Anthracycline-containing neoadjuvant chemotherapy (NACT) is the standard treatment for early triple-negative breast cancer (eTNBC); however, it is associated with substantial toxicity. We performed whole transcriptome profiling of baseline tumor biopsies to identify gene networks predictive and prognostic for pathological complete response (pCR) and survival after de-escalated, anthracycline-free NACT in the WSG-ADAPT-TN trial (NCT01815242).

The addition of 1 year of palbociclib to endocrine therapy (ET) did not improve invasive disease-free survival (iDFS) compared with placebo in the PENELOPE-B trial. In this article we report the final survival results of the PENELOPE-B trial.

To evaluate secondary efficacy endpoints and safety for the ENGOT-OV16/NOVA (NCT01847274) trial of niraparib maintenance therapy after extended follow-up and vital-status-data retrieval. Previously reported analyses (data cutoff, October 1, 2020) indicated benefit of niraparib maintenance therapy beyond first progression, but overall survival (OS) analyses were limited by missing data.

Our goal was to evaluate the impact of level of androgen receptor (AR) expression on outcomes in women with estrogen receptor α (ER) positive breast cancer. We sought to corroborate our preclinical findings that AR-agonists were efficacious in patients with ER-positive tumors that also expressed high levels of AR.

Osimertinib-a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor-is recommended as adjuvant therapy for resected stage IB-IIIA epidermal growth factor receptor-mutated non-small-cell lung cancer, based on significant disease-free survival (DFS) and overall survival improvement shown in the previously reported phase 3 ADAURA trial. A trend toward an increased DFS event rate after completion of 3 years adjuvant treatment in ADAURA suggests that some patients may benefit from longer adjuvant osimertinib treatment. We therefore explored whether tumor-informed, circulating tumor DNA-based, molecular residual disease (MRD) could predict recurrence in an exploratory post hoc analysis of 220 patients (n = 112 osimertinib; n = 108 placebo) from ADAURA. MRD preceded imaging DFS events in this study by a median of 4.7 (95% confidence interval, 2.2-5.6) months. DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio, 0.23 (95% confidence interval, 0.15-0.36)). In the osimertinib group, DFS or MRD events were detected in 28 (25%) patients; most events occurred following osimertinib cessation (19 of 28, 68%) and within 12 months of stopping osimertinib (11 of 19, 58%). At 24 months after osimertinib, the DFS and MRD event-free rate was 66%. In this study, MRD preceded DFS events in most patients across both arms. DFS and MRD event-free status was maintained for most patients during adjuvant osimertinib treatment and posttreatment follow-up, with most MRD or DFS events occurring after osimertinib treatment discontinuation or completion. MRD detection could potentially identify patients who may benefit from longer adjuvant osimertinib, although this requires clinical confirmation. ClinicalTrials.gov identifier: NCT02511106 .

QuANTUM-First (ClinicalTrials.gov identifier: NCT02668653) was a randomized phase III trial in patients with newly diagnosed FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) treated with quizartinib or placebo plus standard induction and consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (allo-HCT), followed by single-agent maintenance therapy. We evaluated the impact of allo-HCT performed in first complete remission (CR1) or composite CR1 (CRc1) on overall survival (OS), considering treatment randomization. Post-hoc extended Cox regression multivariable analyses were conducted in patients who achieved complete remission/composite complete remission by the end of induction, including allo-HCT in CR1/CRc1 as a time-dependent variable to identify prognostic and predictive factors for OS. There were 297 patients with complete remission by the end of induction (quizartinib, N=147; placebo, N=150); of these, 157 (52.9%) underwent allo-HCT in CR1 (quizartinib, N=84; placebo, N=73). There were 368 patients with composite complete remission by the end of induction (quizartinib, N=192; placebo, N=176); of these, 196 (53.3%) underwent allo-HCT in CRc1 (quizartinib, N=110; placebo, N=86). Multivariable analyses revealed quizartinib treatment and allo-HCT in either CR1 (hazard ratio [HR]=0.553, 95% confidence interval [95% CI]: 0.383-0.798, P=0.0015 and HR=0.527, 95% CI: 0.349-0.796, P=0.0023, respectively) or CRc1 (HR=0.645, 95% CI: 0.470‒0.886, P=0.0068 and HR=0.557, 95% CI: 0.391-0.793, P=0.0012, respectively) as significant predictive factors for a longer OS. No new safety signals were identified. Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-transplant-related complications, mostly grade ≥2 graft-versus-host disease, as expected. This post-hoc analysis further supports the use of quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITD-positive AML patients fit for intensive chemotherapy.

