Abstract Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancers and is a marker of aggressive disease. While HER2-targeted therapies have improved ...outcomes in these tumors, resistance to these agents develops in a large proportion of patients. Determining molecular mechanisms underlying resistance might help improve outcomes for patients with HER2-positive disease by allowing development of strategies to overcome resistance. Activation of signaling pathways involving the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway might contribute to the development of resistance to HER2-targeted therapies. Several inhibitors of this pathway are under investigation in this disease setting and phase 3 data for everolimus in combination with trastuzumab and chemotherapy in trastuzumab-refractory, advanced disease are promising. In this review, molecular mechanisms underlying resistance to HER2-targeted therapies are considered and evidence for strategies to manage resistance is evaluated, including the use of inhibitors of the PI3K/Akt/mTOR pathway.
Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from ...chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.
In this randomised, open-label, multicentre, phase 2 study, adult patients (aged ≥18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m2 and intravenous carboplatin (area under the concentration-time curve 2 μg × h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m2 on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual.
Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8·4 months (IQR 3·8–13·6) for group 1, 12·7 months (5·5–17·4) for group 2, and 12·9 months (6·7–16·8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0·8 day (SD 2·4) in group 1, 1·5 days (3·5) in group 2, and 1·0 day (2·6) in group 3 (group 3 vs group 1 one-sided adjusted p=0·70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0·70). Overall survival was 12·6 months (IQR 5·8–15·6) in group 1, 20·1 months (9·4–not reached) in group 2, and 17·8 months (8·8–not reached) in group 3 (group 3 vs group 1 two-sided p=0·0023). The most common treatment-emergent adverse events were anaemia (22 73% of 34), neutropenia (21 70%), and thrombocytopenia (18 60%) in group 1; neutropenia (27 82% of 33), thrombocytopenia (18 55%) and anaemia (17 52%) in group 2; and neutropenia (23 66% of 35), thrombocytopenia (22 63%), and nausea (17 49%) in group 3. There were no treatment-related deaths.
No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted.
G1 Therapeutics.
We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to gemcitabine plus carboplatin ...(GCb) in patients with metastatic triple-negative breast cancer (NCT02978716).
Patients were randomized (1:1:1) to group 1 GCb (days 1, 8); n = 34, group 2 trilaciclib prior to GCb (days 1, 8); n = 33, or group 3 trilaciclib (days 1, 8) and trilaciclib prior to GCb (days 2, 9); n = 35. Subgroup analyses were performed according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment.
Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; P = 0.0016), 17.8 months in group 3 (HR = 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1-positive population. T-cell activation was enhanced in patients receiving trilaciclib.
Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.
Background
Mammalian target of rapamycin (mTOR) inhibitor‐associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The ...objectives are to evaluate two steroid‐based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus.
Materials and Methods
This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor‐positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash MMW 480 mL recipe: 320 mL oral Benadryl diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA, 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone P 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1–2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks.
Results
A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse‐related toxicity.
Conclusion
Prophylactic use of steroid‐containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse.
Implications for Practice
This prospective phase‐II study showed that two steroid‐containing mouthrinses substantially reduced incidences of all‐grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose‐delays and/or dose‐reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost‐effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor‐associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.
