Cutaneous Toxicities Associated With Amivantamab in Patients With Non‐Small Cell Lung Cancer: A Systematic Review

Amivantamab is an epidermal growth factor receptor (EGFR)/mesenchymal-epithelial transition factor (MET) targeting bispecific antibody used for the treatment of non-small cell lung cancer (NSCLC) [1, 2]. Cutaneous adverse events (cAEs) are commonly reported with amivantamab, particularly in clinical trial settings [1, 2]. However, the overall frequency and spectrum of cAEs across clinical trials have not been systematically summarized, and various non-reported toxicities have emerged with its real-world use [3]. The aim of this systematic review was to synthesize the available evidence on amivantamab-associated cAEs. Passaro (2024) https://doi.org/10.1016/j.annonc.2023.10.117 MARIPOSA-2 III Acneiform dermatitis Paronychia Non-specified rash Pruritus 7 (3) 1 (0.4) 12 (5) 17 (7) 0 (0) 0 (0) 0 (0) 0 (0) Acneiform dermatitis Paronychia Non-specified rash Pruritus 26 (20) 48 (37) 56 (43) 20 (15) 5 (4) 3 (2) 8 (6) 0 (0) Acneiform dermatitis Paronychia Non-specified rash Pruritus 62 (24) 133 (51) 126 (48) 30 (11) 17 (6) 11 (4) 17 (6) 0 (0) Zhou (2023) https://doi.org/10.1056/nejmoa2306441 PAPILLON III Acneiform dermatitis Non-specified rash Paronychia 5 (3) 12 (8) 0 (0) 0 (0) 0 (0) 0 (0) Acneiform dermatitis Non-specified rash Paronychia 47 (31) 81 (54) 85 (56) 6 (4) 17 (11) 10 (7) Park (2021) https://doi.org/10.1200/JCO.21.00662 CHRYSALIS Ib Non-specified rash Paronychia Dry Skin Pruritus 202 (78) 104 (40) 33 (13) 49 (19) 7 (3) 3 (1) 0 (0) 0 (0) Leighl (2024) https://doi.org/10.1200/jco.24.01001 PALOMA III SC amivantamab + lazertinib (n = 206) Acneiform dermatitis Paronychia Non-specified rash Pruritus 64 (31) 111 (54) 95 (46) 33 (16) 18 (9) 8 (4) 8 (4) 0 (0) IV amivantamab + Lazertinib (n = 210) Acneiform dermatitis Paronychia Non-specified rash Pruritus 69 (33) 108 (51) 91 (43) 25 (12) 12 (6) 3 (1) 8 (4) 0 (0) Yang (2025) https://doi.org/10.1056/nejmoa2503001 MARIPOSA III Acneiform dermatitis Paronychia Rash Pruritus Dry Skin 127 (30) 291 (69) 271 (64) 107 (25) 72 (17) 37 (9) 49 (12) 73 (17) 2 (< 1) 1 (< 1) Acneiform dermatitis Paronychia Rash Pruritus Dry Skin 55 (13) 127 (30) 136 (32) 75 (18) 67 (16) 0 (0) 2 (< 1) 3 (1) 1 (< 1) 1 (< 1) Cho (2023) https://doi.org/10.1038/s41591-023-02554-7 CHRYSALIS I Amivantamab+ Lazertinib All-treated (n = 91) Rash Pruritus Dry Skin Skin fissures 81 (89) 31 (34) 16 (18) 8 (9) 6 (7) 0 (0) 0 (0) 0 (0) Rash Pruritus Dry Skin Skin fissures 36 (80) 14 (31) 13 (29) 7 (16) 2 (4) 0 (0) 0 (0) 0 (0) Besse (2025) https://doi.org/10.1016/j.jtho.2024.12.029 CHRYSALIS-2 Ib Rash Paronychia Pruritus Dry Skin Skin fissures 131 (81) 84 (52) 30 (19) 39 (24) 19 (12) 17 (10) 8 (5) 1 (1) 0 (0) 0 (0) Arana (2025) https://doi.org/10.1016/j.jaad.2025.02.007 Real-world observational study Acneiform Rash Paronychia Xerosis Skin Fissures Pruritus Mucositis Ulcers/Cutaneous Lesions Maculopapular (non-acneiform) rash Alopecia 50 (68.5) 22 (30.1) 11 (15.1) 11 (15.1) 8 (10.9) 16 (21.9) 3 (4.2) 4 (5.5) 4 (5.5) MEDLINE/PubMed, Scopus, and Web of Science were searched from inception up to December 2025, following the PRISMA guidelines (Table S1 available via: https://data.mendeley.com/datasets/f859xhrp8k/1; PROSPERO: CRD420251245455). Phase I–III clinical trials and real-world observational studies reporting cAEs in patients treated with amivantamab were included, while case series/reports were excluded. Data on the type, frequency, and severity grading of cAEs were extracted as reported in each study. Overall, seven clinical trials and one real-world observational study met the inclusion criteria (Figure 1; Table S2 available via https://data.mendeley.com/datasets/f859xhrp8k/1). Across