ABSTRACT
De-escalation trials in oncology evaluate therapies that aim to improve the quality of life of patients with low-risk cancer by avoiding overtreatment. Non-inferiority randomized trials are commonly used to investigate de-intensified regimens with similar efficacy to that of standard regimens but with fewer adverse effects (ESMO evidence tier A). In cases where it is not feasible to recruit the number of patients needed for a randomized trial, single-arm prospective studies with a hypothesis of non-inferiority can be conducted as an alternative. Single-arm studies are also commonly used to evaluate novel treatment strategies (ESMO evidence tier B). A single-arm design that includes both non-inferiority and superiority primary objectives will enable the ranking of clinical activity and other parameters such as safety, pharmacokinetics, and pharmacodynamics data. Here, we describe the statistical principles and procedures to support such a strategy. The non-inferiority margin is calculated using the fixed margin method. Sample size and statistical analyses are based on the maximum likelihood method for exponential distributions. We present example analyses in metastatic and adjuvant settings to illustrate the usefulness of our methodology. We also explain its implementation with nonparametric methods. Single-arm designs with non-inferiority and superiority analyses are optimal for proof-of-concept and de-escalation studies in oncology.
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BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3. RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Quality of Life , Receptor, ErbB-2 , Antibodies, Monoclonal, Humanized/therapeutic use , Trastuzumab/therapeutic use , Camptothecin/adverse effects , Central Nervous System/pathologyABSTRACT
PURPOSE: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC). PATIENTS AND METHODS: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. RESULTS: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018). CONCLUSIONS: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Piperazines/therapeutic useABSTRACT
BACKGROUND: Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. MATERIALS AND METHODS: Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (nâ =â 486) were randomly assigned 1:1 to receive fulvestrant-palbociclib (FP) or letrozole-palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. RESULTS: A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (Pâ <â .01). CONCLUSION: The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy. CLINICALTRIALS.GOV IDENTIFIER: NCT02491983; https://clinicaltrials.gov/ct2/show/NCT02491983).
Subject(s)
Breast Neoplasms , Pulmonary Embolism , Venous Thromboembolism , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fulvestrant/therapeutic use , Letrozole/therapeutic use , Pulmonary Embolism/etiology , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Venous Thromboembolism/etiologyABSTRACT
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about the PHERGain study, which was published in The Lancet Oncology in May 2021. The study includes 376 women with a type of breast cancer called HER2-positive breast cancer that can be removed by surgery. In the study, researchers wanted to learn if participants could be treated with two medicines called trastuzumab and pertuzumab without the need for chemotherapy. To identify HER2-positive tumors with more sensitivity to anti-HER2 therapies, the researchers used a type of imaging called a FDG-PET scan to check how well the treatments were working. WHAT HAPPENED IN THE PHERGAIN STUDY?: Participants took a treatment before surgery, consisting of either chemotherapy (docetaxel and carboplatin) plus trastuzumab and pertuzumab (group A) or trastuzumab and pertuzumab alone (plus hormone therapy if the tumor was hormone receptor-positive; group B). After two cycles of treatment, participants underwent a FDG-PET scan. Participants assigned to group A completed 6 cycles of treatment regardless of 18F-FDG-PET results. Participants in group B continued the same treatment until surgery if their FDG-PET scan showed the treatment was working. While participants who did not show a response started treatment with chemotherapy in addition to trastuzumab and pertuzumab. All participants then had surgery. WHAT WERE THE RESULTS?: The results revealed that, of the participants in group B who showed a response using FDG-PET scan, 37.9% achieved a disappearance of all invasive cancer in the breast and axillary lymph nodes. This rate appears to be higher than those reported in previous studies evaluating the same treatment. These participants also had less side effects and improved overall quality of life compared with participants taking chemotherapy plus trastuzumab and pertuzumab. WHAT DO THE RESULTS OF THE STUDY MEAN?: Early monitoring of how well participants respond to treatment by FDG-PET scan seems to identify participants with operable HER2-positive breast cancer who were more likely to benefit from trastuzumab and pertuzumab without the need to have chemotherapy. The PHERGain study is still ongoing and results on long-term survival are expected to be released in 2023. Clinical Trial Registration: NCT03161353 (ClinicalTrials.gov).
