Patients Discontinued Treatment Research Articles

Nivolumab and sunitinib in patients with advanced bone sarcomas: A multicenter, single-arm, phase 2 trial.

Herein, we present the results of the phase 2 IMMUNOSARC study (NCT03277924), investigating sunitinib and nivolumab in adult patients with advanced bone sarcomas (BS). Progressing patients with a diagnosis of BS were eligible. Treatment was comprised of sunitinib (37.5 mg/day on days 1-14, 25 mg/day afterword) plus nivolumab (3 mg/kg every 2 weeks). Primary end point was progression-free survival rate (PFSR) at 6 months based on central radiology review. Secondary end points were overall survival (OS), overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and safety. A total of 46 patients were screened, 40 patients entered the study, and 38 underwent central radiological review and were evaluable for primary end point. Median age was 47 years (range, 21-74). Histologies include 17 (43%) osteosarcoma, 14 chondrosarcoma (35%, 10 conventional, four dedifferentiated [DDCS]), eight (20%) Ewing sarcoma, and one (2%) undifferentiated pleomorphic sarcoma. The PFSR at 6 months was 42% (95% confidence interval [CI], 27-58). With a median follow-up of 39.8 months (95% CI, 37.9-41.7), the median PFS and OS were 3.8 months (95% CI, 2.7-4.8) and 11.9 months (95% CI, 5.6-18.2). ORR by RECIST was 5%, with two of 38 partial responses (one of four DDCS and one of 17 osteosarcoma), 19 of 38 (50%) stable disease, and 17 of 38 (45%) progressions. Grade ≥3 adverse events were neutropenia (six of 40, 15%), anemia (5/40, hypertension (6/40, 15%), 12.5%), ALT/AST elevation (5/40, 12.5%), and pneumonitis (1/40, 2.5%). Seventeen percent of patients discontinued treatment due to toxicity, including a treatment-related grade 5 pneumonitis CONCLUSION: The trial met its primary end point in the BS cohort with >15% of patients progression-free at 6 months. However, the toxicity profile of this regimen was relevant.

CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS

Abstract BACKGROUND Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). METHODS Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion. RESULTS Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis. CONCLUSIONS Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.

Pharmacologic properties and results of a clinical study of oxybutynin hydrochloride lotion (APOHIDE® Lotion 20%) as a novel treatment for primary palmar hyperhidrosis

APOHIDE® Lotion 20% is a topical agent for treating primary palmar hyperhidrosis that contains the active ingredient oxybutynin hydrochloride. Oxybutynin hydrochloride has anticholinergic effects and inhibits sweating by binding to the M3 receptor, a subtype of the muscarinic acetylcholine receptor, in eccrine sweat glands. The clinical response to oxybutynin hydrochloride treatment also involves N-desethyloxybutynin, an active metabolite of oxybutynin. A clinical study in Japanese patients with primary palmar hyperhidrosis showed superiority of APOHIDE® Lotion 20% over placebo, i.e., there were significantly more responders (i.e., patients with a reduction in sweat volume ≥50% from baseline) in the APOHIDE® Lotion 20% group (APOHIDE® Lotion 20% group: 52.8%, placebo group: 24.3%; treatment difference: 28.5%; P < 0.001, Fisher's exact test). This and other clinical studies reported some adverse events (AEs) associated with the drug's anticholinergic effects and some application site AEs, but most of the AEs were mild. Clinical response did not decrease with long-term (52-week) treatment, and only a few patients (2 of 125) discontinued treatment because of AEs. Taken together, study results indicate that APOHIDE® Lotion 20% may be an effective and safe new treatment option for patients with primary palmar hyperhidrosis.

Usefulness of Nutritional Assessment Indicators in Predicting Treatment Discontinuation Due to Adverse Events from PARP Inhibitors in Ovarian Cancer Patients.

