BackgroundAdrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of ...pembrolizumab in patients with metastatic ACC.MethodsThis is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019.Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers.ResultsSixteen patients with ACC (including eight women 50%) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13–65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2–43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining.ConclusionsSingle-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor’s hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events.Trial registrationClinicalTrials.gov identifier: NCT02721732, Registered March 29, 2016.
Background
Clinical trials are an important therapeutic option for patients with cancer. Although financial burden in cancer treatment is well documented, the financial burden associated with ...clinical trials is not well understood.
Patients and Methods
We conducted a survey regarding economic burden and financial toxicity in patients with cancer enrolled in phase I clinical trials for >1 month. Financial toxicity score was assessed using the Comprehensive Score for Financial Toxicity survey. Patients also reported monthly out‐of‐pocket (OOP) costs.
Results
Two hundred and thirteen patients completed the survey (72% non‐Hispanic White; 45% with annual income ≤$60,000; 50% lived >300 miles from the clinic; 37% required air travel). Forty‐eight percent of patients had monthly OOP costs of at least $1,000. Fifty‐five percent and 64% of patients reported unanticipated medical and nonmedical expenses, respectively. Worse financial toxicity was associated with yearly household income <$60,000 (odds ratio OR: 2.7; p = .008), having unanticipated medical costs (OR: 3.2; p = .024), and living >100 miles away from the clinical trial hospital (OR: 2.3; p = .043). Non‐White or Hispanic patients (OR: 2.5; p = .011) and patients who were unemployed or not working outside the home (OR: 2.5; p = .016) were more likely to report high unanticipated medical costs.
Conclusion
Among patients with cancer participating in clinical trials, economic burden is high, and most of patients’ OOP costs were nonmedical costs. Financial toxicity is disproportionally higher in patients with lower income and those who travel farther, and unexpected medical costs were more common among non‐White or Hispanic patients. OOP costs can be substantial and are often unexpected for patients.
Implications for Practice
The financial burden of cancer treatment is well documented, but there are limited data regarding the financial burden associated with cancer clinical trials. This study surveyed 213 patients enrolled in early‐phase clinical trials. Monthly out‐of‐pocket costs were at least $1000 for nearly half of patients. Worse financial toxicity was associated with income <$60,000 and living farther away from the hospital. Racial/ethnic minorities had higher rates of unanticipated medical costs. These data help to quantify the high financial burden for patients and may reveal a cause of disparities in clinical trial enrollment for underrepresented populations.
This article assesses the economic burden exhibited by patients with cancer enrolled in early‐phase clinical trials by examining out‐of‐pocket medical and nonmedical costs and patient‐reported financial toxicity.
Background
Triple‐negative breast cancer (TNBC) is a heterogeneous disease with subtypes having different “targetable” molecular aberrations. Metaplastic breast cancers (MpBCs) are typically TNBCs ...and commonly have alterations in the PI3K/Akt/mTOR pathway. We previously reported efficacy for an mTOR‐based chemotherapy regimen in MpBC. To determine if tumor subtype influences prognosis, we compared treatment outcomes of patients with MpBC with those of patients with nonmetaplastic TNBC receiving an mTOR‐based systemic therapy regimen.
Patients and Methods
Patients with advanced MpBC and nonmetaplastic TNBC were treated at our institution from April 16, 2009, through November 4, 2014, using mTOR inhibition (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab (DAT/DAE). Median progression‐free survival (PFS) and overall survival (OS) were estimated by the Kaplan‐Meier method. Cox regression analyses were used to evaluate associations between tumor histology and outcomes. Multivariable models were adjusted for all covariates.
Results
Fourteen patients with nonmetaplastic TNBC and 59 patients with advanced MpBC were treated with DAT/DAE. MpBC patients were older (p = .002) and less likely to have a history of bevacizumab use (p = .023). Median PFS for the nonmetaplastic TNBC and MpBC patients was 2.5 months and 4.8 months, respectively. This difference in PFS was statistically significant on univariable (p = .006) but not multivariable analysis (p = .087). Median OS for the nonmetaplastic TNBC and MpBC patients was 3.7 months and 10.0 months, respectively (p = .0003). MpBC remained significantly associated with improved OS on multivariable analysis (p < .0001).
Conclusion
In our study, DAT/DAE appeared to be more effective in MpBC compared with nonmetaplastic TNBC. These data support patient selection for targeted therapy in TNBC.
