Primary analysis of the phase 3 EMBARK trial reported efficacy and safety outcomes for enzalutamide monotherapy in patients with high-risk biochemical recurrence. Here, we report secondary end points for enzalutamide monotherapy vs leuprolide alone.

HER2-positive and triple-negative breast cancers (TNBC) are aggressive subtypes with poor outcomes. Metformin, a commonly used antidiabetic agent, has demonstrated anticancer potential in preclinical studies. This trial evaluated whether the addition of metformin to neoadjuvant chemotherapy (NACT) improves pathological complete response (pCR) rates in nondiabetic patients with localized HER2-positive or TNBC.

We assessed the overall survival (OS) impact of time to relapse (TTR) in multinational cohorts with independent observational and randomized validation. Patients with nMTCL with frontline complete response were assigned to TTR12 (≤12 months) or without TTR12 based on time to progression or next therapy. OS analyses included modified landmark (m-LM), standard landmark (s-LM), and time-dependent Cox (td-Cox), adjusting for age, histology, and prognostic index for T-cell lymphoma (PIT) score. Across 452 patients, 165 (36.5%) had TTR12, 181 (40%) relapsed at ≥12 months, and 106 (23.5%) remained relapse-free. TTR12 conferred worse OS using m-LM (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.58-2.90; P< .001), s-LM (HR, 1.92; 95% CI, 1.39-2.66; P< .001); and td-Cox (HR, 5.81; 95% CI, 2.94-11.46; P< .001). Results were consistent in the independent validation cohorts. TTR12 consistently conferred worse OS irrespective of frontline stem cell transplantation or PIT score, in peripheral T-cell lymphoma, not otherwise specified (m-LM: HR, 2.32; 95% CI, 1.51-3.55; P< .001; s-LM: HR, 2.10; 95% CI, 1.33-3.31; P = .001), anaplastic large cell lymphoma (m-LM: HR, 3.34; 95% CI, 1.18-9.50; P = .023; s-LM: HR, 2.96; 95% CI, 1.02-8.81; P = .046), and angioimmunoblastic T-cell/T follicular helper cell lymphoma (m-LM only: HR, 1.92; 95% CI, 1.15-3.21; P = .013). Second-line novel therapies improved OS (second-line start to death) vs chemotherapy in TTR12 only (HR, 0.60; 95% CI, 0.37-0.97; P = .038; without TTR12: HR, 0.82; 95% CI, 0.51-1.32; P = .407). TTR12 serves as a prognostic and potential OS surrogate marker, supporting stratification of new risk groups and need for their differential treatment.

Enzalutamide and abiraterone are hormonal treatments that improve survival in metastatic castration-resistant prostate cancer. Identifying genetic variants associated with the clearance of these drugs may aid in improved dosing and outcomes. We performed genetic association studies of enzalutamide and abiraterone oral clearance in the Alliance A031201 clinical trial. Genome-wide genotyping was performed with the primary analysis limited to European-descent participants. Pharmacogene metabolic phenotypes were estimated using PyPGx and Stargazer. Associations of metabolic activity groups for CYP3A4, CYP3A5, CYP2C19 and SLCO1B1 with enzalutamide clearance (N = 706) and CYP3A4, SLCO2B1 and UGT1A4 with abiraterone clearance (N = 323) were tested by linear regression. Targeted SNP associations were assessed for abiraterone clearance at loci proximal to major metabolizing genes. Full genome-wide association studies were performed for both sets of clearance values. No significant associations were identified between metabolic phenotypes and enzalutamide or abiraterone oral clearance SNPs in the SULT2A1 5' flanking region were significantly associated with lower abiraterone clearance, (rs296373, minor allele frequency = 0.15, β = -0.457, p = 3.2E-06). Liver protein and liver and adrenal gland gene expression QTL databases indicated significantly lower SULT2A1 expression patterns for individuals carrying associated alleles, likely explaining the lower abiraterone oral clearance. CYP2C8*3 was associated with higher enzalutamide clearance (p = 0.012), but this was not significant after correction for multiple testing. This study is the first to identify the genetic association of SULT2A1, known to be involved in the metabolism of steroids in the liver and adrenal glands, with abiraterone clearance. Genetic variation in SULT2A1 may be useful to inform personalized dosing of abiraterone. ClinicalTrials.gov Identifier: NCT01949337.

Whole-breast radiotherapy (WBRT) after breast-conserving surgery (BCS) in older patients can be challenging due to the increased presence of comorbidities, comedication, the presence of a pacemaker or difficulties in traveling to treatment every day. Challenging times, such as the pandemic, can also lead to RT not being performed despite the indication. Very short treatment regimens are therefor of special interest in this population reducing overall treatment time and radiation exposure. TARGIT-E is a phase II trial investigating intraoperative radiotherapy (IORT) during BCS in elderly patients. We report long-term follow-up results of TARGIT-E.

