Institutional experiences with panitumumab monotherapy in metastatic colorectal cancer (mCRC) patients (pts) intolerant to cetuximab

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14579-14579 ◽  
Author(s):  
A. D. Langerak ◽  
E. Mitchell ◽  
P. Cheema ◽  
G. L. River ◽  
M. Shing

14579 Background: Two monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor are approved for the treatment (tx) of advanced mCRC - panitumumab (Vectibix™), a fully human mAb, and cetuximab (Erbitux®), a chimeric mAb. Potential for cross-reactivity between these two mAbs with regard to infusion reactions (IR) has not been fully explored. Given the lack of sequence homology between the 2 agents and the fully human nature of panitumumab, it is hypothesized that pts intolerant to cetuximab due to IR could be tolerant to panitumumab. Methods: Single pt tx IND applications to administer panitumumab monotherapy in pts with advanced mCRC were approved by the FDA and local institutions as part of the Panitumumab Compassionate Use program. Eligibility also included previous tx with standard chemotherapy and intolerability to cetuximab, ie. CTCAE v3.0 grade 3 (severe) or grade 4 (life-threatening) IR. Results: Upon informed consent, 4 pts (2M/ 2F) were enrolled in 4 centers. Median (range) age was 62.5 (52, 64) years. 3 pts had colon cancer and 1 pt had rectal cancer. All had surgery and received prior 5-fluorouracil, leucovorin, irinotecan, oxaliplatin, bevacizumab, and cetuximab. One pt had a CTC grade 3 IR and 3 pts had a CTC grade 4 IR to cetuximab. IR symptoms included fever, wheezing, dyspnea, chest/back/abdominal pain, anxiety, hypotension, flushing, tachycardia, and tachypnea. Two IRs occurred within 10 minutes of the first cetuximab infusion. Cetuximab was discontinued and IR symptoms were treated with bronchodilators, diphenhydramine, epinephrine, methylprednisolone, oxygen, intravenous saline, and hospitalization. All pts received panitumumab. Data for pts 1, 2, and 3 are available: pt 1 received 1 infusion of panitumumab at 5 mg/kg Q2W with premedication (diphenhydramine and methylprednisolone); pts 2 and 3 received 7 and 2 panitumumab infusions, respectively, at 6 mg/kg Q2W without premedication. No pt had an IR to panitumumab. Pt 2 had stable disease; pts 1 and 3 died due to disease progression. Conclusions: Panitumumab monotherapy was tolerated without incidence of an IR in these cases of mCRC pts who are intolerant to cetuximab due to a severe or life-threatening IR. Additional data will be presented. No significant financial relationships to disclose.

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4138-4138 ◽  
Author(s):  
M. Peeters ◽  
E. Van Cutsem ◽  
J. Berlin ◽  
J. R. Hecht ◽  
R. Ruiz ◽  
...  

4138 Background: Panitumumab is indicated in pts with EGFr-expressing mCRC refractory to chemotherapy. We present a summary of safety with panitumumab monotherapy in mCRC pts across 10 clinical trials. Methods: Data were pooled from pts enrolled in 10 clinical trials (including 2 extension studies). Pts received at least 1 dose of panitumumab at 2.5 mg/kg QW, 6 mg/kg Q2W, or 9 mg/kg Q3W. Adverse events were graded using NCI-CTC or CTCAE criteria. Results: A total of 920 mCRC pts were included in this analysis: 60% were male; 88% were white; median age (range) was 61 (20, 88) years. All pts had prior therapy; 77% had failed prior fluoropyrimidine, irinotecan, and/or oxaliplatin. Most (80%) pts received panitumumab 6 mg/kg Q2W; 17% and 3% of pts received panitumumab 2.5 mg/kg QW and 9 mg/kg Q3W, respectively. Median (range) follow-up time was 21 (1–124) weeks. A total of 7264 panitumumab infusions were administered with a median (range) of 5 (1–94) infusions/pt. Treatment-related adverse events (AE) were experienced by 94% (grade = 3, 20%) of pts. All pts had = 1 AE. The most common AEs were skin-related and GI toxicities ( table ). Skin-related AEs resulted in discontinuation in 2% of pts. Overall, 12% of pts discontinued panitumumab due to toxicity. Four (0.4%) pts had grade = 3 infusion reactions. In pts with postdose samples (n = 613), increased and persistent postdose levels of anti-panitumumab antibodies were detected in 0.5% of pts by ELISA and in 4.6% of pts by Biacore assay. Conclusions: Skin toxicity was common, but rarely treatment-limiting. Most AEs were mild to moderate and infrequently resulted in discontinuation. Infusion reactions and formation of anti-panitumumab antibodies were rare. The safety profile of 9 mg/kg Q3W panitumumab appeared consistent with other dosages; however, because of the small pt size further evaluation is needed. Panitumumab at 2.5 mg/kg QW and 6 mg/kg Q2W was well tolerated across 10 clinical studies. [Table: see text] No significant financial relationships to disclose.


