Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II ...trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.
Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously IV once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups.
The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio HR, 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806).
Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
Background
Five‐year overall survival (OS) for patients with unresectable stage III non–small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. ...Patients with metastatic NSCLC treated with anti–programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease.
Methods
Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression‐free survival (PFS) and OS.
Results
The median follow‐up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2‐46.6 months). The median TMDD was 30.7 months (95% confidence interval CI, 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4‐33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1‐, 2‐, and 3‐year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%).
Conclusions
Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.
Consolidation pembrolizumab after concurrent chemoradiation for unresectable stage III non–small cell lung cancer demonstrates improved overall survival, progression‐free survival, and time to metastatic disease or death in comparison with a historical control. This study confirms the findings of the PACIFIC trial and further solidifies the role of consolidation immunotherapy as the new standard of care in this setting.
Introduction
Effective treatments for hormone-receptor-positive (HR
+
) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast ...Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population.
Methods
BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR
+
advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints.
Results
Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38–0.54); log-rank
P
< 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31–0.48); log-rank
P
< 0.0001 in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, patients with recurrence during or within 12 months of completion of adjuvant therapy, and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials.
Conclusion
The addition of everolimus to exemestane markedly prolonged PFS in patients with HR
+
advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.
Pelabresib (CPI-0610), a BET protein inhibitor, is in clinical development for hematologic malignancies, given its ability to target NF-κB gene expression. The MANIFEST phase 1 study assessed ...pelabresib in patients with acute leukemia, high-risk myelodysplastic (MDS) syndrome, or MDS/myeloproliferative neoplasms (MDS/MPNs) (NCT02158858). Forty-four patients received pelabresib orally once daily (QD) at various doses (24-400 mg capsule or 225-275 mg tablet) on cycles of 14 d on and 7 d off. The most frequent drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) was 225 mg tablet QD. One patient with chronic myelomonocytic leukemia (CMML) showed partial remission. In total, 25.8% of acute myeloid leukemia (AML) patients and 38.5% of high-risk MDS patients had stable disease. One AML patient and one CMML patient showed peripheral hematologic response. The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125 mg tablet QD.CLINICAL TRIAL REGISTRATION: NCT02158858.
The progressive deterioration in nutrition status frequently seen in cancer
patients is often referred to as cancer cachexia. Unlike starvation, in which
fat stores from adipose are depleted and ...protein is spared from skeletal
muscle, neither fat nor protein is spared in cachexia. Cachexia affects nearly
half of cancer patients, causing the clinical manifestations of anorexia,
muscle wasting, weight loss, early satiety, fatigue, and impaired immune
response. Cachexia does not only impede the response to chemotherapy but also
is a major cause of morbidity and mortality. According to clinical studies,
increasing caloric intake does not necessarily reverse cachexia. The
pathophysiology of cachexia involves more complex mechanisms than simply
caloric deficiency. The process appears to be mediated by circulating
catabolic factors, either secreted by the tumor alone or in concert with
host-derived factors, such as tumor necrosis factor-α (TNF-α),
interleukins (IL-1 and IL-6), interferon (IFN-y), and leukemia inhibitory
factor (LIF). The successful reversal of this process will require in-depth
knowledge of the mechanisms involved, which will then enable the development
of effective pharmacologic interventions that may not only improve quality of
life, but more importantly, improve survival among cancer patients.
Background:
Cardiorespiratory fitness (CRF) varies with sex and is an independent predictor of mortality. We sought to investigate sex differences in the exercise protocol selected, CRF levels, and ...their relationships with long term all-cause mortality.
Methods:
In a 25-year stress testing registry spanning from 1991 to 2014, consecutive all-comer patients who underwent exercise stress testing at Cleveland Clinic were categorized by sex, stress protocol and imaging modality. All tests were conducted by one or more of stress test technicians, sonographers and nuclear medicine technologists, and interpreted by cardiologists. The primary outcome all-cause mortality was analyzed in using multivariable Cox regression.
Results:
In 120,705 patients, the mean age was 53.3 ± 12.5 years, and 41% were female. Females were more commonly referred for non-Bruce exercise protocols (modified Bruce, Cornell 0, 5 and 10, Naughton and modified Naughton) with odds ratio of 2.62; 95% confidence interval (95%CI) (2.54–2.70) after adjusting for age and comorbidities. When also adjusting for the protocol chosen, females achieved lower CRF with beta −1.40, 95% CI (−1.43, −1.37). There were 8426 (6.9%) deaths during a mean follow-up of 8.7 years. Both female sex and CRF were independently associated with lower all-cause mortality with hazards ratio (95%CI) of 0.44 (0.41–0.46) and 0.41 (0.39–0.42) respectively, after adjusting for age, co-morbidities and protocol chosen.
