Cause Of Treatment Discontinuation Research Articles

Liver decompensation is a frequent cause of treatment discontinuation and prognostic factor in intermediate-advanced HCC

Introduction and ObjectivesWith the advent of new therapeutic options for patients with hepatocellular carcinoma (HCC) for intermediate or advanced stages of the Barcelona Clinic Liver Cancer (BCLC), regional real-world data regarding prognostic survival factors are of significant importance. Patients and MethodsA multicenter prospective cohort study was conducted in Latin America including BCLC B or C patients since 15th May 2018. We report here the second interim analysis focusing on prognostic variables and causes of treatment discontinuation. Cox proportional hazard survival analysis was performed, estimating hazard ratios (HR) and 95% confidence intervals (95% CI). ResultsOverall, 390 patients were included, 55.1% and 44.9% were BCLC B and C at the time of study enrollment. Cirrhosis was present in 89.5% of the cohort. Among the BCLC-B group, 42.3% were treated with TACE with a median survival since the first session of 41.9 months. Liver decompensation before TACE was independently associated with increased mortality [HR 3.22 (CI 1.64;6.33); P<.001]. Systemic treatment was initiated in 48.2% of the cohort (n=188), with a median survival of 15.7 months. Of these, 48.9% presented first-line treatment discontinuation (44.4% tumor progression, 29.3% liver decompensation, 18.5% symptomatic deterioration, and 7.8% intolerance), and only 28.7% received second-line systemic treatments. Liver decompensation [HR 2.9 (1.64;5.29); P<.0001], and symptomatic progression [HR 3.9 (1.53;9.78); P=0.004] were independently associated with mortality after first-line systemic treatment discontinuation. ConclusionsThe complexity of these patients, with one-third presenting liver decompensation after systemic therapies, underlines the need for multidisciplinary team management and the central role of hepatologists.

Abstract P6-10-03: Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 mAb covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor selective, tetrapeptide-based cleavable linker. Dato-DXd has previously shown encouraging activity in heavily pretreated patients (pts) with metastatic TNBC (Krop, SABCS 2021). Here we report updated results from the TROPION-PanTumor01 study in pts with advanced/metastatic TNBC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with advanced TNBC that relapsed/progressed on standard therapies; 2 pts received 8 mg/kg prior to selection of 6 mg/kg. The primary objectives were safety and tolerability. Tumor responses, including objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]), were assessed per RECIST v1.1 by blinded independent central review. Results: As of April 29, 2022, 44 pts received Dato-DXd (median follow-up, 16.6 mo [range, 13-22]) at the time of data cutoff. The primary cause of treatment discontinuation was disease progression (86%; PD or clinical progression), and 4 pts are still receiving therapy. Median age was 53 y (range, 32-82); 32% had de novo metastatic disease. Pts were heavily pretreated with a median of 3 (range, 1-10) prior regimens in the metastatic setting. Prior treatments included taxanes (91%), anthracyclines (75%), capecitabine (61%), platinum (52%), immunotherapy (43%), Topo I inhibitor–based ADC therapy (32%), and PARPi (18%). Treatment-emergent adverse events (TEAEs; all cause) occurred in 100% (any grade) and 50% (grade ≥3) of pts, respectively. Most common TEAEs (any grade, grade ≥3) were stomatitis (73%, 11%), nausea (66%, 2%), vomiting (39%, 5%), fatigue (34%, 7%), and alopecia (36%, 0%). One pt had grade 3 decreased neutrophil count; no cases of interstitial lung disease (ILD) or grade ≥3 diarrhea were observed. Serious TEAEs were reported in 9 pts (20%); no deaths associated with adverse events (AEs) were observed. Dose reductions occurred in 8 pts (18%) due to stomatitis (n=3), fatigue (n=2), dry eye (n=1), retinal exudates (n=1), and dysgeusia (n=1); 12 pts (27%) delayed treatment due to stomatitis (n=5), dry eye (n=1), keratitis (n=1), blurred vision (n=1), fatigue (n=1), bronchitis (n=1), skin infection (n=1), musculoskeletal chest pain (n=1), dysgeusia (n=1), chronic obstructive pulmonary disease (n=1), and dyspnea (n=1; &amp;gt;1 AE per pt). One pt (2%) discontinued treatment due to grade 1 pneumonitis (which was centrally adjudicated as not ILD). ORR in all pts was 32% (1 CR, 13 PRs), DCR was 80% (35/44), and clinical benefit rate (CR + PR + SD ≥6 mo) was 34% (15/44). Median duration of response was not yet reached; median progression-free survival (mPFS) was 4.3 mo (95% CI, 3.0-7.3), and median overall survival (mOS) was 12.9 mo (95% CI, 10.1-14.7). In the subset of pts without prior Topo I inhibitor–based ADC therapy and with measurable disease at baseline, ORR was 44% (12/27). Among all pts without prior Topo I inhibitor–based ADC therapy (n=30), mPFS was 7.3 mo (95% CI, 3.0-NE), and mOS was 14.3 mo (95% CI, 10.5-NE). Conclusions: Dato-DXd continues to demonstrate encouraging and durable antitumor activity, along with a manageable safety profile, in heavily pretreated pts with metastatic TNBC. Based on these findings, the phase 3 randomized TROPION-Breast02 (NCT05374512) trial comparing Dato-DXd vs chemotherapy as 1L therapy for pts with metastatic TNBC is currently underway. Citation Format: Aditya Bardia, Ian Krop, Funda Meric-Bernstam, Anthony W. Tolcher, Toru Mukohara, Aaron Lisberg, Toshio Shimizu, Erika Hamilton, Alexander I. Spira, Kyriakos P. Papadopoulos, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Takahiro Kogawa. Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-03.

