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Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients’ prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.

Human lives and nations’ economies have been adversely affected worldwide by the COVID-19 pandemic. The hyperinflammatory state associated with the disease may be related to mortality. Systemic glucocorticoid is the first-line therapy for cytokine storm. Various immunomodulatory drugs such as tocilizumab and baricitinib have been used in those not responding to glucocorticoid monotherapy. Amid the peak crisis of COVID-19 in India, there was an extreme paucity of medications, oxygen, and hospital beds. We describe three patients with COVID-19 who received low-dose tofacitinib (an oral Janus kinase inhibitor) in addition to moderate-dose glucocorticoid. These patients were treated at their homes, as the hospitals were short of beds. Rapid reduction in hypoxemia along with gradual resolution of other signs of the disease were observed. The results are reassuring regarding the feasibility of managing of severe COVID-19 outside the hospital setting when healthcare resources are overwhelmed by pandemic-related caseload.

Background: Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies. Methods: This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to 2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed. Findings: Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8–39·3) for patients with neuroblastoma, 33·2 months (27·9–35·9) for those with IMT, 34·0 months (21·9–46·4) for those with ALCL, and 27·5 months (22·4–36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8–39) of 30 patients with neuroblastoma, seven (70%; 33–93) of ten patients with IMT, six (75%; 35–97) of eight patients with ALCL, and one (14%; 2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations. Funding: Novartis Pharmaceutical Corporation.

Background Polycythemia vera (PV) is a myeloproliferative neoplasm affecting >100,000 people in the United States annually. Patients (pts) with PV are at risk for thromboembolic events (TEs), premature death, and high symptom burden. Hydroxyurea (HU) is recommended for high-risk pts with PV; however, up to 40% of pts become resistant and/or intolerant to the drug (Demuynck T, et al. Ann Hematol. 2019;98:1421-1426). Ruxolitinib (RUX), a Janus kinase (JAK) 1/JAK2 inhibitor, is currently the only FDA-approved treatment option for pts with PV who are resistant to or intolerant of HU. We conducted a retrospective chart review to characterize the reasons pts were switched from HU to RUX and to describe the real-world dosing patterns of RUX in pts with PV. Methods This retrospective medical chart review was conducted at US community hematology/oncology practices in the Cardinal Health Oncology Provider Extended Network. Eligible pts were ≥18 y old, initiated RUX therapy during the index period (January 1, 2015, to December 31, 2016), were previously treated with HU for ≥3 mo, and were seen at least twice during the 6 mo following RUX initiation. Data were collected for the 12 mo prior to RUX initiation (including near the time of HU discontinuation), near the time of RUX initiation (index), and up to the last provider visit. Pt and clinical characteristics were collected, including blood counts, symptoms, TEs, cardiovascular disease risk factors, phlebotomy, and HU and RUX treatment patterns. Target enrollment was 250 pts; interim results are presented here. Results Providers identified 99 pts for inclusion; mean (SD) age was 64 (9.9) y, 56% were male, and 68% had high-risk PV (ie, age ≥60 y and/or history of TE). All pts had been tested for the JAK2V617F mutation, and 99% were positive. At the time of HU discontinuation, 28% of pts had reached an HU dose of ≥2 g/d; median (range) HU treatment duration was 9.7 (3.6-182.4) mo. Causes of HU discontinuation were resistance (63%), intolerance (17%), resistance and intolerance (11%), and other reasons (9%; Table). The most frequent reasons for HU discontinuation due to resistance were hematocrit (Hct) ≥45% (79%), symptoms (45%), leukocytosis (32%), thrombocytosis (31%), and splenomegaly (22%). The most frequent intolerance signs and symptoms were nausea (43%), stomatitis (25%), fever (18%), and skin ulcers (14%). With respect to the RUX starting dose, 44 pts (44%) initiated RUX at the US package insert-recommended dose of 10 mg twice daily (BID); median (range) treatment duration for these pts was 26.4 (3.2-52.0) mo (Table). During the first 6 mo of RUX treatment, dose modification was noted in 19 pts (43%) who initiated at 10 mg BID (dose increase, n=13 [30%]; dose decrease, n=5 [11%]; dose interruption, n=1 [2%]). The most common reasons for dose increase were continued need for phlebotomy (39%) and symptoms (39%). Five pts required a dose reduction; the most common reason was low hemoglobin levels (n=3). Overall, pts starting at 10 mg BID had more dose modifications in the first 6 mo of RUX treatment (43%), with fewer dose modifications needed after 6 mo (25%). Hct control (Hct Conclusions In this interim analysis of real-world data pertaining to pts with PV who discontinued HU and were subsequently treated with RUX, the most common resistance events leading to HU discontinuation were Hct ≥45%, uncontrolled symptoms, leukocytosis, thrombocytosis, and splenomegaly. Discontinuations due to intolerance were most commonly attributed to nausea, stomatitis, fever, and skin ulcers. Of pts who were switched from HU to RUX, the duration of HU treatment was shorter and the proportion of pts treated with HU doses of ≥2 g/d was higher than has been reported for all pts discontinuing HU, irrespective of their next line of therapy (Grunwald MR, et al. ASH Annual Meeting 2017. Poster 1633). Less than half of pts initiated RUX at the recommended dose of 10 mg BID; 41% of pts dosed in accordance with the recommended starting dose experienced dosing modifications (primarily dose increases); however, the majority of pts who discontinued RUX had no dosing modifications during their treatment. Results from the entire cohort of 250 pts will be presented. Disclosures Altomare: Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy; Rigel: Consultancy. Nguyen:Incyte: Employment, Equity Ownership. Parasuraman:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Kish:Cardinal Health: Employment. Lord:Cardinal Health: Employment, Equity Ownership. Colucci:Incyte: Employment, Equity Ownership.

