Infigratinib, an oral fibroblast growth factor receptor (FGFR) 1-3 inhibitor, showed clinical activity and manageable adverse events in the P2 CBGJ398X2204 study and was conditionally approved for adults with previously treated, unresectable, or metastatic cholangiocarcinoma (CCA) with FGFR2 fusion or other rearrangement. PROOF 301, reported in this article, is the confirmatory phase III trial of infigratinib versus gemcitabine plus cisplatin as first-line treatment of FGFR2-rearranged CCA.

Tumor purity (TP), the proportion of malignant cells within a tumor sample, is an important feature of the tumor microenvironment. Using transcriptomic data from the Lung ART-IFCT 0503 trial, we investigated the relevance of TP and its potential to predict benefit from postoperative radiation therapy (PORT).

PD-1 and PD-L1 inhibitors have been shown to synergise with anti-angiogenic agents in non-small-cell lung cancer (NSCLC). We aimed to compare benmelstobart plus anlotinib with pembrolizumab in patients with previously untreated, driver gene-negative, PD-L1-positive, advanced NSCLC.

Background: High-grade gliomas, including isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH wild-type glioblastoma, have a poor prognosis and limited treatment options. The PTPRZ1-MET (ZM) fusion gene is a potential therapeutic target. This study evaluated vebreltinib, a highly selective, adenosine-triphosphate-competitive inhibitor of the mesenchymal-epithelial transition factor (MET), in patients with ZM-fusion-positive glioma. Methods: In this multicenter, open-label ZM FUsion GENe (FUGEN) trial, patients with previously treated astrocytoma, IDH-mutant, grade 4, or glioblastoma, IDH wild-type, harboring the ZM fusion were randomized in a 1:1 ratio to receive vebreltinib (300 mg orally twice daily) or control treatment (temozolomide or cisplatin plus etoposide) in 28-d cycles. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety analyses. Results: Eighty-one patients (42 in the vebreltinib group and 39 in the control group) were included in the full analysis set. As of 2023 April 1, the median follow-up duration was 5.9 (range, 0.8 to 44.7) months in the vebreltinib group and 3.4 (range, 0.5 to 40.5) months in the control group. Median OS was significantly longer in the vebreltinib group than in the control group (6.3 months versus 3.4 months; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.32 to 0.85; stratified log-rank P = 0.007). In the IDH-mutant subgroup, median OS was 7.7 months in the vebreltinib group and 3.3 months in the control group (HR, 0.48; 95% CI, 0.28 to 0.80; stratified log-rank P = 0.005). Among patients with a baseline tumor diameter of ≤3.0 cm, median OS was 32.5 months in the vebreltinib group versus 4.2 months in the control group (HR, 0.27; 95% CI, 0.07 to 1.06; stratified log-rank P = 0.046). Median PFS was also longer in the vebreltinib group (1.9 months versus 1.1 months; HR, 0.54; 95% CI, 0.33 to 0.88; stratified log-rank P = 0.012). The ORR was 9.5% with vebreltinib and 2.6% with control treatment. The incidence of grade ≥3 adverse events was comparable between groups, and no treatment-related deaths were reported. Conclusion: Vebreltinib significantly improved OS in patients with previously treated high-grade glioma harboring the ZM fusion, particularly in the subgroup with IDH-mutant astrocytoma, and the safety profile was manageable. Trial registration: This study was registered with the Chinese Drug Clinical Trial Registry (ChinaDrugTrials.org.cn) under the identifier, CTR20181664 (registration date: 2018 September 19).

Endocrine therapy (ET) resistance in estrogen receptor positive (ER+) advanced breast cancer is often linked to ESR1 mutations, yet responses to oral selective ER degraders vary within mutant subgroups. Through a biomarker analysis of acelERA Breast Cancer (NCT04576455), we show that tumor ER transcriptional activity as well as circulating tumor DNA (ctDNA) genomics and dynamics effectively stratify response to ET, including giredestrant. We find that following first-line therapy, the ctDNA genomic landscape is diverse and influenced by CDK4/6 inhibitor exposure. Despite this complexity, ER activity in ESR1-mutant tumors remains comparable to early breast cancer but is reduced in most non-mutant cases. This maintained ER activity is associated with giredestrant benefit. Furthermore, early ctDNA clearance identifies responding patients, and the combination of low ER activity and high ctDNA burden predicts rapid clinical progression. These findings provide a framework for personalizing future breast cancer therapies by integrating liquid biopsies with tissue-based signatures.