Abstract PD13-08: PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor–Positive/HER2–Negative Breast Cancer (BC)

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd demonstrated compelling single-agent antitumor activity in heavily pretreated patients (pts) with metastatic triple-negative BC (Krop, SABCS 2021). This is the first report of results from the TROPION-PanTumor01 study in pts with unresectable or metastatic hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−; including HER2-low and HER2-zero) BC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical findings and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with unresectable or metastatic HR+/HER2− BC that progressed on standard therapies. The primary objectives were safety and tolerability. Tumor responses, including ORR (complete response [CR] + partial response [PR]) and DCR (CR + PR + stable disease [SD]), were assessed per RECIST version 1.1 by blinded independent central review. Results: As of the April 29, 2022, data cutoff, 41 pts had received Dato-DXd (median follow-up, 10.9 mo [range, 7-13]); 9 pts were ongoing. The primary cause of treatment discontinuation was disease progression (63%; progressive disease [PD] or clinical progression). Median age was 57 y (range, 33-75); 54% had de novo metastatic disease. Pts were heavily pretreated (Table) with a median of 5 (range, 3-10) prior regimens in the advanced setting; 95% had prior CDK4/6i (adjuvant/metastatic). Median time from initial treatment for metastatic disease to the first dose of Dato-DXd was 42.7 mo (range, 10.2-131.1). Treatment-emergent adverse events (TEAEs; all cause) were observed in 98% (any grade) and 41% (grade ≥3) of pts. Most common TEAEs (any grade, grade ≥3) were stomatitis (80%, 10%), nausea (56%, 0%), fatigue (46%, 2%), and alopecia (37%, 0%). Serious TEAEs were observed in 6 pts (15%); 1 pt died due to dyspnea, which was not considered to be treatment related. Dose reductions occurred in 5 pts due to stomatitis (n=3), fatigue (n=2), keratitis (n=1), and decreased appetite (n=1) (&amp;gt;1 AE per pt); 14 pts had treatment delayed due to stomatitis (n=8), retinopathy (n=1), dysphagia (n=1), fatigue (n=1), malaise (n=1), COVID-19 (n=1), cellulitis (n=1), urinary tract infection (n=1), decreased lymphocyte count (n=1), and nasal congestion (n=1; &amp;gt;1 AE per pt). Three pts discontinued treatment due to keratitis (n=1) and pneumonitis (n=2); 1 case of pneumonitis was adjudicated as grade 2 drug-related interstitial lung disease. The ORR was 29% (11 confirmed PRs; 1 pending confirmation), the DCR was 85% (35/41), and the clinical benefit rate (CR + PR + SD ≥6 mo) was 41% (17/41). Conclusions: Dato-DXd demonstrated a manageable safety profile and encouraging antitumor activity, with high disease control in heavily pretreated pts, the majority having received prior CDK4/6i. Based on these findings, the TROPION-Breast01 (NCT05104866) randomized phase 3 study comparing 2L+ Dato-DXd vs investigator’s choice chemotherapy is currently enrolling pts with HR+/HER2− BC. Prior Therapies in the Adjuvant or Metastatic Setting Citation Format: Funda Meric-Bernstam, Ian Krop, Dejan Juric, Takahiro Kogawa, Erika Hamilton, Alexander I. Spira, Toru Mukohara, Takuya Tsunoda, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Aditya Bardia. PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor–Positive/HER2–Negative Breast Cancer (BC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-08.

Effectiveness and safety of encorafenib-cetuximab in BRAFV600E metastatic colorectal cancer: Confidence study.

