This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) ...refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.
Patients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed.
The response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03).
Cetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.
Among patients who had mutations in
BRCA1
or
BRCA2
and were at high risk for disease progression, those who were assigned to a year of olaparib adjuvant therapy had 3-year invasive disease–free ...survival of 86%, as compared with 77% among those who were assigned to placebo. Few patients stopped olaparib owing to side effects.
The Georgia Center for Oncology Research and Education (Georgia CORE) and the Georgia Society of Clinical Oncology (GASCO) held a one-day summit exploring opportunities and evidence-based ...interventions to address disparities in cancer clinical trials. The purpose of the summit was to identify clear and concise recommendations aimed at decreasing clinical trial accrual disparities in Georgia for rural and minority populations. The summit included expert presentations, panel discussions with leaders from provider organizations throughout Georgia, and breakout sessions to allow participants to critically discuss the information presented. Over 120 participants attended the summit. Recognizing the need for evidence-based interventions to improve clinical trial accrual among rural Georgians and persons of color, summit participants identified four key areas of focus that included: improving clinical trial design, providing navigation for all, enhancing public education and awareness of cancer clinical trials, and identifying potential policy and other opportunities. A comprehensive list of takeaways and action plans was developed in the four key areas of focus with the expectation that implementation of the strategies that emerged from the summit will enhance cancer clinical trial accrual for all Georgians.
Purpose
Anti-PD-1 therapy provides clinical benefit in 40–50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is ...typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity.
Methods
Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods.
Results
The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009).
Conclusion
This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.
Abstract
Doxorubicin (Dox) is well-known anthracycline widely used anticancer agent for the treatment of a wide variety of cancers. The major limitations of cancer chemotherapy treatment are low ...cellular uptake, high efflux rate and the development of resistance to a certain dose of anticancer drugs, such as Dox. Improving of cellular uptake and duration of action of Dox is very demanding. This will improve its therapeutic index and decrease its side effects. The biological activity of Dox can potentially be enhanced by increasing and optimizing its hydrophobicity using appropriate hydrophobic linker attachment to the Dox using triphenylmethanol (TPM) which led to higher cellular uptake. In this regard, TPM-Dox prodrugs were designed to deliver and release Dox into cells. The attachment of TPM analogs along with fatty alcohol significantly enhanced the lipophilicity and thus the cellular uptake of these multifunctional conjugates. In this study, a number of TPM derivatives of Dox were synthesized by the reaction of 2-substituted methoxy benzenes and 1,3,5-trioxane in glacial acetic acid in 72-87% yield. The reaction of TPM derivatives with tosylated fatty diol continued with conjugation to Dox to afford eight TPM-Dox conjugates with different hydrophobicity in 44-67% overall yield. Comparative antiproliferative assays between TPM-Dox conjugates and the corresponding noncovalent physical mixtures of the TPM derivatives and Dox were performed. TPM-Dox conjugates inhibited the cell proliferation of human leukemia (CCRF- CEM), ovarian adenocarcinoma (SK-OV-3), colorectal carcinoma (HCT-116), and breast carcinoma (MDA-MB-468) cells by 63-94% at a concentration of 1 µM after 72-120 h of incubation. These data suggest that TPM-Dox derivatives can be used as a potential prodrug for improving the cellular delivery and retention of Dox.
Citation Format: Yousef Beni, Andrew W. Pippas. Design and antiproliferative evaluation of cell-penetrating TPM-Dox conjugates as prodrugs. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2512. doi:10.1158/1538-7445.AM2014-2512
Background. A case of reversible cardiogenic shock linked to 5‐fluorouracil (5‐FU) was observed. Recognizing the increasing use of 5‐FU, the authors tried to map this syndrome.
Methods. They reviewed ...134 additional case reports, retrieved information from literature searches, focused on clinical features, and discussed possible pathophysiologic findings and prevention of this syndrome.
Results. Although angina and electrocardiographic changes were common and reproducible (approximately 90% each), coronary artery disease was found in a few patients. A total of 33 patients had severe left ventricular dysfunction, 28 without evidence of myocardial infarction. The symptoms were responsive to conservative management (90%).
Conclusions. Cardiac toxicity is a little known complication of 5‐FU therapy, with an unknown but significant incidence. It is highly treatable.
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