In this 5-year follow-up from the CheckMate 743 study in patients with unresectable pleural mesothelioma (PM), we evaluated updated efficacy and safety outcomes and biomarkers and performed treatment-switching analyses with first-line nivolumab plus ipilimumab versus chemotherapy. With a median follow-up of 66.8 months, nivolumab plus ipilimumab demonstrated continued overall survival (OS) benefit versus chemotherapy in all randomly assigned patients (5-year OS rates, 14% v 6%; hazard ratio [HR], 0.74 [95% CI, 0.62 to 0.88]); similar benefit was observed regardless of tumor histology. Of biomarker-evaluable patients treated with nivolumab plus ipilimumab (n = 242), high baseline monocytic myeloid-derived suppressor cell (M-MDSC) levels correlated with worse OS versus low M-MDSC levels (HR, 1.25 [95% CI, 1.09 to 1.43]). After adjusting for 24% of patients in the chemotherapy arm who received subsequent immunotherapy, nivolumab plus ipilimumab demonstrated continued OS benefit versus chemotherapy (HR, 0.64 [95% CI, 0.53 to 0.78]). No new safety signals were observed. These results demonstrate long-term, durable clinical benefit with nivolumab plus ipilimumab versus chemotherapy, which continued to be preserved even after treatment-switching adjustment in the chemotherapy arm. Exploratory analyses suggested greater benefit with nivolumab plus ipilimumab in the low M-MDSC subgroup. These results further support first-line nivolumab plus ipilimumab as standard of care for unresectable PM.

Checkpoint blockade of PD-1 with pembrolizumab provides long-term survival to a significant proportion of patients with metastatic melanoma. Pembrolizumab has been successfully used in combination with chemotherapy in non-small-cell lung cancer to increase the response rate. This phase II trial combined pembrolizumab with carboplatin/paclitaxel (CP) to assess its safety and efficacy, and to identify correlates of responses. Thirty patients without prior immunotherapy for unresectable/metastatic melanoma were treated with pembrolizumab and CP. Peripheral blood was collected at baseline and after 2 cycles to characterize systemic immune activity by multiplex assays and flow cytometry. Seventy percent of patients received all 4 cycles of CP; 87% received pembrolizumab for 2 y or until progression. Grade 3 and higher adverse events (AEs) occurred in 50% of the patients. The overall response rate (ORR) and disease control rate (DCR) by irRC criteria were 43% and 53%, respectively. Median overall survival (OS) was 23.8 months. Objective response was associated with a lower frequency of naive CD8 T cells and low plasma CCL3 at baseline, along with a larger proportion of mature NK cells and of CD4 T cells expressing BTLA or LAIR-1. Survival rate was higher for patients with lower baseline of IL-6, IL-8, and CD4+CD39+ T cells. Following treatment, pro-inflammatory soluble factors increased in both responders and non-responders. Addition of CP to pembrolizumab in this study did not appear to result in a response or survival advantage and was less tolerable than immunotherapy alone. Correlative data point to peripheral signals to investigate further as potential biomarkers. Trial registration: clinicaltrials.gov, NCT02617849, registered on December 1st, 2015.

The safety profile and effect on inflammation of non-intubated video-assisted thoracoscopic surgery (NIVATS) remain incompletely understood. This study aimed to evaluate the safety of NIVATS and its effect on the inflammatory state.

The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients' systemic inflammation might provide insights into responsiveness to the METIMMOX regimen.

DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with RNA profiling, and assessed PD-L1 status and number of genes with altered expression. Fifty patients exhibited 58 concordant events, i.e., genomic and expression alteration(s) in the same gene, including 38 copy number events, and 41 patients had statistically significant concordance. We identified 123 gene pairs with significant associations between genomic and expression alterations (p < 0.05), including TP53 alterations with VEGFA overexpression. The median OS for patients with 0-2, 3-5, and ≥6 genes with altered expression was 9.8, 11.9, and 6.7 months, respectively (p = 0.03). These results underscore RNA profiling's potential actionability, and altered expression in ≥6 genes was associated with shorter OS. Significant concordance of TP53 alterations with VEGFA overexpression may partially explain tumor response to bevacizumab in TP53-mutant patients.

