Patients with resectable non-small-cell lung cancer (NSCLC), particularly those with EGFR mutations, face a high risk of recurrence and mortality post-surgery. Aumolertinib, a third-generation EGFR tyrosine-kinase inhibitor, is approved in China for adjuvant treatment in patients with NSCLC harbouring EGFR with an exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation. The ARTS study aimed to evaluate the efficacy and safety of adjuvant therapy with aumolertinib in patients with stage II-IIIB EGFR-mutated NSCLC.

Treatment with encorafenib ± binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/K-mutant advanced melanoma. We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib.

ctDNA may offer a noninvasive means to evaluate tumor response and anticipate disease dynamics before radiologic changes in advanced endometrial carcinoma.

First-line treatment options for cisplatin-ineligible patients with metastatic urothelial cancer (mUC) are limited. We conducted a phase II study of erdafitinib, alone or with cetrelimab, in FGFR-altered mUC.

Clinical guidelines recommend upfront osimertinib monotherapy for asymptomatic brain metastases (BM) in EGFR-mutant NSCLC, despite a lack of randomized trial evidence. We conducted two randomized phase II trials, OUTRUN and LUOSICNS, to evaluate the efficacy and safety of upfront stereotactic radiosurgery (SRS) plus osimertinib versus osimertinib in this patient population.

Frontline ovarian cancer treatment protocols involving bevacizumab, poly (ADP-ribose) polymerase inhibitors, and PD-1/PD-L1 inhibitors have failed to improve overall survival (OS) in patients with homologous recombination-proficient (HRP) tumors. To determine mechanistic mutation signatures associated with OS advantage, we constructed a whole-exome sequencing bioinformatic pipeline assay to analyze all 91 patients enrolled in the double-blind randomized placebo-controlled phase II VITAL trial.

This study evaluated tislelizumab combined with low-dose bevacizumab in recurrent glioblastoma (rGBM), assessing efficacy, safety, and mechanisms of immune escape.

To investigate the efficacy and safety of osimertinib plus savolitinib for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and de novo MET aberrations, we conducted a randomized, multicenter, open-label, phase 2 study (ClinicalTrials.gov identifier: NCT05163249). Treatment-naïve patients with locally advanced or metastatic NSCLC harboring de novo MET amplification or overexpression and EGFR mutations were randomized to receive osimertinib monotherapy (cohort 1, 80 mg orally once daily) or combination therapy (cohort 2, osimertinib 80 mg orally once daily and savolitinib 300 mg orally twice daily). The primary endpoint was the confirmed objective response rate (ORR). A total of 44 patients were randomized to either cohort 1 (n = 23) or cohort 2 (n = 21). The pre-specified study endpoint was achieved. The confirmed ORR was 60.9% (95% confidence interval [CI]: 38.5-80.3) in cohort 1 and 90.5% (95% CI: 69.6-98.8) in cohort 2, with disease control rates of 87% (95% CI: 66.4-97.2) and 95.2% (95% CI: 76.2-99.9). Treatment-related adverse events of grade 3 or higher occurred in 2 patients (8.7%) in cohort 1 and 12 patients (57.1%) in cohort 2. Osimertinib plus savolitinib showed promising antitumor activity and manageable safety.

MOUNTAINEER was a multicenter, open-label, phase 2 trial (NCT03043313) that evaluated the efficacy and safety of tucatinib plus trastuzumab, a dual HER2-targeted chemotherapy-free regimen. Patients were included if they had chemotherapy-refractory, HER2+, RAS wild-type unresectable or metastatic colorectal cancer. This final analysis reports updated efficacy and safety after a median follow-up of 32.4 months. Of the 84 patients who received tucatinib plus trastuzumab, the confirmed objective response rate was 39.3%; median duration of response was 15.2 months. Median progression-free survival was 8.1 months and overall survival was 23.9 months. Efficacy was relatively similar across central HER2+ testing methods. No clear association of treatment response with co-occurring biomarker alterations was seen. Few patients discontinued treatment due to adverse events; no treatment-emergent deaths occurred. Tucatinib plus trastuzumab showed clinically meaningful efficacy and favorable safety. Efficacy was observed irrespective of central HER2+ testing methods and in patients with heterogeneous tumor biomarker profiles.

Increasing germline genetic testing rates may impact contralateral prophylactic mastectomy (CPM) rates in patients with newly diagnosed breast cancer.

