Mefatinib, a novel second-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor that has shown promising antitumor activity in targeting non-small cell lung cancer (NSCLC) with common and uncommon EGFR-activating mutations. In this phase III, randomized, double-blind trial in China, 336 eligible patients with advanced nonsquamous NSCLC harboring EGFR L858R or exon 19 deletion (ex19del) were assigned (2:1) to receive either mefatinib (60 mg daily, n = 223) or gefitinib (250 mg daily, n = 113). The primary endpoint was progression-free survival (PFS), assessed by an independent review committee (IRC). The trial is registered with chinadrugtrials.org.cn (CTR20192297). After a median follow-up of 15.9 months for mefatinib and 18.5 months for gefitinib, mefatinib demonstrated a significantly longer median IRC-assessed PFS compared to gefitinib (13.7 vs. 9.7 months; hazard ratio [HR] = 0.68; 95% confidence intervals [CI]: 0.53-0.87; p = 0.002). The 30-month overall survival rate was 60.2% for mefatinib and 54.3% for gefitinib. Patients with EGFR ex19del had comparable PFS for both treatment arms (p > 0.100), whereas patients with EGFR L858R had significantly longer median PFS when treated with mefatinib than gefitinib (13.7 vs 8.3 months HR = 0.55 [95% CI: 0.38-0.78]; p = 0.001). Patients with EGFR L858R had a 30-month overall survival rate of 56.6% with mefatinib and 43.7% with gefitinib. Treatment-related adverse events ≥grade 3 were reported in 45.7% of the mefatinib group and 24.8% of the gefitinib group. No new safety signals were observed for mefatinib. Mefatinib demonstrated superior efficacy to gefitinib with a similar tolerability profile in the first-line treatment of EGFR-mutated advanced NSCLC.

Benefit from first-line immunotherapy-based treatment in advanced biliary tract cancer (BTC) is heterogeneous, and selection biomarkers are lacking. We investigated whether genomic features could stratify benefit from intensified immunotherapy-based treatment versus chemotherapy.

Glucuronide prodrug strategies may enhance target specificity and reduce the toxicity of PARP inhibitors, but no clinical evaluation has been performed. We evaluated TSL-1502, a novel glucuronide prodrug of a PARP inhibitor, in a randomized, open-label, phase 2 study at 28 sites in China (NCT05420779). Eligible patients were women aged 18-75 years with HER2-negative locally advanced or metastatic breast cancer and germline BRCA mutations. Patients were assigned randomly (2:2:1) to receive TSL-1502 at 350 mg or 500 mg once daily or the investigator's choice of chemotherapy (eribulin, capecitabine, or vinorelbine) in 3-week cycles. Sixty-three patients were enrolled between August 18, 2022, and March 5, 2024. According to the Independent Review Committee assessment, the objective response rates were 36.0% (95% CI, 18.0-57.5) in the 350 mg group, 55.6% (95% CI, 35.3-74.5) in the 500 mg group, and 40.0% (95% CI, 12.2-73.8) in the chemotherapy group. The median progression-free survival times were 5.6 (95% CI, 4.0-8.2), 8.8 (95% CI, 5.7-not assessable [NA]), and 9.2 (95% CI, 1.38-NA) months, respectively, and the overall survival times were 17.4 months (95% CI, 9.1-NA), not reached (95% CI, 16.9-NA), and 19.8 months (95% CI, 9.2-NA), respectively. Grade ≥3 treatment-related adverse events occurred in 60.0%, 59.3%, and 80.0% of patients, with anemia most common in the TSL-1502 group and neutropenia most common with chemotherapy. No treatment-related deaths occurred. TSL-1502 at 500 mg showed promising antitumor activity and a manageable safety profile, supporting further clinical development.

The tumour microenvironment (TME) influences breast cancer progression and treatment response. We investigated whether TME composition predicts tamoxifen benefit in postmenopausal women with oestrogen receptor-positive, HER2-negative (ER+HER2-) breast cancer.