摘要
背景。哺乳动物雷帕霉素靶向基因 (mTOR) 抑制剂相关口腔炎 (mlAS) 是一种与 mTOR 抑制剂疗法相关的常见不良反应(AE)，可能影响治疗依从性。本研究旨在评估两种基于类固醇的漱口液对于使用依维莫司进行转移性乳腺癌(MBC)治疗的患者预防/改善mlAS的效果。
材料和方法。这项前瞻性 II 期随机研究选取美国肿瘤网络中的 100 名激素受体阳性 MBC 的绝经后患者，均已开始芳香化酶抑制剂+依维莫司治疗(AIE; 10 mg/天)。患者随机接受使用其中一种漱口液的预防性治疗 组 1:神奇漱口水 (MMW)480 mL 处方:320 mL 口服苯海拉明(苯海拉明，强生公司，美国新泽西州新布伦瑞克)，2 g四环素，80 mg氢化可的松，40 mL制霉菌素混悬剂，水；或组 2:强的松龙(P)，15 mg/5 mL口服液， 1.8% 酒精浓度。按照指示，患者从 AIE 治疗第一天开始，含漱/吐出 10 mL指定漱口液，每次 1‐2 分钟，每日四次，持续治疗 12 周。
结果。总计 100 名患者接受了治疗(49 人使用 MMW；51 人使用 P)。使用 MMW 和 P 前 12 周的口腔炎/口腔AE发生率分别为 35% (n = 17/49) 和 37% (19/51)。使用 MMW 和 P 的二级口腔AE发生率分别为 14% (7/49) 和 12% (6/51)。另有两例三级口腔AE(MMW 组)，没有四级事件。在前 12 周治疗中，出现一例依维莫司剂量减少 (MMW) 和六例剂量延迟(4 例 MMW，2 例 P)，以及一例剂量减少+延迟(MMW)。没有患者因漱口液相关毒性而停止类固醇漱口水治疗。
结论。预防性使用含有类固醇的漱口液可以防止/改善接受 AIE 治疗的MBC患者的mIAS。MMW+氢化可的松和地塞米松漱口液都是价格合理的治疗选择。
对实践的启示:该前瞻性 II 期研究显示，两种含有类固醇的漱口液大幅度降低了各级别及二级(含)以上口腔炎和相关口腔不良反应的发生率，也减少了接受依维莫司治疗联合芳香酶抑制剂的转移性乳腺癌(MBC)患者中依维莫司剂量延迟和/或剂量减少的数量。两种漱口液都具备良好耐受性，且功效相似。
预防性使用类固醇漱口液提供了经济适用的选项，大幅度降低 mTOR 抑制剂相关口腔炎和相关口腔不良反应的发生率和严重程度，以及接受 mTOR 抑制剂治疗的MBC患者对剂量改变的需求。
Stomatitis is a frequent adverse event associated with mTOR inhibitor therapy. This article evaluates two steroid‐based mouthrinses for preventing or improving mTOR inhibitor‐associated stomatitis in patients with metastatic breast cancer treated with everolimus.
Idiopathic chronic neutropenia (ICN) describes a heterogeneous group of hematologic diseases characterized by low circulating neutrophil levels often associated with recurrent fevers, chronic mucosal ...inflammation, and severe systemic infections. The severity and risk of complications, including serious infections, are inversely proportional to the absolute neutrophil count (ANC), with the greatest problems occurring in patients with an ANC of less than 0.5 × 109/L. This case report describes a 64-year-old female with longstanding rheumatoid arthritis who subsequently developed ICN with frequent episodes of sepsis requiring hospitalization and prolonged courses of antibiotics over a 4-year period. She was treated with granulocyte colony stimulating factors (G-CSF) but had a delayed, highly variable, and volatile response. She was enrolled in a clinical trial evaluating the oral investigational agent ezatiostat. Ezatiostat, a glutathione S-transferase P1-1 inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitor stem cells. She responded by the end of the first month of treatment with stabilization of her ANC (despite tapering and then stopping G-CSF), clearing of fever, and healing of areas of infection. This ANC response to ezatiostat treatment has now been sustained for over 8 months and continues. These results suggest potential roles for ezatiostat in the treatment of patients with ICN who are not responsive to G-CSF, as an oral therapy alternative, or as an adjunct to G-CSF, and further studies are warranted.
The combination of ixabepilone and carboplatin was investigated in a phase II study of 103 patients with hormone receptor-positive (HR+) and triple negative (TN) metastatic breast cancer (MBC) ...previously treated with 0 to 2 chemotherapy regimens for MBC. The objective response rate was 34% and 30.4% in the HR+ and TN cohorts, respectively. Toxicities were manageable without cumulative myelosuppression.
Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2− metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial.
In the present prospective analysis of hormone receptor-positive (HR+)/HER2− and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity.
We enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment.
Ixabepilone plus carboplatin is active even in later-line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.
APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 ...versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen.
HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication).
A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions.
APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC.
: NCT02106494.
Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the ...performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity.
The 6689 participants 2482 cancer (>50 cancer types), 4207 non-cancer were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization.
Performance was consistent in training and validation sets. In validation, specificity was 99.3% 95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR). Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%.
cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.
•Targeted methylation analysis of cfDNA simultaneously detected and localized >50 cancer types, including high-mortality cancers that lack screening paradigms.•Cancers were detected across all stages (stage I–III sensitivity: 43.9%; stage I–IV sensitivity: 54.9%) at a specificity of >99% and a single false positive rate of <1%.•This targeted methylation approach localized the tissue of origin with >90% accuracy, which will be critical for directing follow-up care.•This supports the continued investigation of this test with the goal of population-scale early multi-cancer detection.
Summary
Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B‐cells. Early phase clinical studies with lumiliximab alone and in ...combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID was a phase 2/3, randomized (1:1), open‐label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty‐seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression‐free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.
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