Issues with randomized controlled trial generalizability are well described, but whether these issues result from differences in patient treatment across contexts remains unknown. We studied treatment of patients with high-risk prostate cancer after radical prostatectomy inside and outside a randomized controlled trial evaluating the impact of a genomic classifier on post-radical prostatectomy treatment decision making (Genomics in Michigan Impacting Observation of Radiation [G-MINOR]; ClinicalTrials.gov identifier NCT02783950).

The LAURA study in unresectable stage III EGFR-mutated NSCLC without progression during/after chemoradiotherapy demonstrated significantly improved progression-free survival (PFS) with osimertinib versus placebo after definitive chemoradiotherapy. We report patient-reported outcomes (PROs) from LAURA.

Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL.

Patients with homologous recombination repair gene altered (HRR+) metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis but achieved clinical benefits when treated with first-line niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in the MAGNITUDE trial. We report final exploratory results from MAGNITUDE for the subgroup of patients with Breast Cancer gene-positive (BRCA+) mCRPC enrolled in Asia (NCT03748641).

Low Ki67 after short preoperative endocrine therapy (ET) indicates a favorable prognosis in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC). We investigated predictors of ET response in the West German Study Group (WSG) ADAPT-HR+/HER2- and ADAPTcycle trials.

High-dose-rate brachytherapy boost (HDR-BTb) combined with external beam radiotherapy (EBRT) improves biochemical relapse-free survival (bRFS) in localised prostate cancer (PCa) yet ∼21% of patients relapse despite dose escalation. Hypoxia and angiogenesis biomarkers have been linked to treatment outcomes through immunohistochemistry (IHC) but genomic validation at the transcriptomic level remains lacking. This study hypothesised that hypoxia- and angiogenesis-related gene expression profiles could predict clinical benefit from HDR-BTb escalation, refining patient selection.

Managing unresectable metastatic colorectal cancer (mCRC) requires a comprehensive strategy. While chemotherapy, anti-angiogenic, and anti-epidermal growth factor receptor (EGFR) agents are available, strategy trials are needed to optimize their use and sequencing. The STRATEGIC-1 phase III trial (NCT01910610) was designed to determine the optimal treatment sequence in patients with untreated, unresectable wild-type RAS/BRAFV600E mCRC. Patients were randomized (1:1) to FOLFIRI-cetuximab then mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab then FOLFIRI-bevacizumab followed by EGFR monoclonal antibody +/- irinotecan (arm B). The primary endpoint was the duration of disease control (DDC). Secondary endpoints were overall survival (OS), time to failure of strategy (TFS), progression-free survival (PFS), overall response rate (ORR), salvage surgery rate, safety, and health-related quality of life (HRQoL). Overall, 263 patients (arm A:131, arm B:132) were randomized. After 68.4 months of median follow-up (95% CI, 76.5-98.0), the median DDC was 22.8 months (95% CI, 20.4-28.8) in arm A and 23.5 months (95% CI, 17.9-26.3) in arm B (HR = 1.01, 95% CI, 0.76-1.34; log-rank P = 0.945). The median OS was 40.4 months (95% CI, 32.4-51.1) in arm A and 34.4 months (95% CI, 27.5-42.2) in arm B (HR = 1.30, 95% CI, 0.99-1.72). The ORR was higher in arm A (82.4% versus 65.4%) in the first-line group but not in the second-line group (20.7% versus 16.4%). Adverse events were consistent with the well-known safety profiles. STRATEGIC-1 did not meet its primary endpoint and was inconclusive in identifying the optimal treatment strategy in wild-type RAS/BRAFV600E mCRC.

Metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel and androgen receptor signaling inhibitors (ARSIs) has limited treatment options. Although enzalutamide has shown activity after abiraterone and docetaxel, robust evidence from randomized phase III trials is lacking. Deutenzalutamide, a novel derivative with slower metabolism and improved pharmacokinetics, may offer enhanced safety and efficacy. This phase III, double-blind trial conducted at 36 centers in China enrolled patients whose disease progressed on or who were intolerant to abiraterone and docetaxel, or who were ineligible for docetaxel. Patients were randomized (2:1) to receive deutenzalutamide 80 mg once daily or placebo until progression or unacceptable toxicity; the primary endpoint was radiographic progression-free survival (rPFS). Of 417 patients (276 deutenzalutamide; 141 placebo), all had previously received abiraterone, and 68% had also received docetaxel. Deutenzalutamide significantly improved rPFS (HR, 0.58; P = 0.0001), reducing the risk of progression by 42%. Although the initial OS analysis was not significant (HR, 0.95), sensitivity analyses adjusting for subsequent therapies showed significant OS benefits (HR, 0.65-0.73). Treatment-related grade 3 or higher adverse events occurred in 22.3% of patients treated with deutenzalutamide, compared with 15.0% with placebo. The most common treatment-related adverse event was anemia, reported at any grade in 21.2% versus 17.9%, with grade 3/4 anemia in 6.6% versus 2.9%, respectively. Notably, no seizures or falls were reported. In summary, deutenzalutamide significantly prolonged rPFS and, after adjustment, showed a potential OS benefit with a favorable safety profile, supporting its promise as a new treatment option for mCRPC. Clinical trial registration: NCT03851640.

In PREDIX LumB patients with estrogen receptor positive and human epidermal growth factor receptor negative (ER + /HER2-) breast cancer > 20 mm and/or with lymph node metastasis were randomized 1:1 to receive either paclitaxel weekly for 12 weeks followed by palbociclib and endocrine therapy for 12 weeks (arm A), or the reverse sequence (arm B). Primary endpoint is objective radiologic response at 12 weeks (ORR12), and key secondary endpoints are ORR24, pathologic complete response, event-free survival, safety and correlative studies of tissue and circulating biomarkers. Whole exome sequencing and RNA sequencing were performed on baseline fresh frozen tissue samples. In total, 179 patients comprise the intention-to-treat population. There is no statistically significant difference between the two arms in ORR12 (59% vs 45%, p = 0.058). An exploratory gene expression analysis identified differentially expressed genes and gene sets between responders and non-responders at 12 weeks. A predictive signature, CDKPredX, comprising 31 genes related to proliferation, ER signaling and immune activity was developed to identify patients resistant to chemotherapy but responding to palbociclib plus endocrine therapy (pinteraction=0.03). The predictive signature was independently validated in the CORALLEEN trial (pinteraction=0.048). Clinicaltrials.gov identifier: NCT02603679.

QuANTUM-First demonstrated improved overall survival (OS) in patients with newly diagnosed acute myeloid leukemia with FMS-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) treated with quizartinib + standard chemotherapy. Herein, we evaluated the impact of postconsolidation/posttransplant single-agent maintenance therapy on clinical outcomes in patients receiving maintenance, focusing on measurable residual disease (MRD) status at maintenance onset. OS, event-free survival, and relapse-free survival were prespecified exploratory analyses. Cumulative incidence of relapse, analyses by allogeneic hematopoietic cell transplant (allo-HCT), and analyses by MRD status were post hoc and not powered for statistical significance. Samples for FLT3-ITD MRD analysis were collected from patients with composite complete remission ≤30 days before receiving maintenance and assessed using an ultrasensitive amplicon-based assay. More patients who had received an allo-HCT and quizartinib treatment received maintenance (71%) vs placebo (55%); OS benefit was not demonstrated among these patients. In patients who did not undergo allo-HCT, quizartinib maintenance was associated with a significant OS benefit (hazard ratio [HR], 0.401; 95% confidence interval [CI], 0.192-0.838), including a benefit in patients who were MRD negative at the start of maintenance (OS HR, 0.194; 95% CI, 0.056-0.676). Patients who were MRD negative at the completion of consolidation achieved 89.1% (95% CI, 70.0-96.4) survival at 3 years with quizartinib maintenance in the absence of allo-HCT. These data suggest that for patients who achieve FLT3-ITD MRD negativity after induction and consolidation with quizartinib, maintenance with quizartinib provides a significant survival benefit and, in some patients, may eliminate the need for allo-HCT. This trial was registered at www.clinicaltrials.gov as NCT02668653.