Nutritional status is an important factor influencing toxicity of treatment. Nutritional assessment indicators such as the Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT) score and modified Glasgow Prognostic Score (mGPS) have been reported to be associated with treatment-related adverse events (AEs) for various malignancies. However, there are no reports investigating the relationship between nutritional status and AEs from poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which are widely used in recent years as maintenance therapy for ovarian cancer. The primary objective was to investigate the usefulness of nutritional assessment indicators in predicting treatment discontinuation due to AEs from PARPi. This multicenter retrospective study included patients diagnosed with ovarian cancer who received maintenance therapy with PARPi from January 2018 to December 2023. PNI, CONUT score, and mGPS were calculated based on hematological parameters measured within 7 days before the start of PARPi therapy. A total of 272 patients received maintenance therapy with PARPi during the period, but due to the absence of the blood collection of albumin levels within one week or other exclusion criteria, 71 patients were finally included in this analysis. AEs were seen in 59 patients (83.1%), including 25 (35.2%) severe events (grade ≥3 in Common Terminology Criteria for Adverse Events v5.0). Eighteen patients (25.4%) discontinued treatment due to PARPi-related AEs. Low PNI (<48.44) and high mGPS (≥1) were predictors of treatment discontinuation in both univariate and multivariate analyses. CONUT was not a significant predictor in this study. Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARPi-related AEs before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes.

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

Efficacy and Tolerability of Erenumab and Topiramate for Prevention of Chronic Migraine: A Retrospective Cohort Study

Background and Objectives: Migraine is a chronic neurological disorder affecting approximately 14% of the global population. Beyond physical pain, migraines significantly impact individuals’ quality of life, influencing education, employment, and income levels. Topiramate, a second-generation antiepileptic medication, has demonstrated notable efficacy in reducing the occurrence of chronic migraine. Over the past three decades, extensive research has implicated the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pathogenesis. Erenumab, the first FDA-approved CGRP inhibitor, received approval in 2018. This study aims to compare the clinical efficacy of Erenumab and Topiramate for migraine prevention. Materials and Methods: We conducted a retrospective cohort study of adults with episodic or chronic migraine over a 12-month period, comparing Erenumab (n = 52) and Topiramate (n = 56). Outcomes assessed included changes in the Migraine Disability Assessment (MIDAS) scores from baseline over the last three months of treatment and the proportion of patients achieving a ≥50% reduction in MIDAS scores by the end of the study. Results: The Erenumab group showed significant improvement, with nearly 79% of patients achieving a 50% reduction in their MIDAS score, with a mean reduction of 3.76. Notably, only two patients (3.8.5) discontinued treatment due to adverse events. In contrast, the Topiramate group had over 15% of patients achieve a 50% reduction in MIDAS scores, with a mean reduction of 5.89, and a had discontinuation rate of 14.2% due to adverse events. Conclusions: Both Topiramate and Erenumab are effective for migraine prevention. However, Topiramate has lower tolerability and more side effects, while Erenumab offers better tolerability and safety at a higher cost. Treatment decisions should be individualized based on patient needs, efficacy, safety, and cost considerations.

Semaglutide in patients with kidney failure and obesity undergoing dialysis and wishing to be transplanted: A prospective, observational, open-label study.