Introduction Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methods The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. Results RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2–43.6) best response rate and 89.4% (83.5–93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3–17.4; CP:11.9, 95% CI 7.5–15.6) months (HR 0.79, 0.49–1.27). 6m-SuT rates were similar (IP:80% 66.0–88.7%; CP:78% 63.8–87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8–7.8; CP: 9.2 7.3–11.1) months (HR 1.36, 0.88–2.12). Pazopanib-related adverse events grade 3–4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. Conclusions Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov , number NCT01813136 .

Crizotinib is highly efficacious and more tolerable than chemotherapy for ALK+ non-small-cell lung cancer (NSCLC), but its progression-free survival benefit and intracranial efficacy have limitations. Head-to-head comparisons of next-generation ALK inhibitors in patients with ALK+ NSCLC progressing on crizotinib will contribute toward optimizing survival. This international, Phase III, randomized, open-label study (ALTA-3) will therefore assign patients with locally advanced or metastatic ALK+ NSCLC progressing on crizotinib to receive either brigatinib 180 mg qd (7-day lead-in at 90 mg qd) or alectinib 600 mg twice daily. The primary end point is progression-free survival as assessed by a blinded Independent Review Committee; the key secondary end point is overall survival. Clinical trial registration number: NCT03596866 (ClinicalTrials.gov)

Cong Wei,1,* Xiaoting Zhang,1,* Dan Liang,1 Jilong Yang,1 Jingwen Du,1 Chunyan Yue,1 Lan Deng1,2 1Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lan DengDepartment of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of ChinaTel +86 13724862939Email denglan_76@126.comChunyan YueDepartment of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of ChinaTel +86 15521117300Email doctor_yy@126.comBackground: Graft-versus-host disease (GVHD) is a main complication following allogeneic hematopoietic stem cell transplantation and is a leading cause of non-relapse-related death. Unsatisfactory response to standard first-line therapy with glucocorticoids is a predictor of a poor prognosis in patients with GVHD. Ruxolitinib is a selective Janus kinases 1/2 inhibitor which has been shown to control acute (a) and chronic (c) GVHD while maintaining graft-versus-tumor effects.Objective: This study aims to evaluate the efficacy and safety of ruxolitinib in the treatment of steroid-refractory GVHD (SR-GVHD) in a population of Chinese patients.Methods: We report the results of 55 patients, including 23 patients with aGVHD and 32 patients with cGVHD, who were treated with ruxolitinib as salvage therapy between August, 2017 and December, 2020.Results: In patients with aGVHD, the overall response rate (ORR) was 86.9%, and the 1-year overall survival (OS) was 82.6% (95% CI, 67.1– 98.1%). The 1-year OS was significantly improved in responders than in non-responders (90.0% vs 33.3%, P=0.004). In patients with cGVHD, the ORR was 78.1%, and the 1-year OS was 81.3% (95% CI, 67.8– 94.8%). There was no significant difference in the 1-year OS between responders and non-responders (84.0% vs 71.4%, P=0.327). Cytopenia, cytomegalovirus-reactivation and infections were common adverse events, particularly in patients with aGVHD.Conclusion: Our real-world data from Chinese patients further confirm that ruxolitinib is a safe and effective treatment for SR-GVHD.Keywords: ruxolitinib, allogeneic hematopoietic stem cell transplantation, graft-versus-host disease, steroid-refractory

The article presents a clinical case of successful triple combination therapy in a female patient with functional class III idiopathic pulmonary arterial hypertension. Supplementing the previous macitentan and riociguat treatment with selexipag reduced the severity of clinical manifestations of pulmonary hypertension. Also, the treatment efficacy was demonstrated by improvement of laboratory and instrumental indexes. Time-related changes were evaluated at 3 months after initiation of the selexipag treatment.

A 53-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM) in 2008. Six courses of R-COP (rituximab, cyclophosphamide, vincristine, and prednisolone) resulted in complete remission, but LPL/WM relapsed in 2015. After six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), the M-peak disappeared, but the patient presented with muscle weakness and sensory disturbance in the lower extremities. No lesions were apparent in the brain parenchyma, but T2-weighted magnetic resonance imaging (MRI) showed a signal-hyperintense area with contrast enhancement in the spinal cord at the C2-4 and Th2-3 levels, and cerebrospinal fluid (CSF) examination showed only a few mononuclear cells. In 2020, the patient started to require walking assistance, and MRI findings worsened. Neurologically, lower limb muscle strength was reduced (manual muscle test score 3), and sensations of touch and pain were about 30% of normal. Vibratory sensation was absent at the knees and medial malleoli, accompanied by dysuria due to neurogenic bladder. CSF cell count was 15/μl (all mononuclear cells). Bing-Neel syndrome (BNS) was diagnosed and tirabrutinib was started. Within 2 months of treatment, lower extremity muscle strength had normalized and MRI findings had improved. Tirabrutinib may offer a promising therapeutic option for BNS.

