Prophylactic Interventions to Prevent Severe Skin Toxicities in Patients With Non–Small Cell Lung Cancer Treated With Nivolumab + Ipilimumab With or Without Chemotherapy

Abstract

PURPOSE

The frequent occurrence of immune-related adverse events during immune checkpoint inhibitor therapy for non–small cell lung cancer (NSCLC), particularly dermatologic toxicities, often necessitates treatment modifications and systemic corticosteroid use, negatively affecting patient outcomes. This study evaluated the impact of a multidisciplinary prophylactic intervention on the incidence of severe skin toxicities among patients receiving nivolumab + ipilimumab (NI) with or without chemotherapy.

PATIENTS AND METHODS

This single-center, retrospective, observational study included 154 treatment-naïve patients with NSCLC who received NI with or without chemotherapy. A comparison was made between skin toxicities and clinical outcomes before and after the implementation of a prophylactic intervention consisting of physician-prescribed medications, pharmacist-led patient education, and nurse-guided skincare. The primary end points were the incidence of grade 3 or higher skin toxicities, systemic corticosteroid use, and treatment discontinuation. Secondary end points included progression-free survival (PFS) and overall survival (OS).

RESULTS

The incidence of grade 3 skin toxicities significantly decreased from 21% before the intervention to 8% after the intervention (P = .045). Systemic corticosteroid use and treatment discontinuation rates due to skin toxicities reduced from 36% to 10% (P = .0004) and from 21% to 4% (P = .0012), respectively. Patients with any grade of skin rash exhibited significantly improved PFS and OS compared with those without skin toxicities. However, grade 3 toxicities were associated with poor OS.

CONCLUSION

Prophylactic interventions significantly reduced the severity of skin toxicities and enhanced treatment continuity in patients with NSCLC receiving nivolumab and ipilimumab–based therapy. These findings underscore the importance of proactive, multidisciplinary management strategies to optimize therapeutic outcomes.

INTRODUCTION

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by significantly improving the survival outcomes of patients with various malignancies, including non–small cell lung cancer (NSCLC). Among ICI therapies, the combination of anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and anti–PD-1 antibodies, such as ipilimumab + nivolumab, has demonstrated consistent survival benefits over chemotherapy through landmark trials such as CheckMate 227 and CheckMate 9LA.^1,2 However, ipilimumab + nivolumab treatment is associated with a higher incidence of immune-related adverse events (irAEs) than anti–PD-1 or anti–PD-L1 monotherapies, raising concerns regarding its safety profile.

CONTEXT

• Key Objective

• Can a multidisciplinary prophylactic intervention reduce the incidence of severe skin toxicities in patients with non–small cell lung cancer treated with nivolumab + ipilimumab with or without chemotherapy? This study uniquely evaluates a coordinated approach involving physicians, pharmacists, and nurses to prevent immune-related dermatologic adverse events.

• Knowledge Generated

• The rate of grade 3 skin toxicities decreased from 21% to 8% following the intervention. Systemic corticosteroid use and treatment discontinuation rates due to skin toxicities also significantly reduced.

• Relevance

• Early, proactive management of skin toxicities using a multidisciplinary strategy may reduce treatment interruptions and corticosteroid exposure, potentially preserving the efficacy of immune checkpoint inhibitor–based therapies in clinical oncology.

A substantial proportion of patients treated with ICIs develop irAEs. Patients with NSCLC who experience irAEs during anti–PD-1 or anti–PD-L1 therapy demonstrate better prognoses than those who do not.³ Conversely, patients who develop severe irAEs (grade 3 or higher) exhibit worse outcomes than those with mild irAEs (grade 1 or 2).^4,5 Additionally, severe irAEs often necessitate treatment discontinuation and systemic corticosteroid administration, both of which are associated with significantly poorer prognoses.⁶ Systemic corticosteroid use also increases the risk of adverse events, including life-threatening opportunistic infections.

