Background
Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti–programmed death 1 (anti–PD‐1) immunotherapy, ...pembrolizumab, in programmed death ligand 1 (PD‐L1)–positive, recurrent glioblastoma.
Methods
Adult patients with PD‐L1–positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE‐028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator‐assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD‐L1 expression levels (prospectively) and T‐cell–inflamed gene expression profile score (retrospectively).
Results
After a median follow‐up of 14 months (range, 2‐55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%‐26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression‐free survival (median, 2.8 months; 95% CI, 1.9‐8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0‐26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD‐L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment‐related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune‐mediated adverse events and infusion reactions occurred in 7 patients (27%).
Conclusions
Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal‐finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.
In the phase 1 multicohort KEYNOTE‐028 study (ClinicalTrials.gov identifier, NCT02054806), the antitumor activity and safety of pembrolizumab were evaluated among patients with recurrent glioblastoma. Pembrolizumab monotherapy demonstrates antitumor activity in a subset of patients and has acceptable toxicity in this setting, in which current treatment options provide limited benefit and the prognosis is poor.
An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival ...interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.
This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0–1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.
Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1–32·9) with trastuzumab deruxtecan and 26·5 months (14·5–31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4–37·9) with trastuzumab deruxtecan and 6·8 months (5·6–8·2) with trastuzumab emtansine (hazard ratio HR 0·33 95% CI 0·26–0·43; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months–not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months–not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64 95% CI 0·47–0·87; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 56% patients versus 135 52% patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.
Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.
Daiichi Sankyo and AstraZeneca.
Purpose The KEYNOTE-028 trial ( ClinicalTrials.gov identifier: NCT02054806) was designed to assess the safety and efficacy of pembrolizumab in 20 programmed death ligand 1-positive, advanced solid ...tumor cohorts. Here, we present the results from the cohort of patients with advanced cervical cancer. Methods Patients were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, by investigator review. Safety was a secondary end point. Results Twenty-four patients were enrolled in the cervical cancer cohort. The median age was 42 years (range, 26 to 62 years), 22 patients (92%) had received prior radiation therapy, and 15 patients (63%) had received two or more lines of therapy, including bevacizumab (10 of 24 patients), for advanced disease. At the data cutoff, median follow-up duration was 11.0 months (range, 1.3 to 32.2 months). Overall response rate was 17% (95% CI, 5% to 37%); four patients (17%) achieved a confirmed partial response, and three patients (13%) had stable disease. Median duration of response for the four patients who achieved a partial response was 5.4 months (4.1 to 7.5 months). Treatment related adverse events (AEs) were experienced by 18 patients (75%); only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in ≥ 10% of patients. Five patients experienced grade 3 treatment-related AEs. No grade 4 treatment-related AEs or deaths were observed. Conclusion In patients with programmed death ligand 1-positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with that seen in other tumor types.
The outcomes and best treatment strategies for germline BRCA1/2 mutation (gBRCAm) carriers with metastatic breast cancer (MBC) remain uncertain. We compared the overall survival and the first line ...progression free survival (PFS1) of patients with a gBRCAm identified at initiation of first‐line treatment with those of BRCA wild‐type (WT) and not‐tested (NT) individuals in the ESME real‐world database of MBC patients between 2008 and 2016 (NCT03275311). Among the 20 624 eligible patients, 325 had a gBRCAm, 1138 were WT and 19 161 NT. Compared with WT, gBRCAm carriers were younger, and had more aggressive diseases. At a median follow‐up of 50.5 months, median OS was 30.6 (95%CI: 21.9‐34.3), 35.8 (95%CI: 32.2‐37.8) and 39.3 months (95% CI: 38.3‐40.3) in the gBRCAm, WT and NT subgroups, respectively. Median PFS1 was 7.9 (95%CI: 6.6‐9.3), 7.8 (95%CI: 7.3‐8.5) and 9.7 months (95%CI, 9.5‐10.0). In the multivariable analysis conducted in the whole cohort, gBRCAm status had however no independent prognostic impact on OS and PFS1. Though, in the triple‐negative subgroup, gBRCAm patients had better OS and PFS1 (HR vs WT = 0.76; 95%CI: 0.60‐0.97; P = .027 and 0.69; 95% CI: 0.55‐0.86; P = .001, respectively). In contrast, in patients with HR+/HER2 negative cancers, PFS1 appeared significantly and OS non significantly lower for gBRCAm carriers (PFS1: HR vs WT = 1.23; 95%CI: 1.03‐1.46; P = .024; OS:HR = 1.22, 95% CI: 0.97‐1.52, P = .089). In conclusion, gBRCA1/2 status appears to have divergent survival effects in MBC according to IHC subtype.
What's new?
Despite the recent approval of novel therapeutics for germline BRCA1/2‐mutated metastatic breast cancer, data regarding outcomes and optimal treatment strategies are lacking. This study assessed the impact of germline BRCA mutations on metastatic breast cancer survival using data from a cohort of patients treated in an era predating PARP inhibitors. Although germline BRCA mutation had no independent prognostic impact on survival, divergent prognostic effects according to tumor subtype were observed. These effects were pronounced among germline mutation carriers with luminal breast cancer, who experienced worse progression‐free survival. The observations highlight the importance of deciphering BRCA status early in clinical care.
