C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.

BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation.

BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study. METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety. RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug discontinuation in 6.9% of patients. CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; ClinicalTrials.gov number, NCT03785249.).

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial.

BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. FUNDING: Amgen.

Acquired Resistance to KRASG12C Inhibition in Cancer.

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).

Ezabenlimab (BI 754091), an anti-PD-1 antibody, in patients with advanced solid tumours.

BACKGROUND: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours. STUDY DESIGN: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1). RESULTS: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days. CONCLUSIONS: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings.

Dual-Modified Hyaluronic Acid for Tunable Double Cross-Linked Hydrogel Adhesives.

Conventional techniques for the closure of wounds, such as sutures and staples, have significant drawbacks that can negatively impact wound healing. Tissue adhesives have emerged as promising alternatives, but poor adhesion, low mechanical properties, and toxicity have hindered their widespread clinical adoption. In this work, a dual modified, aldehyde and methacrylate hyaluronic acid (HA) biopolymer (HA-MA-CHO) has been synthesized through a simplified route for use as a double cross-linked network (DCN) hydrogel (HA-MA-CHO-DCN) adhesive for the effective closure and sealing of wounds. HA-MA-CHO-DCN cross-links in two stages: initial cross-linking of the aldehyde functionality (CHO) of HA-MA-CHO using a disulfide-containing cross-linker, 3,3'-dithiobis (propionic hydrazide) (DTPH), leading to the formation of a self-healing injectable gel, followed by further cross-linking via ultraviolet (UV) initiated polymerization of the methacrylate (MA) functionality. This hydrogel adhesive shows a stable swelling behavior and remarkable versatility as the storage modulus (G') has shown to be highly tunable (103-105 Pa) for application to many different wound environments. The new HA-MA-CHO-DCN hydrogel showed excellent adhesive properties by surpassing the burst pressure and lap-shear strength for the widely used bovine serum albumin-glutaraldehyde (BSAG) glue while maintaining excellent cell viability.

A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer. WHAT WERE THE RESULTS?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting. WHAT DO THE RESULTS MEAN?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Psychological interventions to improve pain, fatigue, anxiety, depression, and quality of life in children and adults with hypermobility spectrum disorders and Ehlers-Danlos syndrome: a systematic review.

Hypermobility spectrum disorders (HSD) affect individuals across physical, psychological and social domains, making assessment and management difficult. Management for this condition primarily focuses on addressing the musculoskeletal complaints using physiotherapy rather than the additional manifestations such as fatigue, anxiety and depression. This systematic review aims to identify psychological interventions and assess whether they improve the lived experiences of individuals with HSD. It also aims to assess which psychological interventions were most effective, which symptoms were most effectively managed by a psychological intervention, and whether there were differences between children and adults. Studies were included if they were a randomised controlled trial or pre/post-test design, a sample of any age and clinical diagnosis of HSD (including Ehlers-Danlos syndrome), used a psychological intervention and assessed the effect of the intervention on lived experiences using appropriate outcome measures. Risk of bias was assessed using the Mixed Methods Appraisal Tool. The results were narratively synthesised. Six studies were included in the review, one isolated psychological intervention and five incorporated a psychological intervention within a multidisciplinary programme. The interventions predominantly aimed to reduce pain including intensity, interference, pain-related fear and catastrophising, with anxiety and depression, affect, daily living, fatigue also being evaluated. The most beneficial psychological interventions were those delivered alongside physiotherapy in an outpatient or community setting, improving both the physical and psychological aspects of pain, subsequently improving quality of life. However, there lacks randomised controlled trials with larger samples to definitively confirm the significant findings discussed in this review.

Antibiotic Myths for the Infectious Diseases Clinician.

Antimicrobials are commonly prescribed and often misunderstood. With more than 50% of hospitalized patients receiving an antimicrobial agent at any point in time, judicious and optimal use of these drugs is paramount to advancing patient care. This narrative will focus on myths relevant to nuanced consultation from infectious diseases specialists, particularly surrounding specific considerations for a variety of antibiotics.

3D Macrocyclic Structure Boosted Gene Delivery: Multi-Cyclic Poly(ß-Amino Ester)s from Step Growth Polymerization.