Talazoparib plus enzalutamide improved overall survival (OS) in the biomarker-unselected TALAPRO-2 population, but OS benefit was not statistically significant in the homologous recombination repair (HRR) non-deficient or unknown subgroup, whereas radiographic progression-free survival (rPFS) was prolonged. We explored time-dependent patterns in estimated treatment effects in this subgroup.

We report ophthalmological assessments, patient-reported visual symptoms/functioning, and characterization of visual effect AEs from the SERENA-6 study.

Quizartinib is a potent type II inhibitor of FMS-like tyrosine kinase 3 (FLT3) that demonstrated significant survival benefit among patients with newly diagnosed (ND) acute myeloid leukemia (AML) without FLT3-internal tandem duplication (FLT3-ITD) in the randomized, Phase II QUIWI trial. Here, we present the rationale and design of QuANTUM-Wild, a double-blind, randomized, placebo-controlled, Phase III study to confirm the efficacy and safety of quizartinib plus standard induction and consolidation chemotherapy and as maintenance monotherapy in adult patients with ND FLT3-ITD-negative AML. Eligible patients are randomized 2:2:1 to one of three treatment arms. Patients in Arm A (n ≈ 280) receive quizartinib plus chemotherapy during induction and consolidation (with option for transplant without study drug), followed by up to 36 cycles of single-agent maintenance therapy. Patients in Arm B (n ≈ 280) receive placebo in all treatment phases plus chemotherapy, then as maintenance monotherapy. Patients in Arm C (n ≈ 140) receive quizartinib plus chemotherapy in the induction and consolidation phases, then placebo during the maintenance phase, to specifically assess the utility of quizartinib maintenance. The primary endpoint is overall survival. Secondary endpoints include event-free survival, remission rate, and safety.Clinical trial registration: http://www.clinicaltrials.gov identifier is NCT06578247.

In CAPP2, 600 mg aspirin daily significantly reduced the incidence of colorectal cancer and the incidence of all Lynch syndrome cancers among participants with Lynch syndrome. CaPP3 aimed to assess the efficacy of two lower doses of aspirin.

Pharmacogenomic (PGx) testing can optimize drug efficacy and minimize toxicity, but prescriber adherence to PGx recommendations remains unclear. We aimed to quantify clinician adherence to international PGx recommendations in a cohort of pediatric oncology patients.

The current standard of care for resectable locally advanced colon cancer (LACC) is based on upfront surgery followed by adjuvant chemotherapy (AC). This study aimed to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) in this setting.

To determine if the developed Know Your Risk (KYR) intervention is similar to conventional genetic counseling; we evaluated participants' knowledge of cancer genetics, breast cancer risk perception, attitudes about genetic counseling and testing, and satisfaction with genetic counseling.

Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after anthracycline-based chemotherapy versus 78% after intensified alkylating chemotherapy with autologous stem cell rescue (IACT) in a post-hoc analysis of an earlier randomised controlled trial. In this study, we aimed to prospectively assess 4-year overall survival with IACT and establish whether this approach remains superior to a contemporary HRD-targeting regimen in patients with HER2-negative breast cancer with HRD.

To identify variables associated with early detriment on first-line dual immunotherapy from the phase III CheckMate 227 and CheckMate 9LA studies.

Patients with estrogen receptor-positive (ER+), HER2-negative, early breast cancer (BC) have low pathologic complete response (pCR) rates following neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in programmed death-ligand 1 (PD-L1)-negative tumors, characterized by an immune-cold tumor microenvironment. Here we hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT; 3 × 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. We conducted a phase 2, randomized, multicenter trial (Neo-CheckRay) in 147 female patients with high-risk, ER+HER2- early BC. Patients received neoadjuvant chemotherapy plus iSBRT alone (No_ICI), with anti-PD-L1 durvalumab (Single_ICI) or with durvalumab plus anti-CD73 oleclumab (Double_ICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35.4% with No_ICI, 45.1% with Single_ICI and 47.9% with Double_ICI, without statistically significant differences. pCR rates were 16.7%, 29.4% and 33.3%, respectively (P = 0.059). In the per-protocol population (MammaPrint High Risk, n = 131), pCR rates were 16.3%, 32.6% and 35.6%, respectively (P = 0.040). Among PD-L1-negative tumors (n = 91), pCR rates were 3.4%, 28.1% and 30.0%, respectively. No new safety signals were observed. Baseline transcriptomic analysis showed low immune signature expression in PD-L1-negative tumors. Paired baseline and on-treatment biopsies obtained 1 week after iSBRT demonstrated tumor microenvironment reprogramming toward an inflamed phenotype in the iSBRT + anti-PD-L1 arms. These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER+HER2- BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 .

