectively, p = 0.020). FC levels were higher in patients with primary nonresponse versus primary response at weeks 0, 6, and 14 (week 0: median FC level 1,830 vs. 410 μg/g, ­respectively, p = 0.030; week 6: median FC level 1,150 vs. 230 μg/g, respectively, p = 0.074; week 14: median FC level 1,210 vs. 208 μg/g, respectively, p = 0.060). For the multivariate analysis, the median IFX level at week 14 and median FC level at week 0 were independently associated with primary nonresponse. A significant inverse correlation was determined between FC level at week 0 and IFX level at week 14 (Spearman’s rho correlation, 0.440; p < 0.05). Conclusions: IFX levels (at week 14) and baseline FC levels could predict primary nonresponse after induction IFX therapy in patients with CD. A high baseline inflammatory load might modify the pharmacokinetic processes of anti-tumor necrosis factor drugs. Drug level monitoring and measurement of baseline inflammatory parameters could improve the efficacy of IFX in the induction therapy of patients with active CD.

Influence of early adalimumab serum levels on immunogenicity and long‐term outcome of anti‐TNF naive Crohn's disease patients: the usefulness of rapid testing

Proactive testing of adalimumab serum levels is debated. To study the association between adalimumab serum levels at week 4 and the development of anti-adalimumab drug antibodies and long-term outcome in anti-TNF naive Crohn's disease patients. Serum samples from 116 biologically naive Crohn's disease patients with active disease were prospectively collected at baseline, and weeks 4 and 12. Adalimumab serum levels were measured using the RIDA® QUICK adalimumab lateral flow assay and anti-adalimumab drug antibodies were determined using a drug-resistant assay. Pharmacokinetic data were studied in relation to clinical outcome. Patients who stopped adalimumab by week 12 due to persisting symptoms were considered primary non-responders, whereas initial improvement with increasing symptoms after week 12 was considered loss of response. Adalimumab continuation until the end of follow-up was considered sustained clinical benefit. Patients with low serum levels at week 4 (<8.3μg/mL) were at significantly higher risk of being anti-adalimumab positive by week 12 (46.7% vs 13.0%, P=0.009). After a median follow-up of 89weeks, dose-escalation and sustained clinical benefit were observed in 37.1% and 48.3% of patients. The 21.4% of patients who were anti-adalimumab drug antibody positive by week 12, had a significantly higher need of dose escalation (P<0.001), and experienced sustained clinical benefit less frequently due to primary non-response or secondary loss of response (P=0.02). Our findings support early monitoring of adalimumab serum levels to guide dose optimisation, which may prevent immunogenicity and influence long-term outcome. We validated a novel lateral flow assay for quantitative determination of adalimumab levels, facilitating physicians to optimise therapy immediately at the outpatient clinic.

Development of an evidence-based brief \u2018talking\u2019 intervention for non-responders to bowel screening for use in primary care: stakeholder interviews

BackgroundBowel cancer is the third most common cause of cancer death worldwide. Bowel screening has been shown to reduce mortality and primary care interventions have been successful in increasing uptake of screening. Using evidence-based theory to inform the development of such interventions has been shown to increase their effectiveness. This study aimed to develop and refine a brief evidence-based intervention for eligible individuals whom have not responded to their last bowel screening invitation (non-responders), for opportunistic use by primary care providers during routine consultations.MethodsThe development of a brief intervention involving a conversation between primary care providers and non-responders was informed by a multi-faceted model comprising: research team workshop and meetings to draw on expertise; evidence from the literature regarding barriers to bowel screening and effective strategies to promote informed participation; relevant psychological theory, and intervention development and behaviour change guidance. Qualitative telephone interviews with 1) bowel screening stakeholders and 2) patient non-responders explored views regarding the acceptability of the intervention to help refine its content and process.ResultsThe intervention provides a theory and evidence-based tool designed to be incorporated within current primary care practice. Bowel screening stakeholders were supportive of the intervention and recognised the importance of the role of primary care. Interviews highlighted the importance of brevity and simplicity to incorporate the intervention into routine clinical care. Non-responders similarly found the intervention acceptable, valuing a holistic approach to their care. Moreover, they expected their primary care provider to encourage participation.ConclusionsA theory-based brief conversation for use in a primary care consultation was acceptable to bowel screening stakeholders and potential recipients, reflecting a health promoting primary care ethos. Findings indicate that it is appropriate to test the intervention in primary care in a feasibility study.

Genetic Markers Predict Primary Nonresponse and Durable Response to Anti-Tumor Necrosis Factor Therapy in Ulcerative Colitis.

Despite a high nonresponse rate, predictors of response to anti-tumor necrosis factor (anti-TNF) therapy in ulcerative colitis (UC) remain limited. We aim to determine clinical and genetic predictors of primary nonresponse (PNR) and durable response (DR) to anti-TNF therapy in a large prospective UC cohort. Using the Illumina Immunochip, candidate polymorphisms associated with clinical outcomes of PNR and DR were separately evaluated and combined into weighted genetic risk scores. Combined genetic and clinical multivariable models for PNR and DR were compared with clinical predictive models using area under the receiver operating characteristic (AUROC) curves. Models were internally (DR) or externally (PNR) validated. Multivariable logistic regression was utilized to assess the association of genetic risk scores with infliximab levels and antibodies. Of 231 patients, 28 (12%) experienced PNR and 120 (52%) experienced DR. There was no significant difference in clinical features between primary nonresponders and responders. Eight alleles were associated with PNR. A combined clinical-genetic model (AUROC, 0.87) more accurately predicted PNR compared with a clinical-only model (AUROC, 0.57; P < 0.0001). In an external cohort of 131 patients, increasing tertiles of PNR genetic risk score correlated with increased risk of PNR (P = 0.052). Twelve candidate loci were associated with DR. Genetic risk score quartiles for DR demonstrated a strong dose-response relationship in predicting treatment duration. Genetic risk scores for PNR and DR were not associated with infliximab levels or antibody formation. Genetic polymorphisms enhance prediction of PNR and DR to anti-TNF therapy in patients with UC.