Current Recommendations and Novel Strategies for the Management of Skin Toxicities Related to Anti-EGFR Therapies in Patients with Metastatic Colorectal Cancer.

The use of targeted therapies, when added to conventional chemotherapy, has significantly improved clinical outcomes and survival of cancer patients. While targeted therapies do not have the systemic adverse reactions of chemotherapy, they are associated with toxicities that can be severe and impair patient quality of life and adherence to anti-cancer treatment. Panitumumab and cetuximab, two monoclonal antibodies against epidermal growth factor receptor (EGFR), are recommended for the treatment of metastatic colorectal cancer (mCRC). The majority of patients with mCRC who are treated with anti-EGFR therapy develop skin toxicities, including papulopustular rash (the most common), xerosis, painful cracks and fissures on the palms and soles of the feet, paronychia, pruritus, and abnormal hair and eyelash growth; they are also more prone to skin infections. Given the involvement of EGFR in normal epidermis physiology, development and function, skin toxicities caused by anti-EGFR therapy are not unexpected. In recent years, recommendations have been formulated for the prevention and treatment of anti-EGFR therapy-related skin toxicities. Indeed, proper and timely management of these toxicities is important for ensuring uninterrupted anti-cancer treatment and optimal outcomes. Here, we review the current knowledge of anti-EGFR therapy-related skin toxicities and the latest recommendations for their management. We also present a treatment approach for papulopustular rash based on the combination of fusidic acid plus betamethasone in a lipid-enriched topical formulation. The effectiveness of this approach is documented by the presentation of five cases successfully treated in clinical practice for anti-EGFR therapy-related rash.

Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies.

Epidermal growth factor receptor (EGFR) ectodomain variants mediating primary resistance or secondary treatment failure in cancer patients treated with cetuximab or panitumumab support the need for more resistance-preventive or personalized ways of targeting this essential pathway. Here, we tested the hypothesis that the EGFR nanobody 7D12 fused to an IgG1 Fc portion (7D12-hcAb) would overcome EGFR ectodomain-mediated resistance because it targets a very small binding epitope within domain III of EGFR. Indeed, we found that 7D12-hcAb bound and inhibited all tested cell lines expressing common resistance-mediating EGFR ectodomain variants. Moreover, we assessed receptor functionality and binding properties in synthetic mutants of the 7D12-hcAb epitope to model resistance to 7D12-hcAb. Because the 7D12-hcAb epitope almost completely overlaps with the EGF-binding site, only position R377 could be mutated without simultaneous loss of receptor functionality, suggesting a low risk of developing secondary resistance toward 7D12-hcAb. Our binding data indicated that if 7D12-hcAb resistance mutations occurred in position R377, which is located within the cetuximab and panitumumab epitope, cells expressing these receptor variants would retain sensitivity to these antibodies. However, 7D12-hcAb was equally ineffective as cetuximab in killing cells expressing the cetuximab/panitumumab-resistant aberrantly N-glycosylated EGFR R521K variant. Yet, this resistance could be overcome by introducing mutations into the Fc portion of 7D12-hcAb, which enhanced immune effector functions and thereby allowed killing of cells expressing this variant. Taken together, our data demonstrate a broad range of activity of 7D12-hcAb across cells expressing different EGFR variants involved in primary and secondary EGFR antibody resistance.