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The British Journal of Ophthalmology May 2024In experimental studies, intravitreally applied antibodies against epidermal growth factor (EGF), EGF family members (amphiregulin, neuregulin-1, betacellulin, epigen,...
BACKGROUND
In experimental studies, intravitreally applied antibodies against epidermal growth factor (EGF), EGF family members (amphiregulin, neuregulin-1, betacellulin, epigen, epiregulin) and against the EGF receptor (EGFR) were associated with a reduction in lens-induced axial elongation and decrease in physiological eye elongation in guinea pigs and in non-human primates. Here, we investigated the intraocular tolerability and safety of a fully human monoclonal IgG2-antibody against EGFR, already in clinical use in oncology, as a potential future therapeutic approach for axial elongation in adult eyes with pathological myopia.
METHODS
The clinical, monocentre, open-label, multiple-dose, phase-1 study included patients with myopic macular degeneration of stage 4, who received intravitreal injections of panitumumab in various doses and in intervals ranging between 2.1 months and 6.3 months.
RESULTS
The study included 11 patients (age:66.8±6.3 years), receiving panitumumab injections in doses of 0.6 mg (4 eyes; 1×1 injection, 3×2 injections), 1.2 mg (4 eyes; 1×1 injection, 2×2 injections, 1×3 injections) and 1.8 mg (3 eyes; 1×1 injection, 2×2 injections), respectively. None of the participants showed treatment-emergent systemic adverse events or intraocular inflammatory reactions. Best-corrected visual acuity (1.62±0.47 logarithm of the minimal angle of resolution (logMAR) vs 1.28±0.59 logMAR; p=0.08) and intraocular pressure (13.8±2.4 mm Hg vs 14.3±2.6 mm Hg; p=0.20) remained unchanged. In nine patients with a follow-up of >3 months (mean:6.7±2.7 months), axial length did not change significantly (30.73±1.03 mm vs 30.77±1.19 mm; p=0.56).
CONCLUSIONS
In this open-labelled, phase-1 study with a mean follow-up of 6.7 months, panitumumab repeatedly administered intravitreally up to a dose of 1.8 mg was not associated with intraocular or systemic adverse effects. During the study period, axial length remained unchanged.
TRIAL REGISTRATION NUMBER
DRKS00027302.
Topics: Humans; Panitumumab; Intravitreal Injections; Female; Male; Aged; Middle Aged; Visual Acuity; Myopia, Degenerative; Tomography, Optical Coherence; Treatment Outcome; Macular Degeneration; ErbB Receptors; Dose-Response Relationship, Drug; Follow-Up Studies
PubMed: 37429701
DOI: 10.1136/bjo-2023-323383 -
Annales de Dermatologie Et de... Jun 2024
Topics: Aged; Female; Humans; Antineoplastic Agents, Immunological; Collagen Diseases; Drug Eruptions; Panitumumab
PubMed: 38678770
DOI: 10.1016/j.annder.2024.103271 -
European Journal of Cancer (Oxford,... Aug 2023In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient's perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS
We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4-6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone.
RESULTS
Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance.
CONCLUSIONS
Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.
Topics: Humans; Bevacizumab; Colorectal Neoplasms; Panitumumab; Camptothecin; Colonic Neoplasms; Rectal Neoplasms; Fluorouracil; Antineoplastic Combined Chemotherapy Protocols; Leucovorin
PubMed: 37301718
DOI: 10.1016/j.ejca.2023.05.001 -
Current Problems in Cancer Aug 2023The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes... (Review)
Review
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins B-raf; Mutation; Antineoplastic Agents; Panitumumab; Colorectal Neoplasms
PubMed: 37285606
DOI: 10.1016/j.currproblcancer.2023.100960 -
Current Treatment Options in Oncology Dec 2023Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or... (Review)
Review
Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or panitumumab) or anti-VEGF antibody (bevacizumab). Predictive biomarkers include mismatch repair (MMR) status, and RAS and BRAF mutation status; and important factors in treatment selection include primary tumor location, intent of therapy, and potential toxicity, as well as patient age, comorbidities, and patient preference. To date, single-, double-, or triple-agent cytotoxic chemotherapy all have important roles in appropriately selected patients, with the addition of anti-VEGF or anti-EGFR antibody therapy based on the relevant predictive biomarker. Data indicate that patients with proficient MMR, RAS/BRAF wt mCRC are candidates for an anti-EGFR antibody plus doublet chemotherapy if they have a left-sided primary tumor, or for anti-VEGF (bevacizumab) plus doublet or triplet chemotherapy if they have a right-sided primary tumor. Future studies may provide more predictive biomarkers to further personalize therapy for this heterogeneous disease.