Subject(s)
Breast Neoplasms , Humans , Female , Trastuzumab/adverse effects , Trastuzumab/administration & dosage , Breast Neoplasms/pathology , Fluorodeoxyglucose F18/therapeutic use , Quality of Life , Receptor, ErbB-2 , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoadjuvant TherapyABSTRACT
OBJECTIVES: Severe COVID-19 is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated interleukin 6. Pembrolizumab (P; immune-activating anti-programmed cell death-1 antibody) plus tocilizumab (TCZ; anti- interleukin 6 receptor antibody) might interrupt the hyperinflammation and restore cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care (SOC) in high-risk, hospitalized patients with COVID-19 pneumonia without mechanical ventilation. METHODS: Randomized, controlled, open-label, phase II trial in patients with severe SARS-CoV-2 infection to assess the hospitalization period to discharge. RESULTS: A total of 12 patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41-79) years. The median time to discharge for P + TCZ + SOC and SOC was 10 and 47.5 days (P = 0.03), with zero (n = 1 patient had P-related grade 5 myositis) and two COVID-19-related deaths, respectively. CONCLUSION: The addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone.
Subject(s)
COVID-19 Drug Treatment , Aged , Antibodies, Monoclonal, Humanized , Female , Humans , Interleukin-6 , Male , Proof of Concept Study , Receptors, Interleukin-6 , SARS-CoV-2 , Treatment OutcomeABSTRACT
PURPOSE: The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. PATIENTS AND METHODS: EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. RESULTS: Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). CONCLUSIONS: 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.
Subject(s)
Bone Neoplasms , Prostatic Neoplasms, Castration-Resistant , Abiraterone Acetate/therapeutic use , Androgen Antagonists/therapeutic use , Benzamides , Bone Neoplasms/secondary , Humans , Male , Nitriles/therapeutic use , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant/pathology , Radium , Receptors, AndrogenABSTRACT
Drug approval for early-stage breast cancer (EBC) has been historically granted in the context of registration trials based on adequate outcomes such as disease-free survival and overall survival. Improvements in long-term outcomes have made it more difficult to demonstrate the clinical benefit of a new cancer drug in large, randomized, comparative clinical trials. Therefore, the use of surrogate endpoints rather than traditional measures allows for cancer drug trials to proceed with smaller sample sizes and shorter follow-up periods, which reduces drug development time. Among surrogate endpoints for breast cancer, the increase in pathological complete response (pCR) rates was considered appropriate for accelerated drug approval. The association between pCR and long-term outcomes was strongest in patients with aggressive tumor subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor-negative breast cancers. Whereas in hormone receptor-positive/HER2-negative EBC, the most accepted surrogate markers for endocrine therapy-based trials include changes in Ki67 and the preoperative endocrine prognostic index. Beyond the classic endpoints, further prognostic tools are required to provide EBC patients with individualized and effective therapies, and the neoadjuvant setting provides an excellent platform for drug development and biomarker discovery. Nowadays, the availability of multigene signatures is offering a standardized quantitative and reproducible tool to potentiate the efficacy of standard treatment for high-risk patients and develop de-escalated treatments for patients at lower risk of relapse. In this article, we first evaluate the surrogacies used for long-term outcomes and the underlying evidence supporting the use of each surrogate endpoint for the accelerated or regular drug approval process in EBC. Next, we provide an overview of the most recent studies and innovative strategies in a (neo)adjuvant setting as a platform to accelerate new drug approval. Finally, we highlight some clinical trials aimed at tailoring systemic treatment of EBC using prognosis-related factors or early biomarkers of drug sensitivity or resistance.
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AIM OF THE STUDY: The AZENT (NCT02841579) study aimed to assess the efficacy and safety of first-line osimertinib in patients with epidermal growth factor receptor(EGFR)mutation-positive advanced non-small-cell lung cancer (NSCLC) and with a coexisting low allelic fraction of Thr790Met. METHODS: In this multicentre, single-arm, open-label, phase IIa study, patients with locally advanced or metastatic NSCLC harbouring centrally confirmedEGFR Thr790Met mutation received 80 mg osimertinib daily. The primary end-point was objective response rate (ORR). The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Efficacy was assessed as per Response Evaluation Criteria in Solid Tumours, version 1.1. Blood samples collected at baseline, end of week 2 and disease progression were analysed using next-generation sequencing. As osimertinib was approved as a first-line therapy during the trial, this led to early termination of phase II; thus, analysis is considered exploratory. RESULTS: Twenty-two patients were enrolled and received osimertinib. All 22 patients were included in the efficacy and safety analysis. At the data cutoff, 10 (50%) patients remained on treatment. The median duration of follow-up was 24.4 months (interquartile range 12.9 to 26.0). The ORR was 77.3% (17/22 [95% confidence interval {CI} 54.6 to 89.3]). The DCR was 86.4% (19/22, [95% CI 65.1 to 97.1]). The median PFS was 23.1 months (95% CI 14.1 to NE). The median OS was 28·4 months (95% CI 25.6 to NE). CONCLUSION: Despite early study termination, osimertinib first-line therapy yields an overall PFS of 23.1 months in EGFR-mutant patients harbouring a coexisting low allelic fraction of EGFR Thr790Met mutation.