Among the various irAEs, dermatologic toxicities are among the earliest to appear and occur frequently with ipilimumab + nivolumab therapy.^1,2 In the Japanese subset analysis of the Checkmate 227 study, the incidence of dermatologic toxicities was even higher.⁷ The relationship between skin toxicities and treatment discontinuation is significant, with rates of 1.4%-2.3% for all-grade toxicities and 14.3%-22.2% for grade 3 or higher.^1,2 Although the prophylactic use of tetracycline antibiotics is efficacious in preventing skin toxicities, such as acneiform eruptions and paronychia during molecular-targeted therapies,⁸ key differences exist between molecular-targeted therapies and ICIs. Unlike the almost inevitable occurrence of skin toxicities during molecular-targeted therapy, which typically do not require systemic corticosteroids, ICI-induced skin toxicities, although less frequent at grade 3 or higher, often necessitate systemic corticosteroid use in severe cases. Despite established treatment strategies for ICI-related skin toxicities,^9,10 only a few studies have investigated preventive interventions aimed at mitigating severe dermatologic toxicities, particularly in the context of ipilimumab + nivolumab with or without chemotherapy.

We have encountered several cases of grade 3 or higher skin toxicities during ipilimumab + nivolumab with or without chemotherapy at our institution. Patient-reported issues, such as delaying medical consultation or neglecting skin observation until scheduled visits, have underscored the need for systematic monitoring. Therefore, we implemented a proactive, multidisciplinary approach to skin toxicity prevention for all patients receiving ICIs at our center in October 2021. This intervention includes preprescription by physicians, written instructions by pharmacists, and skin observation and care guidance by nurses. The details of this intervention, summarized in Table 1, provide a practical reference for clinicians managing immunotherapy-related skin toxicities.

TABLE 1.

Recommendations for Skincare and Management of Early Skin Symptoms During Immunotherapy

Intervention Category	Recommended Actions/Advice
Skincare guidelines	Wash skin at least once per day using a gentle, well-lathering soap. Avoid harsh scrubbing
Prevent dryness (moisturization)	Avoid hot or prolonged baths. Apply moisturizer (eg, Hirudoid lotion) within 15 minutes of bathing to lock in moisture. Use low-irritant, over-the-counter options as needed
How to apply moisturizers	Use an amount equivalent to a US penny (about 20 mm in diameter) for an area the size of two palms. Warm the moisturizer in hands and apply evenly. A thin layer that leaves skin slightly tacky is ideal
If itching or skin symptoms appear	Take an antihistamine (eg, bilastine, 1 tablet before bedtime on an empty stomach). Apply topical corticosteroids: betamethasone butyrate propionate ointment for body/limbs and betamethasone valerate cream for the face
Application order for topical agents	Use a finger-tip unit (from fingertip to first joint) per area (equivalent to two palms). Apply twice daily
When to seek medical attention	If symptoms persist, worsen, or if blisters or severe skin changes occur, contact your health care provider immediately

This study aimed to retrospectively evaluate the impact of prophylactic interventions on the incidence of grade 3 or higher skin toxicities in patients with NSCLC treated with ipilimumab + nivolumab with or without chemotherapy. Furthermore, we aimed to assess the rates of systemic corticosteroid use, treatment discontinuation, and relationship between skin toxicity severity and patient outcomes.

PATIENTS AND METHODS

This was a single-center, retrospective observational study conducted at Hakodate Goryoukaku Hospital. Consecutive patients with unresectable or recurrent NSCLC who initiated treatment with nivolumab + ipilimumab, with or without chemotherapy, between December 2020 and December 2023 were enrolled. Key exclusion criteria included epidermal growth factor receptor/anaplastic lymphoma kinase alterations, previous ICI or chemoradiation therapy, and active dermatologic conditions.

A total of 112 patients were included, and eight were excluded due to missing self-care data. The primary end points were the incidence of grade ≥3 skin rashes, systemic corticosteroid use, and treatment discontinuation due to rash. Secondary end points were progression-free survival (PFS) and overall survival (OS).

Prophylactic interventions consisted of physician-prescribed moisturizers, antihistamines, and topical steroids, with instructions provided by pharmacists and nurses. The recommended actions and advice are outlined in Table 1. Adherence to self-care was evaluated at day 22 via nurse interviews and chart review.

Patient characteristics and treatment outcomes were compared using nonparametric and Fisher's exact tests. PFS and OS were analyzed with Kaplan-Meier and Cox regression methods, whereas logistic regression was used to identify predictors of severe skin toxicity. All analyses were conducted using EZR and GraphPad Prism.

