Beyond rash management with amivantamab-lazertinib for EGFR-mutated non-small cell lung cancer: the unresolved challenge of paronychia in the COCOON trial

We would like to comment on the COCOON global randomized controlled trial (NCT06120140) by Cho et al., which was published in the Journal of Thoracic Oncology (1). The main objective of this study was to evaluate the effect of enhanced dermatologic management (COCOON DM) comparing standard of care (SoC) on the incidence of dermatologic adverse events (AEs) in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who received amivantamab-lazertinib.

Amivantamab-lazertinib established as a new SoC for advanced-stage common EGFR-mutated NSCLC based on results of the MALIPOSA phase III study, which demonstrated superiority of overall survival (OS) and progression-free survival (PFS) comparing osimertinib monotherapy (2,3), and is strongly recommended in current guidelines (4). However, in the MALIPOSA study, amivantamab-lazertinib increased grade 3 or higher dermatologic AEs, especially paronychia (12% vs. 1%), rash (17% vs. 8%), and dermatitis acneiform (9% vs. 3%). These dermatologic AEs influence patients’ quality of life (QoL) and treatment delivery/dose intensity, resulting treatment efficacy and survival.

The COCOON trial was a randomized, phase II, open-label, global multicenter study. This study evaluated 201 patients with treatment-naïve metastatic NSCLC harboring EGFR Ex19del or L858R mutations. The primary end point was the incidence of grade ≥2 dermatologic AEs of interest (DAEIs) during the first 12 weeks of amivantamab-lazertinib treatment. The COCOON DM consisted of the following three components (Figure 1):

• Antibiotic prophylaxis (oral doxycycline or minocycline 100 mg twice daily during weeks 1–12, followed by topical clindamycin 1% lotion applied once daily to the scalp at bedtime from week 13 onward);
• Nail care (once-daily washing of the fingernails and toenails with 4% chlorhexidine);
• Long-acting skin hydration (application of a ceramide-based moisturizer to the body and face at least once daily).

Figure 1 Schematic overview of the COCOON DM. The COCOON DM consisted of the following three components: (I) antibiotic prophylaxis (oral doxycycline or minocycline 100 mg twice daily during weeks 1–12, followed by topical clindamycin 1% lotion applied once daily to the scalp at bedtime from week 13 onward); (II) nail care (once-daily washing of the fingernails and toenails with 4% chlorhexidine); and (III) long-acting skin hydration (application of a ceramide-based moisturizer to the body and face at least once daily). AEs, adverse events; DM, dermatologic management.

The COCOON DM significantly reduced the incidence of grade 2 or higher DAEIs [42% vs. 75%; odds ratio (OR) =0.24; P<0.0001] and improved the change of Skindex-16 QoL score at cycle 1 day 15 (7.4 vs. 25.2, P<0.001) and at cycle 6 day 1 (20.4 vs. 29.2, P=0.0310). The authors concluded that prophylactic regimen (COCOON DM) reduced the incidence of DAEIs with amivantamab-lazertinib and the impact of QoL.

Interestingly, oral prophylactic tetracycline antibiotics were administrated only during the first 3 months; however, the reduction in incidence of rash was maintained at 6 months. Therefore, the benefits of tetracycline antibiotic prophylaxis appear to extend beyond the initial period. The COCOON study highlighted that intensive prophylactic strategies improved the incidence of higher-grade dermatologic AEs and sustained QoL.

However, the COCOON DM did not reduce the incidence of grade ≥2 paronychia despite the prophylactic use of tetracycline antibiotics and chlorhexidine to wash the fingernails and toenails (21% vs. 23%, P=0.763). In the management of anticancer therapy-related paronychia, daily antiseptic soaks using agents such as chlorhexidine or povidone-iodine have been suggested as part of routine care in the previous review article (5). Nevertheless, the evidence supporting their effectiveness is limited. Current recommendations are largely derived from expert opinion and small observational reports rather than randomized controlled trials. Consequently, antiseptic soaks should not be regarded as an evidence-based treatment for paronychia itself. Rather, they are generally used as supportive measures intended to reduce microbial colonization and prevent secondary bacterial infection of the periungual tissue.

From biological perspective, evidence regarding the underlying mechanisms of EGFR inhibitor-induced paronychia remains limited. The nail matrix and nail bed contain a large number of keratinocytes (6,7) that highly express EGFR, similar to cutaneous keratinocytes (8). EGFR signaling plays several crucial roles in regulating the proliferation, differentiation, and apoptosis of keratinocytes (9,10). EGFR inhibitors trigger keratinocyte growth arrest and terminal differentiation (11). To date, clear empirical evidence remains lacking regarding how the effects of EGFR inhibitors differ between nail and cutaneous keratinocytes. Insight into the distinct biological features of nail keratinocytes will further refine prophylactic and therapeutic interventions for EGFR inhibitor-induced paronychia.

From clinical relevance viewpoints, mechanical stress and secondary infection serve as key contributing factors to the exacerbation of paronychia. In the COCOON study, approximately 60% of eligible patients were female. Given that many female patients frequently perform household chores and cooking involving repeated exposure to water, such lifestyle factors may contribute to the development or exacerbation of paronychia during amivantamab-lazertinib treatment. According to Asia-Pacific practical consensus, wearing gloves, avoiding restrictive shoes, and regular nail trimming are recommended as daily prophylaxis for patients treating with amivantamab-based therapies (12). Furthermore, the 4% chlorhexidine used in the COCOON DM is considered excessively irritating to human skin. Consequently, this practical consensus recommends 0.005% dilute bleach or 1% dilute white vinegar for daily nail baths.

Moving forward, it is crucial to identify which patient characteristics, such as sex, duration of water exposure, and occupation, are associated with the exacerbation of paronychia in larger cohorts of patients receiving amivantamab-based therapy. Subsequently, prospective clinical trials should be conducted to evaluate the efficacy of above specific prophylactic interventions, including the use of gloves, avoidance of wet work, and restriction of tight-fitting shoes for identified high-risk patients.

Acknowledgments

The author wishes to thank Mr. Jason Tonge from St. Marianna University School of Medicine for reviewing the language of this article.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0681/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0681/coif). N.F. reports personal fees and honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, MSD, Johnson & Johnson, and Regeneron, outside the submitted work. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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