Subject(s)
Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Aged , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Progression-Free Survival , Treatment OutcomeABSTRACT
Importance: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. Objective: To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. Design, Setting, and Participants: In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. Interventions: Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). Main Outcomes and Measures: The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. Results: A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. Conclusions and Relevance: Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02491983.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Female , Fulvestrant , Humans , Letrozole/therapeutic use , Middle Aged , Piperazines , Pyridines , Receptor, ErbB-2ABSTRACT
Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases.
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(1) Background: The transforming growth factor (TGF)-ß plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-ß expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-ß induced suppressor effects, responding to this cytokine undergoing epithelial-mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-ß in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-ß when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-ß in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Epithelial-Mesenchymal Transition/drug effects , Lipid Metabolism/drug effects , Liver Neoplasms/metabolism , Metabolome/drug effects , Transcriptome/drug effects , Transforming Growth Factor beta/pharmacology , Cell Movement/drug effects , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Gene Silencing , Hep G2 Cells , Humans , Metabolome/genetics , Metabolomics , Mitochondria/drug effects , Mitochondria/metabolism , Oxidative Phosphorylation/drug effects , Receptors, Transforming Growth Factor beta/genetics , Receptors, Transforming Growth Factor beta/metabolism , Transcriptome/geneticsABSTRACT
BACKGROUND: Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using 18F-fluorodeoxyglucose (18F-FDG)-PET (18F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy. METHODS: We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I-IIIA, invasive, operable breast cancer (≥1·5 cm tumour size) with at least one breast lesion evaluable by 18F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m2 intravenous), carboplatin (area under the concentration-time curve 6 mg/mL per min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed 18F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of 18F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. 18F-FDG-PET responders in group B continued this treatment for six further cycles; 18F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of 18F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov (NCT03161353), and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3-6·0). 227 (80%) of 285 patients in group B were 18F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6-44·5; p<0·0001 compared with the historical rate) of 227 had a pathological complete response. The most common haematological grade 3-4 adverse events were anaemia (six [9%] of 68 patients in group A vs four [1%] of 283 patients in group B), neutropenia (16 [24%] vs ten [4%]), and febrile neutropenia (14 [21%] vs 11 [4%]). Serious adverse events occurred in 20 (29%) of 68 patients in group A versus 13 (5%) of 283 patients in group B. No deaths were reported during neoadjuvant treatment. Global health status declined by at least 10% in 65·0% (95% CI 46·5-72·4) and 35·5% (29·7-41·7) of patients in groups A and B, respectively INTERPRETATION: 18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy. FUNDING: F Hoffmann-La Roche.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Carboplatin/administration & dosage , Docetaxel/administration & dosage , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Disease-Free Survival , Female , Fluorodeoxyglucose F18/administration & dosage , Humans , Middle Aged , Neoplasm Staging , Postmenopause , Premenopause , Receptor, ErbB-2/genetics , Tamoxifen/administration & dosage , Trastuzumab/administration & dosageABSTRACT
BACKGROUND: Pembrolizumab has modest activity if used in patients with hormone-receptor-positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. METHODS: This single-arm, phase â ¡ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1-2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1â23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. RESULTS: Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56â8%, 95% confidence interval [CI]: 41â0-71â7), objective response in 18 (40â9%, 95% CI: 26â3-56â8), median progression-free survival was 6â0 months (95% CI: 3â7-8â4), and 1-year overall survival was 59â1% (95% CI: 45â8-76â2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45â5%]), anaemia (17 [38â6%]), alopecia (19 [43â2%]), asthenia (19 [43â2%]), diarrhoea (14 [31â8%]), fatigue (14 [31â8%]), and peripheral neuropathy (12 [27â3%]). Serious AEs occurred in 14 (31â8%) patients including febrile neutropenia (3 [6â8%]), neutropenia (2 [4â5%]), fever (2 [4â5%]) and peripheral neuropathy (2 [4â5%]). Immune-related AEs occurred in 11 (25â0%) patients. One (2â3%) patient died of cardiac arrest unrelated to study treatment. CONCLUSION: Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Follow-Up Studies , Furans/administration & dosage , Humans , Ketones/administration & dosage , Middle Aged , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Survival RateABSTRACT
PURPOSE: Treatment guidelines for advanced non-small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC. PATIENTS AND METHODS: Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers (EGFR and ALK) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA. RESULTS: The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue (P < .05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported. CONCLUSION: This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed.