The study was approved by the Institutional Review Board of Hakodate Goryoukaku Hospital (2024-049), with an opt-out consent process. Comprehensive information about the study and its purpose was provided to all potential participants at the hospital facility and on the hospital Web site. Participants were given the opportunity to decline participation, and no patient data were used for those who opted out. Full methodological details are provided in the Supplementary file.

Ethics Approval

This study was conducted with the approval of the Institutional Review Board of Hakodate Goryoukaku Hospital (2024-049) and was performed in accordance with the provisions of the Declaration of Helsinki.

Consent to Participate

Comprehensive information about the study and its purpose was provided to all potential participants at the hospital facility and on the hospital Web site. Participants were given the opportunity to decline participation, and no patient data were used for those who opted out.

RESULTS

Patient Inclusion and Characteristics

In total, 154 patients with advanced NSCLC who had received nivolumab + ipilimumab with or without chemotherapy were identified. The study sample was divided into a no-prophylaxis group (n = 42) that started treatment by September 2021 and did not receive prophylactic skincare, and a prophylaxis group (n = 112) that started treatment in October 2021 or later and received prophylactic skincare (Fig 1; Table 2). No significant differences were observed between the two groups in any item. The data cutoff date was January 31, 2024, and the median follow-up for all patients in the study was 10.0 (0.3-38.0) months.

FIG 1.

Flow chart depicting the process of patient enrollment. Ipi, ipilimumab; irAE, immune-related adverse event; NSCLC, non–small cell lung carcinoma; Nivo, nivolumab.

TABLE 2.

Baseline Characteristics of Patients Included in the Study

Characteristics	No. (%)		P
	No-Prophylaxis Group (n = 42)	Prophylaxis Group (n = 112)
Age
<75 years	24 (57.1)	65 (58.0)	1
≥75 years	18 (42.9)	47 (42.0)
Sex
F	12 (28.6)	32 (28.6)	1
M	30 (71.4)	80 (71.4)
Smoking status
Ex/Current	40 (95.2)	100 (89.3)	.35
Never	2 (4.8)	12 (10.7)
ECOG PS
0	24 (57.1)	64 (57.1)	.17
1	14 (33.3)	45 (40.2)
2	4 (9.5)	3 (2.7)
Histology
NSQ	20 (47.6)	73 (65.2)	.064
SQ	22 (52.4)	39 (34.8)
PD-L1 expression
≥50%	18 (42.9)	35 (31.2)	.42
1%-49%	14 (33.3)	43 (38.4)
<1%	10 (23.8)	34 (30.4)
Stage
III	14 (33.3)	22 (19.6)	.16
IV	22 (52.4)	76 (67.9)
Rec	6 (14.3)	14 (12.5)
Treatment
NIVO + IPI	18 (42.9)	68 (60.7)	.068
NIVO + IPI + Chemo	24 (57.1)	44 (39.3)
Tumor burden
<85 mm	24 (57.1)	71 (63.4)	.58
≥85 mm	18 (42.9)	41 (36.6)
Brain metastasis	7 (16.7)	7 (6.2)	.06
Liver metastasis	4 (9.5)	12 (10.7)	1
Bone metastasis	10 (23.8)	32 (28.6)	.69
Pleural metastasis	8 (19.0)	28 (25.0)	.53

Abbreviations: ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IPI, ipilimumab; NIVO, nivolumab; NSQ, nonsquamous cell carcinoma; SQ, squamous cell carcinoma.

Effectiveness of Prophylactic Intervention for Skin Rashes

The relationship between the prophylactic intervention and the severity of skin toxicity is shown in Table 3. The frequencies of grade 1, grade 2, and combined grade 1 + grade 2 skin toxicities were 10% versus 20%, 26% versus 15%, and 36% versus 35%, respectively, for the no-prophylaxis versus prophylaxis group. No significant differences were observed between the groups. However, the frequency of grade 3 skin toxicities significantly decreased from 21% before the intervention to 8% after the intervention (P = .045). Moreover, the percentage of patients requiring systemic corticosteroid treatment for skin toxicities significantly decreased from 36% before to 10% after the prophylactic intervention (P = .0004). Treatment discontinuation due to skin toxicities significantly reduced from 21% before to 4% after the intervention (P = .0012).