A 71-year-old woman with a four-year history of chronic lymphocytic leukemia (CLL) received ibrutinib as initial treatment due to progressive anemia and thrombocytopenia. Eleven months after the start of the treatments, although her cytopenia had ameliorated, she developed classic Hodgkin lymphoma, a rare form of Richter's transformation. She was successfully treated with two courses of adriamycin, vinblastin, bleomycin and dacarbazine followed by radiotherapy. In general, several clinical, genetic and molecular factors are associated with Richter's transformation. In addition, our present case suggested that ibrutinib could be a potential risk factor for Richter's transformation in CLL patients.

The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.

In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population.

Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. Methods This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Results Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M × 2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R × 2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A × 2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. Conclusions The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

BACKGROUND In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429). METHODS This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed. RESULTS In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05). CONCLUSION This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH.

Background There was no standard treatment for patients who acquired resistance to osimertinib mediated by epidermal growth factor receptor (EGFR) T790M‐cis‐C797S. The aim of this study was to investigate the association between different therapeutic strategies and survival outcomes among these patients. Methods This retrospective cohort study analyzed 46 patients with metastatic lung adenocarcinoma and EGFR T790M‐cis‐C797S after osimertinib progression from January 1, 2017 to October 31, 2020. Among them, 13 patients received brigatinib‐based therapy, 23 patients received chemotherapy in combination of anti‐angiogenics or not, and 10 patients received other targeted treatments like dacomtinib, bevacizumab, or a combined therapy of osimertinib and other targeted drugs. Results Compared to other targeted therapy, brigatinib‐based therapy (median progression‐free survival [mPFS]: 4.40 vs. 1.63 months, hazard ratio [HR] = 0.39, 95% confidence interval [CI]: 0.21–0.73, p = 0.001) and chemotherapy‐based treatment (mPFS: 4.70 vs. 1.63 months, HR = 0.18, 95% CI: 0.06–0.50, p, Epidermal growth factor receptor (EGFR) C797S mutation plays an important role on the resistance of osimertinib in advanced non‐small‐cell lung cancer patients. The clinical efficacy of various treatments was evaluated in 46 patients carrying EGFR T790M‐cis‐C797S mutation. We demonstrated the possibility of brigatinib‐based therapy and chemotherapy plus anti‐angiogenic might bring better clinical outcomes in those patients and the co‐occurring EGFR 19del might have a better survival than EGFR 21L858R.

Primary myelofibrosis (PMF) is a subtype of BCR-ABL1 negative myeloproliferative neoplasm. Its characteristic features include clonal myeloproliferation, dysregulation of kinase signaling pathway, abnormal release of cytokines leading to fibrosis in the bone marrow, osteosclerosis, and extramedullary hematopoiesis. Approximately 20% of deaths occur because of disease progression, but death may also result occur because of cardiovascular complications or as a consequence of either infection or bleeding. The only and curative option for PMF is allogeneic hematopoietic stem cell transplant (allo-HSCT); however, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is highly effective in reducing constitutional symptoms and spleen volume, and has been found to improve survival. Ruxolitinib decreases the activity of type I T-helper cells, leading to decreased release of cytokines including tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, interferon-γ, and production of IL-12, which can be a risk factor for opportunistic infections. In this report, we describe three cases of tuberculosis reactivation shortly after initiation of ruxolitinib therapy followed by a literature review.

Recurrent GLI1 gene fusions have been recently described in a subset of soft tissue tumors showing a distinct monotonous epithelioid morphology with a rich capillary network and frequent S100 protein expression. Three different fusion partners—ACTB, MALAT1, and PTCH1—have been reported with the PTCH1-GLI1 fusion from 2 patients only, both with head and neck tumors. Herein, we report for the first time a PTCH1-GLI1 fusion in a primary ovarian tumor from a female patient aged 54 years who presented with a 21-cm right ovarian mass and mesenteric metastasis. The tumor was diagnosed as “favor malignant melanoma” based on histologic examination and extensive immunohistochemistry studies. The patient received 4 cycles of pembrolizumab and 2 cycles of trabectedin but developed multiple metastases. A next-generation sequencing-based assay detected a PTCH1-GLI1 fusion, which led to a revised pathologic diagnosis and a change of the patient’s management. The patient was switched to the tyrosine kinase inhibitor (TKI) pazopanib to target the sonic hedgehog pathway. Her disease was stable 49 months post TKI therapy. Our case report is the first to show that a tumor with GLI1 oncogenic activation was sensitive to a TKI. The morphologic and immunohistochemistry similarities of our patient’s tumor to other recently described tumors harboring GLI1 fusions suggest that these tumors may all belong to the same entity of GLI1 fusion–positive neoplasms and may be treated similarly.

Background Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking. Methods PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). Results Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48-11.83). 19% of patients (21/109) were long-term responders (on pazopanib for >= 18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%). Conclusions Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies., Novartis Pharmaceuticals Corporation, The PARACHUTE study was sponsored by Novartis Pharmaceuticals Corporation; pazopanib is an asset of Novartis AG as of 1 March 2015.

WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti–tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3‐related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i‐induced cell death. The tumor‐selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double‐strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti–tumor immunity. Furthermore, our study found that immune checkpoint programmed death‐ligand 1 is upregulated by the combination therapy, and blocking PD‐L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment., Combined application of WEE1i and ATRi in vivo and in vitro can inhibit tumor growth. Mechanistically, the combination promoted the accumulation of cytoplasmic dsDNA, which activated the STING‐TBK1‐IRF3 signal axis and induced the production of type I interferon, thereby inducing anti–tumor immunity. The effects of the combination were further enhanced by immune checkpoint PD‐L1 blockade.

In this phase I, dose-escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c-ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab-paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC-MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c-MET) and c-Jun N-terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty-one patients were evaluable for dose-limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression-free survival was 4.8 months. Three out of five response-evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c-MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.

Background Treatment of patients with platinum resistant/refractory epithelial ovarian cancer (EOC) is an unmet need. We evaluated the role of oral metronomic therapy in this setting. Patients and methods Between October 2017 and September 2019 seventy five patients with platinum resistant/refractory EOC were enrolled. Patients received oral etoposide (50 mg, day 1 to 14, cyclophosphamide 50 mg, day 1 to 28, every 4 weeks (Arm A, n = 38). Patients in Arm- B (n = 37) received Pazopanib (400 mg once daily) in addition to etoposide and cyclophosphamide. Quality of life (QoL) was evaluated using the EORTC questionnaire. Serum VEGF and PDGF were estimated at baseline, after 3rd and 6th cycle. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and QoL. Results Patients characteristics were well matched. Median PFS was higher in arm B, 5.1 months (95% CI 3.13 to10.33) compared to 3.4 months (95% CI 3.0 to 6.53) in arm A, p = 0.045. Median OS has ‘not reached’ in Arm B compared to 11.2 months (95% CI, 5.66 - not reached) in arm A, p = 0.032. Therapy was tolerated well; oral mucositis (p = 0.36) and fatigue (p = 0.08) being more in arm B. QoL assessment revealed modest improvement in ‘symptom scales’ in Arm B. Serum VEGF and PDGF levels decreased with therapy in both arms (Arm A-p Conclusion Addition of pazopanib to etoposide and cyclophosphamide could be a novel oral combination for metronomic therapy for platinum resistant/refractory EOC. Trial registration CTRI/2017/10/010219.

PURPOSE This study assessed treatment patterns in patients with mantle cell lymphoma (MCL) and compared health care resource utilization (HRU) and costs of ibrutinib with or without rituximab (I ± R) versus chemoimmunotherapy (CIT) in patients with relapsed/refractory MCL. METHODS For this retrospective cohort study, adults with MCL observed between May 13, 2013, and June 30, 2019, were identified using Optum's de-identified Clinformatics Data Mart Database. Treatment patterns were described among patients who received ≥1 line of therapy (LOT). HRU and costs (payer's perspective) were compared between patients treated with I ± R and CIT in the second or later line (2L+) of therapy. To account for differences in baseline characteristics between the 2 cohorts, inverse probability of treatment weighting was used. Monthly HRU and costs starting from I ± R or CIT treatment initiation (index date) were compared during the first Oncology Care Model (OCM) episode (ie, first 6 months) postindex and during the observed duration of I ± R or CIT LOT (index LOT) using rate ratios (RRs) and mean monthly cost differences (MMCDs), respectively. FINDINGS Among 1346 patients with ≥1 LOT (median follow-up, 15.3 months), 870 (64.6%) were treated with CIT in the first line. Only 348 (25.9%) had a 2L of therapy, of whom 110 (31.6%) were treated with CIT and 98 (28.2%) with an ibrutinib-based therapy. A total of 300 patients were included for the comparison of HRU and costs between 2L+ I ± R and 2L+ CIT. The weighted cohorts (after inverse probability of treatment weighting) included 149 patients treated with I ± R (mean age, 71.6 years; 73.7% men) and 151 treated with CIT (mean age, 71.5 years; 76.2% men). During the first OCM episode and during the index LOT, the I ± R cohort had significantly fewer monthly days with outpatient services compared to the CIT cohort (OCM, RR = 0.63 [P < 0.001]; index LOT, RR = 0.73 [P = 0.004]). Compared to the CIT cohort, the I ± R cohort incurred significantly higher monthly pharmacy costs (MMCDs: OCM, 9938 US dollars [USD] [P < 0.001]; index LOT, 8920 USD [P < 0.001]) that were fully offset by lower monthly medical costs (MMCDs: OCM, -19,373 USD [P < 0.001]; index LOT, -13,548 USD [P < 0.001]), resulting in monthly total health care cost savings (MMCDs, OCM, -9435 USD [P < 0.001]; index LOT , -4628 USD [P = 0.01]). IMPLICATIONS Over a median follow-up of 15.3 months, most patients with MCL were treated with CIT in the first line, and only one fourth had a 2L therapy. Patients with relapsed/refractory MCL treated with I ± R had significantly fewer days with outpatient services and lower monthly total health care costs versus those treated with CIT during the first OCM episode and the index LOT.

Aims Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P, The left panel shows no differences in the change in creatinine (P = 0.18) between the vericiguat and placebo groups, as evaluated by the interaction between treatment and study visit in the model. The right panel shows a natural cubic spline plot showing that the treatment effect of vericiguat on the primary outcome was similar across the full range of estimated glomerular filtration rate (eGFR) (P = 0.23).