Chronic kidney disease (CKD) and obesity are major global health challenges, eventually leading to kidney replacement therapy (KRT), but body mass index (BMI) thresholds hinder kidney transplantation. Glucagon-like peptide-1 receptor agonists induce weight loss, thereby offering attractive treatment options; however, their safety and efficacy have not been systematically investigated in patients undergoing dialysis. We conducted a prospective 12-week, open-label trial with 13 patients who had a BMI ≥ 30.00 kg/m2, were undergoing dialysis (12 haemodialysis and 1 peritoneal dialysis) and had not been listed for transplantation due to their weight. Semaglutide was administered once weekly subcutaneously, and the dose was increased from 0.25 mg to 0.5 mg and then to 1 mg. Study endpoints included change in body weight and BMI (primary - statistically evaluated by repeated measures analysis of variance [ANOVA]), side effects, adverse events, blood parameters and patient-reported outcomes (secondary). At baseline, the mean age ± standard deviation of patients was 64.0 ± 6.4 years, the mean weight was 113.9 ± 16.6 kg, and the mean BMI was 37.3 ± 3.9 kg/m2. At week 12, average weight reduction under semaglutide treatment was 4.6 ± 2.4 kg and ranged from 2.0 to 9.7 kg (p < 0.001 for weight and BMI reduction across the study period). One patient discontinued treatment due to nausea/vomiting, two patients died of unrelated causes and six patients reported side effects. Approximately 9 months after the treatment started, three patients were able to seriously reconsider being listed for transplantation. Semaglutide treatment resulted in significant reduction in weight and BMI in patients with obesity undergoing dialysis, while maintaining an acceptable side effect profile comparable to that of the non-dialysis population.

Long-term safety and efficacy of garadacimab for preventing hereditary angioedema attacks: Phase 3 open-label extension study.

Hereditary angioedema (HAE) is a chronic, unpredictable disease. Long-term prophylactic treatments that offer durable efficacy, safety, and convenience are required to assist patients in achieving complete disease control, per international guidelines. We report an interim analysis of an ongoing phase 3 (VANGUARD) open-label extension (OLE) study evaluating the long-term safety and efficacy of garadacimab for HAE prophylaxis. Adults and adolescents aged ≥12 years with HAE previously participating in phase 2 and pivotal phase 3 (VANGUARD) studies were rolled over to an OLE, alongside newly enrolled patients. Patients received garadacimab 200 mg subcutaneously, once monthly for ≥12 months. The primary endpoint was treatment-emergent adverse events (TEAEs) in patients with C1 inhibitor deficiency/dysfunction. At data cut-off (February 13, 2023; N = 161), median (interquartile range) exposure was 13.8 months (11.9-16.3). For the primary endpoint, 133/159 patients experienced ≥1 TEAE (524 events), equivalent to 0.23 events/administration and 2.84 events/patient-year. Garadacimab-related TEAEs (13% of patients, 52 events) were most commonly injection-site reactions (ISRs). No deaths occurred. One patient discontinued treatment due to garadacimab-related moderate ISR. Most TEAEs were mild/moderate; three events were serious (COVID-19, two events; abdominal HAE attack, one event) and not garadacimab related. No abnormal bleeding, thromboembolic, severe hypersensitivity, or anaphylactic events were observed. Mean HAE attack rate decreased by 95% from the run-in period; 60% of patients were attack-free. Almost all patients (93%) rated their response to garadacimab as "good" or "excellent." Garadacimab has a favorable safety profile suitable for long-term use and provides durable protection against HAE attacks.

Clinical outcomes for 2788 patients with transthyretin amyloidosis: Tafamidis meglumine early access program in France

BackgroundEarly access experience in France with tafamidis meglumine, a selective transthyretin stabilizer for transthyretin-related amyloidosis cardiomyopathy (ATTR-CM), following transthyretin-related amyloidosis (ATTR) polyneuropathy approval and positive ATTR-ACT study results. AimTo describe the characteristics and clinical outcomes for patients in the French ATTR-CM tafamidis meglumine early access programme (28 Nov 2018 to 01 Jun 2021). MethodsPatients with confirmed ATTR-CM received tafamidis meglumine 20mg/day or 80mg/day. Demographic and clinical data were collected prospectively until patients discontinued treatment or died, or the programme ended. ResultsOverall, 222 physicians from 126 centres enrolled 2788 patients. The median age was 82years, 81.6% were male and New York Heart Association severity was class I for 12.8%, class II for 60.1% and class III for 27.0%. Overall, 1943 (74.6%) had genetic testing, and the results were available at tafamidis start for 1208 (62.2%) patients: 995 (82.4%) had wild-type ATTR and 213 (17.6%) had hereditary ATTR. Most patients started treatment≤12months after diagnosis (88.3%): 2268 (81.3%) at 20mg/day, with 401 (17.7%) increasing to 80mg/day. Median follow-up duration was 11.8months. New York Heart Association class improved or remained stable for 1299 (77.6%), whereas 376 (22.4%) worsened between inclusion and last follow-up. Among patients initiated at 80mg, 297 (81.1%) improved or remained stable and 69 (18.9%) worsened. New York Heart Association class progression did not vary with age. The 18-month survival rates were 89.8% (95% confidence interval: 87.0–92.0) among patients aged<80years, and 86.5% (95% confidence interval: 83.9–88.7) among those aged≥80years. ConclusionsEarly tafamidis meglumine access was given to 2788 patients with ATTR-CM. New York Heart Association class progression and survival were consistent with previously published data.

Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. A total of 74 studies with 23,119 participants were included. After 12months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.

Neoadjuvant everolimus in renal angiomyolipoma with or without tuberous sclerosis complex: Results from a multicenter, retrospective study.

To assess the efficacy and safety of preoperative neoadjuvant everolimus in renal angiomyolipomas (AML) patients with or without Tuberous Sclerosis Complex (TSC). This multi-institutional retrospective study enrolled renal AML patients who underwent partial nephrectomy (PN) or total nephrectomy after receiving at least 1 month of pre-operative everolimus. Imaging evaluations were collected before and after treatment, along with demographic, surgical, and follow-up information. The primary outcome was tumor volume reduction of ≥25%, with additional outcomes including recurrence, perioperative outcomes, renal function, and safety. From January 2015 to July 2022, 68 renal AML patients were studied-41 with TSC and 27 without. During everolimus treatment, 61.0% (25/41) of TSC patients and 44.4% (12/27) of non-TSC patients achieved tumor reduction of ≥25%. Additionally, 41.5% (17/41) of TSC patients and 18.5% (5/27) of non-TSC patients achieved a ≥ 50% reduction. Three TSC patients and 1 non-TSC patient discontinued treatment due to side-effects. Most patients (92.7% TSC, 85.2% non-TSC) underwent PN. After everolimus treatment, the necessary total nephrectomy decreased to 41.2% (7/17) from baseline. Postoperatively, 1 grade 3 and 3 grade 2 complications occurred, with no grade 4 or 5 complications. After a median follow-up of 24 months, only 1 TSC patient recurred with a diameter >3 cm. Retrospective nature is the major limitation of this study. Everolimus was effective and well-tolerated in neoadjuvant treatment for renal AML, especially in TSC patients. This neoadjuvant combination strategy of everolimus and PN could effectively controls recurrence and preserves renal function.

Direct determination of chronic myeloid leukemia prevalence in Lombardy-Italy: Global implications.

Lombardy represents the largest region of Italy by population, with almost 10 million residents, a dimension similar to a medium size country like Sweden or Belgium. The CML subcommittee of the Lombardy Hematology Network (REL-CML) conducted a study at the beginning of 2023. Prevalence was calculated by direct input from the 21 centers participating in REL-CML. Tyrosine Kinase Inhibitors (TKI) prescription records collected from the ARIA regional registry were used to estimate the number of CML patients followed in smaller centers not participating in REL-CML. A total of 2285 patients were registered, representing a prevalence of 0.23 ‰. These data were compared to a similar census conducted in 2005, at the beginning of the TKI era, where a prevalence of 0.029‰ was calculated. This indicates that an almost 10 times increase took place during this period of time. Imatinib represents the most frequently prescribed first-line TKI; its use in 2022 still represented 75% of total first line prescriptions. An increased concentration of the care of CML patients in specialized REL centers with a decreased dispersion of patients in small centers was also evident over this 18year period of time. Nineteen % of patients discontinued treatment, highlighting persisting logistical and biological challenges; one some recommendations on CML management are included to this aim.