TABLE 3.

Incidence of Skin Toxicities, Systemic Steroid Use, and Treatment Discontinuation before and After the Prophylactic Intervention

Rash	Prophylactic Intervention for Skin Rashes				P
	No-Prophylaxis Group		Prophylaxis Group
	n = 42		n = 112
All grade	24/42	57%	48/112	43%	.15
Grade 1	4/42	10%	22/112	20%	.16
Grade 2	11/42	26%	17/112	15%	.16
Grade 1 + grade 2	15/42	36%	39/112	35%	1
Grade 3	9/42	21%	9/112	8%	.045
Patients treated with systemic steroids	15/24	63%	11/48	23%	.00016
Discontinuation of treatment due to skin rashes	9/24	38%	4/48	8%	.0068

Next, we investigated the prognosis of 24 patients in the no-prophylaxis group and 48 patients in the prophylaxis group who developed skin rashes; the median PFS was 9.9 (95% CI, 3.0 to 18.7) months and 10.0 (95% CI, 4.8 to 16.7) months (hazard ratio [HR], 1.02; 95% CI, 0.57 to 1.84), respectively (Data Supplement, Fig S1A, online only). The median OS was 26.5 (95% CI, 7.0 to not reached [NR]) months in the no-prophylaxis group and NR (95% CI, 15.1 to NR) months in the prophylaxis group (HR, 0.82; 95% CI, 0.38 to 1.75; Data Supplement, Fig S1B). No significant differences in PFS and OS were observed between the groups, but the OS of the prophylaxis group tended to be better.

Relationships Between Skin Rashes and Therapeutic Effects of Nivolumab + Ipilimumab–Based Therapy

To examine the relationship between skin toxicities and survival outcomes, we evaluated the PFS and OS. The median PFS was 3.7 (95% CI, 2.1 to 5.2) months in the group without skin rashes and 10.0 (95% CI, 5.0 to 14.0) months in the group with skin rashes of any grade (HR, 0.54 [95% CI, 0.37 to 0.79]; P = .001; Fig 2A). Similarly, the median OS was 11.8 (95% CI, 8.6 to 16.1) months in the group without skin rashes and 31.3 (95% CI, 15.8 to NR) months in the group with skin rashes (HR, 0.48 [95% CI, 0.30 to 0.75]; P = .0016; Fig 2B). Patients who developed skin rashes had significantly prolonged PFS and OS.

FIG 2.

Kaplan-Meier curves illustrating PFS (A) and OS (B) for patients who developed skin toxicities (all-grade, red line) or did not develop a rash (blue line) with nivolumab + ipilimumab with or without chemotherapy. HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival.

In the comparison between grade 1/2 and grade 3 skin toxicities, we observed that the median PFS was 10.0 (95% CI, 5.0 to 18.7) months for patients with grade 1 or 2 skin toxicities and 7.7 (95% CI, 2.8 to 15.7) months for those with grade 3 toxicities, with no significant difference (HR, 1.15 [95% CI, 0.59 to 2.23]; P = .66; Data Supplement, Fig S2A); in contrast, the median OS was NR (95% CI, 19.2 to NR) months and 10.8 (95% CI, 6.3 to NR) months, respectively, with a significant OS disadvantage in the grade 3 group (HR, 2.13 [95% CI, 0.89 to 5.13]; P = .047; Data Supplement, Fig S2B).

To evaluate the relationship between skin toxicities and severe irAEs, we analyzed the incidence of severe irAEs (grade 3 or higher) in patients with and without skin rashes. Severe irAEs occurred in 36% of patients with skin rashes and 34% of those without, with no significant difference (P = .87). However, the occurrence of two or more severe irAEs was significantly more common in the skin rash group than in the group without rashes (19% v 7%, P = .031; Data Supplement, Table S1).

We found that among the 26 patients who experienced severe irAEs, five developed only skin-related irAEs, whereas 17 developed severe irAEs involving organs other than the skin. Of these 17 cases, only three developed severe irAEs in other organs (pneumonitis: two cases, hepatitis: one case) before the onset of skin rashes. Notably, 14 (82%) of the 17 patients experienced skin toxicities concurrently with or preceding the onset of severe irAEs in other organs (Data Supplement, Table S2).