126 Background: BRAFV600E mutant metastatic colorectal cancer (mCRC) has a poor prognosis. The BEACON trial demonstrated an improvement in tumor response, overall survival (OS), and progression-free survival (PFS) when administering encorafenib-cetuximab (EC) to patients (pts) who progressed after 1 or 2 therapy lines. This study provides a retrospective analysis of the effectiveness and safety of EC in the real-world setting in Spain. Methods: This retrospective analysis included BRAFV600E mCRC pts treated with EC in 2nd line treatment, recruited from March to July 2022. The Co-primary study endpoints included effectiveness based on PFS and OS. Secondary endpoints included sociodemographic and clinical characteristics of patients before EC initiation, overall response rate (ORR), and safety. Results: From March to July 2022, 81 evaluable pts were included. Sociodemographic and clinical characteristics are displayed.A median (interquartile range [IQR]) of 6.0 (4.0-13.0) cycles of encorafenib and 6.0 (4.0-14.5) cycles of cetuximab were administered. Median treatment duration was 4.4 (2.6-7.8) months (m) and 4.4 m (2.8-7.6) respectively. The ORR and disease control rate was 33.8 % (CI 95% 23.4-45.5) and 68.8 (CI 95% 57.3 – 78.9) respectively. One (1.2%) pt achieved complete response At data cut-offwith a 9.7 median follow-up, 50 (61.7%) pts had died, all of them due to disease progression. Median (95% Confidence Interval, CI) OS was 12.6 m (8.0-17.3) and median PFS was 5.0 m (3.8-6.2). The 12-m OS and 12-m PFS rates were 54.6% (95% CI, 43.3-65.9) and 19.9% (10.5-29.3) respectively. Pts with neutrophils/lymphocyte ratio (NLR) ≥3 had worse OS (HR, 1.8 95% CI 1.0-3.2; p &lt; 0.049) and worse PFS (HR, 2.3, 1.4-3.8; p &lt; 0.002). Disease progression (86.7%) was the most frequent cause of treatment discontinuation, followed by unacceptable AEs (3.7%). Eleven pts (13.5%) experienced treatment-related graded 3 or 4 AEs, mainly acne (3.7%). Treatment-related deaths were not reported. Conclusions: This study provides real-world data of BRAFV600E mCRC pts treated with EC combination in routine clinical practice in Spain. EC effectiveness and safety were consistent with the results obtained in clinical trials. [Table: see text]

A Multi-Center Phase Ib Trial of the Histone Deactylase Inhibitor (HDACi) Entinostat in Combination with Anti-PD1 Antibody Pembrolizumab in Patients with Refractory/Relapsed Myelodysplastic Syndromes (RR-MDS) or Oligoblastic Acute Myeloid Leukemia (RR-AML) after Hypomethylating Agent (HMA) Failure

Introduction: Pts with MDS and HMA failure have a poor prognosis and need novel therapies. Success with anti-PD1 therapy in myeloid malignancies has been limited and resistance mechanisms are poorly understood. Preclinical data suggest that myeloid-derived suppressor cells (MDSCs) contribute to MDS progression (Chen et al. JCI 2013). and may mediate resistance to anti-PD1 therapy (Kim et al. PNAS 2014). As HDACi decrease MDSCs, synergistic anti-tumor efficacy with anti-PD-1 has been hypothesized leading to this phase Ib study (NCT02936752) of the HDACi entinostat and anti-PD1 antibody pembrolizumab in pts with MDS or oligoblastic AML and HMA failure. Methods: We conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program (NCI-CTEP)-sponsored, multicenter, dose escalation and expansion phase Ib trial. Adult (≥18 years) pts with MDS or oligoblastic AML (bone marrow [BM] blasts 20-30%) and HMA failure were enrolled. Pts had to have adequate end organ function and ECOG performance status ≤2. The dose-escalation part used 2 dose levels (DL1: entinostat 8mg PO on days 1 and 8 of each 21-day cycle; DL2: entinostat 8mg PO on days 1, 8, and 15 of each 21-day cycle) with pembrolizumab 200mg IV on day 1 of each 21-day cycle starting with cycle 2. In cycle 1, pts received only entinostat to determine its impact on MDSCs separately from pembrolizumab. Toxicities were tabulated and graded according to CTCAE-5. Dose-limiting toxicities (DLT) were defined as any of the following if deemed possibly related to trial therapy: Grade (G) 3/4 non-hematologic toxicity, any ≥G3 immune related adverse events (IrAEs) or any IrAE resulting in pembrolizumab interruption or discontinuation during the first 2 cycles of combined therapy. Hematologic AEs were considered a DLT only if they were unrelated to MDS and lasted for >42 days. The primary endpoint was safety and determination of the maximum tolerated dose. The secondary endpoint was the overall response rate defined as a composite of complete remission, partial remission, and hematologic improvement (HI) per the 2006 IWG response criteria in MDS and change in MDSCs and PD1/PDL-1 in BM. Results: Between 06/26/2017 and 02/03/2021, we enrolled 28 pts (25 MDS and 3 AML). Median age was 74 years (range [R], 57-86), all pts had received prior HMA with 5 pts (18%) having had ≥3 prior lines of therapy. Median IPSS-R at screening for MDS pts was 5.5 (R: 2-10). Baseline demographic and clinical characteristics are shown in Table 1. During dose escalation, 7 pts were enrolled in DL1 (1 pt not evaluable due to early disease progression during DLT period), and 6 pts were treated on DL2. There was 1 DLT on DL1 (G5 pneumonia/bronchoalveolar hemorrhage (BAH), while 2 pts experienced DLTs at DL2 (G3 pharyngeal mucositis and G3 anorexia). There were no hematologic DLTs during dose escalation. Thus, DL1 was expanded, and another 15 pts were enrolled at DL1. Across the entire study, pts received a median of 3 cycles of therapy (R: 1-12 cycles). The most frequent cause of treatment discontinuation was disease progression in 9 pts. Four pts died during the study, 2 due to therapy-related complications (1 from pneumonia/BAH, 1 from multi-organ failure which occurred after the DLT period in DL2). A summary of the AEs is presented in Table 2. Hematologic AEs were common. The most common non-hematologic ≥G3 AEs independent of treatment attribution were infection (32.1%), hypoxia/respiratory failure (10.7%) and dyspnea (10.7%). Potential IrAEs of any grade were reported in 5 pts including G3 pneumonitis in 2 pts. Serious AEs were reported in 14 pts; 8 of which were potentially attributed to treatment. Among the 19 pts with the first BM efficacy assessment after 3 months, no pt achieved a protocol-defined response. However, 2 pts had mCR (BM blasts decreased from a baseline of 7% and 10% to 2% and 4%, respectively) without HI. Twelve pts had stable disease, while 5 had progressive disease. With a median follow-up of 5.9 months (R: 0.5 - 59.1 months), median OS was 6.9 months (95% CI: 4.8 - 13.6 months). Correlative studies are being conducted. Conclusion: In this multi-center phase 1b investigator-initiated trial in MDS and oligoblastic AML pts after HMA failure, entinostat + pembrolizumab at DL1 was reasonably tolerated but had limited therapeutic efficacy. Ongoing correlative work will explore the disconnect between the preclinical and clinical data regarding potential synergy of entinostat + pembrolizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Step-up titration dosing (TD) of carfilzomib (K) is associated with prolonged duration of therapy and improved treatment outcomes compared to standard dosing (SD) in patients with multiple myeloma (MM).

