Permanent Discontinuation Research Articles

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD. Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated. We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups. During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009). In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade. ClinicalTrials.gov, NCT02065791 and NCT03036150 . This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3.

Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6–18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

Otomozal dominant polikistik böbrek hastalığında tolvaptan kullanımı: Tek merkez deneyimi

Aim: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease that progresses to end-stage renal disease (ESRD). Tolvaptan is a disease-modifying agent that slows cyst growth and kidney disease progression in ADPKD. In this study, we examined the effects and side effects of tolvaptan in high-risk ADPKD patients using tolvaptan. We share our experience of this study.
 
 Methods: Twenty-seven ADPKD patients who were at high risk according to the Mayo Clinical Classification and accepted treatment were included in the study. Tolvaptan 60 mg/day orally was started in patients to slow the ADPKD. The daily dose was increased to 120 mg depending on the patients’ response to tolvaptan treatment and their tolerance to side effects. The patients were followed up during tolvaptan treatment to observe the effects and side effects of the medication.
 
 Results: The mean age of the patients was 40.3±8.2. Hypertension was present in 81.5% of the patients, and they mostly used renin angiotensin aldosterone system inhibitors. As aquaretic side effects of tolvaptan treatment, there was thirst in 14 patients (51.9%), polydipsia in 10 patients (37%), dry mouth in 5 patients (18.5%), and nocturia in 4 patients (14.8%). In addition, although liver enzyme elevation, hypernatremia, and acute kidney injury were observed in one patient each, these side effects did not lead to permanent discontinuation of the drug. Polyuria was observed in all patients, but the patients tolerated the polyuria well and continued to use tolvaptan treatment. 
 
 Conclusion: Although the patients experienced side effects related to tolvaptan treatment, none of the patients discontinued the drug permanently. We observed that patients generally tolerated tolvaptan treatment well.

Upfront tofacitinib in patients with biological-naïve ulcerative colitis - An Indian multicentric experience.

Tofacitinib is a Janus Kinase inhibitor used for treating moderate to severe ulcerative colitis (UC), mainly after the failure of biological therapy. There is a paucity of data on the outcome of tofacitinib in biological-naïve UC patients. The present study wasaimed at analyzing the safety and efficacy of tofacitinib in biological-naïve Indian patients with UC. The present study retrospectively evaluated consecutive patients with biological-naïve moderate-to-severe active UC from six tertiary care centers in India receiving tofacitinib from September 2020 to September 2022. Clinical remission or response assessment was based on partial Mayo score (PMS) calculated at baseline and weeks eight, 16 and 24. Total 47 cases (57.4% male, median age: 32years) were included. After eightweeks of therapy, 33 (70.2%) achieved clinical remission and eight (17.0%) had a primary failure. The baseline serum albumin at treatment initiation was the only independent predictor of remission at eightweeks (Odds ratio: 11.560, 95%CI: 1.478 - 90.404), but not at 16weeks. By 24weeks, 59.6% (28/47) of the patients were in remission and 29.8% (14/47) had stopped tofacitinib either due to failure (27.6%) or adverse events (AEs) (2.1%). Among the 47 patients, 10 (21.2%) cases developed AEs during follow-up, including two tuberculosis (4.2%), one cytomegalovirus (CMV) colitis (2.1%) and one herpes zoster (2.1%). Four patients with infection required temporary drug discontinuations. One required permanent discontinuation (mania). Upfront tofacitinib is effective in biologic-naïve Indian patients with moderate-severe UC. Further randomized studies are required to validate the study findings.

Comparing infusion-related reactions of the first full dose (600 mg) biosimilar ocrelizumab administration with the standard divided protocol in multiple sclerosis patients: a randomized controlled trial study.