Time to Onset of Skin Rashes and Prognosis

We analyzed the time to onset of skin toxicities and found that the median time to onset was 21 (IQR, 10.3-48.8) days for grade 1 or 2 toxicities and 12.5 (IQR, 8.5-21) days for grade 3 toxicities. Notably, the onset of grade 3 skin toxicities was concentrated within 21 days in 15 (83%) of 18 patients (Data Supplement, Fig S3).

To investigate the prognostic impact of early- versus late-onset skin toxicities, we compared survival outcomes based on whether skin toxicities occurred before or after 3 weeks from treatment initiation. The median PFS was 13.0 (95% CI, 4.8 to 31.5) months for the late-onset group and 7.9 (95% CI, 4.4 to 13.3) months for the early-onset group, with no significant difference (HR, 1.39 [95% CI, 0.77 to 2.48]; P = .29). The median OS was NR (95% CI, 10.1 to NR) months for the late-onset group and 21.6 (95% CI, 10.8 to NR) months for the early-onset group (HR, 1.59 [95% CI, 0.74 to 3.43]; P = .27). Patients with early-onset skin toxicities tended to have shorter median PFS and OS than those with late-onset toxicities (Data Supplement, Figs S4A and S4B).

Relationship Between Frequency of Skin Rashes and Use of Chemotherapy

During the study period, nivolumab + ipilimumab therapy (NI) was administered to 86 patients, whereas NI combined with chemotherapy (NICT) was used in 68 patients. The frequencies of all-grade and grade 1 or 2 skin toxicities were similar between the NI and NICT groups. However, grade 3 skin toxicities occurred in 6% of the NI group and 19% of the NICT group, with a significantly higher incidence in the NICT group (P = .021). The proportions of patients requiring systemic steroid treatment and those discontinuing treatment due to skin toxicities were not significantly different between the two groups (Data Supplement, Table S3).

We performed a multivariable analysis of the occurrence of grade 3 skin rashes. On the basis of previous studies, three factors were investigated: tumor burden, skin prophylactic intervention, and combination chemotherapy. The results showed that combination chemotherapy was a risk factor for grade 3 skin rashes in a multivariable analysis (odds ratio, 3.15 [95% CI, 1.04 to 9.57]; P = .043; Data Supplement, Table S4).

Verification of Continuity of Self-Care and Treatment

After the implementation of the prophylactic skincare intervention, a total of 112 patients received instructions from nurses regarding skincare practices. Among them, eight patients were not evaluable owing to missing data at day 22 of treatment, resulting in 104 patients being included in the self-care adherence analysis. On the basis of nurse interviews and chart review, 74 patients (66%) were classified as continuing self-care, whereas 30 patients (27%) were considered as having discontinued self-care. Skin toxicities occurred in 48 patients. Of these, 22 developed skin rashes during hospitalization for initial treatment induction and were excluded from the self-care subgroup analysis. The remaining 26 patients with skin rashes were then categorized based on their self-care status: 18 patients had continued self-care, whereas eight had discontinued it (Fig 3).

FIG 3.

Patient flow diagram for evaluation of self-care continuation and skin rash after prophylactic skincare intervention. Among 112 patients who received prophylactic skincare instructions at the initiation of nivolumab + ipilimumab with or without chemotherapy, 104 were evaluable for self-care adherence at day 22 of treatment. On the basis of nurse interviews and chart review, 74 patients were classified as continuing self-care, whereas 30 discontinued it. A total of 48 patients developed skin rashes; of these, 22 developed rashes during hospitalization and were excluded from the self-care subgroup analysis. The remaining 26 patients were categorized into self-care continuation (n = 18) and discontinuation (n = 8) groups for comparative analysis. irAE, immune-related adverse event.

The details of the skin toxicity grades in each group are shown in the Data Supplement (Table S5). Although there was no significant difference in the overall severity of skin toxicities between the groups, grade 3 toxicities were more frequent in the self-care discontinuation group (37%) than in the group that continued self-care. In the continuation group, patients tended to visit the clinic promptly during the early stages of the toxicities (grade 1 or 2), whereas no patients in the discontinuation group sought urgent medical attention.