Microsatellite-stable (MSS) colorectal cancer (CRC), which accounts for approximately 85% of cases annually, has demonstrated limited responsiveness to immune checkpoint blockade in the metastatic setting. Circulating tumor DNA (ctDNA) enables sensitive detection of minimal residual disease (MRD) following curative-intent therapy and identifies patients at high risk of recurrence who may benefit from additional treatment. The EMPIRE (NSABP FC-13) study is a multicenter, open-label, randomized phase II platform trial evaluating cemiplimab-based immunotherapy in patients with MSS CRC and ctDNA-defined MRD after definitive surgery and chemotherapy. Eligible patients have postoperative ctDNA positivity in the absence of radiographic recurrence and are allocated to one of three treatment arms: cemiplimab monotherapy; cemiplimab plus fianlimab (a lymphocyte activation gene-3 inhibitor); or cemiplimab plus REGN7075 (an EGFR×CD28 costimulatory bispecific antibody). The primary endpoint is ctDNA clearance at 12 weeks assessed by tumor-informed assay, with secondary endpoints including recurrence-free survival, safety and tolerability, longitudinal ctDNA kinetics, and patterns of recurrence. Arms 2 and 3 use single-stage phase II designs, whereas Arm 1 follows a Simon two-stage design with early futility stopping. The study integrates comprehensive correlative analyses to characterize mechanisms of response and resistance.Clinical trial registration: The http://www.clinicaltrials.gov identifier is NCT07058012.

Predictive biomarkers for immune checkpoint inhibitors (ICIs) are largely identified retrospectively, but their prospective clinical utility remains unproven. Here, we report DUTRENEO, a prospective randomized phase 2 trial testing whether a retrospectively validated 18-gene bulk tumor inflammation signature (TIS) can guide neoadjuvant ICI therapy in muscle-invasive bladder cancer. The trial does not meet its primary endpoint, and this demonstrates that bulk gene-expression stratification does not sufficiently enrich for responders. To define the biology underlying this failure, we generate single-cell spatial transcriptomic profiles of 377 genes in ∼5.4 million cells across large tissue areas. Response is governed by spatial architectures invisible to bulk assays, including CD8+ T cell proximity to cancer cells, localized checkpoint co-expression within epithelial cancer-rich neighborhoods, and fibroblast-rich immune-excluded communities in non-responders. We provide a quantitative framework showing that ≥77 genes and ≥3-mm tissue diameter regions preserve predictive spatial signal at scalable throughput. The registration details of the trial are EudraCT 2017-002246-68.

Phosphoinositide 3-kinase (PI3K) pathway, involved in obesity-related signalling, may influence efficacy and toxicity of PI3K inhibitors (PI3Ki). We explored associations between body mass index (BMI) and objective response rate (ORR), safety, molecular features, and breast density in the LORELEI trial.

Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies.

Although third-generation epidermal growth-factor receptor (EGFR)-tyrosine-kinase inhibitors (TKIs) are standard first-line therapies for patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC), their effectiveness is often limited by the emergence of drug resistance and subsequent disease progression. Given the previously established clinical efficacy and adverse event profile of aumolertinib, we aimed to evaluate the efficacy and adverse event profile of aumolertinib in combination with platinum-based chemotherapy versus aumolertinib monotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC patients with EGFR-sensitive mutations.

In the phase III LAURA study, osimertinib demonstrated a statistically significant progression-free survival benefit versus placebo, and a generally tolerable safety profile, after definitive chemoradiotherapy (CRT) in unresectable stage III EGFR-mutated non-small cell lung cancer. We report in-depth safety data from LAURA.