Study of Talimogene Laherparepvec With Atezolizumab for Triple Negative Breast Cancer and Colorectal Cancer With Liver Metastases
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Neoplasm Metastasis,Triple Negative Breast Neoplasms,Colorectal Neoplasms,Metastatic Triple Negative Breast Cancer,Breast Neoplasms
PROVIDER: 2252302 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:We report RNAseq data from tumors obtained from patients with triple negative breast cancer Eight patients with II-III stageTNBC diagnosis (only one patient with IV oligometastatic stage) were included in the study. All patients received neoadjuvant chemotherapy based on sequential anthracyclines and taxanes ± platinum salts plus radiation therapy. Seven patients were evaluable for response and pathological complete response (RCB=0) was reached in 71.4% of the patients (2 patients with RCB=2). No patients received adjuvant systemic therapy.Tumor biopsies were obtained for RNAseq studies.
2022-10-20 | GSE206998 | GEO
Project description:BackgroundUnderstanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer.MethodsPatients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations.ResultsPD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.ConclusionsAlthough A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.
| S-EPMC8328980 | biostudies-literature
Project description:BackgroundIn the phase III IMpassion130 study, atezolizumab plus nab-paclitaxel (A+nP) showed clinical benefit in advanced or metastatic triple-negative breast cancer patients who were programmed death-ligand 1 (PD-L1)+ (tumor-infiltrating immune cells [IC] ≥1%) using the SP142 immunohistochemistry assay. Here we evaluate 2 other PD-L1 assays for analytical concordance with SP142 and patient-associated clinical outcomes.MethodsSamples from 614 patients (68.1% of intention-to-treat population) were centrally evaluated by immunohistochemistry for PD-L1 status on IC (VENTANA SP142, SP263, Dako 22C3) or as a combined positive score (CPS; 22C3).ResultsUsing SP142, SP263, and 22C3 assays, PD-L1 IC ≥1% prevalence was 46.4% (95% confidence interval [CI] = 42.5% to 50.4%), 74.9% (95% CI = 71.5% to 78.3%), and 73.1% (95% CI = 69.6% to 76.6%), respectively; 80.9% were 22C3 CPS ≥1. At IC ≥1% (+), the analytical concordance between SP142 and SP263 and 22C3 was 69.2% and 68.7%, respectively. Almost all SP142+ cases were captured by other assays (double positive), but several SP263+ (29.6%) or 22C3+ (29.0%) cases were SP142- (single positive). A+nP clinical activity vs placebo+nP in SP263+ and 22C3+ patients (progression-free survival [PFS] hazard ratios [HRs] = 0.64 to 0.68; overall survival [OS] HRs = 0.75 to 0.79) was driven by double-positive cases (PFS HRs = 0.60 to 0.61; OS HRs = 0.71 to 0.75) rather than single-positive cases (PFS HRs = 0.68 to 0.81; OS HRs = 0.87 to 0.95). Concordance for harmonized cutoffs for SP263 (IC ≥4%) and 22C3 (CPS ≥10) to SP142 (IC ≥1%) was subpar (approximately 75%).Conclusions22C3 and SP263 assays identified more patients as PD-L1+ (IC ≥1%) than SP142. No inter-assay analytical equivalency was observed. Consistent improved A+nP efficacy was captured by the SP142 PD-L1 IC ≥1% subgroup nested within 22C3 and SP263 PD-L1+ (IC ≥1%) populations.
| S-EPMC8634452 | biostudies-literature
Project description:Purpose: The IMpassion130 trial demonstrated the efficacy of adding atezolizumab to paclitaxel for advanced or metastatic triple-negative breast cancer (TNBC). The current study evaluated the cost-effectiveness of adding atezolizumab to nab-paclitaxel for TNBC from the perspective of Chinese health sector. Methods: A partitioned survival model was implemented for patients with TNBC. The survival data were derived from IMpassion130 trial. Direct costs and utility values were collected from the Chinese Drug Bidding Database and published literatures. The primary analysis outcomes were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to observe model stability. Results: In the base-case analysis, the ICER of atezolizumab plus nab-paclitaxel vs. nab-paclitaxel is respectively, $176,056/QALY, $118,146/QALY, and $323,077/QALY in the ITT, PD-L1(+) and PD-L1(-) group. Conclusion: Adding atezolizumab to nab-paclitaxel could improve survival time significantly in the PD-L1-positive group, but it is not a cost-effective strategy compared to nab-paclitaxel monotherapy for Chinese patients with advanced or metastatic triple-negative breast cancer in the current economic context of China.