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study

ObjectiveThis study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).Design, setting and participantsThis is a phase 1–1b/2, open-label, multinational, multicentre study...

Adverse events associated with benznidazole treatment for Chagas disease in children and adults.

Chagas disease (ChD) affects approximately 7 million people in Latin America, with benznidazole being the most commonly used treatment. Data from a retrospective cohort study in Argentina, covering January 1980 to July 2019, was reanalysed to identify and characterize benznidazole-related adverse drug reactions (ADRs). The study included 518 patients: 449 children and 69 adults (median age in children: 4years; adults: 25 years; age ranges: 1month-17.75 years and 18-59 years, respectively). The median benznidazole doses received were 6.6mg/kg/day for at least 60 days in children and 5.6mg/kg/day for a median of 31 days in adults. Overall, 29.34% (152/518) of patients developed benznidazole-related ADRs, with an incidence of 25.83% (116/449) in children and 52.17% (36/69) in adults (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.19-0.54, P < .001). The incidence rate was 177 cases per 1000 person-years (95% CI = 145-214) in children and 537 per 1000 person-years (95% CI = 360-771) in adults. There were 240 ADRs identified, primarily mild to moderate. Severe ADRs occurred in 1.11% (5/449) of children and 1.45% (1/69) of adults. The skin was the most affected system. A total of 10.23% (53/518) of patients discontinued treatment. More adults than children discontinued treatment (OR = 3.36, 95% CI = 1.7-6.4, P < .001). Although 29.34% of patients experienced ADRs, most were mild to moderate, indicating a manageable safety profile for benznidazole. While optimized dosing schedules and new drugs are needed, avoiding benznidazole solely due to safety concerns is not justified.

Safety and Efficacy of Directly Acting Antivirals (Sofosbuvir &amp; Daclatasvir) in Treatment of Chronic HCV

Abstract Background The introduction of direct-acting antiviral agents, has revolutionized the treatment for chronic HCV with higher cure rates, shorter duration of treatment and more tolerability have been achieved. Aim of the Work The aim of our study is to estimate the efficacy and safety of DAAs in treatment of chronic HCV in patients co-infected with HIV. Patients and Methods This study of previously untreated HCV infection in patients with HCV and HIV co-infection conducted at Abbasia Fever Hospital, from July 2019 to February 2020. Patients included are chronic HCV infection and were receiving antiretroviral therapy for the HIV with a CD4 T-lymphocyte count of 200 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed during treatment by combination of daclatasvir 90mg and sofosbuvir 400mg+/- ribavirin 800mg daily for 12 weeks. Results In this study, the rate of a sustained virologic response (SVR) at post-treatment week 12 (SVR 12) were high (29/30, 96.67%). The most common adverse events were fatigue (73.33%), headache (46.67%), and there was a high safety profile on using DAAs. No patient discontinued treatment because of adverse events. No serious adverse events or mortality were reported. In this study, AST &amp; ALT were significantly decreased at end of treatment and 12 weeks after treatment, CD4 count was significantly increased. Otherwise there are no significant changes in both hematological and biochemical laboratory results. Conclusion Combination of daclatasvir and sofosbuvir have showed 96.67% sustained virologic response at 12 weeks after treatment (SVR 12) among HIV/HCV co-infected patients, with a very good safety profile. Moreover, the treated patients showed a significant increase in CD4 count. Accordingly, HIV/HCV co-infected patients should be treated with sofosbuvir and daclatesvir containing regimens.

Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.

This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549.

Machine learning prediction of the case-fatality of COVID-19 and risk factors for adverse outcomes in patients with non-small cell lung cancer.

