Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg-1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54-0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44-0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41-0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783 .

Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2- BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10%) ER+/HER2- primary BC. In total, 510 patients were randomized to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo (24.5% versus 13.8%; P = 0.0021), with greater benefit observed in patients with programmed death ligand 1-positive tumors (VENTANA SP142 ≥1%: 44.3% versus 20.2% respectively). There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm. Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2- BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066.

The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in patients with lung squamous cell carcinoma (LSCC) is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.

Lasofoxifene, a novel endocrine therapy (ET), showed antitumor activity versus fulvestrant in women with ESR1-mutated, metastatic breast cancer (mBC) that progressed on prior ET (phase 2, ELAINE 1 study). We investigated changes in genitourinary syndrome of menopause (GSM) vulvar-vaginal symptoms with lasofoxifene and how patient/disease characteristics affect baseline vulvar-vaginal symptoms in ELAINE 1.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). In this article, we present results of the embedded randomised phase II trial testing the addition of panitumumab to neoadjuvant FOLFOX compared with FOLFOX alone in RAS and BRAF-wild-type (wt) patients and with biomarker hyperselection.

The randomized GeparOLA trial reported comparable pathologic complete response (pCR) rates with neoadjuvant treatment containing olaparib versus carboplatin. In this study, we evaluate the association between functional homologous recombination deficiency (HRD) by RAD51 foci and pCR and the potential of improving patient selection by combining RAD51 and stromal tumor-infiltrating lymphocytes.

Panitumumab (pan) plus chemotherapy is a preferred first-line therapy for unresectable RAS and BRAF wild type metastatic colorectal cancer (mCRC). Older patients may not be suitable for combination regimens. We investigated 2 lower intensity pan-containing regimens.

BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 ("MORPHO") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC.

This study, conducted as part of a multicenter phase III clinical trial, aimed to assess the utility of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) in comparing the efficacy of short-course and long-course chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). A total of 244 plasma samples from 79 LARC patients undergoing neoadjuvant therapy (NAT) before surgery were collected at various time points. Targeted deep sequencing using a novel MRD panel was performed. During NAT, ctDNA levels declined significantly. Baseline ctDNA-MRD status did not correlate significantly with treatment response. Notably, compared to long-course radiotherapy, microsatellite instability increased significantly after short-course radiotherapy (shortRT). Additionally, ctDNA negativity or lower levels were significantly associated with pathological complete response (pCR). Clearance of ctDNA and MRD after shortRT correlated significantly with pCR. A predictive model based on ctDNA-MRD, combined with carcinoembryonic antigen (CEA), outperformed models using only MRD or only CEA in predicting pCR/non-pCR. These findings provide insights into NAT for LARC and highlight ctDNA-based MRD assessment's potential in tailoring treatment strategies, emphasizing the need for personalized approaches.

Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes.

A randomized double-blind phase 3 trial (CHOICE-01, NCT03856411) demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients without pretreatment. This study presents the prespecified final analysis of overall survival (OS) and biomarkers utilizing circulating tumor DNA (ctDNA) and tissue-based sequencing. Additionally, the analysis revealed a higher median overall survival (OS, 23.8 months) in the toripalimab group than that in the control group (17.0 months). (HR = 0.69, 95%CI: 0.57-0.93, nominal P = 0.01). This survival benefit was particularly notable in the non-squamous subgroup. As the first phase 3 study to perform both baseline tissue whole-exome sequencing (WES) and peripheral blood ctDNA testing, we investigated efficacy predictive biomarkers based on both tissue and ctDNA, Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden, as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment. Furthermore, a ctDNA response observed on cycle 3 day 1, was associated with improved clinical outcomes for patients treated with the combination therapy. In conclusion, Toripalimab plus chemotherapy yields significant improvements in OS as a first-line treatment. The study highlights the utility of ctDNA as a proxy for tumor tissue, providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.

This psychometric analysis generated evidence to support the use of the Functional Assessment of Cancer Therapy item GP5 (GP5) as a measure of tolerability and confirms the appropriateness of categorizing "high side-effect burden" using a rating of 3 or 4 (score ranges 0-4) in patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC).

Genomic profiling is a major component for first-line treatment decisions in patients with NSCLC and the timeliness of biomarker testing is essential to improve time to treatment initiation (TTI) or avoid inappropriate treatment.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein, we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Mutations in DNA damage repair genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients for cystectomy-sparing active surveillance (AS).

NFE2L2/KEAP1/CUL3 mutations have been validated for radioresistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging because of multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure, locoregional failure, disease-free survival (DFS), and overall survival, using samples from a phase III trial in which patients were treated with radiation monotherapy at two controlled doses.

In CLEAR, lenvatinib + pembrolizumab (L + P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (aRCC). We report results from CLEAR biomarker analyses.

To evaluate the prognostic impact of circulating tumor DNA (ctDNA) detection at diagnosis (T0) and its early decrease after one cycle (T1) of neoadjuvant chemotherapy (NACT) in patients with advanced epithelial ovarian cancer (EOC) included in the CHIVA trial (NCT01583322).