Author(s):  
Shigeru Nakagaki ◽  
Ryoichi Matsunuma ◽  
Kei Yamaguchi ◽  
Ryosuke Hayami ◽  
Michiko Tsuneizumi

Aims:Pertuzumab plus trastuzumab and docetaxel is a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Infusion reaction represents one of the common side effects of anti-HER2 agents. There is no standard premedication to prevent infusion reactions, although antihistamines, acetaminophen, and/or corticosteroids are often used for this purpose. This study evaluated the ability of premedication to prevent induction reactions in patients receiving pertuzumab, trastuzumab, and docetaxel. Methods: This retrospective, single-institute study assessed infusion reactions in 72 women with HER2-positive early breast cancer who received pertuzumab, trastuzumab, and docetaxel between November 2018 and April 2021. Thirty-six patients received premedication consisting of oral acetaminophen prior to pertuzumab and trastuzumab administration and dexamethasone and D-chlorpheniramine maleate intravenously prior to docetaxel administration (previous regimen). Thirty-six patients received premedication consisting of acetaminophen, dexamethasone, and D-chlorpheniramine maleate sequentially prior to pertuzumab, trastuzumab, and docetaxel administration (current regimen). Results: The rates of infusion reaction after the initial injection were 55.6 and 16.7% in the previous and current regiment groups, respectively (p = 0.001). Trastuzumab more frequently caused infusion reactions than pertuzumab and docetaxel. Chills, vomiting, and nausea were the major symptoms of infusion reactions. Conclusion: Premedication featuring the upfront use of dexamethasone and D-chlorpheniramine maleate prior to the administration of anti-HER2 targeted agents significantly prevented infusion reactions.


2019 ◽  
Vol 26 (5) ◽  
Author(s):  
R. Arora ◽  
M. Kisiel ◽  
C. MacColl

Mutations in EGFR have been implicated in the pathogenesis of various types of cancer, and therefore antibody therapy directed against the epidermal growth factor receptor (egfr) is increasingly being used in the management of various cancers. Currently, anti-egfr antibodies are used mainly in the management of cancers of the head and neck and metastatic colorectal cancers. Because of this increasing use, we would like to inform the oncology community in North America of a rare, but life-threatening, toxicity associated with anti-egfr antibody therapy. Although cases in white and Japanese men have been documented, we present the first known North American report of panitumumab-induced pulmonary toxicity in a white woman.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3552-3552 ◽  
Author(s):  
J. P. Machiels ◽  
C. Sempoux ◽  
P. Scalliet ◽  
J. C. Coche ◽  
B. Coster ◽  
...  

3552 Background: Capecitabine has the potential to replace 5-FU as standard agent in combination with radiotherapy in rectal cancer. Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. Both agents are active in the treatment of colorectal cancer and have demonstrated radiosensitising properties. The aim of this study was to assess the feasibility of combining cetuximab and capecitabine with concurrent radiation in the preoperative treatment of patients with rectal cancer. Methods: Twenty patients with rectal cancer (T3-T4 and/or N+, endorectal ultrasound) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformal technique) in combination with cetuximab (initial dose 400 mg/m2 given one week before the beginning of radiation followed by 250 mg/m2/week for 5 weeks) and 2 different doses of capecitabine for the duration of radiotherapy (650 mg/m2 twice-daily, first dose level; 825 mg/m2 twice-daily, second dose level, including weekends). During treatment all patients were scored weekly using the NCI-CTC v.2.0. Dose-limiting toxicity (DLT) was defined acccording to Dunst (JCO 2002). Six to 8 weeks after the end of chemoradiation surgery was performed. Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No DLT occurred at either capecitabine dose. Ten additional patients were treated at the higher dose level. Out of these 20 patients, Grade 3 toxicity included diarrhea (n=2), rectal pain (n=5), ileitis (n=2), radiation dermatitis (n=1) and neutropenia (n=1). The most frequent grade 1/2 side effects were acneiform rash (n=16, 80%), fatigue (n=12, 60%), and diarrhea (n=12, 60%). Until now, 2 pathological complete responses were observed in 19 evaluable patients. Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible and well-tolerated with promising efficacy results. The recommended doses for phase II evaluation are capecitabine 825 mg/m2 twice-daily without interruption during the duration of radiotherapy and cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2/week. No significant financial relationships to disclose.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7528-7528
Author(s):  
M. A. Socinski ◽  
T. E. Stinchcombe ◽  
J. S. Halle ◽  
D. T. Moore ◽  
W. J. Petty ◽  
...  