We assessed the benefit of adjuvant aspirin in patients with resected phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated colon cancer.

The COMMODORE study demonstrated the efficacy and safety of gilteritinib versus salvage chemotherapy (SC) treatment in a predominantly Asian population with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-mutated(mut+) acute myeloid leukemia (AML); here we present an exploratory analysis of the study stratified by region (China, South-East Asia and Russia). COMMODORE was a Phase 3, open-label, randomized (1:1), multicenter trial. There were 151, 50, and 33 patients in the China, South-East Asia, and Russia cohorts, respectively. Patients treated with gilteritinib had prolonged median overall survival (OS) versus SC-treated patients in all regions (China: 10.0 vs. 5.7 months, HR [95% CI]: 0.614 [0.385, 0.981]; South-East Asia: 7.8 vs. 4.7 months, HR [95% CI]: 0.887 [0.427, 1.843]; Russia: 8.8 vs. 2.6 months, HR [95% CI]: 0.271 [0.111, 0.662]). Improvements in event-free survival (EFS) were observed in the gilteritinib versus SC arms across all cohorts (China: 2.1 vs. 0.8 months; HR [95% CI]: 0.645 [0.427, 0.974]; South-East Asia 2.4 vs. < 0.1 months; HR [95% CI]: 0.415 [0.208, 0.830]; Russia: 6.2 vs. 0.6 months; HR [95% CI]: 0.221 [0.080, 0.614]). Complete remission rates were numerically higher in the gilteritinib versus SC arm across all three regions. Gilteritinib compared with SC treatment improved OS and EFS with no new safety signals, reinforcing the known efficacy and safety profile of gilteritinib in patients with R/R FLT3mut+ AML, and affirming the clinical benefit of gilteritinib in three different patient populations. ClinicalTrials.gov identifier: NCT03182244.

Early data from the DYNAMIC study of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy (ACT) versus standard approach met its primary outcome demonstrating reduced ACT use without compromising 2-year recurrence-free survival (RFS) for stage II colon cancer. We report here other prespecified analyses of overall survival, ctDNA clearance and ctDNA level. At a median follow-up of 59.7 months, 5-year RFS was 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval -5.8% to 8.0%), and 5-year overall survival is similar (93.8% versus 93.3%, hazard ratio (HR) 1.05; P = 0.887). For treated ctDNA-positive patients, ctDNA clearance was observed at the end of ACT (EOT) in 35 out of 40 patients (87.5%). A higher than median postoperative tumor-derived mutant molecules per milliliter plasma was associated with worse 5-year RFS (HR 10.62; P = 0.005). For treated ctDNA-positive patients, post hoc analysis of ctDNA clearance at EOT assessed by a new assay that evaluated an average of 29 tumor-derived mutations per patient predicted for a favorable 5-year recurrence-free probability of 97% versus 0% for ctDNA persistence (P < 0.001). Mature DYNAMIC outcome data support a ctDNA-guided approach to ACT for stage II colon cancer, with potential to further risk stratify ctDNA-positive patients based on ctDNA burden and EOT results. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615000381583 .

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein-Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

Best practices for improving access to assessment of hereditary cancer risk in primary care are lacking.

Historically, the treatment of patients with advanced stage or recurrent endometrial cancer included paclitaxel plus carboplatin. Immunotherapy in combination with chemotherapy resulted in improved clinical outcomes in several solid tumors. In the phase 3 NRG GY018 study, pembrolizumab plus chemotherapy significantly improved investigator-assessed progression-free survival (PFS; primary endpoint) versus placebo plus chemotherapy in patients with advanced/metastatic/recurrent endometrial cancer regardless of mismatch repair status. Here we report on key secondary endpoints and exploratory analyses. Patients were women ≥18 years old with newly diagnosed stage III or IVA endometrial cancer with measurable disease, or stage IVB or recurrent endometrial cancer with or without measurable disease. Patients (n = 810) were randomized (1:1) to pembrolizumab or placebo plus paclitaxel-carboplatin followed by maintenance pembrolizumab or placebo for up to 24 months. Overall survival was a secondary endpoint and PFS per RECIST v.1.1 by blinded independent central review was an exploratory endpoint. Overall survival data were immature; hazard ratios favored pembrolizumab (mismatch repair-proficient: 0.79 (0.53-1.17); 1-sided nominal P = 0.1157; mismatch repair-deficient: 0.55 (0.25-1.19); 1-sided nominal P = 0.0617). Hazard ratios (95% confidence intervals) for PFS per blinded independent central review favored pembrolizumab (mismatch repair-proficient: 0.64 (0.49-0.85); P = 0.0008; mismatch repair-deficient: 0.45 (0.27-0.73); P = 0.0005). These findings further support the use of pembrolizumab plus chemotherapy as first-line treatment for patients with advanced stage or recurrent endometrial cancer regardless of mismatch repair status. ClinicalTrials.gov identifier: NCT03914612 .