Postoperative lymph node irradiation can affect shoulder morbidity in breast cancer patients, yet widely accepted dose-volume constraints for the shoulder joint are lacking. The SENOMAC trial randomized patients with breast cancer and 1-2 sentinel lymph node (SLN) macrometastases to axillary lymph node dissection (ALND) or SLN biopsy only. We aimed to analyze the association between the radiation dose to the shoulder joint and patient-reported arm morbidity one and three years after surgery using SENOMAC data.

INBRX-105, a tetravalent, PD-L1-targeted TNFRSF9 (4-1BB) agonist, demonstrated preclinical antitumor activity. This first-in-human study evaluated INBRX-105 in solid tumors.

Osimertinib has documented CNS activity, but there is little data on the effect on untreated brain metastases (BM). We assessed the efficacy of osimertinib in patients with or without active BM and investigated whether circulating tumour DNA (ctDNA) at baseline provides prognostic information.

The J-START randomised controlled trial found that adjunctive ultrasonography was associated with significantly higher rates of breast cancer detection than mammography alone. This report aims to evaluate the long-term effect of adjunctive ultrasonography screening on the cumulative incidence of advanced breast cancer as a prespecified secondary outcome of J-START.

Patients with metastatic breast cancer (MBC) often report severe, long-standing concerns with their sexual quality of life (QOL), yet interventions for this population are scarce. This study evaluated the efficacy of a couple-based sexual QOL intervention adapted for MBC couples in a randomized controlled trial.

Recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) patients who failed platinum-based chemotherapy, with or without PD-1/L1 inhibitors, face limited treatment options. We evaluated the efficacy and safety of MRG003 (becotatug vedotin), an epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate (ADC), in previously treated R/M NPC.

Angiogenesis plays an essential role in neuroendocrine tumors (NETs). This study evaluates efficacy and safety of axitinib in extrapancreatic (ep)-NETs.

Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies. In a phase I trial, we observed encouraging efficacy of the combination of regorafenib, ipilimumab, and nivolumab (RIN), with a 27.6% overall response rate and a median overall survival of 20 months. The most pronounced benefits were observed in patients without liver metastases. To uncover immunologic mechanisms underlying response and resistance, we performed correlative studies of the tumor microenvironment (TME) and systemic immune features. Tumor biopsies from 8 patients and peripheral blood samples from 29 patients with MSS mCRC were collected and analyzed at baseline and during treatment. At baseline, tumors from good responders exhibited enhanced proliferation, DNA repair pathways, and STING expression, whereas poor responders showed enrichment of complement and metabolism pathways. In peripheral blood, good responders had a higher CD4/CD8 T-cell ratio, increased dendritic cells, and intact type 1 cytokine responses. In contrast, poor responders exhibited more effector T-cell differentiation, elevated immune checkpoint molecule expression, and increased DNA damage in lymphocytes. In good responders, RIN therapy increased tumor-infiltrating lymphocytes and upregulated immune activation genes, accompanied by heightened T-cell proliferation and activation in peripheral blood, including the expansion of low-frequency T-cell receptor clones in CD8+ T cells. Patients with liver metastases exhibited T-cell senescence and metabolic hyperactivation, correlating with therapeutic resistance. These findings highlight that preexisting tumor immunogenicity and T-cell functional capacity are associated with response to RIN therapy and that RIN treatment may facilitate both systemic T-cell activation and local TME modulation.

The management of metastatic colorectal cancer (mCRC) in late-line settings remains a significant clinical challenge. The SUNLIGHT trial, which investigated the combination of trifluridine-tipiracil (FTD-TPI) and bevacizumab, reported a median progression-free survival (PFS) of 5 months and an objective response rate (ORR) of 6.3%. This phase II study was conducted to evaluate the potential of combining anlotinib with FTD-TPI as a third-line treatment strategy in patients with refractory mCRC.