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line therapy for advanced, EGFR-mutated nonsmall cell lung cancer (NSCLC). However, their benefit is limited in patients who have co-existing tumor suppressor gene (TSG) mutations, highlighting a need for intensified strategies to improve outcomes. ACROSS2 (ClinicalTrials.gov identifier NCT04500717) is the first prospective, multicenter, randomized phase 3 study to compare the third-generation EGFR-TKI aumolertinib in combination with carboplatin-pemetrexed versus aumolertinib monotherapy in patients who had NSCLC with EGFR mutations and concomitant TSG mutations. In total, 126 patients were enrolled and randomly assigned to either combination therapy (n = 62) or monotherapy (n = 64). The primary end point was median progression-free survival (PFS). At a median follow-up of 25.3 months, combination therapy significantly prolonged median PFS compared with monotherapy (19.78 vs 16.53 months; hazard ratio, 0.58; 95% confidence interval, 0.34-0.97). Landmark PFS rates at 12, 18, and 24 months were 78.7% versus 65.3%, 67.2% versus 40.8%, and 41.0% versus 29.9%, respectively. Subgroup analyses demonstrated a clear PFS benefit in patients who had co-existing tumor protein p53 (TP53) mutations. Grade 3 or greater adverse events occurred in 25.9% of patients who received combination therapy versus 17.2% of those who received monotherapy; no drug-related deaths were observed. Overall survival data were immature (data maturity, 4%). The ACROSS2 trial provides the first prospective evidence supporting a genotype-directed, chemotherapy-targeted intensification approach favoring aumolertinib plus carboplatin-pemetrexed for this molecularly defined population.

Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant.

In FLAURA2, first-line osimertinib plus platinum-pemetrexed induction, with osimertinib plus pemetrexed maintenance, improved progression-free survival versus osimertinib alone in epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer (NSCLC; hazard ratio, 0.62; P < 0.001). Combining osimertinib with chemotherapy increased induction grade ≥3 adverse event rates, which reduced during maintenance. We report FLAURA2 patient-reported outcomes (PRO).

The CCTG PA.7 study was a randomized phase II trial comparing chemotherapy with and without dual immune checkpoint inhibition in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In follow-up to the published primary results of the trial, the analysis herein focused on long-term survival and exploratory analysis.Plasma sequencing analysis identified concurrent mutations in DNA damage repair genes BRCA1, POLE, ATM and FANCA in 18/173 (10.40%) of patients, and presence of two or more mutations in these genes was associated with overall survival benefit for patients receiving immunotherapy (median overall survival 26.2 vs. 9.7 months; hazard ratio, 0.34; 95% CI, 0.16-0.68; p = 0.001; interaction p = 0.003). Partial response was observed in 7/11 (63.64%) patients with concurrent DNA damage repair gene mutations in the immunotherapy arm. As a prospective study in PDAC identifying a potential biomarker beyond mismatch repair deficiency for benefit from immunotherapy, these data highlight an actionable subgroup of mPDAC.

QuANTUM-First is a randomised phase 3 trial in individuals with newly diagnosed acute myeloid leukaemia (AML) that is FLT3 internal tandem duplication (ITD) positive, showing a survival advantage for quizartinib versus placebo plus standard induction and consolidation chemotherapy with or without transplantation, followed by single-agent maintenance therapy. We evaluated the impact of quizartinib on patient-reported outcomes and health-related quality of life using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire.

NRG/RTOG 1016 was a phase III noninferiority trial comparing IMRT + cisplatin versus IMRT + cetuximab for human papillomavirus-positive oropharyngeal squamous cell cancer (HPV+ OPSCC). A germline mutation (the KRAS-variant) previously identified patients with improved outcomes to radiation + cetuximab + cisplatin; thus, we investigated whether there may be similar benefits for IMRT + cetuximab.

In the phase III LAURA study, osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in patients with unresectable stage III EGFR-mutated non-small cell lung cancer (NSCLC) without progression during/after definitive chemoradiotherapy (CRT); PFS hazard ratio 0.16; 95 % confidence interval (CI): 0.10-0.24; p < 0.001. Here we report pre-specified exploratory efficacy and safety analyses in the LAURA China cohort (which was a stratification factor).

AIM: To improve patient selection for neoadjuvant endocrine therapy (NET), signal transduction pathway profiles of estrogen receptor (ER)-, androgen receptor (AR), were studied and compared to standard immunohistochemistry (IHC) in postmenopausal patients with HR+ (IHC ER ≥ 50%, progesterone receptor any), HER2- breast cancer of the NEOLBC trial (NCT03283384). METHODS: After two weeks of NET with letrozole, patients with Ki67 (Ki67-2 W) ≥ 1% IHC were randomized to receive letrozole + ribociclib or standard chemotherapy until surgery, while patients with Ki67-2 W < 1% continued NET (letrozole monotherapy). Baseline, two week- and resection FFPE samples of 82 patients were analyzed using mRNA-based OncoSIGNal profiling test, providing the pathway activity score (PAS). RESULTS: Despite samples being ER-IHC ≥ 50%, the ER-PAS varied over a range of 32–78 (scale from 0 to 100) with 20% of the patients showing low ER-PAS (32–45; similar to triple negative breast cancer tissue). At 2 weeks, 89% (73/82) of the patients showed a decreased ER-PAS (11.6 ± 8.6) compared to baseline (p < 0.001), whereas ER-IHC remained unchanged. Patients with complete response (RECIST1.1) appeared to have a higher ER-PAS at baseline compared to those with stable disease (p = 0.03), ROC analysis confirmed ER-PAS at baseline as an acceptable predictive factor for MRI response (AUC ≥ 0.7). Lastly, baseline and 2-week pathway activity profiling could identify targetable escape mechanisms for NET non-responders, which could improve personalized treatment strategies. CONCLUSION: ER IHC+ does not correlate to ER-PAS and ER-PAS is a more dynamic marker that appears to reflect variable NET response more accurately than IHC.

