This phase 1 study aimed to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary efficacy of rucaparib (RUB), a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, combined with liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU) in metastatic gastrointestinal (GI) cancers. RUB targets DNA repair pathways, showing efficacy in tumors with homologous recombination deficiency, such as BRCA mutations. Preclinical data suggest synergy with irinotecan, but overlapping toxicities pose challenges.

Despite advancements in several malignancies, the treatment atlas of natural killer (NK) cell therapy for pancreatic cancer remains inadequate, and the dynamic immune landscape underlying the various responses is still incompletely understood. This phase 1b/2 trial evaluated the safety and efficacy of allogeneic NK cell therapy combined with gemcitabine and S-1 as a first-line treatment for advanced pancreatic cancer (APC) and explored the dynamic responsive immune landscape (ChiCTR1900021764). The administration of 1 × 109 to 8 × 109 NK cells to 24 patients was well tolerated, with no graft-versus-host disease or dose-limiting toxicity. Among the 19 evaluable patients, the objective response rate was 31.6%, and the disease control rate was 73.7%. The median progression-free survival was 6.6 months, and the overall survival was 10.8 months. Further longitudinal single-cell RNA sequencing (scRNA-seq) of 19 paired-blood samples revealed an increased proportion of certain NK cell subsets (c4-ZEB2, c5-IL7, c6-IL15, c10-NCR3, and c11-TNFSF8) and T-cell subsets (CD8+ Teff and CD4+ Tem) in responders, characterized by increased expression of proinflammatory and effector molecules. Bulk T-cell receptor (TCR) Vβ repertoire sequencing of responders indicated potential T-cell clonal expansion, manifested as a greater abundance of large and hyperexpanded clonotypes. Our first-in-human trial demonstrated its safety and potentially preliminary efficacy, warranting further clinical evaluation. Multiomic profiling identified specific circulating NK and T-cell subsets potentially associated with clinical outcomes, providing novel insights into the dynamic transcriptional underpinnings of the immune landscape in response to NK cell-based therapy.

This study aimed to investigate the efficacy and safety of fruquintinib plus sintilimab in mismatch repair-proficient (pMMR)/microstatellite stable (MSS) refractory metastatic colorectal cancer (mCRC).

Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.

Patients with BRAF V600E-mutated/microsatellite stable (MSS) metastatic colorectal cancer (mCRC) are associated with a poor prognosis. Backline treatment has minimal efficacy. Multi-target inhibitors of the RAS-RAF-MEK signaling pathway combined with PD-1 monoclonal antibody may be a promising strategy for BRAF V600E-mutated mCRC.

Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC.

Esophageal squamous cell carcinoma (ESCC) imposes a heavy disease burden in China, accounting for over 50% of global cases and approximately 301,000 annual deaths. Current prognostic markers inadequately predict recurrence in early-stage patients. This study investigates microRNA-107 (miR-107) as a novel prognostic biomarker for ESCC.

The relapse after chimeric antigen receptor (CAR) T-cell therapy remains a critical challenge, and the optimal timing and treatment strategies for CAR T urgently need to be explored. Autologous hematopoietic stem cell transplantation (auto-HSCT) demonstrates comparable leukemia-free survival (LFS) and overall survival (OS) in patients who rapidly achieve MRD-negative complete remission (CR) compared with allogeneic HSCT (allo-HSCT). Thus, combining CAR T cells with auto-HSCT may represent a promising treatment strategy. The trial registration is ClinicalTrials.gov identifier NCT05470777.

Neoadjuvant chemoimmunotherapy does not benefit all non-small cell lung cancer (NSCLC) patients, and reliable biomarkers are urgently needed. We conducted this prospective phase II trial of neoadjuvant chemoimmunotherapy to explore the role of cell-free DNA (cfDNA) features in pathological response assessment.

SOLACE2 (ACTRN12618000686202) investigates whether 12-weeks of olaparib, or cyclophosphamide-olaparib priming, improves subsequent durvalumab-olaparib progression-free survival (PFS), and is superior to olaparib monotherapy without any priming, in platinum-sensitive recurrent ovarian cancer (n = 114). We also evaluate the utility of CUP-CC assay, an immune signature of C-C chemokine receptor type 4 up-regulation, chemokines, and cytokines. Priming with olaparib, or cyclophosphamide-olaparib, followed by durvalumab-olaparib, are both associated with longer PFS compared to olaparib monotherapy, but do not reach the pre-specified primary endpoint of 36-week trial threshold (PFS36). PFS36 rates are 47.4% (95% CI, 31.0-62.1; olaparib priming then olaparib-durvalumab), 48.7% (32.5-63.2; olaparib-cyclophosphamide then olaparib-durvalumab) and 35.1% (20.4-50.3; olaparib monotherapy). PFS is significantly longer for the homologous recombination deficient (N = 71) as compared to the proficient (HRP) (N = 29) subgroups (Hazard Ratio (HR) 0.55, 0.35-0.87). CUP-CC+ subgroup (N = 58) has a significantly longer PFS (HR 0.31, 0.19-0.49) than CUP-CC- (N = 46). Future studies should investigate whether CUP-CC has the potential to personalize poly (ADP-ribose) polymerase inhibitor therapies for patients who are BRCA wild-type, including HRP patients.

Molecular glioblastoma (molGBM) is a variant lacking the full histopathological profile of glioblastoma. We report a trial aimed at addressing the optimal management of this newly recognized rarer form of glioma.

