Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with ...fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing.
Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses.
A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 $3,767) than for nonscreening (€2,817 $3,828), outweighing screening costs.
DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.
Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)‐expressing ...metastatic colorectal cancer could be treated with anti‐EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat‐Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat‐sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti‐EGFR treatment.
In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient.
This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti‐EGFR mAbs. Based on a review of literature, eight meta‐analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti‐EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response.
Implications for Practice
In metastatic colorectal cancer (mCRC), therapy with anti‐epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab is indicated in absence of RAS mutations. Cumulative evidence shows that patients with BRAF mutations, who comprise 10% of the mCRC population, do not benefit from anti‐EGFR‐antibody treatment. Although guidelines state that evidence for BRAF as a predictive marker is insufficient, we highlight that the quality and quantity of evidence is higher than suggested. We therefore encourage the use of BRAF as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected.
This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti‐EGFR monoclonal antibodies. Based on a review of literature, eight meta‐analyses were included in this study, which consistently show that patients with BRAF mutations have a lack of treatment benefit of anti‐EGFR monoclonal antibodies. Considering the quality and quantity of available evidence, current guidelines may be revised.
Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast ...cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis. It has a high prevalence of BRCA1 mutations and an increased Ki-67 expression. This subtype usually responds well to taxanes and/or platinum compounds and poly (ADP-ribose) polymerase (PARP) inhibitors. Studies with PARP inhibitors have demonstrated promising results in the treatment of BRCA-mutated breast and ovarian cancer, and PARP inhibitors have been studied as monotherapy and in combination with cytotoxic therapy or radiotherapy. PARP inhibitor efficacy on poly (ADP-ribose) polymer (PAR) formation in vivo can be quantified by pharmacodynamic assays that measure PAR activity in peripheral blood mononuclear cells (PBMC). Biomarkers such as TP53, ATM, PALB2 and RAD51C might be prognostic or predictive indicators for treatment response, and could also provide targets for novel treatment strategies. In summary, this review provides an overview of the treatment options for basal-like TNBC, including PARP inhibitors, and focuses on the pharmacotherapeutic options in these patients.
Summary
Purpose
Erlotinib (Tarceva®, OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. As high-grade gliomas frequently show amplification, ...overexpression and/or mutation of EGFR, this drug has been tested in several clinical trials with glioblastoma patients, but unfortunately, with little success. As erlotinib is a known substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) we have investigated the effect of these ABC-transporters on the brain penetration of erlotinib.
Study design
Erlotinib (50 mg/kg) was given by i.p. administration to wild-type (WT), Mdr1ab
-/-
(single P-gp knockout), Bcrp1
-/-
(single Bcrp1 knockout) and Mdr1ab
-/-
Bcrp1
-/-
(compound P-gp and Bcrp1 knockout) mice. Drug levels in plasma and tissues were determined by reversed-phase high-performance liquid chromatography.
Results
Relative to Mdr1ab
-/-
Bcrp1
-/-
mice that are deficient for both drug transporters, the area under the concentration time curve in brain tissue (AUC)
brain
of erlotinib decreased significantly by 1.6-fold in Mdr1ab
-/-
mice where Bcrp1 is present (49.6 ± 3.95 versus 31.1 ± 1.7, μg/g*h;
P
< 0.01). In Bcrp1
-/-
mice, were P-gp is present, a more pronounced 3.8-fold decrease to 13.0 ± 0.70, μg/g*h (
P
< 0.01) was observed, which is close to the 4.5-fold decrease in the AUC
brain
of erlotinib found in WT mice where both drug transporters are present (11.0 ± 1.35,
P
< 0.01). The plasma clearance of erlotinib was similar in mice deficient for P-gp and/or Bcrp1 compared with wild-type mice. In all other tissues the differences between the genotypes were negligible.
Conclusions
Both P-gp and Bcrp1 reduce the brain penetration of erlotinib. Although P-gp appears to be the most effective factor limiting the brain penetration of erlotinib, the highest brain accumulation was observed when Bcrp1 was also absent. Strategies to inhibit P-gp/BCRP in patients to improve delivery of (novel molecular-targeted) substrate agents, such as erlotinib, to the brain may be required for treatment of intracranial malignancies.
Recently, there has been a renewed interest in the development of new drugs for the treatment of leishmaniasis. This has spurred the need for pharmacodynamic markers to monitor and compare therapies ...specifically for visceral leishmaniasis, in which the primary recrudescence of parasites is a particularly long-term event that remains difficult to predict. We performed a systematic review of studies evaluating biomarkers in human patients with visceral, cutaneous, and post-kala-azar dermal leishmaniasis, which yielded a total of 170 studies in which 53 potential pharmacodynamic biomarkers were identified. In conclusion, the large majority of these biomarkers constituted universal indirect markers of activation and subsequent waning of cellular immunity and therefore lacked specificity. Macrophage-related markers demonstrate favorable sensitivity and times to normalcy, but more evidence is required to establish a link between these markers and clinical outcome. Most promising are the markers directly related to the parasite burden, but future effort should be focused on optimization of molecular or antigenic targets to increase the sensitivity of these markers. In general, future research should focus on the longitudinal evaluation of the pharmacodynamic biomarkers during treatment, with an emphasis on the correlation of studied biomarkers and clinical parameters.
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum ...tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations n = 1; 125 mg, hyperphosphatemia n = 1; 150 mg, grade 1 corneal toxicity n = 1 and grade 3 aminotransferase elevations n = 1). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses six confirmed) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.
•Nivolumab and pembrolizumab levels in cerebrospinal fluid are much lower than in serum.•Validated enzyme-linked immunoassay can quantify those levels up to 2 ng/mL.•The assay is clinically ...applicable for pharmacokinetics in serum and cerebrospinal fluid.
Immunotherapy with monoclonal antibodies targeting the programmed-death-1 (PD-1) receptor has become standard of care for an increasing number of tumor types. Pharmacokinetic studies may help to optimize anti-PD-1 therapy. Therefore, accurate and sensitive determination of antibody concentrations is essential. Here we report an enzyme linked immunosorbent assay (ELISA) capable of measuring nivolumab and pembrolizumab concentrations in serum and cerebrospinal fluid (CSF) with high sensitivity and specificity. The assay was developed and validated based on the specific capture of nivolumab and pembrolizumab by immobilized PD-1, with subsequent enzymatic chemiluminescent detection by anti-IgG4 coupled with horse radish peroxidase (HRP). The lower limit of quantification for serum and CSF was 2 ng/mL for both anti-PD-1 agents. The ELISA method was validated and showed long term sample stability of >1 year. This method is reliable, relatively inexpensive and can be used in serum and CSF from pembrolizumab and nivolumab treated patients.
The primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with ...suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC).
We tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR).
The sensitivity of the CTC assay was 94% (95% confidence interval CI 80-99) and the specificity was 100% (95% CI 91-100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58-89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor (
). All 5 tested patients with LM demonstrated the primary
driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF.
CTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine
mutations in both cfCSF and isolated CTC from CSF of patients with
-mutated NSCLC and LM.
This study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.
The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesaving therapies affordable for cancer patients. We call here for the formation of new relationships between ...academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices.
The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesaving therapies affordable for cancer patients. We call here for the formation of new relationships between academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices.
Highlights • Combining antibodies, targeting distinct pathways, may induce synergistic effects. • Most antibodies have limited overlapping toxicity and no pharmacokinetic interactions. • Several ...studies showed additive effects of combining antibodies, but a few did not. • It is unknown why some combinations appear to result in an antagonistic effect.
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