Ocrelizumab is a humanized antiCD20, thought to be a highly effective disease-modifying therapy (DMT). Its most frequent adverse effects are infusion-related reactions (IRRs). To reduce these reactions, the first dose of ocrelizumab is administered as two 300 mg infusions separated by two weeks. However, in the phase II trial of ocrelizumab, severe IRRs were not significantly different between two doses of 600 mg dose (two separate 300 mg doses) and 2000 mg dose (two separate 1000 mg doses). We compared the IRRs in undivided full (one 600 mg) and divided (two 300 mg) doses of ocrelizumab which is the standard protocol. MS patients (relapsing or primary progressive MS) who are selected to receive ocrelizumab by neurologist or MS fellowship were enrolled in an open-label randomized controlled trial. Iranian biosimilar of the drug (Xacrel® by Cinnagen, approved by the Iranian Food and Drug Administration in 2021) was used. The participants received the first dose of ocrelizumab as either one 600 mg dose in one session or two 300 mg doses in two weeks apart. IRRs during or in the first 24h after infusion were recorded. Of 332 participants, 150 received two 300 mg doses, and 182 received one 600 mg dose (by random selection). Life-threatening adverse effects were not observed in both groups. Overnight admission or permanent drug discontinuation was not needed. Temporary drug discontinuation was significantly higher in the one 600 mg dose group (p-value < 0.001). During the infusions, malaise (p-value: 0.003), skin reactions (p-value: 0.04), throat swelling (p-value: 0.03), and dyspnea (p-value: 0.01) were significantly increased in the intervention group. However, in the first 24h, there was no significant difference between two different treatment protocols (one 600 mg dose or two 300 mg doses) in the onset of IRRS (p-value: 0.12). These findings suggest one 600 mg dose of ocrelizumab administration for the first dose is relatively safe. With some protocol modifications, it could lead to fewer patient referrals, saving time and cost and improvement the access for patients.

Real-world clinical evidence of lazertinib use in acquired EGFR T790M mutated non-small cell lung cancer.

Lazertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to overcome EGFR T790M mutation. Currently, lazertinib is approved for usage in the acquired EGFR T790M mutation population based on promising clinical and safety profiles. In this study, we evaluated the clinical outcomes of lazertinib in acquired EGFR T790M mutated non-small cell lung cancer (NSCLC) patients in a real-world clinical setting. Clinical outcomes of 103 patients treated with lazertinib, from July 2021 to August 2022, for NSCLC with acquired EGFR T790M mutation were retrospectively analyzed. EGFR T790M mutation was confirmed using either a cell-free EGFR test (48.5%) or a tissue-based test (51.5%). The median follow-up duration was 11.4 months [95% confidence interval (CI): 10.4-13.1], and 58.3% of patients remained on treatment at the time point of data analysis. The objective response rate was 72.8%. The median progression-free survival (PFS) was not reached, and the PFS rates at 6 and 12 months were 81.7% and 65.1%, respectively. The median PFS in a subgroup treated with lazertinib based on T790M-positive tissue was significantly longer than that in a subgroup treated based on T790M-positive plasma (not reached vs. 14.5 months) (hazard ratio, 0.43; 95% CI: 0.21-0.87). Related to adverse events, there was no treatment-related mortality. However, the lazertinib dose was adjusted in 39 patients (37.9%), including 10 patients (9.7%) with permanent discontinuation. Peripheral sensory-motor related adverse events were observed in 65 patients (63.1%) (paresthesia: n=58; muscle cramping: n=24), leading to dose reduction and permanent discontinuation in 17 (16.5%) and 5 (4.9%) patients, respectively. There was no difference in PFS between the groups with and without dose-adjustment (P=0.40). Our result demonstrates the real-world clinical efficacy of lazertinib in acquired EGFR T790M mutation. Although dose reduction due to adverse events was not uncommon, it did not impair clinical efficacy of lazertinib.

Thromboembolic and bleeding complications during interruptions and after discontinuation of anticoagulant treatment in patients with atrial fibrillation and active cancer: A daily practice evaluation

Background and aimsCancer provides challenges to the continuity of anticoagulant treatment in patients with atrial fibrillation (AF), e.g. through cancer-related surgery or complications. We aimed to provide data on the incidence and reasons for interrupting and discontinuing anticoagulant treatment in AF patients with cancer and to assess its contribution to the risk of thromboembolism (TE) and major bleeding (MB). MethodsThis retrospective study identified AF patients with cancer in two hospitals between 2012 and 2017. Data on anticoagulant treatment, TE and MB were collected during two-year follow-up. Incidence rates (IR) per 100 patient-years and adjusted hazard ratios (aHR) were obtained for TE and MB occurring during on- and off-anticoagulant treatment, during interruption and after resumption, and after permanent discontinuation. Results1213 AF patients with cancer were identified, of which 140 patients permanently discontinued anticoagulants and 426 patients experienced one or more interruptions. Anticoagulation was most often interrupted or discontinued due to cancer-related treatment (n = 441, 62 %), bleeding (n = 129, 18 %) or end of life (n = 36, 5 %). The risk of TE was highest off-anticoagulation and during interruptions, with IRs of 19 (14–25)) and 105 (64–13), and aHRs of 3.1 (1.9–5.0) and 4.6 (2.4–9.0), respectively. Major bleeding risk were not only increased during an interruption, but also in the first 30 days after resumption, with IRs of 33 (12–72) and 30 (17–48), and aHRs of 3.3 (1.1–9.8) and 2.4 (1.2–4.6), respectively. ConclusionsInterruption of anticoagulation therapy harbors high TE and MB risk in AF patients with cancer. The high incidence rates call for better (periprocedural) anticoagulant management strategies tailored to the cancer setting.