Tumor clone dynamics in lethal prostate cancer Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane ...
Science translational medicine,
2014-Sep-17, Letnik:
6, Številka:
254
Journal Article
Recenzirano
Odprti dostop
It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease ...progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.
Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem‐like cells (GSC), which ...constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa‐associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor‐mediated NF‐κB activation and B‐cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient‐derived stem‐like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo‐lysosome abundance, impairs autophagic flux, and culminates in lysosomal‐mediated cell death, concomitantly with mTOR inactivation and dispersion from endo‐lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo‐lysosomes.
Synopsis
This study unveils that the paracaspase activity of MALT1, which was previously linked to antigen receptor‐mediated NF‐κB activation and lymphomas, is decisive for the expansion of glioblastoma stem‐like cells (GSC), highlighting potential therapeutic strategies against brain cancers.
Expression and catalytic activity of MALT1 are required for GSC expansion.
Pharmacological targeting of MALT1 is lethal to GSCs and reduces the expansion of established tumors in mice.
MALT1 depletion results in an increased endo‐lysosomal compartment and decreased mTOR signaling.
MALT1 expression negatively correlates to that of RNA‐binding protein Quaking to control endo‐lysosomal biogenesis.
Protease MALT1 impairs lysosome biogenesis and increases mTOR signalling and autophagic flux in glioma stem cells.
The modeled CA-125 elimination constant K (KELIM) is a pragmatic early marker of tumor chemosensitivity in ovarian cancer patients treated with neoadjuvant chemotherapy before interval surgery. The ...primary objective of this study was to assess the prognostic value of KELIM regarding the feasibility of complete surgery, and secondary objectives were to assess the prognostic value of KELIM for the risk of a platinum resistant relapse, progression free survival, and overall survival.
The study was based on a retrospective cohort of 284 patients treated for an advanced serous high grade ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV, with neoadjuvant chemotherapy, followed by interval surgery, in a comprehensive cancer center. CA-125 concentrations at baseline and during neoadjuvant chemotherapy were collected. The KELIM predictive value regarding the tumor radiological response rate, likelihood of complete surgery, risk of subsequent platinum resistant relapse, progression free survival, and overall survival were assessed with univariate and multivariate tests.
In 232 patients, KELIM was an independent and major predictor of the probability of complete surgery and survival. The final logistic regression model, including KELIM (odds ratio (OR) 0.36, 95% confidence interval (CI)0.16 to 0.73, p=0.006) and complete surgery (no vs yes, OR 0.29, 95% CI 0.15 to 0.53, p<0.001), highlighted the complementary impact of chemosensitivity and surgical outcome relative to the complete surgery. In the multivariate analysis, KELIM and complete surgery were significantly associated with a lower risk of early relapse. In the case of an unfavorable KELIM, when surgical efforts allowed complete cytoreduction, median overall survival was similar to that reported in the case of a favorable KELIM (46.3 months (range 34.6-60.3) vs 46.5 months (range 40.6-68.7), respectively).
Primary tumor chemosensitivity, assessed by the modeled CA-125 KELIM, calculated during neoadjuvant chemotherapy, is a major parameter to consider for decision making regarding interval surgery. Complementary to the RECIST score and laparoscopy, this non-invasive tool, available online, helps tailor the interval surgery strategy according to patient tumor chemosensitivity.
The poor outcomes associated with mammary carcinomas (MCs) in dogs and cats in terms of locoregional recurrence, distant metastasis and survival, highlight the need for better management of mammary ...cancers in small animals. By contrast, the outcomes of women with breast cancer (BC) have dramatically improved during the last 10 years, notably thanks to new therapeutic strategies. The aim of this article was to imagine what could be the future of therapy for dogs and cats with MCs if it became inspired from current practices in human BC. This article focuses on the importance of taking into account cancer stage and cancer subtypes in therapeutic plans, on locoregional treatments (surgery, radiation therapy), new developments in endocrine therapy, chemotherapy, PARP inhibitors and immunotherapy. Ideally, multimodal treatment regimens would be chosen according to cancer stage and cancer subtypes, and according to predictive factors that are still to be defined.
Everolimus is an oral drug that inhibits mTOR with immunosuppressive and antiproliferative characteristics. It is commonly used in association with exemestane in hormone receptor (HR)-positive ...advanced breast cancer (ABC).
The current review summarizes the publications relating to everolimus from clinical research in breast cancer. Everolimus showed treatment efficacy and an acceptable safety tolerance with the prevention of side effects in Phase II/III studies. BOLERO-2 study showed a progression-free survival improvement in patients with HR - positive ABC previously treated with aromatase inhibitors (AI) and leading to its acceptance in this indication. The absence of a post-CDK4/6 inhibitor (CDK4/6i.) study and the arrival of new drugs may raise questions about its current place in the therapeutic strategy.
Everolimus is relevant in the management of HR - positive ABC. Because of its efficacy, acceptable tolerability and the absence of drugs that have shown a greater benefit, it remains a second-line treatment option in HR-positive, HER2 negative (score 0) patients without BRCA mutation or visceral crisis and can be discussed with fulvestrant in second line after CDK4-6i. It is likely that within 5 years this treatment will be replaced in second-line HR-positive breast cancer by new emerging treatments: drug-conjugated antibodies, tyrosine kinase inhibitors or immunotherapy in combination with chemotherapy.
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