IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which improved the activity of antibody-dependent cellular cytotoxicity (ADCC) and superior anti-tumor efficacy.

Optimal therapy following breast-conserving surgery in older adults with low-risk, early-stage breast cancer remains uncertain. The EUROPA trial aims to compare the effects of radiotherapy and endocrine therapy as single-modality treatments on health-related quality of life (HRQOL) and ipsilateral breast tumour recurrence (IBTR) outcomes in this population.

Estrogen receptor-positive breast cancer patients have a long-term risk of distant metastatic disease, and premenopausal patients have a higher risk. Randomized studies with long-term follow-up are essential to understand treatment benefit. We elucidated the long-term tamoxifen therapy benefit by menopausal status in the Stockholm tamoxifen trials with 20 years complete follow-up.

Maintenance niraparib at an individualized starting dose (ISD) is established in platinum-sensitive recurrent ovarian cancer (PSROC). However, patients' perspectives on the burden of prolonged maintenance therapy have not been reported in prospective trials or routine practice.

The study aims to investigate the absorption, metabolism, and excretion of donafenib, a deuterated derivative of sorafenib, in healthy Chinese male volunteers.

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring c-KIT mutations.

Tuspetinib (TUS) is a well-tolerated, once daily, oral kinase inhibitor in clinical development for treatment of acute myeloid leukemia (AML). Nonclinical studies show that TUS targets key prosurvival kinases with IC50 values in the low nmol/L range, including SYK, wild-type (WT) and mutant forms of FLT3, mutant but not WT forms of KIT, RSK2, and TAK1–TAB1 kinases, and indirectly suppresses expression of MCL1. Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3-mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax (VEN) or 5-azacytidine. In vitro, TUS demonstrated potent killing of AML lines [concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) = 1.3–5.2 nmol/L] and Ba/F3 cells expressing WT (GI50 = 9.1 nmol/L) or various mutant forms of FLT3 (GI50 = 2.5–56 nmol/L). In AML lines, the multikinase targeting capacity of TUS suppressed phosphorylation of SYK, FLT3, STAT5, MEK, ERK, AKT, mTOR, 4E-BP1, and S6K kinases. Cells selected for stable acquired resistance to TUS exhibited increased BAX and hypersensitivity to VEN (1900 fold), navitoclax, and MCL1 inhibitors. MV-4-11 FLT3-ITD clones expressing NRASG12D revealed that high-level expression of NRASG12D generated modest resistance to TUS and greater resistance to VEN, yet the TUS/VEN combination exhibited synergy in the NRASG12D AML model. Favorable preclinical safety and pharmacology properties, the efficacy of the TUS/VEN combination in a murine model, and the synthetic lethal vulnerability to VEN that accompanies TUS resistance provide the basis for exploration of the TUS/VEN combination in patients with relapsed or refractory AML.

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment1. Yet, response rates are still limited, and tumour progression commonly occurs2. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition3. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

To investigate the efficacy of a novel approach using a sterile caliper for anterior chamber (AC) decompression in reducing post-intravitreal injection (IVI) intraocular pressure (IOP) spikes.

FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.

To investigate the clinical effect of electroacupuncture (EA) in preventing chemotherapy-induced peripheral neuropathy (CIPN).

Discrete choice experiments (DCEs) are increasingly used to understand and quantify patient preferences for a variety of treatments, services or screening in order to analyse the choices patients make when faced with different alternatives.

Convenient multiday dosing of antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting (CINV) are needed in pediatric patients, who are more likely than adults to be treated with emetogenic chemotherapy over multiple consecutive days. Intravenous (IV) fosaprepitant is approved for the prevention of CINV in children aged 6 months and older. This open-label, single-arm study assessed the safety and tolerability of a 3-day fosaprepitant regimen (consecutive daily IV administration on days 1-3) plus a serotonin receptor antagonist with or without dexamethasone in pediatric patients (6 months to 17 years) receiving emetogenic chemotherapy. Study treatment was initiated at the start of a chemotherapy cycle (cycle 1); patients completing cycle 1 could participate in optional cycles 2 and 3. Primary endpoints included adverse events (AEs) and AE-related discontinuation during cycle 1.98/100. Patients completed cycle 1; 69 participated in optional cycles 2 and 3. The AE profile during cycle 1 was typical of cancer patients receiving emetogenic chemotherapy; 80/100 (80.0%) patients experienced ≥1 AE. AE rates were generally similar between patients aged 6 months to <2 years (11/15 patients [73.3%]), 2 to <6 years (22/30 [73.3%]), 6 to <12 years (24/25 [96.0%]), and 12-17 years (23/30 [76.7%]). Rates of drug-related AEs (4/100 [4.0%]) and AE-related discontinuations (2/100 [2.0%]) were low. Similar trends in safety outcomes were observed during cycles 2 and 3. No deaths were reported. The 3-day IV fosaprepitant regimen for the prevention of CINV was generally well tolerated in pediatric patients receiving emetogenic chemotherapy.

ACCL0431 was a randomized clinical trial that demonstrated efficacy of sodium thiosulfate (STS) for preventing cisplatin-induced hearing loss (CIHL) among patients 1-18 years old. The purpose of this study was to evaluate possible differential STS otoprotection among patient subgroups.

Early intervention in smoldering multiple myeloma (SMM) may delay progression to MM. Here, we present the final analysis of the phase 2 CENTAURUS study. In total, 123 patients with intermediate/high-risk SMM were randomized to IV daratumumab 16 mg/kg after a long-intense (n = 41), intermediate (n = 41), or short-intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the long-intense, intermediate, and short-intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P < .0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the long-intense or intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per-protocol treatment. The median duration of study treatment was 44.0 (range, 1.0-91.6), 35.2 (range, 1.9-90.6), and 1.6 (range, 0.1-1.9) months in the long-intense, intermediate, and short-intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ∼7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. This trial was registered at www.ClinicalTrials.gov as #NCT02316106.

Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

In a global phase I/II study (GO29781; NCT02500407), single-agent mosunetuzumab had a manageable safety profile and induced durable complete responses in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma, including in patients with R/R follicular lymphoma (FL). In this analysis, the efficacy and safety of mosunetuzumab monotherapy were evaluated in an expansion cohort, FLMOON-1, in Japanese patients with R/R FL who had received  ≥ 2 prior lines of therapy in a phase I study (JO40295, jRCT2080223801).

In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (21, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.