e20016 Background: K is a 2nd-generation proteasome inhibitor (PI) approved for the treatment of multiple myeloma (MM). K-based regimens are associated with higher rates of CV toxicity compared with other PIs. We conducted a retrospective analysis to assess incidence of CV adverse events (AE) and outcomes of MM patients (pts) treated with K using a step-up TD schedule compared to SD protocol. Methods: A retrospective chart review was performed of MM pts treated with K at The Ohio State University Comprehensive Cancer Center (OSUCCC) from 1/1/13 to 9/1/19. Pt demographics, disease and K-related characteristics, CV AE, and follow-up information were collected. Pts were excluded if treated at both local center and at OSUCCC, not K-naïve when receiving treatment at OSUCCC, received a single dose of K while inpatient with no intent to continue treatment outpatient, or had a treatment plan entered but never received it. Results: Of the 166 pt charts analyzed, 36 were treated using a TD method (ex. step-wise C1D1 20mg/m2, C1D8 27mg/m2, C1D15 36mg/m2, for goal C2D1 56mg/m2 onwards) and 130 pts were treated using a standard dosing method (ex. C1D1 20mg/m2 and C1D8 56mg/m2 onwards). Pre-existing CV risk factors were similar between the two groups. There was a slight difference in baseline renal function (TD: median CrCl 94mL/min, SD: 76mL/min; p=0.01) and prior PI use (TD: 86.1%, SD: 95%; p=0.048) between the two groups. In pts treated with TD, hypertension (HTN) developed earlier compared with SD (p=0.02). There was a lower incidence of onset of dyspnea in the TD group compared to SD group (16.7% vs 36.2%, respectively; p=0.03). There were no differences in incidence of HTN, congestive heart failure, ischemic heart disease, arrythmias, or pulmonary HTN. The median number of cycles administered to titrated pts was 7 (range: 2-56) compared to 3 (range: 1-44) for standard pts (p&lt;0.001). There was no statistical difference in CV AE being the cause for treatment discontinuation between the two groups. The overall response rate (ORR) was higher in the TD group compared to the SD group (63.9% vs 42.8%, respectively; p=0.04). Five-year overall survival (OS) was improved in patients treated with TD than with SD (43.8% vs 17.5%, respectively; p&lt;0.001). By multivariable analysis, TD was associated with improved OS compared to SD (HR 0.47; 95% CI 0.29-0.77-3.58; P=0.003). Conclusions: A simple modification of K titration dosing improved the tolerability of MM therapy without compromising efficacy. Although there were no differences in AE being the cause of treatment discontinuation between the two groups, an improvement in duration of therapy, ORR, and OS was observed in the TD group. As a result, TD is the standard-of-care dosing for MM pts treated with K at the OSUCCC. Prospective trials are needed to confirm the safety and efficacy of this dosing regimen.

Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial.