Topics: Humans; Bevacizumab; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Antineoplastic Agents; Cetuximab; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Microsatellite Repeats; Antineoplastic Combined Chemotherapy Protocols; Mutation
PubMed: 37966682
DOI: 10.1007/s11864-023-01142-8 -
JAMA Network Open Apr 2024The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF...
IMPORTANCE
The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies.
OBJECTIVE
To evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC.
DESIGN, SETTING, AND PARTICIPANTS
This nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months).
INTERVENTION
Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy.
MAIN OUTCOMES AND MEASURES
Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported.
RESULTS
Overall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects.
CONCLUSIONS AND RELEVANCE
These findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.
Topics: Humans; Male; Middle Aged; Cetuximab; Colonic Neoplasms; ErbB Receptors; Irinotecan; Liver Neoplasms; Panitumumab; Prospective Studies; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; Retrospective Studies; Trifluridine; Female; Adult; Aged; Aged, 80 and over
PubMed: 38592721
DOI: 10.1001/jamanetworkopen.2024.5635 -
The Oncologist Dec 2023Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to...
INTRODUCTION
Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC.
METHODS
Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status.
RESULTS
No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment.
CONCLUSIONS
The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).
Topics: Humans; Panitumumab; Colorectal Neoplasms; Benzimidazoles; Colonic Neoplasms; Rectal Neoplasms; ErbB Receptors; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras)
PubMed: 37597246
DOI: 10.1093/oncolo/oyad210 -
Proceedings of the National Academy of... Mar 2024FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to...
FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different hotspot mutations in human colon organoids. Functionally, mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.
Topics: Humans; F-Box-WD Repeat-Containing Protein 7; Ubiquitin-Protein Ligases; Epidermal Growth Factor; Proteomics; ErbB Receptors; Neoplasms; F-Box Proteins
PubMed: 38483988
DOI: 10.1073/pnas.2309902121 -
Oral Oncology Jan 2024The well-studied role of epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (NSCLC) has enabled the...
The well-studied role of epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (NSCLC) has enabled the development of drugs that target this molecule, including panitumumab for the former and osimertinib for the latter. Oral adverse events due to those agents are rarely described in the literature and their exact characterization is hampered by inadequate reporting and/or incorrect terminology used. We report two cases of panitumumab- and osimertinib-associated oral ulcerations with emphasis on their possible pathogenesis and optimal management.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Panitumumab; Lung Neoplasms; Antineoplastic Agents; Aniline Compounds; Mutation; Protein Kinase Inhibitors
PubMed: 38086198
DOI: 10.1016/j.oraloncology.2023.106660 -
Clinical Cancer Research : An Official... Oct 2023High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in...
PURPOSE
High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis.
EXPERIMENTAL DESIGN
Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS).
RESULTS
A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection.
CONCLUSIONS
High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.
Topics: Humans; Amphiregulin; Epiregulin; Cetuximab; Panitumumab; Retrospective Studies; Colorectal Neoplasms; Artificial Intelligence; Intercellular Signaling Peptides and Proteins; Colonic Neoplasms; Rectal Neoplasms; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors
PubMed: 37363997
DOI: 10.1158/1078-0432.CCR-23-0859