Van Tine BA, Govindarajan R, Attia S, Somaiah N, Barker SS, et al.
Journal of oncology practice •
Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports. Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti-galactose-α-1,3-galactose (anti-α-Gal) antibodies. In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti-α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti-α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials. Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.
There are two highly selective antibodies to the epidermal growth factor receptor (EGFR) now available for use in metastatic colorectal cancer (mCRC). In KRAS wild type patients, cetuximab (Cmab)-an IgG1 chimeric molecule--has activity alone and in combination with chemotherapy for the first, second and third-line settings. Panitumumab (Pmab)--a fully humanized IgG2 molecule--has activity as a single agent in chemorefractory mCRC and shows promising activity in combination with chemotherapy. It remains unclear which antibody to use. This retrospective review of our experience with Pmab in 13 EGFR antibody-naive patients and in 22 patients previously treated with Cmab for mCRC highlights a lack of hypersensitivity reactions (HSR) with Pmab, even in patients who experienced HSR to Cmab. In patients who received Cmab, 22% developed grade 3-4 HSR. There were no HSR on subsequent treatment with Pmab. We demonstrate similar activity in 95% of cases, between Cmab and Pmab both alone and in combination with chemotherapy in the treatment of mCRC. In one case we report unique sensitivity to Pmab after progression with Cmab.
Determine the safety and efficacy of cetuximab plus paclitaxel and carboplatin as initial treatment of stage III/IV ovarian cancer. An initial intravenous [IV] dose of cetuximab (400 mg/m(2)) was administered over 120 min followed by weekly IV infusions of cetuximab (250 mg/m(2)) administered over 60 min. Paclitaxel (175 mg/m(2)) and carboplatin (area under the curve [AUC] of 6) were administered IV every 21 days for 6 cycles. The order of administration was cetuximab followed by paclitaxel and then carboplatin. Patients achieving a clinical complete response after 6 cycles were eligible to continue weekly cetuximab for 6 months or until toxicity or disease progression. Safety was evaluated using NCI Common Toxicity Criteria version 2.0. Progression-free survival (PFS) at 18 months was determined and compared with historical controls. Forty-one patients were enrolled in this study; 40 received treatment and were evaluable for toxicity, and 38 were evaluable for PFS. Grade 3/4 treatment-related toxicities included febrile neutropenia (12.5%), rash (2.5%), hypersensitivity reaction (7.5%), and hypomagnesemia (12.5%). Common grade 1/2 toxicities attributed to cetuximab included acneiform rash (82.5%), hirsutism (7.5%) or abnormal hair growth (25%), and nail disorders (22.5%), which in 3 cases resulted in the patient's discontinuation from the study. Median PFS was 14.4 months, and PFS at 18 months was 38.8%. The combination of cetuximab with paclitaxel and carboplatin is adequately tolerated as primary therapy for ovarian cancer but did not demonstrate prolongation of PFS when compared to historical data.
Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, et al.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology •
Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy. We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy (cetuximab) with chemoradiotherapy. Eligible patients had stage III or IV, M0, squamous cell head and neck cancer. Treatment included concomitant boost radiotherapy (1.8 Gy/d weeks 1 to 6; boost: 1.6 Gy 4 to 6 hours later weeks 5 to 6; 70 Gy total to gross disease), cisplatin (100 mg/m2 intravenously weeks 1 and 4), and cetuximab (400 mg/m2 intravenously week 1, followed by 250 mg/m2 weeks 2 to 10). Twenty-two patients were enrolled (median age, 57 years; range, 41 to 72 years; median Karnofsky status, 90%; range, 70% to 90%; oropharynx primary tumor, 59% of patients; T4, 36%; N2/3, 77%; stage IV disease, 86%). One patient did not receive study treatment because of an ineligible diagnosis. The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths (one pneumonia and one unknown cause), one myocardial infarction, one bacteremia, and one atrial fibrillation. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56%, and the 3-year locoregional control rate is 71%. This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.