Trabectedin is standard for r/r soft tissue sarcomas. tTF-NGR accumulates in tumor vasculature leading to tumor vascular occlusion and tumor infarction. Both compounds in sequence could trap trabectedin inside tumors and increase its efficacy, which then optimizes the pro-coagulatory activity of tTF-NGR. This report summarizes translational data and results of the safety run-in patient cohort of the TRABTRAP trial combining trabectedin plus tTF-NGR. A dose of trabectedin of 1.5 mg/m2 (24 h, day 1) combined with 1.0 mg/m2 of tTF-NGR (1 h, days 2 and 3, q day 22) represents the approx. Maximum tolerated dose (MTD) and with 0.5 mg/m2 tTF-NGR (days 2 and 3) the recommended starting dose for the randomized part of TRABTRAP. None of the 6 patients on 0.5 mg/m2 tTF-NGR had dose-limiting toxicity (DLT). Higher doses or additional days of application of tTF-NGR led to grade 3 DLT including early troponin T high sensitivity increase, a reversible non-ST-elevation myocardial infarction in one patient, and reversible thromboembolic events. Pharmacokinetics explain the difference of the MTD between the phase I study and in TRABTRAP. Experimental and clinical efficacy and tolerability of the combination between trabectedin and tTF-NGR supports the active randomized part of TRABTRAP.

In Study 309/KEYNOTE-775 (NCT03517449), lenvatinib+pembrolizumab versus chemotherapy significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in advanced endometrial cancer (EC). We report 5-year follow-up results.

Neoadjuvant treatment comprising six to nine cycles of anti-HER2 based chemotherapy yields high pathological complete response rates and excellent survival outcomes in patients with stage II-III HER2-positive breast cancer but comes with noteworthy side-effects. The TRAIN-3 study investigated if patients treated with this regimen who have a rapid complete radiological response on MRI are candidates for early surgery. The study showed that one-third of patients with hormone receptor-negative tumours and one-sixth of patients with hormone receptor-positive tumours had a pathological complete response after only three cycles of chemotherapy. Here, we report the results of the primary endpoint, 3-year event-free survival.

The neoadjuvant chemoradiotherapy (nCRT) might accentuate surgical complications and toxicity in the treatment of locally advanced rectal cancer (LARC) while neoadjuvant chemotherapy (nCT) alone shows promise as an alternative treatment. However, which patients deserve most from the nCT need further clarify. This trial aimed to assess the non-inferiority of nCT with capecitabine plus oxaliplatin (CAPOX) versus nCRT with capecitabine in LARC with uninvolved mesorectal fascia (MRF).

Cancer-related fatigue (CRF) is a common and debilitating symptom in palliative care, with limited effective treatments. This study evaluated the efficacy and safety of K-style contact needle technique (CNT), a non-invasive form of traditional Japanese acupuncture, for alleviating CRF.

Immune checkpoint inhibition (ICI) benefits only a subset of patients with metastatic triple-negative breast cancer and determinants of response remain unclear. We assembled a longitudinal cohort of 103 female patients from the phase 2 TONIC trial, with samples spanning primary tumors, pretreatment metastases and on-treatment metastases during nivolumab therapy. We profiled 37 proteins in 270 tumors using highly multiplexed imaging and developed SpaceCat, an open-source pipeline that extracts more than 800 imaging features per sample, including cell density, diversity, spatial interactions and functional marker expression. Metastatic but not primary tumors contained features predictive of outcome. Spatial metrics such as immune diversity and T cell infiltration at tumor borders were most informative, while ratios of T cells to cancer cells and PDL1 on myeloid cells were also associated with response. Multivariate models stratified patients with the highest performance on treatment (area under the curve = 0.90). Bulk RNA-seq confirmed the predictive value of on-treatment samples. These findings highlight the value of longitudinal profiling to resolve evolving tumor microenvironment dynamics driving ICI response.