Fulzerasib, a KRASG12C inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRASG12C inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored.

Background: From 2019 July 15 to 2022 February 14, the REZOR study enrolled 369 treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R mutation). Patients were randomly assigned 1:1 to receive either rezivertinib (180 mg/d) plus gefitinib placebo or gefitinib (250 mg/d) plus rezivertinib placebo. Previous results demonstrated significantly improved progression-free survival (PFS) with rezivertinib versus gefitinib and a favorable safety profile. Here, we update the analyses of central nervous system (CNS) outcomes in patients with baseline CNS metastases. Methods: All patients underwent brain magnetic resonance imaging at baseline and each subsequent efficacy evaluation until radiological disease progression or any other treatment discontinuation criteria were met. EGFR mutation status was determined by testing using tissue or plasma samples during screening. Patients with stable, asymptomatic CNS metastasis were eligible for enrollment. The CNS full analysis set (cFAS) comprised patients with baseline CNS metastasis identified on magnetic resonance imaging and evaluated by blinded independent central review according to the Response Assessment in Neuro-Oncology Brain Metastases criteria. Patients with measurable CNS target lesions formed the CNS evaluable-for-response set (cEFR). Results: As of the 2023 November 30 data cutoff, 159 patients had baseline CNS metastasis in the cFAS (rezivertinib: n = 81; gefitinib: n = 78) and 25 in the cEFR (rezivertinib: n = 12; gefitinib: n = 13) per blinded independent central review. In the cFAS, 59 CNS PFS events occurred (rezivertinib: n = 30; gefitinib: n = 29). Median CNS PFS was significantly longer with rezivertinib (24.9 months; 95% confidence interval [CI], 16.5 months-not estimable [NE]) than with gefitinib (15.2 months; 95% CI, 10.5 months-NE), with a hazard ratio of 0.58 (95% CI, 0.34 to 0.99; P = 0.047). In the cEFR, the CNS objective response rate was 83.3% (95% CI, 51.6% to 97.9%) with rezivertinib and 76.9% (95% CI, 46.2% to 95.0%) with gefitinib (odds ratio = 1.50; 95% CI, 0.20 to 11.0; P = 0.690). No new safety findings were observed. Conclusions: Rezivertinib demonstrated a statistically significant superior CNS efficacy over gefitinib as first-line treatment in advanced EGFR-mutated non-small cell lung cancer patients with baseline CNS metastases. The safety profile was consistent with previous analyses. Trial registration: NCT03866499 (ClinicalTrials.gov).

Psychologically Informed Reminder Messages (PIRMs) may promote health-behavior change, but their impact on preventive genetic screening is unclear. Due to low adherence to a screening program, Clalit Health Services initiated an intervention to encourage BRCA1/2 carrier screening in July 2022. This observational study assesses the effectiveness of the intervention in encouraging screening and its spillover effect on related healthcare utilization, focusing on Ashkenazi Jewish females aged 25-50 with no relevant cancer history. Patients were randomly assigned to receive one of five PIRMs. Four PIRMs utilized different psychological strategies, while the fifth served as a control. The effectiveness of the intervention on screening adherence was assessed using a regression discontinuity analysis. A Cox regression assessed the effectiveness of the four PIRMs compared to the control. Spillover effects on healthcare utilization were evaluated using logistic regressions. The intervention showed a positive correlation with increased adherence to screening (β = 0.37, 95% CI: 0.01-0.72). The "Barrier Remover" PIRM emphasized ease (hazards ratio = 1.09, 95% CI: 1.02-1.16), while the "Health Control" PIRM focused on autonomy (hazards ratio = 1.07, 95% CI: 1.01-1.14), both indicating greater effectiveness than the control. The findings suggest a positive short-term spillover effect of the "Health Control" PIRM on healthcare utilization compared to the control (odds ratio = 1.16, 95% CI: 1.04-1.29). PIRMs effectively increased BRCA1/2 carrier screening adherence, demonstrating a scalable, low-cost intervention to improve preventive healthcare uptake. The effect varied by the psychological strategies, highlighting the potential of tailored behavioral interventions to enhance public health.