Implications for Practice
Metaplastic breast cancers (MpBCs) represent <1% of all breast cancers, demonstrate mesenchymal differentiation, and are typically resistant to chemotherapy. Patients with advanced MpBC treated with an mTOR‐based systemic therapy regimen had better long‐term outcomes compared with patients with nonmetaplastic triple‐negative breast cancer treated with the same regimen, suggesting that metaplastic histology may predict benefit from agents targeting the PI3K/Akt/mTOR pathway.
摘要
背景。三阴性乳腺癌 (TNBC) 是一种异质性疾病,其亚型具有不同的“可靶向”分子畸变。化生性乳腺癌 (MpBC) 通常是 TNBC,并且 PI3K/Akt/mTOR 通路通常发生改变。我们之前报告了基于 mTOR 的化疗方案对 MpBC 的效果。为了确定肿瘤亚型是否影响预后,我们比较了 MpBC 患者与接受基于 mTOR 的系统治疗方案的非化生性 TNBC 患者的治疗效果。
患者和方法。2009 年 4 月 16 日至 2014 年 11 月 4 日,我们机构采用 mTOR 抑制剂(替西罗莫司或依维莫司)搭配脂质体多柔比星和贝伐珠单抗 (DAT/DAE) 对晚期 MpBC 和非化生性 TNBC 患者进行治疗。我们通过 Kaplan‐Meier 法估算了患者的中位无进展生存期 (PFS) 和总生存期 (OS)。我们采用 Cox 回归分析评估了肿瘤组织学与预
后之间的关系 并针对所有协变量调整了多变量模型。结果。14名非化生性 TNBC 患者与 59 名晚期 MpBC 患者接受了 DAT/DAE 的治疗。MpBC 患者年龄较大 (p = 0.002)和贝伐珠单抗使用史的较少 (p = 0.023)。非化生性 TNBC 和 MpBC 患者的中位 PFS 分别为 2.5 个月和 4.8 个月。PFS 的这种差异在单变量分析中具有统计学意义 (p = 0.006),但在多变量分析则不具有统计学意义 (p = 0.087)。非化生性 TNBC 患者和 MpBC 患者的中位 OS 分别为 3.7 个月和 10.0 个月 (p = 0.000 3)。在多变量分析 (p < 0.0001) 中,MpBC 始终与 OS 的改善关系密切。
结论。我们的研究显示,DAT/DAE 对 MpBC 的效果优于对非化生性 TNBC 的效果。这些数据可帮助 TNBC 患者选择靶向治疗方案。
对临床实践的提示: 化生性乳腺癌 (MpBC) 占所有乳腺癌的比例 <1%,表现出间质分化,并且通常对化疗具有耐药性。采用基于 mTOR 系统治疗方案的晚期 MpBC 患者的长期预后效果优于采用相同治疗方案的非化生三阴性乳腺癌患者的长期预后效果,表明化生组织可能预测针对 PI3K/Akt/mTOR通路的制剂的疗效
This article reports the results of a post hoc analysis of a clinical trial, comparing outcomes of 14 patients with advanced nonmetaplastic triple‐negative breast cancer and 59 patients with advanced metaplastic triple‐negative breast cancer treated with targeted therapy using mTOR inhibition (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab.
We conducted a phase II study of combination of the anti-insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non-small-cell ...lung cancer (NSCLC).
Patients were randomly assigned (2:1) to paclitaxel 200 mg/m(2), carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI(10-20) patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI(20) was enrolled on completion of the randomized study.
A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI(10) and 50 patients received PCI(20) in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI(20)/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship.
These data suggest that PCI(20) is safe and effective in patients with NSCLC.
The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically ...nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.
To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.
A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011.
Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.
Prostate cancer incidence.
This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio HR, 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.
Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.
Clinicaltrials.gov Identifier: NCT00006392.
Fatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and ...cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients' reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory-Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = - 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients' fatigue severity and improves their quality of life.
Preclinical cancer models harboring
amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to ...assess the antitumor activity of adavosertib in patients with
-amplified, advanced refractory solid tumors.
Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring
amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR).
Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue.
Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring
amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in
-amplified epithelial ovarian cancer is warranted.
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response ...to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
Intratumorally injected
-NT (nontoxic; lacking the alpha toxin), an attenuated strain of
, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in ...animals, which warrants clinical investigation.
This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of
-NT across 6 dose cohorts (1 × 10
to 3 × 10
spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.
Among 24 patients, a single intratumoral injection of
-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 10
spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (
= 2) and grade 4 gas gangrene (
= 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (
= 1), limb abscess (
= 1), soft-tissue infection (
= 1), respiratory insufficiency (
= 1), and rash (
= 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined.
-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.
Single intratumoral injection of
NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of
NT in humans.
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