Ruxolitinib is an FDA-approved orally administered Janus kinase (JAK 1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, Phase 2, open label trial, ruxolitinib (10 mg, bid) was administered to HIV(+), virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART), for 5 weeks. Study objectives were to assess safety, tolerability, pharmacokinetics (PK), and modulation of ongoing inflammation that persists even with viral suppression. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (wk1, N = 39 participants) and week 4 or 5 (wk4/5, N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical CL for participants administered efavirenz (a known CYP3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical CL/F versus the integrase inhibitor regimen (INSTI) group (22.5 versus 12.9 L/hr; N = 14 versus 25). Post hoc predicted CL/F were likewise, more variable and higher (p < 0.0001) in those administered efavirenz. There was ~ 25% variation in ruxolitinib plasma exposures between wk1 and wk4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, INSTI based ART regimens may be preferred over efavirenz based regimens when ruxolitinib is administered to HIV(+) individuals.

This study aims to evaluate the quality of life (QoL) of chronic myeloid leukemia (CML) patients prescribed with nilotinib as a second-line therapy and explores the influential factors. A multicenter retrospective survey was conducted via face-to-face interviews based on the EORTC QLQ-C30 questionnaire. A total of 121 adult CML patients resistant to imatinib and used nilotinib for at least 3 months were enrolled. The influential features were assessed by multiple linear regression models. Patients had the mean age of 47.49 (SD = 13.67) years, dominated by middle-aged and male groups. The mean scores of functions ranged from 75 to 83, and those of symptoms were from 5 to 28, with the highest of fatigue (28.28), insomnia (22.87), and pain (21.07). The mean global health status/QoL score was 67.70 (SD = 16.80) with considerable financial difficulties (52.34 (SD = 32.15)). Male patients reported higher functional scores and fewer symptoms compared with female patients. All aspects of QoL became worse with increasing age. Besides age and gender, level of education, duration of nilotinib usage, and comorbidities were also significantly influential factors in many QoL domains. A predicted model for expected mean scores of QoL domains was built based on these factors. The CML patients treated with nilotinib had the above-moderate QoL scores, a light decrease of functional scores, great financial difficulties, and still experienced symptoms. Strategies and more therapeutic considerations to enhance QoL for CML patients targeted toward women, the old, low educational level, and long duration of nilotinib usage, and many comorbidities are needed in the setting.

Purpose: Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling. Patients and Methods: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control. Results: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials. Conclusions: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans. See related commentary by Shastri and Adrianzen-Herrera, p. 6069

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients with suspected acute myocardial infarction. After single‐dose emergency treatment with selatogrel, patients are switched to long‐term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long‐term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three‐compartment model. The PD model included a receptor‐pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel‐receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS? The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Model‐based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by fibrosis of the skin and internal organs, autoimmunity-driven damage and vasculopathy. The current approved disease-modifying treatments have limited efficacy, and treatment is guided toward alleviating organ complications. Thus, there is an unmet need for discovering new effective treatment options. There is recent evidence that the JAK/STAT signaling pathway is markedly activated in SSc patients. To assess the efficacy and safety of tofacitinib (TOF) on skin and musculoskeletal involvement as compared to methotrexate (MTX) in systemic sclerosis (SSc). In this 52-week pilot study, 66 patients with SSc were enrolled: 33 patients received 5 mg of oral TOF twice a day; 33 received 10 mg of MTX weekly. The proportion of dcSSc and lcSSc patients was similar (dcSSc: 42% TOF group and 36% MTX group; lcSSc: 58% TOF group and 64% MTX group). The primary outcome was the change in the modified Rodnan skin score (mRSS). Secondary outcomes included ultrasound (US) skin thickness and musculoskeletal involvement (US10SSc score). Digital ulcers (DUs) and adverse events (AEs) were documented through the treatment. Both groups had similar characteristics and medians on the outcome measures at baseline. At week 52, the TOF median mRSS was significantly lower than the MTX (p p p = 0.002); mean reduction of 10.21 versus 5.27 in the MTX group. Healing of DUs with no new occurrences was observed in the TOF group. There was no significant difference between the groups in the number of AEs from baseline to week 52. TOF showed greater efficacy than MTX in reducing mRSS, skin thickness and musculoskeletal involvement in SSc and a satisfactory safety profile.

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC, and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared with placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after week 5 were significantly reduced with trilaciclib versus placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared with placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC. This article is protected by copyright. All rights reserved.

Pleomorphic liposarcoma of the uterus (PLU) is an extremely rare disease with poor prognosis. Limited treatment options exist for these patients, and disease recurrence usually occurs rapidly within months of initial diagnosis. Few case reports of metastatic PLU are available in the literature. We describe a 70-year-old woman who presented with a large uterus and ovarian mass on imaging and negative serum tumor markers and endometrial biopsy. Staging revealed localized disease. Surgical resection revealed PLU on pathology. Immunohistochemistry was negative for smooth muscle actin (SMA), S100, and MDM2, and positive for CD10 and cyclin-D1. She was treated with adjuvant therapy and experienced disease recurrence in the liver at 15 months from surgery. Genetic testing of the metastasis showed IQGAP-NTRK3 gene fusion. She was given entrectinib but continued to show progression in the liver. Right partial hepatectomy was performed, showing positivity for CD10, BCL-1, MDM2, and SMA on tumor staining. Treatment was switched to pazopanib with disease progression in the neck. She was treated with larotrectinib last, showing no disease progression and adequate tolerance of therapy after 18 months of this treatment. This is the first case in the literature of metastatic PLU with NRTK3 fusion treated with sequential first-generation NRTK inhibitors. More case reports are needed to identify commonalities and therapeutic options. Genetic testing in all PLU cases is needed for targeted therapy approaches.