To explicitly assess the impact of theory in implementation strategies, it is essential to isolate theoretical components while controlling other variables.

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.

Breast cancer is the most commonly diagnosed cancer in women globally. Our previous MIRACLE trial (NCT02313051) demonstrated that everolimus plus letrozole (E + L) significantly improves progression-free survival compared with letrozole (L) monotherapy in premenopausal patients with endocrine therapy-resistant, hormone receptor-positive, HER2-non-amplified advanced breast cancer. This study aims to investigate spatially resolved biomarkers linked to survival benefits from E + L to guide precision therapies. Patients from MIRACLE were stratified by overall survival (OS ≤ 3 vs. >3 years). Spatial Whole Transcriptome Atlas analysis was used to evaluate tumor-, immune-, and stroma-specific gene expression, co-expression network patterns, and survival correlations. Among patients with shorter survival (OS ≤ 3 years), we identified a distinctive gene interaction network characterized by tumor-derived S100A9 and CALML5, which is associated with mTORC1 activation. This finding suggests that tasquinimod, an S100A9 inhibitor, could be a viable therapeutic option. Additionally, an interaction between CALML5 and SLPI across tumor and immune areas indicated a potential role in maintaining tumor integrity and mitigating immune-mediated damage. Conversely, patients with longer survival (OS > 3 years) exhibited SERPINA1 as a hub gene linked to estrogen receptor activation, and an interaction between FKBP5 and SESN3 associated with AKT/mTORC1 inhibition within tumor-rich regions. Furthermore, the interaction between MMP11 and COL16A1 in stroma-rich regions suggests that cancer-associated fibroblasts may contribute to improved outcomes. Our study underscores the critical role of spatial gene expression analysis in elucidating the tumor microenvironment and its impact on prognosis in patients undergoing E + L treatment, thereby opening new avenues for targeted interventions.

Primary results from COSMIC-313 demonstrated significantly longer progression-free survival (PFS) with first-line cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with advanced renal cell carcinoma. Final efficacy and safety results, as well as data from exploratory biomarker analyses, are reported here.

Follicular lymphoma (FL) patients are at risk of disease transformation to aggressive high-grade lymphoma (tFL). While several genetic alterations have been implicated in tFL, the role of microenvironmental interactions and post-transcriptional regulation by non-coding RNAs remains poorly understood. We performed the first matched profiling of mRNAs and short non-coding RNAs (miRNAs) in paired FL and tFL samples (n = 11 pairs). This revealed differential expression of 1,075 mRNAs and 19 miRNAs, including repression of miR-29 family in tFL (miR-29a/b/c). Further analysis uncovered that MYC directly transcriptionally represses miR-29 in tFL, resulting in the upregulation of its target TRAF4. TRAF4 upregulation contributes to CD40 signaling being strongly activated in tFL and supports malignant B-cell proliferation. Notably, this increased CD40 pathway activity in 90% of tFL and contrasted with the reduced T-cell numbers in tFL niches. Thus, the MYC-miR-29-TRAF4 axis and increased CD40 signaling propensity may serve as tFL cells' adaptation to reduced numbers of CD40L+ T-cells. Moreover, lower levels of all miR-29s(a/b/c) were associated with shorter overall survival (OS) and progression-free survival in FL (n = 185), including in a multivariate analysis. Low miR-29c was also associated with shorter OS in a validation cohort (n = 92) from the first-line R-CHOP therapy clinical trial (SWOG S0016, NCT00006721).

Prostate cancer (PCa) is a malignancy with high heterogeneity arising from tumor microenvironment and histological subtypes. Identifying conserved progression drivers within such heterogeneity is essential for improving clinical outcomes. Using imaging mass cytometry, this study analyzes 38 proteins across paracancerous tissue and four histological subtypes: low-grade prostate acinar adenocarcinoma (LgPAC), high-grade PAC (HgPAC), intraductal carcinoma (IDC), and ductal adenocarcinoma (DAC). Results reveal that eIF1A is overexpressed in high-risk subtypes including HgPAC, IDC, and DAC and correlates with poor prognosis. In luminal cells, EIF1A knockdown and the translation inhibitor homoharringtonine (HHT) both suppress HIF-1α translation and tumor growth, while promoting infiltration of anticancer immune cells including PD-1- T cells and CD163- macrophages. Clinically, neoadjuvant HHT combined with androgen deprivation therapy reduces hypoxia and enhances immune cell infiltration, as shown by single-cell RNA sequencing. Collectively, this work defines conserved molecular features across PCa subtypes, providing promising insights for clinical management. This study was registered at Clinicaltrials.gov (NCT06834321).