Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal ...antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed.
S‐1 is an oral fluoropyrimidine anti‐neoplastic agent that is converted by CYP2A6 to 5‐fluorouracil (5FU). We prospectively studied the pharmacokinetics and pharmacodynamics of S‐1 in two groups of ...East Asian and Caucasian patients with solid malignancy refractory to standard chemotherapy, or for which 5FU was indicated, to elucidate differences in relation to CYP2A6 genotype and phenotype. S‐1 was given orally at 30 mg/m2 b.i.d. for 14 days every 21 days. Dose normalized AUC0–48 h for tegafur (P = 0.05) and gimeracil (P = 0.036) were higher in East Asians; conversely, AUC0–48 h of fluoro‐β‐alanine was higher in Caucasians (P = 0.044). Exposure to 5FU was similar in both groups (P = 0.967). Mean cotinine:nicotine ratio was 54% higher in the Caucasian group (P = 0.03), and correlated with oral clearance of tegafur (r = 0.59; P = 0.002). Grade 3/4 gastrointestinal toxicities were more common in Caucasians than Asians (21%vs 0%). Treatment with S‐1 yields no significant difference in 5FU exposure between Caucasians and East Asians. (Cancer Sci 2011; 102: 478–483)
Objectives/Hypothesis: The objective was to develop an abbreviated voice handicap assessment instrument and compare it with the Voice Handicap Index (VHI).
Study Design: Item analysis of the VHI in ...individuals without voice disorders and patients with voice disorders and creation and validation of the abbreviated VHI.
Methods: Clinical consensus review of the VHI items was held to prioritize the clinical value of each of the VHI items (30 items in all). Item analysis of the VHI was performed using the VHI responses of 100 patients with voice problems and 159 control subjects. The 10 most robust VHI items were selected using the item analysis and clinical consensus results to form the Voice Handicap Index‐10 (VHI‐10). Statistical analysis comparing the validity of the VHI‐10 with the VHI was performed with 819 patients representing a wide spectrum of voice disorders.
Results: Statistical analysis of the VHI and VHI‐10 scores from the study group showed no statistically significant differences between the VHI and the VHI‐10. Irrespective of diagnosis, the correlation between the VHI and the VHI‐10 was greater than .90 (P = .01). The ratios of the VHI‐10 to VHI scores for a variety of voice disorder categories were analyzed and found to be consistently greater than the expected value (33%). This suggests that the VHI‐10 may be a more robust instrument than the VHI.
Conclusion: The VHI‐10 is a powerful representation of the VHI that takes less time for the patient to complete without loss of validity. Thus, the VHI‐10 can replace the VHI as an instrument to quantify patients' perception of their voice handicap.
Patients with advanced, incurable thyroid cancer not amenable to surgery or radioactive iodine ((131)I) therapy have few satisfactory therapeutic options. This multi-institutional study assessed the ...activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer.
Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I were enrolled onto a single-arm phase II trial to receive axitinib orally (starting dose, 5 mg twice daily). Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors was the primary end point. Secondary end points included duration of response, progression-free survival (PFS), overall survival, safety, and modulation of soluble (s) VEGFR.
Sixty patients were enrolled. Partial responses were observed in 18 patients, yielding an ORR of 30% (95% CI, 18.9 to 43.2). Stable disease lasting > or = 16 weeks was reported in another 23 patients (38%).
responses were noted in all histologic subtypes. Median PFS was 18.1 months (95% CI, 12.1 to not estimable). Axitinib was generally well tolerated, with the most common grade > or = 3 treatment-related adverse event being hypertension (n = 7; 12%). Eight patients (13%) discontinued treatment because of adverse events. Axitinib selectively decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT, demonstrating its targeting of VEGFR.
Axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advanced thyroid cancer.
We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in ...combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.
Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.
As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease.
MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.
Purpose In this pharmacokinetic/pharmacodynamic meta-analysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including ...patients with gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC). Methods Pharmacodynamic data were available for 639 patients of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD. Models to express endpoint values and/or changes from baseline by the highest-correlating exposure measures were developed in S-PLUS or NONMEM using fixed- and mixed-effects modeling. Results Tentative relationships were identified between (1) steady-state AUC of total drug (sunitinib + its active metabolite SU12662) and time to tumor progression (TTP), overall survival (OS), with AUC significantly associated with longer TTP and OS in patients with GIST and mRCC, and incidence, but not severity, of fatigue; (2) steady-state AUC of sunitinib and response probability, with AUC significantly associated with objective response in patients with mRCC and stable disease in patients with both mRCC and GIST (with no such correlations in patients with solid tumors); (3) dose and tumor size reductions; (4) total drug concentration and diastolic blood pressure (DBP), with a typical patient on sunitinib 50 mg QD (the recommended dose) predicted to experience a maximum DBP increase of 8 mmHg; and (5) cumulative AUC of total drug and absolute neutrophil count (ANC), with ANC reductions occurring predominantly after one treatment cycle. Conclusions The results of this meta-analysis indicate that increased exposure to sunitinib is associated with improved clinical outcomes (longer TTP, longer OS, greater chance of antitumor response), as well as some increased risk of adverse effects. A sunitinib 50-mg starting dose seems reasonable, providing clinical benefit with acceptably low risk of adverse events.
PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, ...Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.
Learning Objectives
After completing this course, the reader will be able to:
Compare and contrast the mechanism of action for angiogenesis inhibitors currently being explored for the treatment of ...cancer.
Compare the efficacy of standard chemotherapy alone to that of chemotherapy combined with an antiangiogenic agent for the treatment of metastatic colorectal cancer.
Describe the rationale for the use of angiogenesis inhibitors in the treatment of breast cancer.
Assess recent data describing the efficacy of angiogenesis inhibitors in the treatment of NSCLC.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumors requires constant vascular growth and remodeling in order for solid tumors to grow beyond 1–2 mm3 in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which makes them attractive therapeutic targets. A multitude of VEGF‐targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.
This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), ...as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors.
Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m
) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1.
Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients.
The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
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