High-quality endoscopic reports are crucial for clinical decision-making in gastric lesions. However, manually generated reports often suffer from inconsistencies, resulting in incomplete lesion documentation and insufficient descriptions. The objective is to validate an artificial intelligence (AI) reporting system for improving the quality of gastric lesion documentation with a particular focus on narrowing the experience gap among endoscopists.

Garsorasib (D-1553), a highly selective, oral KRASG12C inhibitor, has shown clinical efficacy in NSCLC and CRC and is under evaluation in pancreatic cancer.

Adoptive cell transfer-based immunotherapy holds promise for treating advanced cancer. However, a key challenge remains: generating sufficient numbers of lymphocytes capable of recognizing and targeting a broad range of cancer antigens. We recently developed Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT), a novel procedure for selecting, expanding and maturing polyclonal lymphocytes from peripheral blood with the capacity to target cancer cells. In this single-center phase Ib trial, we evaluated the safety, tolerability, and preliminary efficacy of ALECSAT in combination with standard carboplatin and gemcitabine in patients with locally advanced or metastatic triple-negative breast cancer (mTNBC).

Gastrin-releasing peptide receptor (GRPR) is overexpressed in a range of tumor types, making it an attractive candidate for novel treatment approaches. NeoB binds to GRPR with high affinity and can be radiolabeled with 68Ga ([68Ga]Ga-NeoB) for imaging or 177Lu ([177Lu]Lu-NeoB, hereafter 177Lu-NeoB) for therapy, making it suitable for theranostics. Methods: NeoRay is a prospective, phase 1/2a, open-label, multicenter, first-in-human study of 177Lu-NeoB. Patients with selected advanced solid tumors with GRPR expression (confirmed by [68Ga]Ga-NeoB lesion uptake) were enrolled. Here, we report preliminary data (cutoff, April 29, 2024) from phase 1, which aimed to identify the maximum tolerated dose and/or recommended phase 2 dose of 177Lu-NeoB. Patients were scheduled to receive at least 3 cycles of 177Lu-NeoB at an interval of at least 6 wk. A Bayesian optimal interval design was used, with dose-escalation decisions based on dose-limiting toxicities (DLTs) during cycle 1 of each dose level. The primary endpoint was the incidence and nature of DLTs. Safety was assessed before and throughout each cycle. Dosimetry was assessed after the first administration. Results: Seventeen patients (median age, 65 y; 71% male) with advanced gastrointestinal stromal tumors, prostate cancer, glioblastoma, or breast cancer received 177Lu-NeoB activities of 1.85 GBq (cycle 1) and then 5.55 GBq (cycles 2-4) (n = 3), 9.25 GBq (n = 9), or 11.1 GBq (n = 5). Four DLTs were observed in 3 patients who received 11.1 GBq: grade 3 anemia (n = 2), grade 4 neurologic decline (n = 1), and grade 3 encephalopathy (n = 1). No DLTs were observed at lower administered activities. Overall, 4 of 17 patients (23.5%) had treatment-related adverse events of grade 3 or higher. Among patients with at least 1 evaluable dosimetry measurement (n = 16), the mean absorbed dose coefficient was 0.10 Gy/GBq (SD, 0.056 Gy/GBq) in the kidneys, 0.055 Gy/GBq (SD, 0.039 Gy/GBq) in the pancreas, and 0.018 Gy/GBq (SD, 0.0076 Gy/GBq) in the red marrow. Conclusion:177Lu-NeoB has a favorable organ dosimetry profile in patients with advanced solid tumors expressing GRPR, with a large safety margin compared with accepted external beam radiation therapy thresholds for organ toxicity. The maximum tolerated dose of 177Lu-NeoB was identified as 9.25 GBq, and the recommended phase 2 dose for the phase 2a dose expansion is 9.25 GBq.

Perioperative immunotherapy, particularly anti-programmed cell death protein 1 therapy, combined with neoadjuvant chemotherapy has emerged as one of the standard-of-care options for resectable non-small-cell lung cancer (NSCLC). We report the final analysis of RATIONALE-315, a randomized, double-blind, phase III trial evaluating the efficacy and safety of perioperative tislelizumab plus neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in patients with resectable, stage II-IIIA NSCLC.

KRASG12C mutations are present in around 4% of patients with colorectal cancer and are associated with lower treatment response rates and overall survival. EGFR signalling has been identified as a primary mechanism of resistance to KRASG12C inhibitors. We aimed to evaluate the efficacy and safety of a novel, covalent, small molecule KRASG12C inhibitor, glecirasib (JAB-21822), as monotherapy or in combination with the anti-EGFR cetuximab, in patients with KRASG12C-mutated colorectal cancer.