Managing the Risk of Lung Toxicity with Trastuzumab Deruxtecan (T-DXd): A Canadian Perspective.

Ongoing advances in precision cancer therapy have increased the number of molecularly targeted and immuno-oncology agents for a variety of cancers, many of which have been associated with a risk of pulmonary complications, among the most concerning being drug-induced interstitial lung disease/pneumonitis (DI-ILD). As the number of patients undergoing treatment with novel anticancer agents continues to grow, DI-ILD is expected to become an increasingly significant clinical challenge. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2 that is gaining widespread use in the metastatic breast cancer setting and is undergoing exploration for other oncologic indications. ILD/pneumonitis is an adverse event of special interest associated with T-DXd, which has potentially fatal consequences if left untreated and allowed to progress. When identified in the asymptomatic stage (grade 1), T-DXd-related ILD can be monitored and treated effectively with the possibility of treatment continuation. Delayed diagnosis and/or treatment, however, results in progression to grade 2 or higher toxicity and necessitates immediate and permanent discontinuation of this active agent. Strategies are, therefore, needed to optimize careful monitoring during treatment to ensure patient safety and optimize outcomes. Several guidance documents have been developed regarding strategies for the early identification and management of T-DXd-related ILD, although none have been within the context of the Canadian health care environment. A Canadian multidisciplinary steering committee was, therefore, convened to evaluate existing recommendations and adapt them for application in Canada. A multidisciplinary approach involving collaboration among medical oncologists, radiologists, respirologists, and allied health care professionals is needed to ensure the proactive identification and management of T-DXd-related ILD and DI-ILD associated with other agents with a similar toxicity profile.

Review of Targeted Therapy, Vismodegib, for the Treatment of Periocular Basal Cell Carcinoma.

Periocular locally advanced basal cell carcinoma (POLA-BCC) is characterized by orbital involvement and/or extensive invasion of periocular structures. Hedgehog pathway inhibitors have been used for POLA-BCC with promising outcomes. The authors reviewed 11 articles published in English literature from January 2012 to July 2022 and reported the outcomes of patients with POLA-BCC who were treated with vismodegib. A total of 384 patients were treated with vismodegib. The mean age was 72 years, and the median treatment duration was 9 months. The overall response rate was 75% with a median follow-up time of 14.4 months. Following vismodegib treatment, the median number of patients who required adjuvant surgery was 43% with a median time to surgery of 6.5 months. The exenteration rate was 6% (overall 8 patients). In total 93.7% of patients experienced grade I adverse events, 26.7% to 37.5% grade II, 8.8% to 10% grade III-IV, and 0.8% to 4.8% grade V. Major side effects included dysgeusia (30-100%), muscle spasm (15-100%), alopecia (47-75%), weight loss (23-83%), and decreased appetite (19-42%). The median percentage of patients who discontinued treatment due to toxicity was 29% with a median interval of 5 months before the development of side effects. The median recurrence rate following discontinuation of vismodegib was 7.8% with a median recurrence duration of 20 months. In patients with POLA-BCC, vismodegib, a hedgehog pathway inhibitor, provided high rates of orbital preservation, reducing exenteration rates to 6%. Neoadjuvant therapy with vismodegib can also be suggested for patients with POLA-BCC. While extremely effective, side effects lead to temporary or permanent discontinuation of vismodegib in small numbers of patients.

Late-onset cardiotoxicity in patients with HER2-positive metastatic breast cancer receiving trastuzumab-based therapy.

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. Thirty-seven patients were included. Mean age was 56 years (range: 33-78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14-140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11-29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2-6.6, SD 1.1). Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon.

Safety outcomes of rapid- versus standard-infusion rate oxaliplatin.