The Z-drugs (zolpidem, zopiclone, zaleplon) are widely used to treat insomnia in patients receiving prescription opioids, and the risk of overdose resulting from this coprescription has not been explored. The authors compared the rates of overdose among patients using opioids plus Z-drugs and patients using opioids alone.All individuals 15 to 85 years of age receiving prescription opioids, regardless of underlying indication and without evidence of cancer, were identified in the IBM MarketScan database (2004-2017). Patients with concomitant exposure to Z-drugs were matched 1:1 to patients with exposure to prescription opioids alone based on opioid prescribed, morphine equivalents, number of days' supply, and hospitalization within the past 30 days. The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days, using an intention-to-treat approach. Fine stratification on the propensity score was used to control for confounding.A total of 510,529 exposed patients and an equal number of matched reference patients were analyzed. There were 217 overdose events among the exposed patients (52.5 events per 10,000 person-years) and 57 events among the reference patients (14.4 events per 10,000 person-years), corresponding to an unadjusted hazard ratio of 3.67 (95% CI=2.75, 4.90). Using fine stratification on the propensity score (c-statistic: 0.66), the adjusted hazard ratio was 2.29 (95% CI=1.79, 2.91). Results were consistent across sensitivity analyses.Among patients receiving prescription opioids, after controlling for all confounding factors, concomitant treatment with Z-drugs was associated with a substantial relative increase in the risk of overdose. The potential implications are significant given the large number of opioid-treated patients receiving Z-drugs.

Tam Metin / Full Text Q4 SCI-Expanded WOS:000668244900016 PMID: 33315343 The aim of this study is to assess the efficacy and safety of ruxolitinib in patients with myelofibrosis. Materials and methods: From 15 centers, 176 patients (53.4% male, 46.6% female) were retrospectively evaluated. Results: The median age at ruxolitinib initiation was 62 (28–87) and 100 (56.8%) of all were diagnosed as PMF. Constitutional symptoms were observed in 84.7%. The median initiation dose of ruxolitinib was 30 mg (10–40). Dose change was made in 69 (39.2%) patients. Forty seven (35.6%) and 20 (15.2%) of 132 patients had hematological and nonhematological adverse events, respectively. The mean spleen sizes before and after ruxolitinib treatment were 219.67 ± 46.79 mm versus 199.49 ± 40.95 mm, respectively (p < 0.001). There was no correlation between baseline features and subsequent spleen response. Overall survival at 1-year was 89.5% and the median follow up was 10 (1–55) months. We could not show any relationship between survival and reduction in spleen size (p = 0.73). Conclusion: We found ruxolitinib to be safe, well tolerated, and effective in real-life clinical practice in Turkey. Ruxolitinib dose titration can provide better responses in terms of not only clinical benefit but also for long term of ruxolitinib treatment

Mobocertinib (TAK‐788) is an investigational oral tyrosine kinase inhibitor targeting epidermal growth factor receptor and human epidermal growth factor 2. A phase 1 open‐label, 2‐period, fixed‐sequence, 2‐part study ({"type":"clinical-trial","attrs":{"text":"NCT03928327","term_id":"NCT03928327"}}NCT03928327) characterized effects of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of mobocertinib and its active metabolites, AP32960 and AP32914. Healthy volunteers (n = 12 per part) received a single dose of mobocertinib alone (20 mg, part 1; 160 mg, part 2) and with multiple doses of itraconazole 200 mg once daily (part 1) or rifampin 600 mg once daily (part 2). Coadministration of itraconazole with mobocertinib increased the combined molar area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) of mobocertinib, AP32960, and AP32914 by 527% (geometric least‐squares mean [LSM] ratio, 6.27; 90% confidence interval [CI], 5.20‐7.56). Coadministration of rifampin with mobocertinib decreased the combined molar AUC0‐∞ of mobocertinib, AP32960, and AP32914 by 95% (geometric LSM ratio, 0.05; 90%CI, 0.04‐0.07). Based on these results, the strong CYP3A inhibitor itraconazole and inducer rifampin significantly influenced the PK of mobocertinib and its active metabolites. Coadministration of mobocertinib with moderate and strong CYP3A inhibitors or inducers is not recommended in ongoing clinical trials.

Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

Aims/Introduction This study investigated the impact of the dipeptidyl peptidase‐4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relationship to glycemic status. Materials and Methods Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 weeks of anagliptin therapy were compared with a placebo. HIC was calculated as the ratio, C‐peptide area under the curve 0–120 min to insulin area under the curve 0–120 min, after a meal tolerance test. To explore the effects of baseline HIC levels on variables, participants receiving anagliptin were divided according to quartiles of baseline HIC. Furthermore, multivariate analysis investigated the association between baseline HIC levels and glycemic status. Results Anagliptin significantly reduced glycosylated hemoglobin levels (P, Anagliptin affected hepatic insulin clearance (HIC) levels according to HIC baseline levels. Anagliptin reduced HIC in the relatively higher HIC group (baseline HIC ≥median). Anagliptin increased HIC in the relatively lower HIC group (baseline HIC

Background Pathogenesis of atopic dermatitis (AD) involves the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. A cream formulation of ruxolitinib, a potent selective JAK1/JAK2 inhibitor, was developed for topical delivery. Method Pharmacokinetic data were obtained from three double-blind, vehicle-controlled studies in patients with AD: a phase II study with ruxolitinib cream 0.15%, 0.5%, or 1.5% once daily or 1.5% twice daily (BID), and two phase III studies with 0.75% or 1.5% BID. Effects of baseline characteristics on pharmacokinetics were examined. Correlations were attempted between plasma concentrations and change in hematological parameters over time. Results Ruxolitinib plasma concentrations at steady-state (Css) increased with cream strength in a less-than-dose-proportional manner. In the phase III studies, overall mean (standard deviation [SD]) Css after ruxolitinib cream 0.75% and 1.5% BID (23.8 [35.0] and 35.7 [55.0] nM) were a fraction of the half-maximal inhibitory concentration for thrombopoietin-stimulated phosphorylated STAT3 inhibition (281 nM), a JAK/STAT signaling marker. Three covariates were identified for Css: dose, percent body surface area (%BSA) treated, and baseline Investigator’s Global Assessment score. Mean (SD) bioavailability of ruxolitinib cream 1.5% BID was 6.22% (7.66%). There were no correlations between Css and any hematological changes except for a transient increase in platelets at week 2. Conclusions Plasma ruxolitinib concentrations after treatment with topical ruxolitinib cream in patients with up to 20% BSA affected by AD are not expected to lead to systemic plasma concentrations that may be associated with adverse effects commonly associated with oral JAK inhibitors. ClinicalTrials.gov NCT03011892; NCT03745638; NCT03745651. Supplementary Information The online version contains supplementary material available at 10.1007/s40257-021-00610-x.

Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). Results In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. Trial registration ClinicalTrials.gov NCT01988493.

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

Objectives Treatment of both platinum resistant high grade (HG) and low‐grade (LG) ovarian cancer (OVCA) poses significant challenges as neither respond well to conventional chemotherapy leading to morbidity and mortality. Identification of novel agents that can overcome chemoresistance is therefore critical. Previously, we have demonstrated that OVCA has basal upregulated unfolded protein response (UPR) and that targeting cellular processes leading to further and persistent upregulation of UPR leads to cell death. ONC201 is an orally bioavailable Dopamine Receptor D2 inhibitor demonstrating anticancer activity and was found to induce UPR. Given its unique properties, we hypothesized that ONC201 would overcome platinum resistance in OVCA. Methods Cisplatin sensitive and resistant HG OVCA and two primary LG OVCA cell lines were studied. Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Apoptosis and mitochondrial membrane potential were investigated using flow cytometry. Analysis of pathway inhibition was performed by Western Blot. mRNA expression of UPR related genes were measured by qPCR. In vivo studies were completed utilizing axillary xenograft models. Co‐testing with conventional chemotherapy was performed to study synergy. Results ONC201 significantly inhibited cell viability and migration in a dose dependent manner with IC50’s from 1‐20 µM for both cisplatin sensitive and resistant HG and LG‐OVCA cell lines. ONC201 lead to upregulation of the pro‐apoptotic arm of the UPR, specifically ATF‐4/CHOP/ATF3 and increased the intrinsic apoptosispathway. The compensatory, pro‐survival PI3K/AKT/mTOR pathway was downregulated. In vivo, weekly dosing of single agent ONC201 decreased xenograft tumor size by ~50% compared to vehicle. ONC201 also demonstrated significant synergy with paclitaxel in a highly platinum resistant OVCA cell‐line (OV433). Conclusions Our findings demonstrate that ONC201 can effectively overcome chemoresistance in OVCA cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. This is a promising, orallybioavailable therapeutic agent to consider in clinical trials for patients with both HG and LG OVCA., ONC201 can effectively overcome chemoresistance in both high‐grade and low‐grade ovarian cancer cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. A weekly oral dose of ONC201 lowers the tumor burden in mice. This is a promising therapeutic agent in OVCA treatment and might consider for clinical translation.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC). However, almost all patients eventually develop progressive disease on first-line ALK TKIs (e.g., crizotinib, alectinib and ceritinib). Brigatinib, a second-generation ALK TKI, may show efficacy in alectinib- and ceritinib-refractory ALK+ NSCLC. We describe the rationale and design of ALTA-2, a Phase II study of brigatinib in patients with locally advanced/metastatic ALK+ NSCLC and documented progressive disease on alectinib or ceritinib. The primary end point is confirmed objective response rate per independent review committee using response evaluation criteria in solid tumors version 1.1. Secondary end points include duration of response, progression-free survival, overall survival, safety and health-related quality of life.

Purpose: We studied the IOP-lowering effects of NCX 1741, a novel nitric oxide (NO)-donating derivative of the phosphodiesterase type-5 inhibitor, avanafil, in Cynomolgus monkey with laser-induced ...

Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin

CB-5083 is an inhibitor of p97/valosin-containing protein (VCP), for which phase I trials for cancer were terminated because of adverse effects on vision, such as photophobia and dyschromatopsia. Lower dose CB-5083 could combat inclusion body myopathy with early-onset Paget disease and frontotemporal dementia or multisystem proteinopathy caused by gain-of-function mutations in VCP. We hypothesized that the visual impairment in the cancer trial was due to CB-5083's inhibition of phosphodiesterase (PDE)-6, which mediates signal transduction in photoreceptors. To test our hypothesis, we used in vivo and ex vivo electroretinography (ERG) in mice and a PDE6 activity assay of bovine rod outer segment (ROS) extracts. Additionally, histology and optical coherence tomography were used to assess CB-5083's long-term ocular toxicity. A single administration of CB-5083 led to robust ERG signal deterioration, specifically in photoresponse kinetics. Similar recordings with known PDE inhibitors sildenafil, tadalafil, vardenafil, and zaprinast showed that only vardenafil had as strong an effect on the ERG signal in vivo as did CB-5083. In the biochemical assay, CB-5083 inhibited PDE6 activity with a potency higher than sildenafil but lower than that of vardenafil. Ex vivo ERG revealed a PDE6 inhibition constant of 80 nM for CB-5083, which is 7-fold smaller than that for sildenafil. Finally, we showed that the inhibitory effect of CB-5083 on visual function is reversible, and its chronic administration does not cause permanent retinal anomalies in aged VCP-disease model mice. Our results warrant re-evaluation of CB-5083 as a clinical therapeutic agent. We recommend preclinical ERG recordings as a routine drug safety screen. SIGNIFICANCE STATEMENT: This report supports the use of a valosin-containing protein (VCP) inhibitor drug, CB-5083, for the treatment of neuromuscular VCP disease despite CB-5083's initial clinical failure for cancer treatment due to side effects on vision. The data show that CB-5083 displays a dose-dependent but reversible inhibitory action on phosphodiesterase-6, an essential enzyme in retinal photoreceptor function, but no long-term consequences on retinal function or structure.

Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer. In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed. Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p

This study aimed to observe the safety and clinical efficacy of early application of ruxolitinib to prevent acute graft-versus-host disease (aGVHD) after alternative donor transplantation in acute leukemia. There were 57 patients undergoing allo-HSCT at the Affiliated Cancer Hospital of Zhengzhou University from July 2017 to October 2019. They were divided into control(16 patients) and ruxolitinib (41 patients) groups. For aGVHD prophylaxis, the control group received post-transplantation cyclophosphamide, antithymocyte globulin-Fresenius, cyclosporine A, and mycophenolate mofetil, while in the ruxolitinib group, ruxolitinib 5 mg/d in adults or 0.07–0.1 mg/(kg d) in children was administered from the day of neutrophil engraftment to 100 days post-transplantation based on control group. We found 55 patients had successful reconstitution of hematopoiesis; No significant difference was found in cGVHD, hemorrhagic cystitis, pulmonary infection, intestinal infection, Epstein-Barr virus infection, cytomegalovirus infection, relapse, death, and nonrelapse mortality. The incidences of aGVHD (50 vs. 22%, P = 0.046) and grade II–IV aGVHD (42.9 vs. 12.2%, P = 0.013) were significantly higher in the control group than in the ruxolitinib group. No significant differences were observed in overall survival (P = 0.514), disease-free survival (P = 0.691), and cumulative platelet transfusion within 100 days post-transplantation between two groups. This suggests early application of ruxolitinib can reduce the incidence and severity of aGVHD and patients are well tolerated.

Background This study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH). Methods Eleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed. Results In group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2–2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up. Conclusion Ruxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

Objective.Tofacitinib (TOF) is the first Janus kinase (JAK) inhibitor approved for psoriatic arthritis (PsA). It has shown efficacy in patients refractory to anti–tumor necrosis factor-α in randomized controlled trials (RCTs). Our aim was to assess efficacy and safety of TOF in clinical practice.Methods.This was an observational, open-label multicenter study of PsA patients treated with TOF due to inefficacy or adverse events of previous therapies. Outcome variables were efficacy, corticosteroid dose-sparing effect, retention rate, and safety. A comparative study of clinical features between our cohort of patients and those from the OPAL Beyond trial was performed.Results.There were 87 patients (28 women/59 men), with a mean age of 52.8 ± 11.4 years. All patients were refractory to biologic disease-modifying antirheumatic drugs (DMARDs) and/or to conventional synthetic DMARDs plus apremilast. TOF was started at 5 mg twice daily after a mean follow-up of 12.3 ± 9.3 years from PsA diagnosis. At first month, Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) decreased from median 4.8 (IQR 4.1–5.4) to 3.7 (IQR 2.8–4.7,P< 0.01), Disease Activity Index for Psoriatic Arthritis from median 28 (IQR 18.4–34.1) to 15.5 (IQR 10.1–25.7,P< 0.01), and C-reactive protein from median 1.9 (IQR 0.3–5.0) to 0.5 (IQR 0.1–2.2) mg/dL (P< 0.01). Also, TOF led to a significant reduction in prednisone dose. Mild adverse effects were reported in 21 patients (24.13%), mainly gastrointestinal symptoms. TOF retention rate at Month 6 was 77% (95% CI 65.2–86.3). Patients in clinical practice were older with longer disease duration and received biologic agents more commonly than those in the OPAL Beyond trial.Conclusion.Data from clinical practice confirm that TOF seems to be effective, rapid, and relatively safe in refractory PsA despite clinical differences with patients in RCTs.

SummaryBackground Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non–small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate 2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.