the clinical trials, 258 patients received amivantamab monotherapy, 281 received amivantamab plus chemotherapy, 1090 received amivantamab plus lazertinib, and 263 received amivantamab plus lazertinib and chemotherapy (Table 1). Paronychia was the most common cAE reported across clinical trials, ranging from 37% to 69%. The rate of paronychia was higher with amivantamab combined with lazertinib (57.3%) than with amivantamab plus chemotherapy (47.3%) or amivantamab monotherapy (40%). Grade > 3 paronychia was reported in up to 12% of patients receiving amivantamab plus lazertinib in the phase 3 MARIPOSA study. Acneiform dermatitis was also common, with reported rates ranging from 20% to 34%. It affected 25.9% of patients treated with amivantamab plus chemotherapy versus 31.1% of patients treated with amivantamab plus lazertinib, with around 5% of patients experiencing grade > 3 adverse events. Importantly, the addition of chemotherapy to amivantamab and lazertinib did not substantially reduce the incidence of cutaneous toxicities, with similarly high rates of paronychia (50.6%) and acneiform dermatitis (23.6%) observed. Other reported cAEs included pruritus (range: 11%–34%), dry skin (range: 13%–29%), and skin fissures (range: 9%–16%), with severe events being uncommon (≤ 1%). In the phase 3 PALOMA study, subcutaneous and intravenous formulations of amivantamab combined with lazertinib demonstrated comparable rates of cAEs, indicating no relevant impact of administration route on dermatologic toxicity. In contrast to clinical trial data, real-world evidence suggests a different toxicity pattern. In the observational study by Arana et al., acneiform dermatitis was more frequent than paronychia (68.5% vs. 30.1%) [3]. Moreover, erosive pustular dermatosis (15.1%) and ulcerative skin lesions (4.2%) were reported in a notable proportion of patients, toxicities that had not been adequately characterized in clinical trials. The phase III clinical trials evaluated were assessed as having low to moderate risk of bias (Figure S1 available via: https://data.mendeley.com/datasets/f859xhrp8k/1). The remaining studies were considered of lower methodological quality due to their observational design, phase I setting, and the absence of comparators. Overall, available evidence indicates that amivantamab combined with lazertinib is associated with higher rates of cutaneous toxicities, particularly paronychia and acneiform dermatitis. While this may reflect enhanced EGFR inhibition, direct cross-trial comparisons should be interpreted cautiously due to differences in study design, patient populations, cAE grading, and reporting. Importantly, the spectrum of amivantamab-associated cAEs appears to be expanding as real-world experience increases. Recent prospective data suggest that proactive dermatologic management, including oral tetracyclines, topical clindamycin to the scalp, chlorhexidine application to fingernails and toenails, and ceramide-based moisturizers, may reduce the incidence and severity of cAEs, although certain toxicities, particularly paronychia, remain difficult to prevent and treat [4]. For established cAEs, treatment options include topical or systemic tetracyclines, corticosteroids, and local wound care [5]. Increased awareness and early recognition of amivantamab-associated cAEs are essential to prevent treatment interruptions and optimize patient care by maintaining oncologic outcomes. Large-scale pharmacovigilance studies are needed to better define the spectrum of amivantamab-related dermatologic toxicities and inform evidence-based management strategies. The publication of this article in OA mode was financially supported by HEAL-Link. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.