Small cell lung cancer (SCLC) is an aggressive tumour type accounting for 10-15 % of lung cancers. The role of thoracic radiotherapy (TRT) in extensive stage SCLC (ES_SCLC) in the era of checkpoint inhibitors (CPIs) is undefined.

Observational studies have associated use of aspirin and selective cyclooxygenase inhibitors with decreased recurrence and improved survival in patients with colon cancer. While randomized clinical trials have not shown benefit across all patients, these findings suggest that select subgroups may benefit from their use. Despite the well-established prognostic value of circulating tumor DNA (ctDNA), its role in guiding treatment remains unclear.

In late-line treatment for advanced gastric cancer (AGC), evidence supporting the use of irinotecan in older patients remains limited. We conducted a post-hoc age-subgroup analysis of the phase III RINDBeRG study, which randomized AGC patients previously treated with ramucirumab-based chemotherapy to receive ramucirumab plus irinotecan (RAM + IRI) or irinotecan alone (IRI).

Salivary gland cancer (SGC) is rare and has various histological types. This rarity and heterogeneity have hindered elucidation of the therapeutic contribution of systemic therapy, including immune checkpoint inhibitors, to recurrent or metastatic SGC (RM-SGC). The purpose of this trial was to investigate the efficacy and safety of nivolumab for platinum-refractory RM-SGC.

A newly developed tip-type needle injection knife (TK) can pump fluid through its tip. In this study, we aimed to evaluate the efficacy and safety of a TK in colorectal endoscopic submucosal dissection (ESD) compared with a conventional sheath-type needle injection knife (DK).

18F-FDG PET-CT has emerged as a powerful imaging tool for initial staging and prognosis evaluation of patients with Breast Cancer (BC). However, previous studies are inconsistent on attributing a predictive value to the pathological Complete Response (pCR) determined by PET-CT. Our objective was to assess the association between pCR and 18F-FDG PET-CT findings in patients with HER2+ BC in neoadjuvant setting.

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). Primary objectives include objective response rate (ORR) and rate of progression-free survival (PFS) at 6 months (PFS6) while secondary objectives include PFS, overall survival, duration of response and toxicity. Twenty-five patients initiate protocol therapy [letrozole 2.5 mg orally (PO) once a day (qd), abemaciclib 150 mg PO twice a day (bid) and metformin 500 mg PO qd]. ORR is 32% (3 complete and 5 partial responses, 95% CI 14.9%-53.5%), Kaplan Meier estimate of PFS6 is 69.8% (95% CI 46.9%-84.3%) and median PFS is 19.4 months (95% CI 5.7 months-not estimable). No patients discontinue therapy because of toxicity. There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure.

The phase 3 IMpower150 trial in treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) demonstrates significantly longer progression-free (PFS) and overall survival (OS) with first-line atezolizumab (anti-PD-L1)-bevacizumab (anti-VEGF)-carboplatin-paclitaxel (ABCP) than with bevacizumab-carboplatin-paclitaxel (BCP). We characterise four molecular NSCLC subtypes identified by unsupervised clustering of transcriptomes of 564 pre-treatment primary tumour samples from IMpower150 using non-negative matrix factorization (NMF1-4). Each subtype has distinct tumour PD-L1 expression levels, epithelial characteristics, immune composition, and treatment outcomes. Both NMF2 (enriched in tumour proliferation signal, macrophages, and monocytes) and NMF4 (enriched in B cells and T cells) have elevated tumour PD-L1 expression. Of these two, only NMF4 demonstrates PFS and OS benefits with ABCP versus either BCP or atezolizumab-carboplatin-paclitaxel (ACP). Patients with NMF1 (enriched in basal and squamous-like cells) have improved outcomes on ABCP compared with ACP or BCP; those with NMF3 (enriched in adenocarcinoma signatures) show similar outcomes among treatments. These insights could help inform individualised first-line treatment for metastatic NSCLC.

Patients with relapsed or refractory T-cell acute lymphoblastic leukaemia have limited responses to conventional chemotherapy and poor prognoses. T-cell precursors exhibit high expression of BCL-2 and are sensitive to BCL-2 inhibitors. Retrospective case series have reported the successful use of venetoclax combined with chemotherapy or hypomethylating agents when treating relapsed or refractory T-cell acute lymphoblastic leukaemia. The study aimed to evaluate the activity and safety of the venetoclax plus azacitidine regimen in patients with relapsed or refractory T-cell acute lymphoblastic leukaemia.