| S-EPMC8585931 | biostudies-literature
Project description:BackgroundThe effectiveness of atezolizumab plus nab-paclitaxel for advanced triple-negative breast cancer (TNBC) has been demonstrated. We aimed to evaluate its cost-effectiveness on advanced TNBC from the US payer perspective.MethodsA Markov model was adopted to project the disease course of newly diagnosed advanced TNBC. The clinical data were gathered from the IMpassion130 trial. Cost and health preference data were derived from the literature. The incremental cost-effectiveness ratio (ICER) was measured, and one-way sensitivity analysis and probabilistic sensitivity analysis were performed for exploring the model uncertainties.ResultsOur results demonstrated that atezolizumab plus nab-paclitaxel augmented versus nab-paclitaxel therapy cost $104,278 and $149,465 and yielded an additional 0.371 and 0.762 of quality-adjusted life year (QALY) in in all patients with unknown PD-L1 status and subpopulation with PD-L1-positive, respectively, which led to an ICER of $281,448 and $196,073 per QALY gained. In all patients with unknown PD-L1 status, atezolizumab plus nab-paclitaxel treatment guiding by PD-L1 expression testing resulted in an ICER of $183,508 per QALY gained. Atezolizumab plus nab-paclitaxel could maintain a trend of positive incremental net health benefits and >50% probabilities of cost-effectiveness at the threshold of $200,000/QALY in more than half of subgroups with PD-L1-positive. One-way and probabilistic sensitivity analyses revealed the results were most sensitive to the hazard ratios (HRs) of overall survival (OS) of atezolizumab plus nab-paclitaxel versus nab-paclitaxel treatment.ConclusionThe atezolizumab plus nab-paclitaxel treatment is likely to be a cost-effective option compared with chemotherapy based on nab-paclitaxel for the patients with PD-L1-positive advanced TNBC.
| S-EPMC7222249 | biostudies-literature
Project description:Immune checkpoint blockade therapy has clearly shown clinical activity in patients with triple-negative breast cancer, but less than half of the patients benefit from the treatments. While a number of ongoing clinical trials are investigating different combinations of checkpoint inhibitors and chemotherapeutic agents, predictive biomarkers that identify patients most likely to benefit remains one of the major challenges. Here we present a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that incorporates detailed mechanisms of immune-cancer cell interactions to make efficacy predictions and identify predictive biomarkers for treatments using atezolizumab and nab-paclitaxel. A QSP model was developed based on published data of triple-negative breast cancer. With the model, we generated a virtual patient cohort to conduct in silico virtual clinical trials and make retrospective analyses of the pivotal IMpassion130 trial that led to the accelerated approval of atezolizumab and nab-paclitaxel for patients with programmed death-ligand 1 (PD-L1) positive triple-negative breast cancer. Available data from clinical trials were used for model calibration and validation. With the calibrated virtual patient cohort based on clinical data from the placebo comparator arm of the IMpassion130 trial, we made efficacy predictions and identified potential predictive biomarkers for the experimental arm of the trial using the proposed QSP model. The model predictions are consistent with clinically reported efficacy endpoints and correlated immune biomarkers. We further performed a series of virtual clinical trials to compare different doses and schedules of the two drugs for simulated therapeutic optimization. This study provides a QSP platform, which can be used to generate virtual patient cohorts and conduct virtual clinical trials. Our findings demonstrate its potential for making efficacy predictions for immunotherapies and chemotherapies, identifying predictive biomarkers, and guiding future clinical trial designs.
| S-EPMC7883871 | biostudies-literature
Project description:PurposeTo evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC).Patients and methodsThe single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance.ResultsAmong 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels.ConclusionsIn patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.
