In early breast cancer, HER2-directed therapies are approved for the treatment of patients with HER2-positive invasive breast cancer as defined by HER2 protein overexpression, or HER2 gene amplification with HER2/CEP17 ratios ≥2.2. Beyond this cut-off, however, it is unknown whether the efficacy of HER2-directed therapy improves with increasing HER2/CEP17 ratios. We evaluated whether quantitative assessment of the HER2/CEP17 ratio predicts pathological complete response (pCR) and event-free survival (EFS) in patients treated with neoadjuvant HER2-based regimen in the prospective phase III NeoALTTO trial.

While neoadjuvant endocrine therapy (NET), with or without a CDK4/6 inhibitor, is an established treatment option for estrogen receptor-positive breast cancers, optimal patient selection and second-line treatment for non-responders remain uncertain.

Patients with recurrent high-grade glioblastoma have a median survival of 6-8 months, with limited therapeutic options. In recent years, interest has grown in applying chimeric antigen receptor T (CAR-T) cells to solid cancers, including advanced gliomas. Here we generated off-the-shelf CRISPR-Cas9-edited IL-13Rα2-specific allogeneic universal CAR-T cells (MT026) by disrupting the endogenous TCR to prevent graft-versus-host disease and knocking out HLA class I molecules to mitigate the host-versus-graft response, and observed minimal NK-cell-mediated rejection in preclinical studies. In a first-in-human, single-center, open-label investigator-initiated trial (ChiCTR2000028801) in patients with high-grade glioma with prior therapy failure and short life expectancy, intrathecal injection of MT026 via lumbar puncture (1.0-3.0×10^7 cells per dose) demonstrated favorable tolerability and safety (primary outcome), pharmacokinetic characteristics, and preliminary clinical activity (secondary outcomes). Among the five patients enrolled, one achieved a complete response and three achieved partial responses. No grade ≥3 adverse events were observed; the predominant treatment-related toxicities were grade 1-2 pyrexia, hypoxia, and vomiting. Trial enrolment was halted after enrolment of the first five patients, however these preliminary clinical data support the potential benefit of locally administered allogeneic universal CAR-T cell therapy for recurrent glioblastoma.

This phase II trial prospectively assessed the efficacy and safety of induction chemoimmunotherapy followed by sequential concurrent chemoradiotherapy plus immunotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were ineligible for surgery.

We report long-term outcomes from the phase 3 SAKK 09/10 trial that randomly assigned men with biochemical progression after radical prostatectomy to conventional-dose (64 Gy) or dose-intensified (70 Gy) salvage radiotherapy (SRT) to the prostate bed without hormonal therapy. The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), and late toxicity. Between February 2011 and April 2014, 350 patients were randomly assigned (175 per arm). Median prostate-specific antigen (PSA) at randomization was 0.3 ng/ml. After median follow-up of 8.6 yr, median FFBP was 8.7 yr (95% confidence interval [CI] 7.1-not reached [NR]) after 64 Gy and 8.7 yr (95% CI 6.7-NR) after 70 Gy (log-rank p = 0.87), with a hazard ratio of 1.03 (95% CI 0.75-1.41). There was no significant difference in clinical PFS, time to hormonal treatment, or OS. While late genitourinary toxicity did not significantly differ between the arms, late grade 2 and 3 gastrointestinal toxicity was more frequent with 70 Gy (p = 0.015). After long-term follow-up dose-intensified SRT was not superior to conventional-dose SRT, but was associated with a higher rate of late grade ≥2 gastrointestinal toxicity. PATIENT SUMMARY: The optimal radiotherapy dose for patients who have higher levels of tumor markers after surgery for prostate cancer is unclear. Our long-term follow-up confirms that a higher dose only increases the chances of gastrointestinal side effects without providing any benefits to the patient. This trial is registered on ClinicalTrials.gov as NCT01272050.

The phase 3 ENGOT-en9/LEAP-001 trial (NCT03884101) comparing first-line lenvatinib+pembrolizumab with carboplatin+paclitaxel did not meet pre-specified statistical criteria for overall survival or progression-free survival in participants with advanced/recurrent endometrial cancer. We report results after an additional year of follow-up (overall median 54.5 [range; 46.5-69.0] months).

Prostate-specific membrane antigen (PSMA) has been identified as a therapeutic target for metastatic castration-resistant prostate cancer (mCRPC). The recent success of radioligands targeting PSMA spurred development of new PSMA-targeting agents including immunotherapy. JNJ-80038114 is a bispecific antibody that binds PSMA on tumor cells and CD3 on T cells to induce anti-tumor activity.

Transperineal (TP) prostate biopsy is increasingly preferred due to lower infection rates but is associated with procedural pain and patient anxiety. Lack of knowledge about the procedure contributes significantly to distress and reduces satisfaction. This study investigated whether video-animated patient information improves anxiety, pain perception, satisfaction, and tolerability during TP prostate biopsy under local anesthesia.