The National Comprehensive Cancer Network guidelines state that the oxaliplatin dose of 85 mg/m2 used in various gastrointestinal cancer regimens may be infused over a rapid rate of 85 min instead of the standard time of 120 min. We evaluated the safety outcomes of rapid administration of oxaliplatin compared to standard infusion. We performed a retrospective, cohort study by chart review. Adult patients who received oxaliplatin as part of a FOLFOX, FOLFOXIRI, or FOLRINOX chemotherapy regimen from January 1, 2018, through June 30, 2021, were included. Primary outcomes were the incidence of hypersensitivity reaction (HSR) and treatment modification of oxaliplatin due to adverse drug events. Secondary outcomes included peripheral neuropathy (PN), myelosuppressive signs, and oxaliplatin-related emergency department visit and/or hospital admission. A total of 178 patients were included (90 and 88 in the rapid-rate and standard-rate groups, respectively). Rapid-rate oxaliplatin was not associated with increased HSR or difference in toxicity requiring dose reduction, delayed dose, or slowed infusion rate, but was associated with increased rate of permanent discontinuation of oxaliplatin, 7.8% and 1.1% in the rapid-rate group and standard-rate groups, respectively (p = 0.032). Peripheral neuropathy occurred in 72.2% and 42% of patients in the rapid-rate group and standard-rate groups, respectively (relative risk for PN, 2.09; 95%, CI: 1.43-3.04; p < .001). There were no differences in any other adverse drug event measured. Rapid-rate oxaliplatin was associated with minimal treatment modifications; however, there was an increase in PN incidence. A faster rate of oxaliplatin administration may not be worth the increased risk of PN.

Long term use of eltrombopag in children with chronic immune thrombocytopenia: extended real life retrospective multicenter experience of the Italian Association of Pediatric Hematology and Oncology.

The present multicenter retrospective study on eltrombopag administration in Italian children with chronic ITP aims to extend follow-up of our previous study. This retrospective multicenter study was conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). Patients were classified into three subgroups: group 1 included patients who discontinued treatment due to a stable platelet count; group 2 included patients who discontinued treatment due to ineffectiveness; group 3 included patients who did not permanently discontinue treatment. 56 patients were eligible for analysis. The median duration of eltrombopag treatment was 40 months (7-71 months). Twenty patients (36%) discontinued permanently eltrombopag. The reasons of permanent discontinuation were adverse effects (n = 1), inefficacy (n = 10), stable platelet count (n = 9). All patients of group 1 maintained a durable response without additional treatments after eltrombopag discontinuation. We found that patients of group 2 were on treatment for less time (median treatment time: 13.5 months, min: 6.0 - max: 56.0) than patients of group 1 (median treatment time: 34 months, min: 16.0 - max: 62.0) (p < 0.05). Patients of group 2 mostly did not achieve a stable platelet count in the first 6 months of treatment and underwent concomitant therapies during follow-up respect of group 1 and group 3 (p < 0.01). Our study found that the benefits of eltrombopag treatment, in terms of platelet count improvement and use of additional therapies, are identifiable from the first 6 months of treatment.

Measuring Safety and Outcomes for the Use of Compassionate and Off-Label Therapies for Children, Adolescents, and Young Adults With Cancer in the SACHA-France Study

Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected. To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines. This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022. All patients treated in a French Society of Pediatric Oncology (SFCE) center. Collection of adverse drug reactions and anticancer activity attributable to the treatment. A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population. This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.

Two-Drug Combinations Therapy of Different Doses of Valsartan Existing Diverse Significance for Hypertensive Patients.