In March 2024, ponatinib received accelerated FDA approval for the treatment of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) in combination with chemotherapy based on the Phase 3 PhALLCON study (NCT03589326), which demonstrated a higher rate of minimal residual disease (MRD)-negative complete remission (CR) at the end of induction (EOI) with ponatinib (34.4%) versus imatinib (16.7%; p = 0.002). Patients received ponatinib (30 mg QD with reduction to 15 mg QD upon achievement of MRD-negative CR at EOI) or imatinib (600 mg QD) combined with 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; and maintenance: 11 cycles). Ponatinib pharmacokinetics (PK) were similar in patients in PhALLCON and patients in a previous population PK analysis. Bayesian re-estimation of the previously developed population PK model adequately described PhALLCON PK data. Exposure-efficacy analyses did not identify a significant relationship between ponatinib exposure and the probability of MRD-negative CR at EOI (p = 0.619), suggesting a consistent efficacy benefit across exposures. Ponatinib exposure was not a significant predictor of arterial occlusive events, venous thromboembolic events, thrombocytopenia, or lipase increase (p > 0.05). However, higher exposures were associated with a higher probability of hypertension (p = 0.0340) and alanine aminotransferase (ALT) increase (p = 0.0034). Dose reduction from 30 to 15 mg was predicted to decrease the odds of experiencing hypertension by 37.7% and ALT increase by 44.2%. Collectively, exposure-response analyses support a favorable benefit-risk profile of the approved ponatinib dosage (30 mg QD reduced to 15 mg QD upon achievement of MRD-negative CR at EOI), combined with chemotherapy, for frontline treatment of Ph + ALL.

ABC-lung explores the potential effect of combining atezolizumab and bevacizumab with either carboplatin/paclitaxel (ABCPac) or pemetrexed (ABPem) in patients with EGFR-mutant NSCLC, resistant to tyrosine kinase inhibitors (TKIs).

Several cancer types have increased PFKFB3, a glycolytic enzyme for which potent inhibitors have been found. Inhibition of PFKFB3 impairs DNA repair after irradiation of cancer cells, making it a possible radiosensitization target. The SweBCG91RT trial, in which breast cancer patients were randomized to postoperative radiotherapy or not, was used to investigate PFKFB3 as a clinical marker of sensitivity to adjuvant radiotherapy.

This study investigated the effect of myo-inositol on apoptosis-related genes expression in cumulus cells of polycystic ovary syndrome (PCOS) patients undergoing intracytoplasmic sperm injection (ICSI), and its relationship with the of quality oocyte and embryo. In the study of placebo-controlled clinical trial, sixty infertile women with PCOS undergoing ICSI were randomly assigned to two groups: 1) the placebo (PLA) group obtained a placebo involving 1 mg of folic acid twice a daily for 6 weeks. 2) The MYO group obtained 2000 mg Myo-inositol + 1 mg folic acid twice a daily for the same duration, beginning concurrently with the ICSI cycle. Real-time polymerase chain reaction (real-time PCR) was used to assess the expression of Survivin, Bcl-2, Caspase-3, Caspase-7, and TNF-α in cumulus cells. Although the levels of Survivin and Bcl-2 expression were significantly increased in the MYO group compared to the placebo, levels of Caspase-3, Caspase-7, and TNF-α expression were significantly lower. A strong correlation was found between the expression levels of these genes and embryos with good quality. These findings suggest that Myo-inositol administration in PCOS patients undergoing ICSI may improve of apoptosis-related genes expression (Survivin, Bcl-2, Caspase-3, Caspase-7, and TNF-α) in cumulus cells. Nevertheless, additional expected surveys are essential to verify these results and create their clinical applicability. (Registration details: Date: 2022.10.19, Registry: https://irct.behdasht.gov.ir/trial/66005 , and Trial registration: IRCT202220921056008N1).

The phase III NATALEE trial reported a statistically significant invasive disease-free survival benefit with ribociclib plus nonsteroidal aromatase inhibitor (NSAI) versus an NSAI alone in stage II/III hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer. In this study, we report health-related quality of life (HRQOL) data from NATALEE.