Since the emergence of coronavirus disease 2019 (COVID-19) across the globe, patients with cancer have been found to have an increased risk of infection with COVID-19 and are highly likely to experience a severe disease course. This study analyzed the clinical outcomes of COVID-19 in patients with non-small cell lung cancer (NSCLC) and identified the risk factors for adverse outcomes. The study included patients diagnosed with COVID-19 between January 2020 and April 2022 at the Samsung Medical Center in Seoul, Republic of Korea, who have a history of NSCLC. The case-fatality rate and risk factors for COVID-19 were analyzed using a machine-learning prediction method. Additionally, the study investigated the effect of COVID-19 on the systemic treatment of patients with advanced-stage NSCLC. Overall, 1,127 patients were included in this study, with 10.3% of the patients being older than 75 years; of these patients, 51.8% were ex- or current smokers. Among the 584 patients cured after surgery, 91 had stable disease after concurrent chemo-radiotherapy, and 452 had recurrent or metastatic NSCLC. Among 452 patients with recurrent or metastatic NSCLC, 387 received systemic treatment in a palliative setting during COVID-19. Of these, 188 received targeted therapy, 111 received cytotoxic chemotherapy, 63 received immunotherapy +/- chemotherapy, and 26 received other agents. Among them, 94.6% of patients continued systemic treatment after the COVID-19 infection. Only one patient discontinued treatment because of complications of the COVID-19 infection, and 18 patients changed their systemic treatment because of disease progression. The case fatality rates were 0.86% for patients with early-stage NSCLC, 4.4% for patients with locally advanced NSCLC, and 9.96% for patients with advanced NSCLC. The factors associated with fatalities included palliative chemotherapy, type of palliative chemotherapy, age (≥75 years), diabetes, smoking history, history of lung radiotherapy, hypertension, sex, and chronic obstructive pulmonary disease (COPD). The predictive model using logistic regression and eXtreme Gradient Boosting (XGB) performed well [area under the curve (AUC) for logistic regression =0.84 and AUC for XGB =0.84]. The case fatality rate in patients with NSCLC was 4.8%, while most patients with advanced NSCLC continued to receive systemic treatment. However, patients with risk factors require careful management of COVID-19 complications.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Safety and efficacy of iparomlimab and tuvonralimab in combination with gemcitabine and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm, phase 2 trial (DUBHE-N-302).

6026 Background: Programmed cell death 1 (PD-1) inhibitor plus chemotherapy has been the standard first-line (1L) treatment for patients with recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Iparomlimab and tuvoralimab (QL1706), a novel bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen 4, indicated promising anti-tumor activity for advanced solid tumors including NPC in phase 1/1b trial. This study aimed to evaluate the safety and efficacy of QL1706 combined with chemotherapy as 1L treatment in R/M NPC. Methods: This multicenter, single-arm, phase 2 study (NCT05576272) recruited patients with NPC who had no prior systemic therapy in the R/M setting. Intravenous injection of QL1706 5 mg/kg (day 1) combined with gemcitabine 1000 mg/m² (days 1 and 8) and cisplatin 80 mg/m² (day 1) was administered for four to six cycles (21 days per cycle), followed by maintenance treatment of QL1706. The primary endpoint was safety and tolerability. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). Results: From May 19 2022 to Dec 9 2022, 29 patients were included. The median age was 50 years (range, 25-65), with 24 (83%) being male. Seven patients (24%) had an Eastern Cooperative Oncology Group Performance Status of 1. Nineteen (66%) had recurrent disease. As of the data cut-off on Dec 31 2023, the median follow-up was 15.5 months. Treatment-related adverse events (TRAEs) occurred in 29 patients (100%). TRAEs of grade 3 or 4 occurred in 18 patients (62%), with the most common being decreased neutrophil count (41%), decreased white blood cell count (35%), anemia (21%), and decreased platelet count (21%). Twenty patients (69%) experienced immune-related adverse events, with the most common being grade 1-2 hypothyroidism (38%). Serious TRAEs occurred in five patients (17%). Three patients (10%) discontinued treatment due to adverse events. No treatment-related deaths occurred. Among the 28 evaluable patients, the ORR was 82.1% (95% confidence interval [CI], 63.1% to 93.9%), including one achieving complete response. The DCR was 96.4% (95% CI, 81.7% to 99.9%). The median PFS was 12.5 months (95% CI, 5.7 to not evaluable [NE]), and the median DoR was 14.1 months (95% CI, 7.6 to NE). In 14 patients with high expression level of programmed cell death ligand 1 (combined positive score≥50), the median PFS was 16.2 months (95% CI, 9.9 to NE). The median OS was not reached. Conclusions: Iparomlimab and tuvoralimab combined with chemotherapy showed tolerable safety and promising efficacy as 1L treatment for patients with R/M NPC. Clinical trial information: NCT05576272 .