International data from 2002 report 10.9 million new cases of cancer and 6.7 million cancer deaths. Chemotherapy is an essential component in the multidisciplinary management of most cancers. Cutaneous reactions to chemotherapeutics are common and may contribute significantly to the morbidity, and rarely to the mortality, of patients undergoing such treatments. Recognition and management of these reactions is important to provide optimal care. This article aims to present the most common cutaneous reactions to frequently used chemotherapies and provides management guidelines. A MEDLINE search from 1966 through June 2005 was conducted to identify reports of common cutaneous toxicities with systemic chemotherapy and their appropriate management. An analysis of our literature search is presented in review form outlining common chemotherapy-related cutaneous reactions and their management, as well as the chemotherapeutics responsible for the cutaneous toxicity. Chemotherapy-related cutaneous toxicity includes generalized rashes such as the spectrum between erythema multiforme and toxic epidermal necrolysis, and site-specific toxicity such as mucositis, alopecia, nail changes, extravasation reactions, or hand-foot syndrome. Most of the toxicity is reversible with chemotherapy dose reductions or delays. Certain toxicities can be effectively treated or prevented, allowing optimal delivery of chemotherapy (e.g. premedications to prevent hypersensitivity, prophylactic mouthwashes to prevent mucositis). Newer non-chemotherapeutic targeted therapies such as epidermal growth factor receptor inhibitors (e.g. gefitinib, cetuximab) may also be associated with cutaneous toxicity and can be distressing for patients. Recent data suggest that skin toxicity associated with these agents may correlate with efficacy. Cutaneous toxicity occurs frequently with chemotherapy and non-chemotherapeutic biologic therapies. Early recognition and treatment of the toxicity facilitates good symptom control, prevents treatment-related morbidity, and allows continuation of anti-cancer therapy.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology •
To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Phase II, open-label clinical trial. Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation. Patients were required to have received irinotecan, either alone or in a combination regimen, and to have demonstrated clinical failure on this regimen before study entry. Cetuximab was administered weekly by intravenous infusion. The first dose of 400 mg/m(2) was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m(2) during the course of 1 hour. Fifty-seven eligible patients were treated. All were assessable for toxicity and response. The most commonly encountered grade 3 to 4 adverse events, regardless of relationship to study drug, were an acne-like skin rash, predominantly on the face and upper torso (86% with any grade; 18% with grade 3), and a composite of asthenia, fatigue, malaise, or lethargy (56% with any grade, 9% with grade 3). Two patients (3.5%) experienced grade 3 allergic reactions requiring discontinuation of study treatment. A third patient experienced a grade 3 allergic reaction that resolved, and the patient continued on the study. Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months. Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease.
The chemical synthesis of the bacterial O-antigen from Salmonella serogroup E1, 3-O-(4-O-beta-D-mannopyranosyl-alpha-L-rhamnopyranosyl)-alpha-D-galactos e, presents a particular challenge because it contains a beta-(1-->4) mannosidic linkage to L-rhamnose. We report a chemoenzymatic synthesis of this crucial antigenic material which culminates in the enzymatic formation of the critical beta-mannosyl connection catalyzed by Salmonella GDP-alpha-D-Man:alpha Rha1-->3 alpha Gal-PP-Und beta-(1-->4)-mannosyltransferase (ManT beta 4). In comparison with previous synthetic routes, this method is advantageous since it utilizes intermediates, available in significant yield, which can be readily derivatized from the reducing end to present flexibility for analog construction, while the enzymatic construction of the Man1-->4Rha glycosidic bond is both rapid and occurs in high yield. Furthermore, the reported spectroscopic and enzymatic structural characterization of the trisaccharide product furnishes the first indisputable functional link between wbaO and ManT beta 4 and clearly sets the stage for the future mechanistic study and exploitation of this fascinating glycocatalyst.
Kalisiak A, Oosterwijk E, Minniti JG, Old LJ, Scheinberg DA
Glycoconjugate journal •
A monoclonal antibody (mAb 8281) specific for the terminal beta-galactose (beta Gal) of glycosphingolipids (GSL) and glycoproteins was produced from mice immunized with lipid extract from fresh acute lymphocytic leukemia (ALL) cells. Immuno-thin layer chromatography (ITLC) and competition assays with purified neutral GSL standards, free sugars, and synthetic neoglycoproteins showed mAb 8281 to be strongly reactive with LacCer, GalCer and Gal-beta-O-(CH3)2S(CH3)2-CONH-(Gal-beta-O-CETE) linked to bovine serum albumin (BSA). The penultimate sugar also played a role in binding. The antibody was not reactive with carbohydrates with terminal alpha Gal structures and unrelated terminal moieties. Indirect immunoperoxidase staining and flow cytometry with mAb 8281 demonstrated positive staining on numerous tissues, including smooth muscle, gastrointestinal mucosa, lymph node B cells and monocytes. ITLC analysis of the GSL composition of fresh B cell neoplasms using mAb 8281 confirmed the presence of lactosylceramide and galactosylceramide in neoplasms of varying stages of differentiation. Because of its specificity for terminal beta Gal carbohydrate residues, mAb 8281 may be useful in structural and functional analyses of GSL.