The use of topical steroids was significantly higher in the self-care continuation group (78%) than in the discontinuation group (13%; P = .0033). Therefore, consistent self-care practices may play a crucial role in mitigating the severity of skin toxicities and promoting timely intervention.

DISCUSSION

The results of this study underscore the efficacy of a multidisciplinary prophylactic intervention in reducing the incidence of severe skin toxicities (grade ≥3) associated with ipilimumab + nivolumab with or without chemotherapy in patients with NSCLC. Our findings demonstrate a significant reduction in grade 3 toxicities, systemic corticosteroid use, and treatment discontinuation rates following the implementation of pre-emptive skincare strategies. These outcomes suggest that early and proactive management of irAEs can improve treatment tolerability and continuity without compromising treatment efficacy.

The reduction in grade 3 skin toxicities from 21% to 8% after prophylactic intervention is particularly noteworthy. Severe skin toxicities have been reported as a major contributor to treatment interruptions and adverse outcomes in ICI therapy.¹¹

We found that a maculopapular rash was the most frequently observed dermatologic irAE in our study, indicating its high prevalence among skin toxicities caused by ICIs. Typically, this rash covers a broad area, often exceeding 30% of the total body surface area.¹² By definition, even in cases classified as grade 3, the application of topical corticosteroids is recommended, whereas systemic corticosteroid administration should be avoided.¹² However, without appropriate treatment, these conditions can worsen and progress to severe systemic manifestations, such as drug reaction with eosinophilia and systemic symptom syndrome.⁹ Our intervention, which integrated physician-prescribed medications, pharmacist-led patient education, and nurse-guided skincare practices, likely addressed multiple aspects of dermatologic toxicity management, including early detection and timely initiation of treatment. The intervention (Table 1) clearly outlined actionable recommendations for skincare and early symptom management, which may explain the observed reductions in severe skin toxicities and improved treatment continuity. However, the findings also highlighted a significant concern, namely that a substantial number of patients who received self-care instructions were unable to sustain these measures. The present study did not investigate barriers to self-care adherence, such as socioeconomic factors, patient education levels, or distance from the hospital. To improve adherence, it may be beneficial to go beyond written instructions and incorporate tools like medication diaries or self-care checklists to promote self-awareness and strengthen commitment to self-care practices.

The significantly lower rates of systemic corticosteroid use (36%-10%) further highlight the benefits of early intervention, given the known association between corticosteroid use and poor oncologic outcomes.¹³ For skin lesions corresponding to grade 2 severity (involving up to approximately 30% of body surface area), the topical corticosteroids used in this study are estimated to result in systemic absorption equivalent to approximately 5-10 mg/day of prednisolone. Topical application can achieve higher effective concentrations within the skin than oral administration¹⁴ while generally resulting in lower plasma concentrations and shorter systemic exposure.¹⁵ Furthermore, the dosage and potency of the topical corticosteroid can be tapered or discontinued based on symptom improvement. As the skin lesions improve and skin barrier recovers, the absorption of topical agents decreases. Therefore, topical administration may pose a lower risk of systemic adverse effects than oral corticosteroids, including those related to antitumor immunity. Furthermore, although no statistically significant difference was observed in OS before and after the intervention, the trend toward improved OS (Fig 2) may be a suggestive outcome reflecting the marked decrease in treatment discontinuations owing to skin disorders (from 21% to 4%).

Consistent with previous findings, our data reveal a positive correlation between the occurrence of skin toxicities and improved survival outcomes. Patients who developed any grade of skin rash exhibited significantly prolonged PFS and OS compared with those without skin toxicities. Previous studies have reported similar trends, suggesting that the occurrence of irAEs, particularly dermatologic ones, may serve as a surrogate marker for ICI treatment efficacy.¹⁶ However, grade 3 skin toxicity was observed to be associated with a trend toward shorter OS than grade 1 or 2 toxicity. Among all patients who developed grade 3 skin toxicity in this study, NI was discontinued, and systemic corticosteroids were administered. Although the presence of skin toxicity may reflect enhanced immune activation, severe toxicity can hinder treatment continuity. Furthermore, the use of systemic corticosteroids might suppress antitumor immunity, potentially contributing to poor clinical outcomes. These findings underscore the need for balancing immune activation and toxicity management during combination ICI therapy.