Subject(s)
Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/blood , Lung Neoplasms/blood , Lung Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Biopsy/methods , Carcinoma, Non-Small-Cell Lung/diagnosis , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Lung Neoplasms/diagnosis , Male , Middle Aged , Progression-Free Survival , Prospective Studies , Standard of Care , Treatment OutcomeABSTRACT
The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m2) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m2 of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m2 administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.
ABSTRACT
INTRODUCTION: Non-inferiority (NI) analysis is not usually considered in the early phases of clinical development. In some negative phase II trials, a post-hoc NI analysis justified additional phase III trials that were successful. However, the risk of false positive achievements was not controlled in these early phase analyses. We propose to preplan NI analyses in superiority-based Simon's two-stage designs to control type I and II error rates. METHODS: Simulations have been proposed to assess the control of type I and II errors rates with this method. A total of 12,768 two-stage Simon's design trials were constructed based on different assumptions of rejection response probability, desired response probability, type I and II errors, and NI margins. P-value and type II error were calculated with stochastic ordering using Uniformly Minimum Variance Unbiased Estimator. Type I and II errors were simulated using the Monte Carlo method. The agreement between calculated and simulated values was analyzed with Bland-Altman plots. RESULTS: We observed the same level of agreement between calculated and simulated type I and II errors from both two-stage Simon's superiority designs and designs in which NI analysis was allowed. Different examples has been proposed to explain the utility of this method. CONCLUSION: Inclusion of NI analysis in superiority-based single-arm clinical trials may be useful for weighing additional factors such as safety, pharmacokinetics, pharmacodynamic, and biomarker data while assessing early efficacy. Implementation of this strategy can be achieved through simple adaptations to existing designs for one-arm phase II clinical trials.
ABSTRACT
OBJECTIVE: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC). METHODS: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3. RESULTS: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events. CONCLUSIONS: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.
Subject(s)
Biomarkers, Tumor/analysis , Endometrial Neoplasms/therapy , Neoadjuvant Therapy/methods , Phthalazines/administration & dosage , Piperazines/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant/methods , Cyclin D1/analysis , Cyclin D1/genetics , DNA-Binding Proteins/genetics , Dose-Response Relationship, Drug , Endometrial Neoplasms/blood , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/genetics , Endometrium/drug effects , Endometrium/pathology , Endometrium/surgery , Female , Gene Expression Regulation, Neoplastic/drug effects , Glucose Transporter Type 1/antagonists & inhibitors , Glucose Transporter Type 1/blood , Humans , Hysterectomy , Immunohistochemistry , Middle Aged , Neoplasm Staging , Phthalazines/adverse effects , Piperazines/adverse effects , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Prospective Studies , Tablets , Time Factors , Transcription Factors/genetics , Treatment OutcomeABSTRACT
BACKGROUND: Case reports are usually excluded from systematic reviews. Patients with rare diseases are more dependent on novel individualized strategies than patients with common diseases. We reviewed and summarized the novelties reported by case reports in mucopolysaccharidosis type II (MPS-II) patients treated with enzyme replacement therapy (ERT). METHODS: We selected the case reports included in a previous meta-analysis of patients with MPS-II treated with ERT. Later clinical studies evaluating the same topic of those case reports were reported. Our primary aim was to summarize novelties reported in previous case reports. Secondary objectives analyzed the number of novelties evaluated in subsequent clinical studies and the time elapsed between the publication of the case report to the publication of the clinical study. RESULTS: We identified 11 innovative proposals in case reports that had not been previously considered in clinical studies. Only two (18.2%) were analyzed in subsequent nonrandomized cohort studies. The other nine novelties (81.8%) were analyzed in later case reports (five) or were not included in ulterior studies (four) after more than five years from their first publication. CONCLUSIONS: Case reports should be included in systematic reviews of rare disease to obtain a comprehensive summary of the state of research and offer valuable information for healthcare practitioners.