Older adults with HER2-positive early breast cancer are underrepresented in clinical trials, and the benefit of chemotherapy in this population remains uncertain. We evaluated the HER2DX genomic assay within the randomized RESPECT trial (NCT01104935), which compared adjuvant trastuzumab with or without chemotherapy in patients aged 70-80 years. In this prespecified translational analysis (Trans-RESPECT), HER2DX scores were available for 154 patients. The HER2DX risk score classified 74.0% as low risk and 26.0% as high risk. Ten-year relapse-free and overall survival were higher in the low-risk group. HER2DX remained independently associated with overall survival in multivariable analysis. The HER2DX immune, luminal, and proliferation signatures that compose the risk score were also prognostic. While the HER2DX pCR score was not prognostic overall, exploratory subgroup analyses suggested a potential survival benefit from chemotherapy in the pCR-high group. HER2DX offers prognostic value and may guide chemotherapy use in older patients with HER2-positive early breast cancer. Clinical Trial Information NCT01104935.

Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are generally resistant to targeted therapy with tyrosine kinase inhibitors (TKIs), such as imatinib, and there are no standard therapeutic options for advanced SDH-deficient GISTs. The precise oncogenic mechanisms of SDH mutations in GIST have not been elucidated. Olverembatinib, a novel multikinase inhibitor, has shown promising activity in treating imatinib-resistant GIST. We conducted a phase 1 study (NCT03594422) to evaluate the safety and antitumor activity of olverembatinib in 66 patients with unresectable/metastatic GIST/other solid tumors, including 26 with TKI-failed SDH-deficient GISTs. To our knowledge, this is the largest prospective clinical trial for this rare GIST subtype. The median follow-up was 14.5 (0.9-57.5) months. Olverembatinib was well tolerated; treatment-emergent adverse events (≥20%) included increases in hepatic transaminases, increases in leukocytes and neutrophils, anemia, and pyrexia. For SDH-deficient GISTs, confirmed partial responses were observed in 6 of the 26 evaluable patients (objective response rate, 23.1%; 95% CI, 9-43.7); an additional 16 (61.5%) did not progress during the first 6 months of treatment. This resulted in a clinical benefit rate of 84.6% (95% CI, 65.1-95.6), and the median progression-free survival was 25.7 months (95% CI, 12.9-NR). As a putative mechanism of action, translational research revealed significant lipid enrichment with the overexpression of lipid uptake-related genes and proteins, including CD36, fatty acid binding proteins, fatty acid transport proteins, and lipid metabolites, in SDH-deficient GIST patients, and olverembatinib suppressed lipid uptake and CD36 expression in GIST cells. Olverembatinib also exerts antitumor effects by inhibiting tumorigenic signaling pathways associated with hypoxia, angiogenesis, proliferation, and survival.

In this preclinical human immune system patient-derived xenograft (HIS-PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite-stable (MSS) colorectal cancer.

Patritumab deruxtecan (HER3-DXd) is a novel antibody-drug conjugate targeting HER3, which is overexpressed in CNS metastases of advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the activity and safety of HER3-DXd in patients with advanced NSCLC and newly diagnosed brain metastases or brain metastases progressing after local therapy.

Ataxia telangiectasia and Rad3-related (ATR) inhibition with berzosertib potentiates the efficacy of irinotecan in preclinical models. The authors hypothesize that this combination is well tolerated, modulates the DNA damage response to irinotecan, and is associated with clinical activity in advanced solid tumors.

Anti-programmed cell death protein 1 (anti-PD-1) immunotherapy has shown efficacy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but current biomarkers have limitations in predicting immunotherapy response accurately. Chromosome 11q13 amplification, prevalent in HNSCC, has been associated with reduced efficacy of anti-PD-1 therapy. This study aims to prospectively evaluate 11q13 amplification as a biomarker for guiding first-line treatment in R/M HNSCC. We hypothesize that excluding patients with 11q13 amplification from anti-PD-1 therapy may enhance survival outcomes.

Cervical cancer, a prevalent female malignancy, is treated with surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapy. Yet, prognosis remains influenced by multiple factors. Epithelial-mesenchymal transformation (EMT) is an important link in the malignant progression of tumor cells and has an important impact on the progression and prognosis of cervical cancer. This study aimed to analyze effect of Baofukang suppository on the related indexes of EMT of tumor cells in cervical cancer patients. Eighty patients with cervical cancer received in The First Affiliated Hospital of Anhui Medical University from March 2020 to March 2022 were randomized into a control group (chemotherapy alone, n=40) and a study group (chemotherapy + Baofukang, n=40). Post-treatment, the study group showed significantly lower mRNA levels of EMT markers Vimentin and N-cadherin, and higher E-cadherin and β-catenin (p<0.05). Additionally, interleukin-6 (IL-6) decreased while interleukin-2 (IL-2) and interferon-γ (INF-γ) increased (p<0.05). Immune function improved, with higher CD3+, CD4+ and CD4+/CD8+ ratios, and lower CD8+ (p<0.05). The adverse reactions between two groups were not unconspicuous (p>0.05). The adjuvant therapy of Baofukang Suppository can effectively regulate the relevant indexes of tumor cell EMT, delay or prevent the EMT of tumor cells.

COMPEL (NCT04765059) was a global, randomized, double-blind study that evaluated osimertinib plus chemotherapy versus placebo plus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) following non-central nervous system (CNS) progression on first-line osimertinib.

Cancers that do not respond to immunotherapy typically harbor a non-T cell-inflamed tumor microenvironment (TME), characterized by the absence of type I/II interferon signaling and CD8+ T cell infiltration. We previously reported IDH1 somatic mutations were enriched in this phenotype across histologies. Mutant IDH1 (mIDH1) drives immune exclusion via metabolic reprogramming of the TME, and preclinical models show that IDH inhibition can restore anti-tumor immunity. We conducted a Phase II study assessing the preliminary activity of ivosidenib, an IDH1 inhibitor, plus nivolumab, an anti-PD1 antibody, in patients with mIDH1 advanced solid tumors (NCT04056910).