The incidence of hypertension and clinical complications (e.g., heart, cerebrovascular and kidney injury) is increasing worldwide. It is widely known that a relatively large dose of valsartan (320 mg) could alleviate clinical complications. The current network meta-analysis assessed which drug could be combined with a relatively large dose of valsartan to control blood pressure (BP) more effectively. And which combination therapy with different dosages of valsartan did not induce excessive BP reduction with increasing dosages of valsartan. The PubMed, Embase, Medline, Cochrane Library, CNKI, Wanfang, and CSTJ databases were searched from inception to October 2022 for relevant randomized controlled trials (RCTs). The search strategies included concepts related to hypertension and two-drug combination therapy of different doses of valsartan, and there were no language or data restrictions. The outcomes included adverse effects and changes in systolic BP and diastolic BP. Permanent discontinuations related to treatment were the most accurate and objective measure of adverse effects. The common adverse effects of most studies (i.e., dizziness, headache, nasopharyngitis, asthenia and urticaria) were also included. A Bayesian network meta-analysis was performed, and mean differences with 95% confidence intervals were calculated. ADDIS and STATA were used for Bayesian model network meta-calculation. Thirty-four RCTs were included involving 26,752 patients, and the interventions included different doses of valsartan combined with various types and doses of drugs. Among many combination therapies, the combination of valsartan 320 mg with amlodipine 10 mg (p 0.01) had the best antihypertensive effect without significant adverse effects. Compared with valsartan 80 mg and 160 mg, valsartan 320 mg combined with hydrochlorothiazide 25 mg (p 0.05) did not further reduce BP and was not shown to increase the incidence of adverse effects. Combination therapy with a relatively large dose of valsartan could control BP and improve clinical complications effectively. However, for hypertensive patients with different treatment requirements, specific choices should be made regarding whether to control BP, treat clinical complications, or both.

P64 Efficacy of baricitinib in patients with different degrees of severe alopecia areata: 52-week results from BRAVE-AA1 and BRAVE-AA2

Abstract Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, demonstrated efficacy in adults with severe alopecia areata (AA) over 36 weeks in two phase III, randomized, double-blind, placebo-controlled trials, BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259). Using integrated data from the long-term extension periods of both trials, we report treatment response to baricitinib by the AA severity subgroup based on the Severity of Alopecia Tool (SALT) score over 52 weeks. Patients randomized to baricitinib at baseline (n = 855) retained their treatment allocation (2 mg/4 mg) through to week 52 in both trials and were included in week 52 analyses; placebo nonresponders were rescued at week 36. Severity of AA at baseline was defined as severe (SALT score 50–94) or very severe (SALT score 95–100). Key inclusion criteria were SALT score ≥ 50, current AA episode lasting &amp;gt; 6 months to &amp;lt; 8 years without spontaneous improvement within 6 months prior to screening, and no previous inadequate response to oral JAK inhibitors. Efficacy endpoints included the proportion of patients achieving a SALT score ≤ 20 and the proportion of patients achieving Clinician-Reported Outcome (ClinRO) Measure for Eyebrow/Eyelash Hair Loss™ 0,1 (no, minimal gaps) with ≥ 2-point improvement from baseline among patients with baseline scores 2,3 (significant gaps, no notable eyebrows/eyelashes). Analyses were presented descriptively for each subgroup up to week 52. Nonresponder imputation was used for missing data. Data collected after permanent study drug discontinuation or at remote visits due to the COVID-19 pandemic were excluded. In total, 1200 patients were enrolled (BRAVE-AA1, n = 654; BRAVE-AA2, n = 546). At baseline, the overall mean (SD) age was 37.5 (12.9) years; 60.7% were female and 46.8% and 53.2% of patients had severe and very severe AA, respectively. At week 52, a SALT score ≤ 20 was achieved by 36.1% and 51.2% of patients on baricitinib 2 mg and baricitinib 4 mg, respectively, with severe AA and 12.4% and 27.7% of patients on baricitinib 2 mg and baricitinib 4 mg, respectively, with very severe AA. Eyebrow/Eyelash Hair Loss™ scores 0,1 with ≥ 2-point improvement from baseline at week 52 were achieved by 19.4% and 26.0% (baricitinib 2 mg) and 37.5% and 38.5% (baricitinib 4 mg) of patients with severe AA and 24.3% and 25.3% (baricitinib 2 mg) and 47.6% and 48.1% (baricitinib 4 mg) of patients with very severe AA. Following 52 weeks of treatment with both baricitinib doses, clinical responses of SALT score ≤ 20 were observed both in patients with severe and very severe AA. Proportions of patients achieving full coverage or minimal gaps in eyebrows and eyelashes were similar at week 52, regardless of scalp hair-loss severity. Funding sources: Eli Lilly and Company.

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7·0-10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company.

Clinical Relevance of High Plasma Trough Levels of the Kinase Inhibitors Crizotinib, Alectinib, Osimertinib, Dabrafenib, and Trametinib in NSCLC Patients.

the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients. In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups. A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups. For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib.