Induction and consolidation with a quadruplet therapy of a CD38-targeting monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug and dexamethasone are a standard-of-care treatment in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM) with the optimal drugs to be used still under debate. The ongoing, phase 3 EMN24 IsKia trial randomized 302 TE patients with NDMM aged ≤70 years 1:1 to isatuximab-carfilzomib-lenalidomide-dexamethasone (Isa-KRd) versus KRd pretransplant induction and post-transplant consolidation. The primary endpoint was the rate of measurable residual disease (MRD) negativity (sensitivity of 10-5 or better) by next-generation sequencing (NGS) after consolidation. Key secondary endpoints were the rates of NGS-MRD negativity after induction and progression-free survival (PFS). MRD negativity rates at higher sensitivity (10-6 or better) were exploratory. Post-consolidation MRD negativity was significantly higher with Isa-KRd versus KRd at the 10-5 (77% versus 67%; odds ratio (OR) 1.67, P = 0.049) and 10-6 (68% versus 48%; OR 2.36, P = 0.0004) sensitivities. Deep MRD responses were rapid (post-induction Isa-KRd versus KRd: 10-5 46% versus 27%, OR 2.32, P = 0.0007; 10-6 28% versus 14%, OR 2.44, P = 0.0029) and durable (1-year sustained 10-6 MRD negativity 52% versus 38%, OR 1.82, P = 0.012). At current follow-up, PFS data were immature. Grade 3-4 non-hematologic adverse events (AEs), treatment discontinuations and deaths due to AEs were similar in the two arms. Isa-KRd significantly improved NGS-MRD negativity in TE patients with NDMM, with a manageable safety profile. ClinicalTrials.gov registration: NCT04483739 .

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).

Trastuzumab-based chemotherapy has improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, but treatment benefit varies among patients. Predictive signatures are needed to identify patients most likely to respond to these therapies.

Quemliclustat potently inhibits CD73, a key enzyme producing immunosuppressive adenosine. In a phase 1b trial (ARC-8), we evaluated safety and efficacy of quemliclustat combined with gemcitabine/nab-paclitaxel (G/nP) with or without zimberelimab (anti-programmed cell death protein 1 (PD-1)) in first-line metastatic pancreatic ductal adenocarcinoma (PDAC). During the dose-escalation phase, 22 patients were enrolled across five dose levels of quemliclustat (25 mg, 50 mg, 75 mg, 100 mg or 125 mg) with G/nP + zimberelimab. During the dose-expansion phase, 116 patients were enrolled, beginning with a single-arm, non-randomized cohort receiving quemliclustat 100 mg + G/nP + zimberelimab, followed by a randomized cohort in which patients were assigned in a 2:1 ratio to receive quemliclustat 100 mg + G/nP with or without zimberelimab. The primary endpoint was safety and tolerability; secondary endpoints included assessments of clinical activity and survival. In all treatment arms, the safety profile was consistent with that of G/nP. Clinical response rates and survival outcomes were encouraging. NR4A family gene expression was upregulated by adenosine in vitro and by chemotherapy in human PDACs. High tumor NR4A expression was associated with improved overall survival (OS) in ARC-8 but not in two external cohorts from the PRINCE (G/nP + nivolumab (nivo)) or Morpheus-PDAC (G/nP) trials. Spatial tissue analyses revealed a scarcity of activated T cells near regions with high NR4A1 expression, consistent with an immunosuppressed tumor microenvironment. In paired pretreatment/posttreatment biopsies, maximal downregulation of NR4A expression was associated with T cell activation and improved OS, pointing to a biological link between tumor adenosine and clinical benefit. ClinicalTrials.gov identifier: NCT04104672 .

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.

Cascade genetic testing in families with hereditary cancer syndromes is an important strategy to reduce the burden of cancer, but testing of relatives is low. Direct engagement of relatives through cancer survivors is a promising approach to bridge this gap.

To characterize the occurrence, duration, and outcomes of the most common non-hematological (nausea, vomiting, fatigue/asthenia) and hematological (anemia, neutropenia) adverse events experienced by patients receiving olaparib in the phase III SOLO2 trial.

Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC), but clinical trials are lacking. This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The co-primary endpoints are determination of dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy +/- carboplatin. Secondary endpoints include safety, survival, and RR by tumor histology. After enrollment of 4 patients to combination therapy, the trial was modified to a single arm study of alrizomadlin monotherapy due to excess toxicity. 1 DLT was seen in the combination arm, all patients had ≥ G3 treatment related adverse events (TRAE). 37 patients were enrolled to alrizomadlin monotherapy. 3 DLTs were encountered, 67% of patients had ≥ G3 TRAE. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC.

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.