Redefining Clinical Trial Strategic Design to Support Drug Approval in Medical Oncology.

Randomized clinical trials represent the gold standard for the introduction of innovative therapies in medical oncology, and they provide the highest level of evidence to ascertain the clinical activity of new drugs or novel combinations. However, the current infrastructure of clinical trials supporting innovative drug approvals is challenged by an increased body of knowledge concerning tumor biology and therapy resistance, a fast-growing armamentarium of novel anti-cancer compounds, an impressively upscaled data analysis capacity, as well as increasing costs related to clinical trials' management. In this scenario, modern clinical trial designs need to evolve to expedite new drug approvals by tailoring patients' treatment strategies according to their medical needs.

Results of a patient-level pooled analysis of three studies of trastuzumab deruxtecan in HER2-positive breast cancer with active brain metastasis.

Background: Brain metastases (BMs) are common in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, increasing morbidity and mortality. Systemic therapy for BMs can be effective, with the triple combination of trastuzumab, capecitabine, and tucatinib being a potential standard. More recently, intracranial activity of antibody-drug conjugates has been reported, but the size of individual studies has been small.

Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of progesterone and estrogen receptors and low (or absent) HER2 expression. TNBC accounts for 15-20% of all breast cancers. It is associated with younger age, a higher mutational burden, and an increased risk of recurrence and mortality.

Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in patients with HER2-positive early breast cancer (EBC).

Background: In human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), we investigated tumor and immune changes during neoadjuvant treatment and their impact on residual disease (RD) biology and prognostic implications across four neoadjuvant studies of trastuzumab with or without lapatinib, and with or without chemotherapy: CALGB 40601, PAMELA, NeoALTTO, and NSABP B-41.

Patients And Methods: We compared tumor and immune gene expression changes during neoadjuvant treatment and their association with event-free survival (EFS) by uni- and multivariable Cox regression models in different cohorts and timepoints: 452 RD samples at baseline including 169 with a paired RD, and biomarker changes during neoadjuvant therapy, evaluating model performance via the c-index.

Results: Analysis of 169 paired tumor samples revealed a shift in intrinsic subtype proportions from HER2-enriched at baseline (50.

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer.

Background: Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα ().

Methods: In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib.

Neoadjuvant letrozole and palbociclib in patients with HR-positive/HER2-negative early breast cancer and Oncotype DX Recurrence Score ≥18: DxCARTES study.

Background: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18.

Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial.

Background: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet.

Methods: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC.

Sacituzumab govitecan for hormone receptor-positive HER2-negative advanced breast cancer.

Introduction: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody-drug conjugates (ADCs) has provided new treatment alternatives in this context.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study.

Purpose: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm).

Methods: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled.

HER2DX Genomic Assay in HER2-Positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from the PHERGain Phase II Trial.

Purpose: The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer.

Experimental Design: HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy).

Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer.

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study.

A Low Number of Baselines γδ T Cells Increases the Risk of SARS-CoV-2 Post-Vaccination Infection.

The COVID-19 pandemic is the biggest global health problem in the last hundred years. The efficacy of the vaccine to protect against severe disease is estimated to be 70-95% according to the studies carried out, although there are aspects of the immune response to the vaccine that remain unclear. Humoral and cellular immunity after the administration of three doses of the Pfizer-BioNTech and Oxford AstraZeneca vaccines against SARS-CoV-2 over one year and the appearance of post-vaccination COVID-19 were studied.

Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.

Background: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3.

Anti-Anisakis antibodies in colon cancer patients and their relationship with γδ T-cells.

Many pathogens are related to carcinogenesis. Chronic inflammation, as a result of persistent infection, leads to DNA damage, higher expression of oncogenes, decreased apoptosis and immunosuppression, which are some of the reasons for cancer induction. Among parasites, Schistosoma, Opistorchis and Clonorchis are recognised as infectious agents which contribute to cancer.

Preventing alpelisib-related hyperglycaemia in HR+/HER2-/-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/-mutated advanced breast cancer (ABC).

Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.

Clinicopathological and molecular predictors of [F]FDG-PET disease detection in HER2-positive early breast cancer: RESPONSE, a substudy of the randomized PHERGain trial.

Background: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [Fluorine]fluorodeoxyglucose-positron emission tomography ([F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [F]FDG-PET disease detection were evaluated.

Methods: A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.

3-year invasive disease-free survival with chemotherapy de-escalation using an F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.

Background: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy.

Methods: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries.

Optimal [F]FDG PET/CT Cutoff for Pathologic Complete Response in HER2-Positive Early Breast Cancer Patients Treated with Neoadjuvant Trastuzumab and Pertuzumab in the PHERGain Trial.

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [F]FDG PET/CT. [F]FDG PET/CT responders were defined as patients with an SUV reduction (ΔSUV) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy).

Correlation between trophoblast cell-surface antigen-2 (Trop-2) expression and pathological complete response in patients with HER2-positive early breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab.

Purpose: The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study.

Methods: Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors.

Landscape of Baseline and Acquired Genomic Alterations in Circulating Tumor DNA with Abemaciclib Alone or with Endocrine Therapy in Advanced Breast Cancer.

Purpose: To identify potential predictors of response and resistance mechanisms in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) treated with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib ± endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes.

Experimental Design: MONARCH 3: postmenopausal women with HR+, HER2- ABC and no prior systemic therapy in the advanced setting were randomly assigned to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2- metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomly assigned to abemaciclib alone (two doses) or plus tamoxifen.