417 Safety of long-term dupilumab treatment in adults with moderate-to-severe atopic dermatitis: results from an open-label extension trial up to 5 years

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease requiring long-term management; however, sustained AD treatment with systemic immunosuppressants is not recommended due to safety concerns. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin (IL)-4 and IL-13, inhibiting the signaling of these key and central drivers of type 2 inflammation in multiple diseases. Data from the open-label extension (OLE) study, LIBERTY AD OLE (NCT01949311), previously demonstrated acceptable dupilumab safety in adult patients up to 204 weeks (approximately 4 years), consistent with the known safety profile in parent studies. This study aims to assess the long-term safety of dupilumab administered in adult patients with AD up to 5 years (the end of this OLE study). Adults with moderate-to-severe AD who had participated in any dupilumab parent study (phase 1 through phase 3) were enrolled into the long-term, multicenter OLE trial with a duration of up to 5 years. During the OLE, patients were treated with 300-mg dupilumab weekly (qw). In 2019, patients transitioned to 300 mg every 2 weeks to align with approved dosage. Concomitant treatments for AD were permitted, including topical corticosteroids (TCS) and topical calcineurin inhibitors. Because the OLE trial lacked a control arm, LIBERTY AD CHRONOS (NCT02260986) 52-week safety results for adults with moderate-to-severe AD receiving dupilumab 300 mg qw plus TCS were provided as a comparison. Data shown are for the overall study population (n = 2677). Of the 2677 patients who enrolled, 2207 completed treatment up to Week 52, 362 up to Week 172 and 334 up to Week 260. The most common reason for study withdrawals during the OLE study period was dupilumab approval and commercialization in the patient’s country of enrollment [708 (51.3%)]. The exposure-adjusted incidence rate (EAIR) of patients with ≥1 treatment-emergent adverse event (TEAE) was lower in this OLE vs. the 300 mg qw + TCS arm of the 52-week CHRONOS trial (166.0 vs. 322.4 number of patients/100 patient-years). Over this 5-year OLE, 10.6% of patients had ≥1 serious TEAE, 10.0% had ≥1 severe TEAE, 1.2% had ≥1 serious TEAE related to the study drug and 3.8% of patients experienced a TEAE resulting in permanent drug discontinuation. The most common TEAEs observed were nasopharyngitis (28.9%) and conjunctivitis [20.0%, using a narrow customized MedDRA query (CMQ) containing conjunctivitis and related terms conjunctivitis allergic/bacterial/viral, and atopic keratoconjunctivitis]. Of the patients under narrow CMQ, 95.0% reported mild/moderate conjunctivitis TEAEs and 87.7% of conjunctivitis events were recovered/resolved. The safety profile observed in this OLE trial up to 5 years is acceptable and consistent with the known safety profile of dupilumab observed in controlled studies. The EAIRs of TEAEs overall did not increase over time and were lower than previously reported in the 3- and 4-year analyses of this OLE trial and an earlier 52-week placebo-controlled trial.

Treatment outcomes of multidrug-resistant tuberculosis patients receiving ambulatory treatment in Shenzhen, China: a retrospective cohort study.

WHO recommended multidrug-resistant tuberculosis (MDR-TB) should be treated mainly under ambulatory model, but outcome of ambulatory treatment of MDR-TB in China was little known. The clinical data of 261 MDR-TB patients treated as outpatients in Shenzhen, China during 2010-2015 were collected and analyzed retrospectively. Of 261 MDR-TB patients receiving ambulatory treatment, 71.1% (186/261) achieved treatment success (cured or completed treatment), 0.4% (1/261) died during treatment, 11.5% (30/261) had treatment failure or relapse, 8.0% (21/261) were lost to follow-up, and 8.8% (23/261) were transferred out. The culture conversion rate at 6 months was 85.0%. Although 91.6% (239/261) of patients experienced at least one adverse event (AE), only 2% of AEs caused permanent discontinuation of one or more drugs. Multivariate analysis showed that previous TB treatment, regimens containing capreomycin and resistance to FQs were associated with poor outcomes, while experiencing three or more AEs was associated with good outcomes. Good treatment success rates and early culture conversions were achieved with entirely ambulatory treatment of MDR-TB patients in Shenzhen, supporting WHO recommendations. Advantageous aspects of the local TB control program, including accessible and affordable second-line drugs, patient support, active monitoring and proper management of AEs and well-implemented DOT likely contributed to treatment success rates.

Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation

Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10−5 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).