CD19-negative relapse occurs in ~30% of persons with relapsed or refractory large B cell lymphoma (LBCL) who respond to axicabtagene ciloleucel (axi-cel; CD19-directed chimeric antigen receptor (CAR) T cell therapy). In this phase 2 single-arm study, 26 participants with chemorefractory LBCL received axi-cel in combination with rituximab. The primary endpoint was investigator-assessed complete response rate; select secondary endpoints included duration of response (DOR), axi-cel pharmacokinetics and safety. The complete response rate was 73%. Median DOR was 26.0 months; 46% of participants had an ongoing response at data cutoff. Peak CAR T cell (normalized by tumor burden) and rituximab area-under-the-curve levels were elevated in participants with complete or ongoing response. Axi-cel plus rituximab treatment led to durable responses with no new safety signals despite persistent B cell aplasia and pharmacokinetics of axi-cel were unaffected, indicating that dual targeting of CD19 and CD20 is a feasible and safe approach to potentially limit antigen escape. ClinicalTrials.gov registration: NCT04002401 .

The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER+ breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ).

Combining immunotherapy with chemoradiation is effective in locally advanced cervical cancer. However, the impact of induction combination immunotherapy on immune modulation and treatment response is poorly understood. In this phase II trial (NCT04256213), 40 females with locally advanced cervical carcinoma received one cycle of nivolumab-plus-ipilimumab immunotherapy before standard chemoradiation, followed by maintenance nivolumab. We show, using multiplex-immunofluorescence tissue imaging, a significantly increased CD8+/FOXP3+ cell ratio (primary endpoint; increase of 0.87 cells/mm², P = 0.0164) and proliferative CD8+ T-cell density after one cycle of combination immunotherapy. HOT score (27-gene-based signature identifying immunologically active tumors) also increased significantly (exploratory analysis; 0.17, P < 0.0001). Objective response rates (secondary endpoint) were 13% immediately after combination immunotherapy, 98% (65% complete response) after chemoradiation, and 90% at treatment completion. High HOT score at baseline and immune changes induced by combination immunotherapy were associated with complete response at treatment completion. Induction immunotherapy may prime tumors for improved response to standard therapy.

The benefit of treatment intensification in metastatic colorectal cancer (mCRC) may be influenced by host-related factors that are not accounted for in clinical trials or standard care. We investigated the prognostic and predictive value of the muscle/bone ratio (MBR), a sarcopenia marker automatically derived from computed tomography (CT) images, in patients with mCRC from the prospective PanaMa study and a real-world validation cohort.

Self-expanding metal stents (SEMS) are widely used as a bridge to surgery in obstructive colon cancer, offering short-term benefits by reducing postoperative complications and avoiding emergency stoma creation. Additionally, early initiation of systemic chemotherapy may improve oncological outcomes. However, the safety and feasibility of preoperative chemotherapy following SEMS placement remain unclear. This study aims to evaluate the safety and efficacy of neoadjuvant CAPOX chemotherapy after SEMS placement in patients with obstructive colon cancer.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic neoplasm that expresses CD123, is often observed in the bone marrow (BM), as well as skin, blood, and viscera. Tagraxofusp, a first-in-class CD123-targeted therapy, is the only drug approved to treat BPDCN.

Microsatellite-stable metastatic colorectal cancer (MSS-mCRC) is generally unresponsive to immune checkpoint inhibitors (ICIs). Combining vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) with ICIs improves outcomes but often causes severe toxicities. Our previous preclinical work demonstrated that electroacupuncture (EA) potentiates anti-PD-1 therapy in MSS-CRC models by reprogramming the immunosuppressive microenvironment. Based on this rationale, we conducted a phase II trial to evaluate whether integrating EA with fruquintinib (a potent, selective small molecule inhibitor of VEGFR 1, 2, and 3) and sintilimab (a monoclonal antibody against PD-1) could improve tolerability and efficacy in MSS-mCRC. In this single-arm, investigator-initiated study, patients with histologically confirmed MSS-mCRC who had progressed through at least two prior regimens received 21-day cycles of EA (day 1-7), intravenous sintilimab (200 mg, day 8), and oral fruquintinib (5 mg/day, day 8-21). The primary endpoint was investigator-assessed objective response rate (ORR). From May 2024 to May 2025, 31 patients were enrolled and 28 were efficacy-evaluable. ORR was 21.4% [95% confidence interval (CI), 10.2-39.5] and DCR was 92.9% (95% CI, 77.4-98.0). Median PFS was 6.1 months (95% CI, 4.8-9.9) and median OS was 12.4 months (95% CI, 11.0-NA). TRAEs occurred in 80.6% of patients, with grade ≥3 in 29.0%, lower than rates reported for historical TKI-ICI combinations. No EA-related toxicity was observed. Overall, EA plus fruquintinib and sintilimab was feasible and showed an acceptable safety profile while maintaining antitumor activity in MSS-mCRC, warranting further evaluation in larger randomized trials.