| S-EPMC10870115 | biostudies-literature
Project description:BACKGROUND:In the randomised Phase 3 IMpassion130 trial, atezolizumab combined with nab-paclitaxel (atezo + nab-P) in 902 patients with triple-negative breast cancer (TNBC) showed prolonged progression-free survival (PFS) in both the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-positive subgroup compared with placebo plus nab-P (plac + nab-P). This study assessed the efficacy and safety of atezo + nab-P in the IMpassion130 Japanese subpopulation. METHODS:Eligible patients had unresectable locally advanced or metastatic TNBC previously untreated with chemotherapy for metastatic disease. Patients were randomised 1:1 to receive either atezo + nab-P or plac + nab-P. Co-primary endpoints were investigator-assessed PFS and overall survival (ITT population and PD-L1-positive subgroup). These were also assessed in the Japanese subpopulation. RESULTS:There were 65 Japanese patients (34 atezo + nab-P; 31 plac + nab-P). The PD-L1-positive subgroup included 25 patients (12 atezo + nab-P; 13 plac + nab-P). Median PFS was 7.4 months (atezo + nab-P) versus 4.6 months (plac + nab-P; hazard ratio [HR], 0.47; 95% CI, 0.25-0.90). In the PD-L1-positive subgroup, median PFS was 10.8 months (atezo + nab-P) versus 3.8 months (plac + nab-P; HR, 0.04; 95% CI, <0.01-0.35). Safety results in the Japanese subgroup were consistent with those in the overall population. The Japanese subgroup had a lower incidence of adverse events leading to treatment withdrawal than the overall population. More patients in the atezo + nab-P arm had neutrophil count decreases and stomatitis than patients in the plac + nab-P arm. CONCLUSIONS:Atezo + nab-P efficacy in Japanese patients was consistent with the overall IMpassion130 population. No new safety signals were observed, and tolerability was consistent with that of the overall population.
| S-EPMC6935297 | biostudies-literature
Project description:BackgroundThis trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple-negative breast cancer (mTNBC).MethodsEligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression-free survival (PFS), response rate, and overall survival.ResultsRP2D for Arm A (n = 10) was ipatasertib 300 mg daily, carboplatin AUC2, and paclitaxel 80 mg m-2 days 1, 8, and 15 every 28 days. RP2D for Arm B (n = 12) was ipatasertib 400 mg daily and carboplatin AUC2 days 1, 8, and 15 every 28 days. RP2D for Arm C (n = 6) was likely ipatasertib 300 mg 21 days on 7 days off, capecitabine 750 mg m-2, twice a day, 7 days on 7 days off, and atezolizumab 840 mg days 1 and 15 every 28 days. The most common (≥10%) grade 3-4 AEs at RP2D for Arm A (N = 7 at RP2D) were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%); Arm B had diarrhea (17%) and lymphopenia (25%); and Arm C had anemia, fatigue, cognitive disturbance, and maculopapular rash (17% each). Overall responses at RP2D were 29% Arm A, 25% Arm B, and 33% Arm C. PFS was 4.8, 3.9, and 8.2 months for patients on Arms A, B, and C, respectively.ConclusionsContinuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs.Trial registrationNCT03853707.
| S-EPMC10322142 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, which shows resistance to common breast cancer therapies, as it lacks the expression of the most common breast cancer targets. Therefore, TNBC treatment remains a challenge. Targeting programmed cell death-ligand 1 (PD-L1) by monoclonal antibodies (mAbs), for example, atezolizumab, has revolutionized the treatment for various cancer types. However, the therapeutic efficacy of targeting PD-L1 in TNBC is currently under investigation. In this study, we investigated the molecular mechanisms by which the human TNBC cell line MDA-MB-231, expressing PD-L1, responds to atezolizumab, using RNA-Seq. Transcriptome analysis revealed 388 upregulated and 362 downregulated genes in response to atezolizumab treatment. The expression of selected genes, from RNA-Seq data, was subsequently validated using RT-qPCR in the MDA-MB-231 and MDA-MB-468 TNBC cells following atezolizumab treatment. Bioinformatics analysis revealed that atezolizumab downregulates genes promoting cell migration/invasion and metastasis, epithelial-mesenchymal transition (EMT), cell growth/proliferation/survival, and hypoxia. On the contrary, genes associated with apoptosis and DNA repair were upregulated in response to atezolizumab treatment. Gene set enrichment analyses revealed that a significant number of these genes are related to the NF-kB, PI3K/Akt/mTOR, MAPK, and CD40 signaling pathways. Using functional assays, we confirmed that atezolizumab increases MDA-MB-231 cell apoptosis/necrosis, and reduces their proliferation and viability. Collectively, our findings provide novel insights into the molecular mechanisms/signaling pathways by which atezolizumab exerts inhibitory effects on TNBC, thereby inhibiting EMT/metastasis, tumor growth/survival, and the induction of hypoxia.
| S-EPMC6721435 | biostudies-literature