107 Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. A phase I, open-label study (NCT03530397) of MEDI5752 monotherapy 2.25–2500 mg IV Q3W showed encouraging antitumor activity in advanced solid tumors. Maximum tolerated dose was not reached; doses &lt;1500 mg were better tolerated than doses ≥1500 mg. Here we present preliminary results in pts with advanced RCC in the escalation (ESC) and expansion (EXP) cohorts. Methods: Eligible pts were ≥18 yrs old (ECOG PS 0–1). In ESC and EXP, pts could be treatment-naïve (1L) or refractory. Eligible EXP pts had clear cell component (ccRCC), were immunotherapy-naïve (IO-naïve) and limited to ≤2 prior lines of therapy. Pts were treated until progression or unacceptable toxicity. Primary objectives were safety and tolerability (ESC), and antitumor activity by objective response per RECIST v1.1 (EXP). Results: Overall, 46 RCC pts were treated: 19 ESC, 27 EXP. In ESC, pts (all IO-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2000 mg (n=16) and 2500 mg (n=2). Seven pts (36.8%) had objective responses (all PRs); 4 of these were 1L, including 1 each with papillary and sarcomatoid histology. In EXP, pts (all IO-naïve, 63.0% prior nephrectomy, 48.1% 1L [of whom 69.2% had IMDC intermediate/poor risk], 96.3% clear cell histology) received MEDI5752 1500 mg IV Q3W. Ten (38.5%) had objective responses (2 CRs, 8 PRs). In 1L EXP pts, 58.3% had objective responses (1 CR and 6 PRs); disease control rate (DCR) was 91.7% (Table). Grade 3/4 treatment-related adverse events (TRAEs) were seen in 68.4% of ESC and 74.1% of EXP pts. In EXP, treatment-emergent AEs (TEAEs), particularly hepatotoxicity, were the most common cause of treatment discontinuation (D/C). At a median duration of follow-up of 14.6 mo, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median PFS and OS were NR in 1L EXP pts. Conclusions: MEDI5752 monotherapy showed deep and durable antitumor activity in pts with advanced RCC, despite high rates of treatment D/C, particularly in the 1L setting. To better characterize the risk-benefit profile, MEDI5752 is now being explored at doses &lt;1500 mg in 1L ccRCC expansion cohorts. Clinical trial information: NCT03530397. [Table: see text]

Real-world use of mycophenolate mofetil in inflammatory bowel disease: Results from the ENEIDA registry.

Studies to evaluate the use of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) are limited after the appearance of biological treatments. Our primary objective was to evaluate the effectiveness and safety of MMF in IBD. IBD patients who had received MMF were retrieved from the ENEIDA registry. Clinical activity as per the Harvey-Bradshaw Index (HBI), partial Mayo score (pMS), physician global assessment (PGA) and C-reactive protein (CRP) were reviewed at baseline, at 3 and 6 months, and at final follow-up. Adverse events and causes of treatment discontinuation were documented. A total of 83 patients were included (66 Crohn's disease, 17 ulcerative colitis), 90% of whom had previously received other immunosuppressants. In 61% of patients systemic steroids were used at initiation of MMF, and in 27.3% biological agents were co-administered with MMF. Overall clinical effectiveness was observed in 64.7% of the population. At the end of treatment, 45.6% and 19.1% of subjects showed remission and clinical response, respectively. MMF treatment was maintained for a median of 28.9 months (IQR: 20.4-37.5). Our study suggests, in the largest cohort to date, that MMF may be an effective alternative to thiopurines and methotrexate in IBD.

Evaluation of voriconazole related adverse events in pediatric patients with hematological malignancies.

Despite therapeutic drug monitoring and pharmacogenetic-guided dose selection are recommended for pediatric patients, safety of voriconazole is mostly monitored by clinical assessment. Having comprehensive knowledge of safety profile and distinguishing incidental events from the reactions that are truly related to voriconazole use are crucial for safer and uninterrupted treatment. This study aimed to address adverse reactions during the first month of voriconazole use by systematically evaluating retrospective records of all adverse events. Patients/Methods: It is a single-center, retrospective analysis of patients who received voriconazole from 1 September 2010 to 1 September 2020. Severity of abnormal findings in medical records were systematically graded. Causality between voriconazole and the events was evaluated by Liverpool Causality Assessment Tool (LCAT), Naranjo Algorithm and World Health Organization Causality Assessment System. The events with possible or probable causal relation to voriconazole are classified as adverse reaction. Records of 45 patients included in the study. The overall frequency of adverse reactions was 51.1%. Hepatobiliary laboratory adverse reactions identified in 48.9% of the patients and led to treatment discontinuation in 20.0%. Amylase and lipase elevation (2.2%), ventricular extra systoles (2.2%), hallucination and nightmares (2.2%) were other adverse reactions. Hepatobiliary abnormalities were the most common adverse reactions and the most common cause of treatment discontinuation. For safer treatment in critically ill patients, the dose should be personalized. To clearly identify the accurate frequency and the causality of all adverse reactions, prospective studies with much larger sample size are needed.

Efficacy of retreatment with oxaliplatin-based regimens in metastatic colorectal cancer patients: The RETROX-CRC retrospective study.

