A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study

Se trata de la publicación del estudio de fase 3 ASPEN que comparó en pacientes con macro-globulinemia de Waldenström (WM) la eficacia y la seguridad de ibrutinib, un inhibidor de la tirosi-na quinasa Bruton (BTK) de primera generación, familia que ha demostrado ser un tratamiento eficaz en estos pacientes, frente a zanubrutinib, un nuevo inhibidor de BTK de 2ª generación, altamente selectivo. Los pacientes con enfermedad MYD88L265P se asignaron al azar 1:1 al tratamiento con ibrutinib o zanubrutinib. El criterio principal de valoración fue la proporción de pa-cientes que lograron una respuesta completa (RC) o una respuesta parcial muy buena (RPMB) mediante una revisión independiente. Los criterios secundarios clave de valoración incluyeron la tasa de respuesta mayor (RM), la supervivencia libre de progresión (SLP), la duración de la res-puesta (DR), la carga de la enfermedad y la seguridad. Se randomizaron 201 pacientes y 199 recibieron al menos 1 dosis del tratamiento del estudio. Veintinueve (28%) pacientes tratados con zanubrutinib y 19 (19%) pacientes tratados con ibrutinib lograron una RPMB, diferencia que no alcanzó la significación estadística (P = 0,09). Las RM fueron del 77% y del 78%, respectivamen-te. No se alcanzó la mediana de DR y SLP, ya que el 84% y el 85% de los pacientes tratados con ibrutinib y zanubrutinib estaban libres de progresión a los 18 meses. La fibrilación auricular, hema-tomas, diarrea, edema periférico, hemorragia, espasmos musculares y neumonía, así como los eventos adversos que condujeron a interrumpir el tratamiento, fueron menos frecuentes entre los receptores de zanubrutinib. La incidencia de neutropenia fue mayor con zanubrutinib, aunque las tasas de infección de grado ≥3 fueron similares en ambos grupos (1,2 y 1,1 eventos por 100 me-ses-persona). Estos resultados demuestran que zanubrutinib e ibrutinib son altamente efectivos en el tratamiento de la WM, pero zanubrutinib se asoció con menor toxicidad y una tendencia hacia una mejor calidad de respuesta y menos toxicidad, particularmente toxicidad cardiovascular.[EN]Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.BeiGene CoBeiGene C

Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis

Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM). We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for “myeloma,” “minimal residual disease,” and “clinical trial.” Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia.42 For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive. Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy. These results support the claim that MRD status can be used as a surrogate for PFS in NDMM. A surrogate endpoint that can support accelerated approval of a drug in newly diagnosed multiple myeloma is clearly needed. Here, we performed a meta-analysis of 6 randomized trials to evaluate the potential of minimal residual disease (MRD) status in predicting clinical benefit. A strong correlation between the relative changes of experimental to control treatments in MRD-negative rates and progression-free survival supported MRD status as a surrogate endpoint

Patient-reported outcomes and quality of life in anemic and symptomatic patients with myelofibrosis: results from the MOMENTUM study

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients’ quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit

Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab.

PurposeWe assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.Experimental designThis double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).ResultsOne hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).ConclusionThe addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions

Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab.

PurposeWe assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.Experimental designThis double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).ResultsOne hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).ConclusionThe addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions

Sorafenib or Placebo with Either Gemcitabine or Capecitabine in Patients with HER-2–Negative Advanced Breast Cancer That Progressed during or after Bevacizumab

PurposeWe assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.Experimental designThis double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).ResultsOne hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).ConclusionThe addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM):results from an international, double-blind, randomised, controlled, phase 3 study

Background Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.Methods MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs >= 22), spleen size (<12 cm vs >= 12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs >= 5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as >= 50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.Findings 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0 center dot 0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).Interpretation Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. Copyright (c) 2023 Elsevier Ltd. All rights reserved

Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer

Purpose Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. Patients and Methods Patients were randomly assigned to first-or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). Results In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand-foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). Conclusion Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.RocheRocheSOLTI GroupSOLTI GroupOnyx PharmaceuticalsOnyx PharmaceuticalsBayer HealthCare PharmaceuticalsBayer HealthCare Pharmaceutical