A phase I/II open-label clinical trial of CPI-613 in combination with modified FOLFIRINOX in patients with locally advanced (LAPC) or borderline resectable pancreatic cancer (BRPC).

4172 Background: Pancreatic ductal adenocarcinoma (PDA) carries a poor prognosis with a 5-year relative survival rate of 13%. Surgical resection is the only curative treatment option, but less than 20% of patients are eligible at diagnosis. A subset of patients with locally advanced disease can become candidates for resection with neoadjuvant (NA) therapy. mFOLFIRINOX is the standard of care in the adjuvant setting, with extrapolated data supporting its use in the NA setting. CPI-613/Devimistat (D) is a small molecule that targets mitochondrial metabolism in tumor cells leading to ROS-mediated apoptosis. A phase III trial of mFOLFIRINOX + D at 500 mg/m2 in metastatic PDA did not meet primary endpoint of overall survival (OS). Here we present the results of the combination’s use at standard and escalated doses in LAPC and BRPC. Methods: In this investigator-initiated, single-center, phase I/II, open-label trial treatment-naïve patients with investigator assessed LAPC or BRPC were treated with mFOLFIRINOX in 14 day cycles + D. In the standard dosing (SD) cohort, patients received D at 500mg/m2 while in the dose escalation (DE) cohort; D at 750 mg/m2 or 1000 mg/m2 was used. Radiographic response was assessed every 8 weeks. Patients who remained unresectable after 12 cycles could receive additional standard treatments, including chemoradiotherapy. The primary endpoint was median overall survival (mOS), with the study powered to show a mOS improvement from the historical standard of 14 months to 28 months with mFOLFIRINOX + D. Secondary endpoints were median progression free survival (mPFS), percent resected, and safety outcomes. NCT03699319 Results: Between Dec 2018 and Mar 2022, 37 patients and 11 patients enrolled in the SD and DE cohorts. Median age 69 years (range 47-78), male/female (27/21), Caucasian (83%), LAPC/BRPC (34/14). One patient (2%) withdrew, 4 patients (8%) discontinued treatment due to toxicity, 9 patients (19%) had progressive disease prior to completion of 12 cycles. In all patients mOS was 16.3 months and mPFS was 10.7 months. By cohort: SD/DE mOS: 16.2/17.6 months (p=0.56). Fourteen patients (29%) had partial response by RECIST 1.1. Twenty patients (41.7%) had resection; mOS 29.7 months. In the SD cohort, 78% and 24% of patients had grade 3 and/or 4 AEs. There were no dose limiting toxicities (DLT) in the DE cohort, and eight patients received the maximum dose of 1000 mg/m2 of D. After the DLT period, 100% patients in DE cohort had grade 3 toxicity and 55% had grade 4 toxicity. For all the most common toxicities (gr3,4) were neutropenia (27%,25%), diarrhea (25%,0), anorexia wt. loss (23%,0), nausea/vomiting (23%,0). Conclusions: The combination of mFOLFIRINOX and D is feasible in the LAPC/BRPC population at increased dose levels of D; however, it did not meet the primary endpoint of doubling OS compared to historical controls. Clinical trial information: NCT03699319 .