127 Background: Oxaliplatin in association with fluoropyrimidines is universally considered one of the most effective drugs for colorectal cancer and the mainstay of front-line treatment of metastatic patients. In contrast the efficacy and safety profile of oxaliplatin based regimens in the late-care treatment space have been poorly and conflictingly reported. Methods: We identified a real-world cohort of metastatic colorectal cancer (mCRC) patients undergoing repeated oxaliplatin treatments in a single institution and retrospectively analysed their clinicopathological features to identify potential efficacy-predictive determinants of oxaliplatin response at retreatment (RETROX-CRC Study). Results: Out of 2,606 consecutive mCRC patients referred to Niguarda Cancer Center, 119 fulfilled the eligibility criteria of the study. The response rate (RR) and the disease control rate (DCR) after oxaliplatin retreatments were respectively 21.6% (95% CI 14.4-31.0%), and 57.8% (95% CI 47.7-67.4). A trend towards better RR and DCR was observed among patients who were exposed to oxaliplatin in the adjuvant setting, while a significantly poorer outcome was observed when two or more intervening treatments were delivered in between oxaliplatin exposures. Median progression-free survival (PFS) was 5.1 months (95% CI 4.3-6.1), significantly lower if oxaliplatin was re-administered beyond the third line (HR 2.02; 1.25-3.25; p=0.004). Safety data were reliably retrieved in 65 patients (54,6%). Of these 18.5% (12/65) and 7.7% (5/65) of them had G3-4 toxicities. Overall, toxicity was the cause of treatment discontinuation in almost a third of cases (28.6%; 34/119), with hypersensitivity reactions as the most prevalent reason for stopping treatment (58.8%; 20/34). Conclusions: In this large real-world series of 2,606 mCRC patients, less than 5% were re-treated with oxaliplatin. A late-disease control was achieved in almost 60% of patients, with a clinically acceptable sustained PFS and safety. Given the low performance of current standard drugs in late care of mCRC, retreatment with oxaliplatin might be considered a viable alternative especially if hopefully biology-based predictive markers for improving patient selection could be found.

Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)

Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)

Tapentadol Safety and Patient Characteristics Associated with Treatment Discontinuation in Cancer Therapy: A Retrospective Multicentre Study in Japan.

IntroductionTapentadol has analgesic effects comparable to those of conventional opioids and is associated with fewer side effects, including gastrointestinal symptoms, drowsiness, and dizziness, than other opioids. However, the safety of tapentadol in the Japanese population remains unclear; the present multicentre study aimed to examine the safety of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events.MethodsThe safety of tapentadol was assessed retrospectively in patients with any type of cancer treated between August 18, 2014 and October 31, 2019 across nine institutions in Japan. Patients were examined at baseline and at the time of opioid discontinuation. Multivariate analysis was performed to identify factors associated with tapentadol discontinuation owing to adverse events.ResultsA total of 906 patients were included in this study, and 685 (75.6%) cases were followed up until tapentadol cessation for any reason. Among patients who discontinued treatment, 119 (17.4%) did so because of adverse events. Among adverse events associated with difficulty in taking medication, nausea was the most common cause of treatment discontinuation (4.7%), followed by drowsiness (1.8%). Multivariate analysis showed that those who were prescribed tapentadol by a palliative care physician (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.36–4.99, p = 0.004), patients switching to tapentadol due to side effects from previous opioids (OR 2.19, 95% CI 1.05–4.56, p = 0.037), and patients who did not use naldemedine (OR 5.06, 95% CI 2.47–10.37, p < 0.0001) had an increased risk of treatment discontinuation owing to adverse events.ConclusionsThis study presents the safety profile of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events in the Japanese population. Prospective controlled trials are required to evaluate the safety of tapentadol and validate the present findings.Trial Registration NumberUMIN 000044282 (University Hospital Medical Information Network).

Treating CLL with Bruton Tyrosine Kinase Inhibitors: The Role of the Outpatient Oncology Nurse.

To summarize the role of Bruton tyrosine kinase (BTK) inhibitors in the management of chronic lymphocytic leukemia with a focus on the nursing role in relation to patients with chronic lymphocytic leukemia being treated with BTK inhibitors. These include published articles (PubMed) and national and international guideline documents. BTK inhibitors have revolutionized the therapy of chronic lymphocytic leukemia and have become the most frequently used therapy today. Despite the many advantages of BTK inhibitors, adverse events remain a leading cause of treatment discontinuation, particularly for the first-in-class BTK inhibitor. Second-generation BTK inhibitors appear to have a better tolerability profile but still require adverse event management given their prolonged duration of therapy. Awareness and management of side effects by the oncology care team is essential for ensuring both compliance and safety with ongoing treatment. Chronic lymphocytic leukemia is a chronic illness with a long-life expectancy. For the patients who require therapy, BTK inhibitor therapy is a frequently applied treatment with impressive efficacy. BTK inhibitors are continued indefinitely until disease progression or significant toxicity; therefore, the overall principles of careful assessment for side effects, diligent management for these, and individualized patient support provided by oncology nurses is vital in this patient population.

Sustained Long-Lasting Responses after Lenalidomide Discontinuation in Patients with Chronic Lymphocytic Leukemia

Sustained Long-Lasting Responses after Lenalidomide Discontinuation in Patients with Chronic Lymphocytic Leukemia

A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers.

Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood. We conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered. Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding. Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

Real-world outcomes for the treatment of relapsed/refractory multiple myeloma patients with lenalidomide-dexamethasone combinations in a Latin American country. A retrospective cohort study from grupo argentino de mieloma múltiple