The high incidence of grade 3 skin toxicities in the NICT group suggests a synergistic effect between chemotherapy and ICI-related dermatologic toxicity. Although chemotherapy is generally associated with immunosuppression through leukocyte reduction, including lymphopenia and neutropenia, this mechanism alone does not appear to explain the increased dermatologic toxicity observed. In the CheckMate 9LA study,² the incidence of neutropenia of any grade was reported to be only 9.8%, suggesting that profound cytopenia was not common. Notably, the chemotherapy used in the CheckMate 9LA regimen consisted of only two cycles, yet the combination still resulted in a high incidence of dermatologic adverse events. Paradoxically, rather than suppressing immune responses, chemotherapy may enhance immune-related skin toxicities through mechanisms such as increased antigen presentation, release of damage-associated molecular patterns, or local tissue inflammation. This hypothesis is supported by previous studies indicating that chemotherapy-induced inflammation can potentiate immune-mediated adverse events.^17,18 Consistent with findings from the Japanese LIGHT-NING study, in which the incidence of grade ≥3 rash/dermatitis was 3.5% with NI alone and 9.0% with the addition of chemotherapy,¹⁹ our study also demonstrated a significantly higher frequency of severe skin toxicities in the combination group. Moreover, multivariable analysis identified chemotherapy as an independent risk factor for grade 3 skin toxicities. These results underscore the importance of implementing tailored prophylactic strategies, especially in combination regimens that include short-course chemotherapy.

Grade 3 toxicities predominantly occurred within the first 3 weeks of treatment. In the LIGHT-NING study, the median time to the onset of grade 3 or higher rash/dermatitis was 2.9 months in the NI group, whereas it was 0.3 months in the NI with chemotherapy group, indicating a concentration of events in the early phase of treatment for the chemotherapy combination group.¹⁹ Clinicians should be vigilant about the potential for severe dermatologic adverse events occurring early during treatment using NI with chemotherapy.

This study had some limitations. First, this study was conducted at a single institution in Japan, which may have led to the establishment of patient characteristics that are not representative of broader regional or international NSCLC populations. The absence of a prospective validation cohort to strengthen the study's conclusions was another limitation. Notably, Japanese patients may be more prone to skin disorders than Western patients. Moreover, the coadministration of chemotherapy and changes in health care delivery at the time of treatment initiation—such as accessibility to medical care in the event of skin disorders and the experience level of clinical staff—could have introduced selection bias. Additionally, the small sample size, particularly in the before group, may limit the statistical validity and generalizability of the findings. These factors should be carefully considered when interpreting the study's findings. Furthermore, although our intervention reduced severe toxicities, additional investigations are required to clarify the mechanisms underlying these effects. In the future, larger sample sizes, extended follow-up periods, and prospective multicenter studies should be used to determine whether these interventions influence OS. In addition, efforts should be made to develop optimized intervention protocols tailored to different patient subgroups.

A multidisciplinary prophylactic approach significantly reduces the incidence and severity of skin toxicities as well as the need for systemic corticosteroids and treatment discontinuation in patients with NSCLC undergoing NI-based therapy. By improving patient adherence to skincare practices and addressing toxicity early, therapeutic continuity and outcomes can be enhanced. These insights underscore the need for proactive management strategies in ICI-based regimens, particularly in patients receiving combination chemotherapy.

DATA SHARING STATEMENT

The datasets generated and analyzed in the current study are available from the corresponding author upon reasonable request.

AUTHOR CONTRIBUTIONS

Conception and design: Toshiyuki Sumi, Shunsuke Tsuji, Masahumi Kagawa

Financial support: Toshiyuki Sumi

Administrative support: Toshiyuki Sumi

Provision of study materials or patients: Toshiyuki Sumi, Yuichi Yamada

Collection and assembly of data: All authors

Data analysis and interpretation: Toshiyuki Sumi

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Prophylactic Interventions to Prevent Severe Skin Toxicities in Patients With Non–Small Cell Lung Cancer Treated With Nivolumab + Ipilimumab With or Without Chemotherapy

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