Patients with TP53-mutated acute myeloid leukemia (AML) have an extremely poor prognosis, necessitating new treatments. The global, randomized, phase 3 ENHANCE-2 trial evaluated the anti-CD47 monoclonal antibody magrolimab plus azacitidine (Magro/Aza) for previously untreated TP53-mutated AML. Patients determined ineligible for intensive therapy were randomized to receive Magro/Aza or venetoclax plus Aza (Ven/Aza); those eligible for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. The primary end point was overall survival (OS) in the nonintensive arm. At interim analysis, nonintensive-arm OS hazard ratio (HR) between treatment groups was 1.191 (95% confidence interval [CI], 0.744-1.906), meeting the study's definition for futility and resulting in study termination. At final analysis, median OS was 4.4 vs 6.6 months (HR, 1.132; 95% CI, 0.783-1.637; P = .5070) in the nonintensive arm (n = 205) and 7.3 vs 11.1 months (HR, 1.434; 95% CI, 0.635-3.239; P = .3798) in the intensive arm (n = 52) between Magro/Aza and control groups, respectively. Incidences of grade ≥3 adverse events were similar across Magro/Aza and control groups (nonintensive, n = 194: 96.9% and 95.9%; intensive, n = 50: 92.6% and 95.7%), including grade ≥3 anemia (nonintensive: 27.1% and 23.5%; intensive: 25.9% and 21.7%). Grade ≥3 infections were observed in 50.0% and 53.1% of patients in the nonintensive arm and 44.4% and 65.2% of intensive-arm patients. ENHANCE-2 did not meet its primary end point of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397.

Venetoclax (VEN) combined with hypomethylating agents is approved for frontline therapy in older/unfit patients with acute myeloid leukemia (AML). However, prospective data on this low-intensity therapy in treatment-naive younger patients with AML are lacking. This study investigated the efficacy and safety of VEN plus decitabine (VEN-DEC) as induction in untreated young fit patients with AML in a randomized trial. Patients aged 18 to 59 years eligible for intensive chemotherapy were randomized 1:1 to receive VEN-DEC or IA-12 (idarubicin and cytarabine). All patients achieved composite complete remission (CRc) underwent high-dose cytarabine consolidation. The primary end point was CRc rate after induction. Of 255 screened, 188 were enrolled and randomly assigned, with 94 in each group. In the intention-to-treat population, CRc was 89% (84/94) in the VEN-DEC group vs 79% (74/94) in the IA-12 group (noninferiority P = .0021), with measurable residual disease negativity rates of 80% (67/84) vs 76% (56/74), respectively. VEN-DEC showed superior CRc in patients aged ≥40 years (91% vs 75%) and those with adverse risk (91% vs 42%) or epigenetic mutations (91% vs 67%), but lower CRc in RUNX1::RUNX1T1 fusion cases (44% vs 88%) than IA-12. Patients in the VEN-DEC group experienced fewer grade ≥3 infections (32% vs 67%) and shorter severe thrombocytopenia duration (median, 13 vs 19 days; P < .001). At a median follow-up of 12.1 months, overall and progression-free survival were similar between groups. In conclusion, VEN-DEC demonstrated noninferior response rates with superior safety over IA-12 in young patients with AML. The trial was registered at www.clinicaltrials.gov as #NCT05177731.

Fixed-duration venetoclax-rituximab (VenR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in the phase 3 MURANO trial resulted in superior progression-free survival (PFS) and overall survival (OS) vs bendamustine-rituximab (BR). We report the final analyses of MURANO (median follow-up, 7 years). Patients were randomized to VenR (venetoclax 400 mg daily for 2 years plus monthly rituximab for 6 months; n = 194) or BR (6 months; n = 195). In a substudy, patients with progressive disease (PD) received VenR as retreatment or crossover from BR. At the final data cut (3 August 2022), the median PFS with VenR was 54.7 months vs 17.0 months with BR. The 7-year PFS with VenR was 23.0%. The 7-year OS was 69.6% and 51.0%, respectively. Among VenR-treated patients with undetectable minimal residual disease (MRD; uMRD) and no PD at end of treatment (EOT; n = 83), the median PFS from EOT was 52.5 vs 18.0 months in patients with MRD at EOT (n = 35; P < .0001). Fourteen patients had enduring uMRD. Three distinct mutations in BCL2 in 4 patients were identified. In the substudy, 25 patients were retreated with VenR, and 9 patients crossed over to VenR; the median PFS was 23 and 27 months, and the best overall response rate was 72% and 89%, respectively. At the end of combination treatment (EOCT), after retreatment or crossover, 8 and 6 patients achieved uMRD, respectively. No new safety findings were observed. Overall, these final MURANO analyses support consideration of fixed-duration VenR therapy for patients with relapsed/refractory CLL. This trial was registered at www.clinicaltrials.gov as #NCT02005471.