To evaluate the long-term efficacy and safety of gilteritinib compared with salvage chemotherapy (SC) in patients with relapsed/refractory FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). In the phase 3 COMMODORE (NCT03182244) trial, patients with relapsed/refractory FLT3-mutated AML from China, Russia, Singapore, Thailand, and Malaysia were randomized to gilteritinib (120 mg/day) or SC. The long-term follow-up included assessments every 3 months for a maximum of 3 years from the end-of-treatment visit. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), complete remission (CR) rate, hematopoietic stem cell transplantation (HSCT) rate, and transfusion maintenance and conversion rates. Overall, 276 patients (gilteritinib, n = 137; SC, n = 139) completed the long-term follow-up. Most (88.0%) patients were Asian. The median (95% confidence interval [CI]) OS was longer with gilteritinib versus SC (10.3 [8.8, 12.7] vs 5.4 [4.1, 8.1] months, respectively; hazard ratio [HR; 95% CI], 0.612 [0.451, 0.832]), with a median follow-up of 34.6 months. The median (95% CI) EFS was longer with gilteritinib versus SC (2.1 [< 0.1, 3.2] vs 0.6 [0.2, 1.2] months, respectively; HR [95% CI], 0.589 [0.438, 0.792]). The CR rate was 20.4% and 11.5% in the gilteritinib and SC arms, respectively. During the entire study period, 22.6% and 7.9% of patients in the gilteritinib and SC arms underwent HSCT, respectively; 18.2% of patients in the gilteritinib arm received on-study HSCT. No new safety concerns were identified. Long-term gilteritinib treatment improved clinical outcomes compared with SC and was well-tolerated in a predominantly Asian population with relapsed/refractory FLT3-mutated AML.

Chimeric antigen receptor (CAR)-T cell therapies have the potential to transform treatment of autoimmune disease by resetting the immune system. However, adoption of cell therapies in the autoimmune space is limited by hurdles such as inpatient administration, lymphodepletion and safety concerns around cytokine release syndrome and non-specific immunosuppression. RNA-based cell therapy has potential to address these limitations. Here we report prespecified exploratory analyses from a successful placebo-controlled, double-blind, randomized phase 2b trial in patients with generalized myasthenia gravis who received Descartes-08, an autologous, RNA-encoded anti-B cell maturation antigen (BCMA) CAR-T cell therapy. In 66.7% of patients (n = 10/15), transient targeting of BCMA with Descartes-08 administered in an outpatient setting without lymphodepletion resulted in durable clinical efficacy. Comparison of Descartes-08-treated (n ≤ 19) and placebo (n ≤ 15) cohorts by flow cytometry, serum profiling, multiplexing cytokine analysis and bulk/single-cell transcriptional analysis reveals a precision retuning of self-reactivity demonstrated by increased pro-immune function, decreased activity of BCMA+ plasma cells and plasmacytoid dendritic cells and reductions in disease-associated cytokines, such as IL-6. Furthermore, antibody and T cell receptor analysis revealed altered circulating repertoires of self-reactive antibodies and T cell clones among Descartes-08 participants. These effects occurred without immune suppression, indicated by the lack of decline in vaccine-specific antibodies or hypogammaglobulinemia. Our findings unveil a new type of immune reset and support the development of BCMA-targeted RNA cell therapies as a more accessible therapy for autoimmune diseases. ClinicalTrials.gov identifier: NCT04146051 .

Myasthenia gravis (MG) is driven by the secretion of autoantibodies from pathogenic B cell maturation antigen (BCMA)-expressing plasma cells. In this phase 2b randomized, controlled, double-blind trial, we evaluated Descartes-08, an autologous BCMA-directed mRNA chimeric antigen receptor T cell therapy, in patients with generalized MG (gMG). Patients (n = 26) were randomly allocated to receive once-weekly intravenous infusions of Descartes-08 (n = 15) or placebo (n = 11) over 6 weeks. The primary endpoint was a ≥5-point improvement in the MG Composite (MGC) score at month 3. Secondary endpoints included the mean change from baseline in MGC, MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) scores by month 12. At month 3, the proportion of patients achieving a ≥5-point improvement in the MGC score was significantly higher for those treated with Descartes-08 compared to placebo in the overall population (66.7% (n = 10/15) versus 27.3% (n = 3/11), P = 0.0472) and in a subpopulation of those positive for autoantibodies to the acetylcholine receptor (63.6% (n = 7/11) versus 12.5% (n = 1/8), P = 0.0258). For patients treated with Descartes-08, the changes from baseline in mean MGC, MG-ADL and QMG scores at month 4 were -7.1, -5.5 and -4.8, respectively, with 83.0% of patients achieving a sustained and clinically meaningful response at month 12. Notably, 33.0% of patients achieved minimum symptom expression (MSE) (MG-ADL score ≤1) by month 6, which was sustained through month 12. Among biologic-naive patients, 55.60% achieved MSE by month 6, which was maintained through month 12 without additional treatment. Descartes-08 was generally safe and well tolerated. Infusion-related reactions were the most common adverse events reported (Descartes-08, 80.0% (n = 16/20); placebo, 56.3% (n = 9/16)). In summary, a single course of six once-weekly infusions of Descartes-08 was well tolerated and resulted in sustained clinically meaningful responses among patients with gMG. ClinicalTrials.gov identifier: NCT04146051 .