The topological structures of polymers play a critical role in determining their gene delivery efficiency. Exploring novel polymeric structures as gene delivery vectors is thus of great interest. In this work, a new generation of multi-cyclic poly(ß-amino ester)s (CPAEs) with unique topology structure was synthesized for the first time via step growth polymerization. Through controlling the occurrence stage of cyclization, three types of CPAEs with rings of different sizes and topologies were obtained. In vitro experiments demonstrated that the CPAEs with macro rings (MCPAEs) significantly boosted the transgene expression comparing to their branched counterparts. Moreover, the MCPAE vector with optimized terminal group efficiently delivered the CRISPR plasmid coding both Staphylococcus aureus Cas9 nuclease and dual guide sgRNAs for gene editing therapy.

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours.

BACKGROUND: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. METHODS: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). RESULTS: Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). CONCLUSIONS: At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. CLINICAL TRIAL REGISTRATION: NCT02579226.

A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies.

BACKGROUND: This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers. METHODS: Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle. RESULTS: A total of 35 patients were enrolled in 6 cohorts; 30 patients were female; 4 patients had SCLC and 19 patients had ovarian cancer. Median prior lines of therapy were 3 (1-10). Median duration of treatment was 7.1 weeks (0.1-174). The most frequent grade 3/4 treatment-related adverse events were thrombocytopenia (51.43%) and anemia (31.43%). ORR was 9.7%; 58% of patients had SD. The study was stopped early before the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) were determined. CONCLUSION: The addition of LCL161 to oral topotecan caused more myelosuppression when dosed together than what was associated with either drug alone. Moreover, the drug combination did not improve outcomes. The study was terminated early (ClinicalTrials.gov Identifier: NCT02649673).

Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib.

Adagrasib (MRTX849) is a KRASG12C inhibitor with favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration. As of September 1, 2022, a total of 853 patients with KRASG12C-mutated solid tumors, including patients with CNS metastases, had received adagrasib (monotherapy or in combination). Adagrasib-related treatment-related adverse events (TRAEs) are generally mild to moderate in severity, start early in treatment, resolve quickly with appropriate intervention, and result in a low rate of treatment discontinuation. Common TRAEs seen in clinical trials included gastrointestinal-related toxicities (diarrhea, nausea, and vomiting); hepatic toxicities (increased alanine aminotransferase/aspartate aminotransferase) and fatigue, which can be managed through dose modifications, dietary modifications, concomitant medications (such as anti-diarrheals and anti-emetics/anti-nauseants) and the monitoring of liver enzymes and electrolytes. To manage common TRAEs effectively, it is imperative that clinicians are informed, and patients are fully counseled on management recommendations at treatment initiation. In this review, we provide practical guidance on the management of adagrasib TRAEs and discuss some best practices for patient and caregiver counseling to facilitate optimal outcomes for patients. Safety and tolerability data from the phase II cohort of the KRYSTAL-1 study will be reviewed and presented with practical management recommendations based on our experience as clinical investigators.

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

A phase Ib study of adavosertib, a selective Wee1 inhibitor, in patients with locally advanced or metastatic solid tumors.

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2-4.1 h; mean half-life was 5-12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

The biopsychosocial impact of hypermobility spectrum disorders in adults: a scoping review.

Joint hypermobility affects approximately 30% of the United Kingdom (UK) population, characterised by the ability to move joints beyond the physiological limits. Associated conditions include Ehlers-Danlos syndrome and hypermobility spectrum disorders, affecting individuals across physical, psychological and social levels detrimentally impacting their health and wellbeing. The scoping review aims to describe the known biopsychosocial impact of joint hypermobility conditions in adults over the last decade. Additional objectives include to (1) identify the types of studies that address these factors, (2) to understand how the impact of the condition is measured and managed and (3) what healthcare professionals (HCPs) are involved. The scoping review was conducted using the five-stage framework by Arksey and O'Malley. The search strategy related to two main keywords, "hypermobility" and, "biopsychosocial" across a number of electronic databases. A pilot search was conducted to determine the suitability of the databases and terms. Following the search, the data was extracted and charted, summarised and narratively reported. 32 studies met the inclusion criteria. The majority were conducted in either the UK or United States of America and case-control in design. The biopsychosocial impact was wide-ranging including, but not limited to, musculoskeletal system and dermatology, gastroenterology, mood and anxiety disorders, education and employments. This review is the first of its kind to summarise all reported symptoms and impact of joint hypermobility conditions in adults, highlighting a clear need to promote a multidisciplinary and holistic approach in raising awareness of these conditions and improving their management.