7528 Background: Therapies directed at both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways have been shown to improve survival in NSCLC and also have radiosensitizing properties. Methods: Pts receive Ind Cb (AUC 6), P (225 mg/m2) and B (15 mg/kg) on d1 and 22. PET scans are done pre- and post-I. On day 43, pts receive weekly Cb (AUC 2 x 7) and P (45 mg/m2 x 7) with 74 Gy (2 Gy/d) of thoracic conformal radiotherapy (TCRT). Cohort I (n=5) received B at 10 mg/kg q2wks during C therapy. Cohorts II and III (both n=5) received the same dose of B as in cohort I but also received Er at 100 mg and 150 mg po Tuesday - Friday of each week of C therapy, respectively. The primary endpoint is PFS at 1 year. All histologies are allowed including squamous (SQ) (an early stopping rule is in place for pulmonary hemorrhagic (PH) complications in SQ pts). Results: Thus far, 31 eligible PS 0–1 pts have been accrued (med age 62 yrs, range 41–74, 19 non- squamous, 12 SQ, 63% IIIA, 37% IIIB). Ind CbP + B has been well tolerated (1 gr 3 hypertension). No PH during Ind has been seen (including the 12 SQ cell pts). Response after Ind, 37% PR, 59% SD, 4% PD. Tumor volumes and PET SUVs have significantly decreased comparing pre- and post-Ind studies (p=0.0001 and p=0.0002, respectively). Cohort II has been expanded as the phase II regimen. To date, 25 of 26 (96%) pts have achieved the dose of 74 Gy (1 pt stopped at 60 Gy due to ILD). During Conc therapy, the principal toxicity has been esophagitis (53.8% gr 2, 19.2% gr 3). One grade 3 PH occurred in 1 SQ pt. One gr 5 late (> 2 mos after treatment) PH occurred in a SQ pt. Overall response rate following treatment - 68.2% (95% CI, 45–86%). The PFS at 1 year is 58% (95% CI, 34–76%) with an estmated 1-year overall survival rate of 79% (95% CI, 53–92%) which compares favorably to our historical experience. Conclusions: Preliminarily, we conclude that 1) Incorporation of B and E into this treatment paradigm appears feasible, 2) Esophagitis remains the primary toxicity, 3) Phase II accrual continues but early analysis of survival appears promising. Further details regarding the TCRT parameters and toxicity will be presented. [Table: see text]


2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA7005-LBA7005 ◽  
Author(s):  
G. D. Goss ◽  
I. Lorimer ◽  
M. S. Tsao ◽  
C. J. O'Callaghan ◽  
K. Ding ◽  
...  

LBA7005 Background: In meta-analyses, platinum-based adjuvant (adj) chemotherapy (CT) in completely resected NSCLC increased cure rate by ∼5%. At BR.19 initiation, adj study results with third-generation agents were unavailable. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed activity in monotherapy trials. We report a trial of adj gefitinib versus placebo after complete resection of NSCLC. Methods: Patients (pts) with stage IB-IIIA NSCLC were stratified by sex, stage, histology, post-op radiation, and after Jan 2003, adj CT. Pts were randomized to gefitinib 250 mg or placebo daily x 2 years. Study endpoints included overall survival (OS), disease free survival (DFS), toxicity, preplanned correlative studies. Study closed prematurely in Apr. 2005. Trial committee and NCIC CTG staff remained blinded to study drug. Results: 503 pts randomized (Sep 2002-Apr 2005); median age 67, males 54%, PS 0 54%; stage IB 49%, II 38%, III 13%; adenocarcinoma 59%, squamous 28%; ever smokers 89%; adj CT 17%; lobectomy 82%. Commonest grade 3/4 toxicities = fatigue 5%, rash 4% and diarrhea 5%. grade 3+ pneumonitis in 7 (1.4%) pts and led to death in 1. Median follow-up is 4.7 yrs; median treatment time is 4.8 mos. For gefitinib versus placebo, median DFS is 4.2 yrs versus not yet reached (NYR) HR1.22 (95% C.I. 0.93-1.61), p=0.15 and median OS 5.1 yrs versus NYR HR 1.24 (95% C.I. 0.94-1.64), p=0.14. In multivariate analysis, tumor size >4cm was predictive of poor DFS (p<0.0001) and never smoking for better OS with gefitinib (p=0.02). Results for KRAS and EGFR copy are available on 350 and 348 pts respectively. KRAS mutations were neither prognostic HR 1.12 (95% C.I. 0.67-1.86), p=0.66 nor predictive of gefitinib benefit (p = 0.16) on OS. EGFRcopy whether low/high polysomy or amplification was neither prognostic (p=0.77) nor predictive of OS benefit from gefitinib. Conclusions: Adjuvant gefitinib after complete resection of early stage NSCLC did not confer DFS or OS advantage in overall population. KRAS and EGFR copy were neither prognostic nor predictive of benefit from gefitinib. EGFR mutational analysis will be presented. [Table: see text]