We report 5-year results of the phase III randomized TRIPLETE study. Eligible patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) received first-line modified fluorouracil, leucovorin, oxaliplatin (mFOLFOX)/panitumumab (control group, n = 217) versus modified fluorouracil, leucovorin, oxaliplatin, irinotecan (mFOLFOXIRI)/panitumumab (experimental group, n = 218). We present overall survival (OS) and updated outcomes in the intention-to-treat population. The median follow-up was 60.2 months (IQR, 49.3-70.0). The median OS was 41.1 and 33.3 months for experimental and control groups, respectively (hazard ratio [HR], 0.79 [95% CI, 0.63 to 0.99]; P = .049). OS outcomes favored the experimental group regardless of clinical features. No differences in objective response rate (primary end point; 75%/78%, odds ratio, 0.84 [95% CI, 0.54 to 1.31]; P = .442), early tumor shrinkage rate (P = .954), depth of response (P = .573), no residual tumor resection rate (P = .329), and progression-free survival (HR, 0.95 [95% CI, 0.78 to 1.16]; P = .606) were confirmed. Among patients alive at the time of disease progression, the median postprogression survival was 24.6 and 17.7 months for experimental and control groups, respectively (HR, 0.79 [95% CI, 0.62 to 1.01]; P = .062). Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: second line 73%/71%, third line 51%/49%, fourth line 31%/32%), as well as nonpalliative locoregional treatments (control/experimental: 16%/16%). Upfront mFOLFOXIRI/panitumumab significantly improves OS compared with mFOLFOX/panitumumab in patients with RAS/BRAF wild-type mCRC.

Aromatase inhibitors (AI) are used to treat estrogen receptor (ER)-positive low-grade endometrioid endometrial cancer. In breast cancer, ESR1 mutations are rare at diagnosis (<5%) but are frequently acquired in AI-resistant cases and are considered one of the major resistance mechanisms to endocrine therapy. This study aimed to assess the prevalence of ESR1 mutations in hormonotherapy-naïve endometrial cancer samples and correlate them with molecular profiles, ER expression, and clinical outcomes.

In NSCLC, TP53 mutations are heterogeneous with varied effects on protein synthesis, function and clinical outcomes. We hypothesize that a refined classification of TP53 mutations, beyond binary categorization, could improve prognostication. Furthermore, specific mutations could be associated with enhanced benefit from immune checkpoint inhibitors (ICI) versus chemotherapy. To investigate this, we analyzed data from randomized trials (OAK and POPLAR) which compared atezolizumab to chemotherapy in previously treated advanced driver-negative NSCLC.

Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT. We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multikinase inhibitor dasatinib in adult patients with CBF-AML. Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg daily on days 8 to 21 in induction, and on days 6 to 28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg daily. Primary end point was event-free survival (EFS). Secondary end points included overall survival, relapse-free survival, and cumulative incidence of relapse. A total of 202 patients were randomly assigned to the standard arm (n = 102) and to the dasatinib arm (n = 100). Median age was 49 years (range, 18-77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); and 58 (28.7%) patients had a KIT comutation. There was no statistically significant difference in EFS (hazard ratio, 0.92; 95% confidence interval, 0.63-1.33; P = .66) or secondary end points between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%). In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.ClinicalTrials.gov as NCT02013648.

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.

Background: Men treated with androgen deprivation therapy (ADT) for prostate cancer are at risk for cognitive decline. Patient genetics and endocrine state may shape gut microbiome features that relate to cognition. Methods: We studied a subsample of 79 prostate cancer survivors with prior ADT exposure previously enrolled in a randomized controlled exercise trial comparing three training modalities (strength training, Tai Chi training, or stretching control) who completed an additional food-frequency questionnaire and remote Montreal Cognitive Assessment (MoCA) and provided saliva and stool for APOE genotyping, salivary testosterone, and 16S rRNA sequencing. We used beta regression for MoCA (scaled 0-1), linear models for testosterone, alpha diversity regressions, PERMANOVA for beta diversity, and DESeq2 for genus-level differential abundance, with false-discovery correction. Results: Compared to post-stretching control, post-strength training testing was associated with higher MoCA scores whereas post-Tai Chi testing was not. APOE ε4 carriers exhibited a greater testosterone increase with strength training than non-carriers. Testosterone, and its interactions with exercise modality and APOE ε2 status, was related to presence/absence-based community structure; APOE ε4 interacted with exercise intervention to influence alpha diversity. At the genus level, exercise was linked to lower levels of Bacteroidota taxa (including Muribaculaceae) and higher levels of Enterobacteriaceae; APOE ε4 status was linked to higher Megamonas and lower Rikenellaceae RC9 levels; and higher salivary testosterone levels were linked to higher Prevotellaceae taxa and Succinivibrio levels. Higher MoCA scores were associated with lower abundances of several Firmicutes genera. Conclusions: Endocrine state and APOE genotype may condition the gut microbiome's response to exercise intervention in ADT-treated prostate cancer survivors, with downstream associations with cognition. These findings could inform precision survivorship strategies pairing strength training with genotype- and hormone-informed microbiome monitoring to optimize cognitive performance.

Pancreatic cancer (PC) remains a highly lethal disease with few reliable biomarkers to guide chemotherapy choices. New biomarkers for selecting anticancer drugs are needed to enhance the effectiveness of current multimodal treatment approaches. This study aimed to find a new biomarker by using clinical data and specimens collected for a Japanese randomized controlled trial (RCT).