Conclusions:
Women were more likely referred for less demanding exercise protocols, more imaging protocols and achieved lower CRF than men. Despite this, female sex was associated with significantly lower long term mortality for equivalent CRF level in adjusted analyses.
•This large 25-year exercise test registry included 120,705 patients and 8426 deaths.•Females were more often referred for non-Bruce exercise and imaging protocols.•Female sex and higher CRF are independently associated with greater survival.•Regardless of stress test modality, females had better prognosis at equivalent CRF.
Tc99m-pyrophosphate (Tc99m-PYP) scintigraphy has emerged as a diagnostic modality for transthyretin (TTR) cardiac amyloidosis (CA). We sought to examine the variability in test utilization across ...multiple centers in the US.
An electronic, web-based survey addressing specifics on Tc-99m PYP imaging was emailed to ASNC members, totaling 2785 recipients. Only one response per institution was allowed.
Responses were collected from 101 centers between July 2 and July 27, 2015. Among the respondents, 24% performed Tc-99m PYP specifically for CA diagnosis. The most commonly used dose was 20 mCi (37%) and most centers (35%) imaged 1 hour after injection. Scans were most often interpreted by cardiologists (60%). Quantification of uptake was performed in 57% of institutions with almost half (43%) utilizing the heart-to-contralateral lung (H/CL) ratio.
This national survey shows relatively low penetrance and high variability in Tc99m-PYP scintigraphy for CA diagnosis highlighting the need for standardization.
In the randomized phase 3 VALOR-HCM study (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) of patients ...with obstructive hypertrophic cardiomyopathy, mavacamten reduced the need for septal reduction therapy. Because mavacamten improves ventricular compliance, this sub-study examined the effects of treatment with this cardiac myosin inhibitor on diastolic function.
Symptomatic obstructive hypertrophic cardiomyopathy patients on maximally tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. At baseline and week 16, a resting and stress echocardiogram was performed with interpretation by a core laboratory. In this exploratory substudy, the principal end point was the change in parameters used to define the grade of diastolic function in patients treated with mavacamten and placebo. A related objective was to assess the proportion of patients with an improvement in diastolic function grade. A secondary aim was to assess for correlation between diastolic function parameters and the secondary end points from VALOR-HCM: New York Heart Association class, quality of life, and cardiac biomarkers.
Diastolic dysfunction grade was evaluable in 98 patients at baseline and week 16. Among patients treated with mavacamten, 29.4% (15 of 51) demonstrated improvement in diastolic function grade compared with 12.8% (6 of 47) patients with placebo (
=0.05). Average E/e' ratio decreased significantly in patients treated with mavacamten (-3.4±5.3) compared with placebo (0.57±3.5;
<0.001). Indexed left atrial volumes (mL/m
) also decreased significantly in patients who received mavacamten (-5.2±7.8) compared with placebo (-0.51±8.1;
=0.005). After adjustment for change in left ventricular outflow tract gradient and mitral regurgitation, mavacamten was significantly associated with a decrease in average E/e' ratio and indexed left atrial volumes. Change in average E/e' ratio was significantly correlated with the secondary end points from VALOR-HCM.
In this exploratory substudy, after 16 weeks of therapy, mavacamten improved diastolic function, and this change correlated with improvement in clinical and biomarker end points.
URL: https://www.
gov; Unique identifier: NCT04349072.
Assessing for coronary artery disease (CAD) in patients with left bundle branch block (LBBB) is difficult with noninvasive cardiac imaging. Few studies report the prevalence of LBBB associated ...septal-apical perfusion defects using regadenoson stress on Positron Electron Tomography (PET) imaging.
We identified 101 consecutive patients with baseline LBBB, and without known CAD, who underwent rest-stress regadenoson PET. Investigators have the ability to prospectively identify studies, whose quality is limited by LBBB artifact. With the infusion of regadenoson, resting to peak stress heart rate rose from a median of 78 to 93 BPM. Despite this, LBBB perfusion artifacts were not identified in any studies. 10 individuals had both regadenoson SPECT and PET within 1 year. 3 of the 10 SPECT studies had LBBB artifacts, all of which were not seen on subsequent PET. 21 patients with PET had subsequent coronary angiography. Of these, 9 PETs were without significant inducible ischemia, and angiogram was without flow-limiting disease. 3 PETs identified inducible ischemia, but did not have flow-limiting disease on angiogram. 9 PETs identified inducible ischemia and had flow-limiting disease on angiogram.
In patients with LBBB undergoing regadenoson PET stress imaging, artifactual septal perfusion defects are rare.
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