2014 ◽  
Vol 32 (25) ◽  
pp. 2750-2757 ◽  
Author(s):  
Véronique Diéras ◽  
Nadia Harbeck ◽  
G. Thomas Budd ◽  
Joel K. Greenson ◽  
Alice E. Guardino ◽  
...  

Purpose The antibody–drug conjugate trastuzumab emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) –targeted, antitumor properties of trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. Patients and Methods Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. Results Among 884 T-DM1–exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%. Conclusion In this analysis of 884 T-DM1–exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings.


2002 ◽  
Vol 20 (21) ◽  
pp. 4292-4302 ◽  
Author(s):  
J. Baselga ◽  
D. Rischin ◽  
M. Ranson ◽  
H. Calvert ◽  
E. Raymond ◽  
...  

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.


2021 ◽  
Author(s):  
Takahiro Arai ◽  
Yukiyoshi Fujita ◽  
Hisao Imai ◽  
Hiroe Matsumoto ◽  
Miho Yamazaki ◽  
...  

Abstract Seasonal climatic changes may affect the development of the rash that is characteristic of treatment with anti-epidermal growth factor receptor (EGFR) antibodies. This study evaluated the association between seasons and rash incidence among patients with cancer in Japan. Data of patients with colorectal or head and neck cancer treated with cetuximab or panitumumab during summer (S group; N = 34) or winter (W group; N = 37) between June 2014 and February 2019 were collected to retrospectively examine patient characteristics and rash incidence for ≤8 weeks after treatment initiation. Rashes were observed in 73.5% (N = 25) and 78.4% (N = 29) and grade 3 rashes were observed in 17.6% (N = 6) and 2.7% (N = 1) of the patients in the S and W groups, respectively, indicating higher rash incidence during summer (p = 0.09). Incidence of grade ≥2 rash in men in the S group was higher than that in the rest of the patient groups (p < 0.01), suggesting that rashes were more severe in men during summer. The higher incidence of skin rashes in men during summer might be attributed to the effects of ultraviolet light, lack of skincare, male hormones, and secretion of anti-EGFR antibodies in sweat. These findings highlighted the need for research on preventive measures for such rashes.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15509-15509
Author(s):  
A. T. Chan ◽  
B. Ma ◽  
E. P. Hui ◽  
A. King ◽  
M. Kam ◽  
...  

15509 Background: Our preclinical work has shown that epidermal growth factor receptor (EGFR) is expressed in ∼ 80% of undifferentiated NPC & gefitinib is a small molecule inhibitor against EGFR with anti-proliferative activity in NPC in vitro. Methods: We report the preliminary result of a phase II study of gefitinib in patients (pts) who progressed after 1–2 lines of chemotherapy (at least 1 line had to contain platinum) for metastatic or locoregionally recurrent NPC. Fourteen Chinese pts were accrued, of whom the median age was 48 years (range 34–64 years), 12 were males, 9 had metastatic & 5 had locoregionally recurrent NPC. All received gefitinib at 500mg/day orally, every 28 days with radiological assessment performed every 2 cycles for a maximum of 8 cycles. Ten pts had 1 line & 5 pts had 2 lines of prior chemotherapy. Results: The median number of administered cycles was 2 (range 1–8). Of the 14 pts evaluable for toxicity, the most commonly reported were acneiform rash (86%, grade 1–2, n = 10; grade 3, n = 4), dry skin (86%, grade 1–2), diarrhea (71%, grade 1–2), fatigue (64%, grade 1–2), anorexia (64%, grade 1–2) & nausea (20%, grade 2). Other grade 3–4 toxicities included fever (n = 2, skin cellulitis, infective pneumonia), hyponatremia (n = 2), near-syncope (n = 2), anemia (n = 1). Dose reduction to 250mg/day was required in 4 pts who encountered grade 3 skin rash. Of the 11 pts evaluable for response, 2 had stable disease (SD) for ≥ 6 months (m) (mean 6.8 m) 9 progressed and no partial responders. Five pts have died mostly of progressive disease & there were no treatment-related deaths. Conclusions: Gefitinib is well tolerated in pts with advanced NPC with some pts experiencing disease stabilization for over 6 months & study accrual is ongoing. No significant financial relationships to disclose.


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