ABSTRACT Objectives We compared the efficacy of lenalidomide-dexamethasone (Rd) based treatments for relapsed/refractory multiple myeloma patients (pts), in a real-world setting. In addition, we evaluated adverse events (AE), progression-free survival (PFS) and overall survival (OS). Methods In our retrospective, multicentric study, 156 pts with RRMM were included. 74/156 pts (47%) were refractory to bortezomib (V) and 43/156 (27%) pts to lenalidomide (R), with 24/156 (15%) of pts double refractory. Eighty-six pts (55%) received Rd with carfilzomib (KRd), 30 pts (19%) bortezomib (VRd), 30 pts (19%) daratumumab (DRd), and 10 pts (6%) ixazomib (IRd). Results The overall response (ORR) (≥ partial response) for the entire cohort was 71%, with a very good partial response rate or better (≥VGPR) of 35%. We found no significant differences in CR or ≥VGRP rates between treatments (p:0.229). Regardless of the combination received, those patients who achieved CR had significantly improved PFS (p: 0.007). The most frequent cause of treatment discontinuation was disease progression in 55/156 pts (35%). 8 pts (5%) discontinued treatment due to treatment-related adverse events (AE). Conclusion This is the first report of Rd combinations for the treatment of RRMM in Latin America. All combinations proved to be effective with an acceptable toxicity.

Abstract PS10-49: Phase 3b CompLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer: Final results from the UK cohort

Abstract Background: Ribociclib is an oral selective CDK4/6 inhibitor approved for use in combination with an aromatase inhibitor (AI) or fulvestrant, in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in several countries, including the UK. Ribociclib plus endocrine therapy (ET) significantly improved PFS outcomes in phase III registration studies (MONALEESA-2, -3, and-7) compared with placebo plus ET; and significantly increased OS in combination with AI in premenopausal women (MONALEESA-7), and in combination with fulvestrant in postmenopausal women (MONALEESA-3). This analysis aims to report the final efficacy and safety results for the UK cohort of CompLEEment-1, a phase 3b trial evaluating ribociclib plus letrozole in an expanded patient population.Methods: Patients with HR+, HER2- ABC, ≤1 line of prior chemotherapy (CT), and no prior ET in the advanced setting, received ribociclib + letrozole. Baseline characteristics and interim results of the UK cohort have been reported previously (Ring et al. SABCS 2019. Poster 443).Results: A total of 139 UK patients received ≥1 dose of study treatment at UK sites. At the cut-off date, November 8th 2019, 53 patients (38.1%) had completed treatment and 86 discontinued due to disease progression (30.9%), adverse events (24.5%), physician or subject/guardian decision (2.9% each), and protocol deviation (0.7%). The mean age of patients was 61.3 (SD10.67). 138 (99.3%) patients were female, 125 (89.9%) were post-menopausal and 50 (35.9%) had an ECOG status of ≥1. 85 (61.1%) patients had received prior chemotherapy in any setting.89 (64.0%) patients had measurable disease at baseline. 80 (60.4%) patients presented with visceral disease, 35 (25.2%) with bone-only metastases and 4 (2.9%) had CNS metastases. 59 (42.5%) of patients had ≥3 metastatic sites. The median duration of exposure to study treatment was 18.4 months with a median time to progression of 27.6 months. The overall response rate was 25.9% (95% CI: 18.8, 34.0) and clinical benefit rate was 74.1% (95% CI: 66.0, 81.2). Overall, the adverse event (AE) profile was consistent with previous phase III trials. Neutropenia (68.3%), nausea (59.7%), and fatigue (54%) and neutropenia (48.9%) were the most common adverse events (all grades). Neutropenia was the most common AE leading to dose reduction (12.2%) or interruption (33.8%), with ALT increase the most common cause for treatment discontinuation (10.1%). QT prolongation (all grades) led to 3 (2.2%) dose interruptions and 2 (1.4%) dose reductions, but no treatment discontinuations. Conclusions: This subgroup analysis of the COMPLEEMENT-1 study provides further clinically meaningful outcomes on first-line ribociclib and letrozole treatment in a UK cohort. This treatment combination showed consistent efficacy and side effect profile in UK HR+, HER2- ABC patients, consistent with the overall ITT population as well as results observed in the other pivotal ribociclib registration studies. NCT02941926. Citation Format: Mark Tuthill, Hardeep Marwaha, Christoph EA Hartmann. Phase 3b CompLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer: Final results from the UK cohort [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-49.

Determinants of doctors’ antibiotic prescriptions for patients over 75 years old in the terminal stage of palliative care

IntroductionNotwithstanding high prevalence of presumably bacterial infections in elderly persons (EP) in palliative care (PC), there exists no recommendation on the role of antibiotic therapy (ABP) in this type of situation. ObjectiveTo describe the determinants of antibiotic prescription by general practitioners (GP) and by doctors practicing in institutions (DPI) for patients>75 years, in end-of-life situations in PC. MethodDescriptive investigation by anonymous self-administered questionnaire disseminated in France by e-mail. ResultsA total of 301 questionnaires analyzed: 113 GP, 188 DPIs. The latter were mainly geriatricians (69, 36.6%) and infectologists/internists (41, 21.8%). Sixty-three (55,75%) GPs and 144 (78.7%) DPIs stated that they had prescribed antibiotics. Practice in "EHPAD" retirement homes or intensive care was often associated with non-prescription of antibiotics. Age, PC training and number of patients monitored bore no influence. Family involvement in decision-making was more frequent for GPs than for DPIs. The main purpose of antibiotic therapy was to relieve different symptoms (fever, respiratory congestion, functional urinary signs). Most of the doctors (81%) had previously encountered complications (allergy, adverse effect), which represented the main causes of treatment discontinuation. ConclusionAntibiotic use in end-of-life EPs in PC seems frequent. In accordance with the principle of beneficence, its goal of often symptom-related; that said, in the absence of scientific data, antibiotic prescription in end-of-life situations should be individualized in view of observing the other ethical caregiving principles (beneficence, non-maleficence, justice, patient autonomy) and re-evaluated daily.