Primary central nervous system lymphoma (PCNSL) is an aggressive, immune-privileged, large B-cell lymphoma with limited frontline treatment options.

Teclistamab is the first approved bispecific antibody targeting B-cell maturation antigen. It has demonstrated rapid, deep, durable responses with manageable safety in patients with triple-class exposed relapsed/refractory multiple myeloma (TCE RRMM).

Class 2 and 3 non-V600E BRAF mutations are oncogenic drivers in many cancer types. Currently, there are no established targeted therapies with proven efficacy for cancers with non-V600E BRAF mutations. We developed the investigator-initiated, Phase II BEAVER clinical trial (NCT03839342) to evaluate the efficacy of BRAF and MEK inhibitors in patients with non-V600E BRAF mutations. The primary outcome was objective response rate (ORR). The best ORR was 14% (3/21), the primary endpoint was not met. By analyzing genomic data from patient tumors, circulating tumor DNA (ctDNA), patient-derived xenograft (PDX) models generated from enrolled patients, and Class 2 & 3 BRAF mutant cell lines, we discovered MAPK-dependent and independent mechanisms of resistance to BRAF/MEK inhibition. These mechanisms include the acquisition of new mutations in NRAS, MAP2K1, RAF1, and RB in ctDNA at the time of disease progression. CDK4/6 and SHP2 emerge as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 & 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors in preclinical models show greater efficacy than BRAF/MEK inhibitors alone in these cancers.

T cell therapy has proven challenging for pancreatic ductal adenocarcinoma (PDAC), partly due to heterogeneous expression of tumor-associated antigens (TAAs). To address tumor heterogeneity and mitigate immune evasion, an ex vivo expanded, polyclonal, T helper 1 cell-polarized T cell product targeting five TAAs-PRAME, SSX2, MAGEA4, Survivin and NY-ESO-1-was developed. These antigens were chosen based on their tumor specificity, oncogenicity, immunogenicity and level of expression. In a phase 1/2 trial, this autologous nonengineered T cell product was administered (1 × 107 cells m-2 per infusion) monthly to patients with advanced PDAC responding (arm A, n = 13) or refractory (arm B, n = 12) to first-line chemotherapy or with resectable disease (arm C, n = 12). Primary endpoints were safety and feasibility of completing six infusions, whereas exploratory efficacy endpoints included persistence and evaluating the relationship between clinical benefit and the expansion of the infused effector T cells, as well as the induction of de novo immune responses. Of 56 participants procured, 37 were infused, with only 1 treatment-related serious adverse event. Disease control rates in arms A and B were 84.6% (95% confidence interval: 54.6-98.1%) and 25% (95% confidence interval: 5.5-57.2%), respectively. In arm C, two of nine resected participants remained disease free after 66 months of follow-up. The infused cells persisted up to 12 months posttreatment and elevated levels of tumor-directed T cells were detected during dosing (P = 0.027) and follow-up in responders compared to nonresponders. Clinical outcomes correlated with peripheral expansion of functional TAA-targeted T cell clones and treatment-emergent antigen spreading. Thus, further investigation of this approach, either as a single agent or combined with other complementary modalities, is warranted (ClinicalTrials.gov identifier: NCT03192462 ).

Immune checkpoint blockade-based multimodal therapy is widely used across oncology; yet drivers of resistance in most cancer types are not well understood. Here, we comprehensively characterized the tumor genome, microenvironment and microbiome in a phase 3 international randomized trial ( NCT02952586 ) to identify factors that shape outcomes to anti-PD-L1 avelumab plus standard-of-care chemoradiotherapy versus placebo/chemoradiotherapy in individuals with locally advanced head and neck cancer. Patients receiving avelumab whose tumors contained distinct immunologic and genetic features had superior outcomes compared to those receiving placebo. By contrast, patients with increased myeloid/neutrophil activities had worse outcomes with avelumab than those treated with placebo. Strikingly, these tumors possessed telltale intratumoral bacteria, elevated tumor-associated neutrophils, high systemic neutrophil-to-lymphocyte ratios and suppressed adaptive immunity. We define tumor ecosystems associated with benefit to chemoimmunotherapy. Our data demonstrate how intratumoral bacteria affect immune checkpoint blockade response within a randomized trial. These discoveries enhance our understanding of combination immunotherapy, provide a useful multiomic resource and identify unanticipated interactions that may guide future therapeutic strategies.