Standard adjuvant chemotherapy for stage III colon cancer consists of a fluoropyrimidine-plus-oxaliplatin regimen. Whether the addition of atezolizumab (an anti-programmed death ligand 1 agent) to a modified FOLFOX6 regimen (fluorouracil, oxaliplatin, and leucovorin; called mFOLFOX6) would improve outcomes in patients with stage III colon cancer with mismatch repair-deficient (dMMR) status is unclear.

SHR-A1811, an antibody‒drug conjugate consisting of the anti-HER2 antibody trastuzumab conjugated via a cleavable linker to a topoisomerase I inhibitor payload, demonstrated substantial antitumor activity in patients with heavily treated HER2-expressing or mutated advanced solid tumors. The main analysis was reported, and this is a long-term follow-up of the HORIZON-X trial (NCT04446260). This global, multicenter, first-in-human, phase 1 trial enrolled patients aged ≥ 18 years with unresectable, advanced, or metastatic HER2-expressing or mutated solid tumors refractory or intolerant to standard therapies across 38 hospitals. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every three weeks. The primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. From September 7, 2020, to June 4, 2024, 396 patients with a median of three prior treatment regimens (IQR 2-5) received SHR-A1811. As of March 12, 2025, the median follow-up was 17.1 months for HER2-positive breast cancer, 10.6 months for HER2-low expressing breast cancer, and 4.3 to 8.2 months in non-breast cancers. The safety profile remained consistent with that of previous reports. Grade 3 or higher treatment-related adverse events occurred in 261 patients (65.9%), and any grade interstitial lung disease was observed in 10 patients (2.5%). The median progression-free survival was 25.0 months (95% CI 17.2-33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2-13.8) for HER2-low expressing breast cancer, and 3.5 to 17.2 months for non-breast tumors. This final analysis further confirmed the long-term efficacy and favorable safety profile of SHR-A1811 among heavily prior-treated advanced solid tumors, reinforcing its potential as an effective HER2-targeted therapy.

To investigate long-term outcomes for triple‑negative breast cancer (TNBC) patients enrolled in JBCRG-22.

Colorectal cancer (CRC) is a major health burden globally and in China, where 3%-5% of cases involve the BRAFV600E mutation, which is associated with aggressive disease and therefore a poor prognosis. Although the combination of encorafenib and cetuximab has demonstrated improved survival in BRAFV600E mutant metastatic CRC (mCRC), such treatments remain unavailable as chemotherapy-free options in China.

Treatments for leptomeningeal metastasis (LM) are limited and prognosis is poor. In this phase 2, nonrandomized, single-arm, multicenter study, we evaluated a tucatinib-trastuzumab-capecitabine regimen in patients with newly diagnosed LM and human epidermal growth factor receptor 2-positive (HER2+) breast cancer. The primary endpoint was overall survival; secondary endpoints included central nervous system progression-free survival, LM objective response, neurological symptom improvement, pharmacokinetics and safety. The trial met its prespecified interim efficacy threshold and exceeded the historical control of 4.4 months. Among 17 enrolled women, all had magnetic resonance imaging-confirmed LM, 15 (88%) were symptomatic and 8 (47%) had abnormal cerebrospinal fluid cytology. For a median follow-up of 18 months (range 9.0-26.7 months), 6 of 17 (41%) remained alive. Tucatinib reached therapeutic levels in the cerebrospinal fluid. The median overall survival was 10 months (95% confidence interval 4.1 months, not reached). The median time to central nervous system progression was 6.9 months (95% confidence interval 2.8, 13.8 months). Of 13 response-evaluable patients, 5 (38%) achieved composite LM objective response. Of 12 evaluable patients, 7 (58%) had improved neurological deficits. This prospective study suggests clinical benefit with a systemic regimen for HER2+ LM including objective responses, improved symptoms and extended survival. These data support systemic therapy as an approach in HER2+ breast cancer LM. ClinicalTrials.gov registration: NCT03501979 .