Effectiveness of Dimethyl Fumarate in Real-World Clinical Practice and Strategy to Minimize Adverse Effects and Use of Healthcare Resources.

BackgroundDimethyl fumarate (DMF) has shown efficacy in reducing relapse rates in patients with multiple sclerosis (MS). However, associated adverse effects (AE) such as gastrointestinal (GI) AE, flushing and lymphopenia are the main cause of treatment discontinuation. The aim of this study was to evaluate the effectiveness of DMF, and to assess strategies to reduce treatment discontinuation rates in routine clinical practice.Patients and MethodsNinety patients started DMF treatment between August 2015 and February 2020. Prior to DMF therapy, patients received written information regarding treatment and the management of AE, along with medical prescriptions. Clinical and analytical data were collected at clinical visits performed at least 6-monthly, and disease progression was evaluated by brain magnetic resonance imaging (MRI).ResultsPrior to DMF, 78.7% of patients had an annualized relapse rate (ARR) of 1.07 (range: 1–3) and median Expanded Disability Status Scale (EDSS) score of 1.0 (range: 0–2). At final follow-up, ARR and median EDSS scores were significantly reduced to 0.09 (range: 0–2; p< 0.001) and 0 (range: 0–1.625; p< 0.001), respectively. Just over one quarter of patients with brain MRI (26.8% of 71 patients) showed improvement in disease activity based on MRI evaluation. Lymphopenia was associated with previous treatment lines (p=0.042) and longer disease duration (p=0.032). A total of twelve patients abandoned DMF treatment, mainly due to lymphopenia (7.9%), but none did it because of GI AE or flushing.ConclusionIn our series, DMF showed high clinical and radiological efficacy. Providing patients with complete information prior to treatment on the management of associated AE helps them to better understand what to expect, improves tolerance and reduces clinical and telephone consultations, which may help to reduce the use and cost of healthcare resources.

P027 Factors Associated with Biologic Discontinuation in Patients with Inflammatory Bowel Disease in TARGET-IBD.

BACKGROUND: A substantial portion of patients who initiate biologic therapy for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD) discontinue therapy within 6-12 months of induction. To better understand patterns of treatment discontinuation in the real-world management of patients with inflammatory bowel disease (IBD), we identified factors associated with treatment discontinuation among patients enrolled in TARGET-IBD, an observational registry of patients with IBD. METHODS: TARGET-IBD is a longitudinal cohort of patients receiving care at 34 community and academic practices in the United States. Patients with IBD enrolled between July 24, 2017 and August 17, 2020 were included in this analysis. To be included, patients were required to initiate a biologic drug of interest during the study period, with no biologic use in the 6 months prior to induction. If less than 10 participants were treated with a given therapy class, they were excluded from multivariable analyses. The primary outcome was calculated as time (continuous months) from biologic start date to the earliest of: discontinuation (event), total colectomy/proctocolectomy, death, or date of last clinical contact. Variables to include in the multivariable models were determined based on a manual stepwise approach. The primary outcome was assessed using Kaplan-Meier testing and Cox proportional hazards modeling. We also examined reasons for treatment discontinuation. RESULTS: A total of 856 patients were included (39% UC, 61% CD). The median disease duration at therapy initiation was 4 years among patients with UC and 5 years among patients with CD; 92% of patients with UC were biologic naïve, as were 74% of patients with CD. Among all 856 patients, 268 (31%) discontinued therapy during the study period. The median time to discontinuation or censoring was 10.6 months (IQR 4.1– 18.6 months). In multivariable analysis among patients with UC, discontinuation was less likely in patients treated with an anti-integrin (Hazard Ratio [HR] 0.51, 95% CI 0.30 – 0.86) relative to anti-tumor necrosis factor alpha (anti-TNF), adjusting for disease duration, concomitant methotrexate/thiopurine use, and C-reactive protein. Patients with CD using anti-integrin or IL-12/IL-23 inhibitors were less likely to discontinue therapy compared to patients treated with anti-TNF (HR 0.66, 95% CI 0.43 – 1.02); this difference was not statistically significant after adjustment for sex, insurance, previous biologic exposure, age at disease onset, disease location, and history of perianal fistula. The most frequent reasons for treatment discontinuation were primary non-response/lack of efficacy (21%), secondary non-response/lack of efficacy (31%), and side effects of therapy (23%). Development of antibodies was specifically noted among 10% of participants as a cause of treatment discontinuation. CONCLUSION: In a multicenter cohort of patients with IBD, nearly one-third discontinued biologic treatment. The most common reason for discontinuation was secondary loss of response followed by side effects, then primary non-response. Primary non-response and secondary loss of response remain concerns in the treatment of patients with CD and UC, and continued emphasis on proactive strategies to maintain durability of therapies should be considered.