ABM-1310 is an investigational, orally bioavailable BRAF V600 inhibitor with high blood-brain barrier (BBB) penetration.

Translational Breast Cancer Research Consortium 048 was a proof-of-principle trial demonstrating responses to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients (pts) with metastatic breast cancer (MBC) with germline (g) PALB2 or somatic (s) BRCA mutations (sBRCAm). Here we report results from the expansion cohorts in a larger sample of pts with gPALB2m or sBRCAm.

CDK4/6 inhibitors (CDK4/6i) improve outcomes for estrogen receptor (ER) positive/HER2-negative breast cancers (BCs), yet intrinsic and acquired resistance exist. Here, we evaluated anastrozole in combination with palbociclib (ANA/PAL) in the NeoPalAna Endocrine-Resistant cohort (NCT01723774). Thirty-four patients with clinical stage II/III ER + /HER2- BCs resistant to standard neoadjuvant endocrine therapy (on-treatment Ki67 > 10%) received neoadjuvant ANA/PAL, with serial biopsies analyzed. The primary endpoint, complete cell cycle arrest (CCCA; Ki67C1D15 ≤ 2.7% at cycle 1, day 15), was achieved in 57.6% of patients (95%CI: 39.2-74.5%). Resistance to ANA/PAL (Ki67C1D15 > 10%) was associated with higher pre-treatment tumor grade, Ki67, and specific PAM50 subtypes. Resistant tumors demonstrated reduced ER signaling and upregulation of cell cycle, mTOR, interferon, JAK/STAT, and immune checkpoints. Additionally, a 33-gene signature that predicted neoadjuvant Ki67 response to ANA/PAL was prognostic in a metastatic validation cohort. These findings underscore dysregulated oncogenic pathways as potential resistance mechanisms and biomarkers of response to CDK4/6i.

Arm D of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, activity, and biomarkers of the PARP inhibitor olaparib with irinotecan in pediatric patients with recurrent/refractory malignancies.

We previously reported a phase II Kyoto trial for platinum-resistant ovarian cancer (n = 20) using nivolumab (anti-programmed cell death-1 [PD-1] antibody). We evaluated the associations between clinical outcomes and transcriptomics and T and B cell clonality from tumor and blood cells.

SMET12 is a bispecific T-cell engager targeting epidermal growth factor receptor (EGFR) and CD3. This phase 2 clinical trial aimed to investigate the efficacy and safety of SMET12 plus toripalimab and chemotherapy among advanced non-small-cell lung cancer (NSCLC) patients tested positive for EGFR protein, including treatment-naïve patients, patients with resistance to first-line immune checkpoint inhibitors-containing therapy and EGFR-mutated patients with resistance to first-line EGFR tyrosine kinase inhibitors (TKIs), and to examine the associations of lymphocyte numbers and differentiation patterns with therapeutic efficacy among advanced NSCLC patients.

Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive malignancy. Dabrafenib plus trametinib has shown efficacy in BRAFV600E-mutant ATC, but effective therapies remain limited for patients without this mutation. This study aimed to evaluate the efficacy and safety of anlotinib plus sintilimab in BRAFV600E-negative ATC.

A multicenter, randomized phase II trial to compare two first-line triplet treatments for advanced pancreatic ductal adenocarcinoma (PDAC).

Hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (mBC) is biologically distinct from early-stage disease, with a higher prevalence of genomically defined nonluminal subtypes, particularly the HER2-enriched (HER2-E) and basal-like subtypes. These tumors are highly proliferative, less dependent on hormone signaling, and associated with poor outcomes and early resistance to endocrine therapy and CDK4/6 inhibition (CDK4/6i). This biological shift highlights the need for biomarker-driven strategies in the CDK4/6i-resistant setting.

There is an urgent need to identify those who may benefit from immunotherapy-based chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR). This single-arm, phase-II trial (NCT05450029), enrolled 46 treatment-naïve patients with histologically confirmed T3-4N0M0 or T1-4N+M0 LARC with intermediate or high Immunoscore. Patients received 6 cycles of mFOLFOX6 and long-course radiotherapy (50 Gy in 25 fractions) followed by surgery. Sintilimab was added during CRT (2nd-6th cycle). The primary endpoint, pathologic complete response (pCR) rate, was 65.2% [30/46, 95%CI: 49.7-78.6], with 85.7% (6/7) in high and 61.5% (24/39) in intermediate Immunoscore, meeting the pre-specified primary endpoint. Secondary endpoints included R0 resection rate (97.8%), the clinical tumor response (ORR 93.5%), the complication rate and safety, 3-year event-free survival rate, and 3-year overall survival rate (immature). The most common treatment related adverse event (TRAE) was leukopenia (69.6%, 32/46). The TRAE of Grade 3 occurred in 7 patients (15.2%). Four patients had postoperative complications (all grade ≤2). Here, we showed that PD-1 blockade combined with long-course CRT yielded promising therapeutic effects with a favorable pCR rate and acceptable safety profile among patients with intermediate/high-Immunoscore pMMR LARC.

Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study's primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR+CD38+CD8+ T cell abundance serving as a potential predictor of therapeutic benefit.

Osimertinib is a standard treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC). The EGFR C797S mutation is one of the most common resistant mechanisms to osimertinib. Based on our preclinical data, the safety and efficacy of brigatinib combined with panitumumab was evaluated in phase 1/2 study.

Tyrosine kinase inhibitors (TKIs) discontinuation is the standard option for patients with chronic myeloid leukaemia (CML) in deep molecular response (MR) with imatinib. This study aimed to evaluate the efficacy and safety of one year consolidation with ponatinib on treatment-free remission (TFR) rate. This was a multicenter open-label, single-arm, phase II, exploratory clinical trial including patients with CML treated ≥4 years with imatinib therapy, and MR4.0 ≥12 months. Patients entered the TFR phase after receiving ponatinib at 15 mg/day for one year. Twenty three patients received ponatinib and 19 completed consolidation. Among the patients with detectable BCR::ABL1, 70% deepened response. The 48-weeks MR4.0 rate was 68.4% (95%CI: 43.4-87.4). The 48-week TFR rate as classically defined was 73.7% (95% CI: 8 56.3-96.4). Five restarted TKIs and all regained MR. The most frequent adverse events (AEs) were constipation (34.8%), asthenia (30.4%) and myalgia (21.7%). Patients who remained relapse-free one year after ponatinib discontinuation exhibited higher levels of NK and NKT-like cells with degranulation capacity. Consolidation with ponatinib showed a high TFR rate and adequate safety, granting further research.

Neoadjuvant chemotherapy (NCT) has been accepted as the standard management for locally advanced rectal cancer (LARC) without high-risk factors. However, many patients experience poor pathologic response, necessitating early-prediction tools. We investigated dynamic circulating tumor DNA (ctDNA) analysis for early response monitoring in patients with LARC undergoing NCT.

The mechanisms underlying resistance to neoadjuvant immunotherapy and chemoradiotherapy (nICRT) in locally advanced esophageal squamous cell carcinoma (ESCC) remain poorly understood. Through a single-arm phase II trial (n = 22) with 44.4-month median follow-up, we observed a significant survival disparity: patients achieving major pathologic response (MPR) exhibited superior 3-year event-free survival (EFS) and overall survival (OS), with no recurrence in MPR patients versus 71.4% recurrence in non-major pathological response (NMPR) patients (HR = 17.69, 95% CI 2.25-139.20, p = 0.0063). Integrating single-cell RNA/TCR sequencing and functional validation, we identified a PRDM1+ malignant cell subcluster enriched in NMPR patients and associated with treatment resistance. These cells exhibit strong lipid peroxidation characteristics, a state linked to the transcriptional activation of CTSB and MFSD12 mediated by PRDM1. This state renders the PRDM1+ malignant cell cluster more susceptible to ferroptosis induction. PRDM1+ cells further recruited immunosuppressive regulatory T cells (Tregs) through IL1A-IL1R2 interactions and activated lipid-metabolizing TREM2+ macrophages via CD47-SIRPA signaling, fostering an immune-evasive microenvironment. Conversely, MPR patients displayed expanded cytotoxic T-effector clones with enhanced tumor-killing capacity. Our findings identify PRDM1 as a key factor associated with nICRT resistance and suggest that targeting ferroptosis pathways or disrupting PRDM1+ cell-mediated immune suppression may represent a viable strategy in ESCC. Clinical trial registration number: NCT03940001.

Progression-free survival (PFS) with first-line third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors remains suboptimal in EGFR L858R-mutated advanced non-small-cell lung cancer (NSCLC), highlighting a need for strategies to delay resistance. This single-arm, phase II study (FIRM; ChiCTR2200060897) evaluates first-line double-dose firmonertinib (160 mg/day) in adults with L858R-mutated locally advanced or metastatic NSCLC. With a median follow-up of 27.5 months in 33 patients, primary endpoint was a median PFS of 21.1 months. Secondary endpoints include an unreached median overall survival, an objective response rate of 75.8%, a disease control rate of 90.9%, and an 18-month PFS rate of 63.1%. Grade ≥3 treatment-emergent adverse events occur in 6.1% of patients. Baseline circulating tumor DNA (ctDNA) variant allele frequency predicts ctDNA clearance at cycle 3 day 1, which correlates with longer PFS. Double-dose firmonertinib shows promising efficacy and tolerability, supporting its preliminary potential as first-line treatment for EGFR L858R-mutated advanced NSCLC.

Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting ~1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy based on a heterologous prime boost using great ape adenovirus and modified vaccinia virus Ankara encoding 209 FSPs shared across MSI neoplasms. We present the results from cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45). Safety and immunogenicity were coprimary endpoints. Safety was assessed in 45 participants. Vaccination was safe with no intervention-related serious adverse events (AEs). The most common AEs were injection-site reactions (any grade in 91% of participants after prime and 76% after boost with no grade 3) and fatigue (any grade in 80% after prime and 53% after boost with 4% grade 3 after prime or after boost). Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity (mean response at peak of ~1,100 interferon-γ spot-forming cells per million peripheral blood mononuclear cells). The immune response was durable and detectable at 1 year in 85% of participants. Both CD8+ and CD4+ T cells were induced, recognizing multiple FSPs. Peptide-human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro. Immunogenic FSPs were found in independent datasets of LS MSI colorectal precancers and cancers. These results highlight Nous-209 ability to efficiently stimulate immunity against neoantigens in LS, supporting its development for cancer interception (ClinicalTrials.gov identifier: NCT05078866 ).

Systemic treatments are limited for patients with meningiomas that have progressed after surgery or radiation. Loss of NF2 and CDKN2A/CDKN2B is common in higher-grade meningiomas and promotes progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, as one arm of the Alliance umbrella trial A071401, a genomically driven phase 2 study in recurrent and progressive meningiomas. Eligible patients with grade 2 or 3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate as defined by local review; the trial would be declared positive if either endpoint was met. The success threshold for PFS6 was 8 or more of 24 patients; for the response rate, it was 3 or more of 24 patients. Ninety-six patients were screened and 36 patients received treatment. The mean number of treatment cycles was nine and the median follow-up was 21 months. The first 24 patients who met the eligibility criteria and began treatment could be evaluated for the primary endpoint. The observed PFS6 rate was 58% (14 of 24 patients, 95% confidence interval = 37-78%), thus meeting the PFS6 criteria for promising activity. The best response was stable disease in 16 of 24 patients. Of the 36 patients who started treatment, nine had a grade 3 and two had grade 4 adverse events at least possibly related to treatment. Grade 4 toxicities included alanine aminotransferase elevation (1), aspartate aminotransferase elevation (1) and vomiting (1). The trial met its primary endpoint. Abemaciclib was well tolerated and resulted in improved PFS6. Abemaciclib warrants further investigation for patients with progressive grade 2 or 3 meningiomas harboring NF2 or CDK pathway alterations. ClinicalTrials.gov registration no. NCT02523014 .

In this phase 2 study (NCT05047991), patients with unresectable metastatic pancreatic adenocarcinoma were randomized to receive NALIRIFOX (liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin) or gemcitabine plus nab-paclitaxel. The primary endpoint was progression free survival (PFS). Secondary endpoints included other efficacy outcomes (overall survival, objective response rate, disease control rate, and duration of response), as well as safety, pharmacokinetic parameters, and evaluation of the relationship between UGT1A1*6 and UGT1A1*28 polymorphisms and safety. A total of 117 patients were enrolled and randomly assigned to NALIRIFOX (n = 78) or gemcitabine plus nab-paclitaxel (n = 39). At a median follow-up of 18.7 months (interquartile range [IQR], 7.5-22.1) for NALIRIFOX and 12.1 months (IQR: 6.4-14.8) for the gemcitabine plus nab-paclitaxel, median PFS was 7.6 months (95% CI 5.52-9.23) with NALIRIFOX versus 3.7 months (95% CI 3.38-5.32) with gemcitabine plus nab-paclitaxel (hazard ratio, 0.56; 95% CI, 0.35-0.88; P = 0.0115). ≥ Grade 3 treatment-emergent adverse events (TEAEs) occurred in 73.1% of patients receiving NALIRIFOX and 84.6% of patients receiving gemcitabine plus nab-paclitaxel, respectively. Despite the premature termination (predetermined sample size of n = 153 not reached) of the study, NALIRIFOX demonstrated improvement in PFS compared with gemcitabine plus nab-paclitaxel, with a manageable safety profile in Chinese patients with advanced pancreatic adenocarcinoma.

Polycystic ovary syndrome (PCOS) is a set of symptoms related to menstrual irregularities that can cause infertility in women of reproductive age. Unfortunately, there are currently no authorized treatment medications for PCOS. The Tianjing Zelan (TJZL) formula, a herbal formulation developed from the ancient Chinese medical classic Beiji Qianjin Yaofang in Tang Dynasty, is employed in the clinical management of menstrual irregularities and amenorrhea. However, its clinical characteristics and mechanism have not been systematically evaluated.