Background: Clear cell sarcoma (CCS) is an ultrarare sarcoma driven by a specific chromosomal translocation, most commonly the EWS RNA binding protein 1-activating transcription factor 1 fusion (EWSR1::ATF1), for which chemotherapy shows limited activity, with a median progression-free survival (PFS) of approximately 3 months in retrospective series. In the present trial, a CCS cohort was selected based on signals of activity observed in the IMMUNOSARC I phase I/II trial evaluating nivolumab in combination with sunitinib in sarcomas. Methods: Patients aged 12 to 80 years with advanced, progressive, and measurable CCSs were enrolled after central pathology review, and molecular confirmation of an EWSR1 rearrangement was required. Sunitinib was administered at 37.5 mg/d during the first 2 weeks and then at 25 mg/d along with nivolumab at 240 mg every 2 weeks. The primary end point was the 6-month PFS rate, defined under the null (H0) and alternative (H1) hypotheses as 25% and 55%, respectively. Under Simon's 2-stage minimax design (α = 0.05, power = 0.90), a minimum of 10 of 23 patients needed to be progression-free at 6 months. Results: At the time of cutoff, 23 patients were evaluable for the primary end point. With a median follow-up of 23.0 months (95% confidence interval [CI], 10.0 to 35.0 months), the 6-month PFS rate was 50.1% (95% CI, 29.1% to 71.1%), while the median PFS was 6.2 months (95% CI, 3.0 to 9.3 months). Of 21 patients who underwent at least 1 radiological assessment, 3 (14.3%) achieved partial response, 14 (66.7%) had stable disease, and 4 (19.0%) had progressive disease. The median overall survival was 17.0 months (95% CI, 95% CI, 5.6 to 28.5 months). The main all-grade drug-related toxicities were lymphocytopenia (46.2%), leukopenia (38.5%), anemia (38.5%), and neutropenia (38.5%). Two grade 4 toxicities were reported: Alanine aminotransferase increased and ischemia (each 3.8%), while 31 grade 3 toxicities occurred, with anemia and lymphocytopenia being the most common (each 23.1%). A higher programmed death-ligand 1 composite score was associated with better PFS: 21.2 months (95% CI, 6.0 to 36.4 months) versus 4.2 months (95% CI, 2.7 to 5.6 months), P = 0.045. Conclusions: While further studies are needed, initial findings suggest that nivolumab plus sunitinib could be a valuable addition to the current armamentarium for CCS management. Trial registration: ClinicalTrials.gov ID NCT03277924 (date of registration: 2017 September 6).

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).

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.

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.

To evaluate the safety and efficacy of izalontamab brengitecan (iza-bren) in patients with non-small cell lung cancer (NSCLC) harboring actionable genomic alterations (GAs) outside of classical epidermal growth factor receptor (EGFR) mutations.

For patients with high-risk melanoma who are unresponsive or intolerant to immune checkpoint inhibitors, cancer vaccines may provide benefit with a favorable toxicity profile. CD4+ T cells provide essential help to dendritic cells (DCs) for optimal CD8+ T cell priming in the antitumor response, and induction of tumor-cognate CD4+ T cell responses may enhance vaccine efficacy. We report on a first-in-human approach to treat patients with high-risk melanoma using a vaccine composed of six non-mutated melanoma-specific helper peptides (6MHP) and a shared mutated BRAF-V600E neoantigen helper peptide (mBRAF) co-administered locally with a TLR3 agonist (poly-ICLC) and agonistic CD40 antibody (CDX-1140).

Findings from a phase I study show that the p53 reactivator rezatapopt is safe and can elicit responses in patients with a range of solid tumors containing the Y220C mutation. Although the drug was ineffective in tumors with KRAS mutations, and whether the strategy can be applied to more common missense mutations remains unclear, the findings offer proof of concept for p53 reactivation.

Rezatapopt is an investigational, first-in-class, oral, selective p53 reactivator that specifically binds to Y220C-mutated p53, which stabilizes p53 in its wild-type conformation and restores its functionality.

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.

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.