SUMMARY

• RYBREVANT (amivantamab-vmjw) is a low fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).¹
• LAZCLUZE (lazertinib) is a third-generation EGFR tyrosine kinase inhibitor (TKI).²
• MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study evaluating the efficacy and safety of RYBREVANT and LAZCLUZE combination therapy (open-label, n=429) vs osimertinib (double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment in patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic NSCLC.^2-4
  • Among patients treated with RYBREVANT plus LAZCLUZE, grade ≥3 rash, dermatitis acneiform, paronychia, and pruritus were reported in 15%, 8%, 11%, and 0.5% of patients, respectively (Table: MARIPOSA: Incidence of Dermatologic AEs).⁴
  • In the final overall survival (OS) analysis with a median follow-up of 37.8 months (range, 0-48.1), grade ≥3 rash, paronychia, dermatitis acneiform, pruritus, and dry skin were reported in 73 (17%), 49 (12%), 37 (9%), 2 (<1%), and 1 (<1%) patients treated with RYBREVANT plus LAZCLUZE, respectively. (Table: MARIPOSA Final OS Analysis: Incidence of Dermatologic AEs).⁵ 
• PAPILLON (NCT04538664) is an ongoing, phase 3, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR exon 20 insertion (Exon20ins) mutations.^6,7
  • Among patients treated with RYBREVANT plus chemotherapy, grade ≥3 rash, dermatitis acneiform, and paronychia were reported in 17 (11%), 6 (4%), and 10 (7%) patients, respectively (Table: PAPILLON: Incidence of Dermatologic AEs).
• MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-LAZCLUZE-chemotherapy (pemetrexed and carboplatin; n=263) and RYBREVANT-chemotherapy (pemetrexed and carboplatin; n=131) vs chemotherapy alone (pemetrexed and carboplatin; n=263) in patients with EGFR-mutated (Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC on or after osimertinib monotherapy.^8,9
  • Grade ≥3 treatment-emergent rash, dermatitis acneiform, paronychia, and pruritus were reported in 17 (6%), 17 (6%), 11 (4%), and 0 patients treated with RYBREVANT-LAZCLUZE-chemotherapy, respectively, and in 8 (6%), 5 (4%), 3 (2%), and 0 patients treated with RYBREVANT-chemotherapy, respectively (Table: MARIPOSA-2: Incidence of Treatment-Emergent Dermatologic AEs).
• CHRYSALIS (NCT02609776) is an ongoing phase 1, open-label, multicenter, dose escalation and dose expansion study evaluating the safety, efficacy, and pharmacokinetics of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR mutations who had disease progression during or after previous standard of care (SOC) treatment.¹⁰
  • Among 114 patients in the safety population, grade ≥3 rash was reported in 4 (4%) patients while grade ≥3 pruritus and dry skin were not reported in any patients. Among all patients treated at the recommended phase 2 dose (RP2D, n=258), grade ≥3 rash was reported in 7 (3%) patients while grade ≥3 pruritus and dry skin were not reported in any patients (Table: CHRYSALIS: Incidence of Dermatologic AEs in Patients Treated at the RP2D).
  • In a long-term analysis of 114 patients in the CHRYSALIS study cohort D with a median follow-up of 19.2 months, grade ≥3 rash (grouped term) was reported in 5 (4%) patients. Among all patients treated at the RP2D (n=474), grade ≥3 rash (grouped term) was reported in 17 (4%) patients.¹¹
  • In a post hoc analysis of 380 patients in the CHRYSALIS study receiving RYBREVANT at the RP2D with a median follow-up of 7.6 months, treatment-related rash and/or paronychia was reported in 296 (78%) patients. Treatment-emergent rash and paronychia were reported in 288 (76%) and 164 (43%) patients, respectively. The majority of patients with paronychia also experienced rash (143/164, 87%). No grade 4 events were reported (Table: CHRYSALIS Post Hoc Analysis: Incidence of Treatment-Emergent Dermatologic AEs in Patients Treated at the RP2D).^12,13
• COCOON (NCT06120140) is an ongoing, phase 2, open-label, randomized study evaluating the impact of enhanced vs standard dermatologic management on the incidence of dermatologic AEs among treatment-naïve patients with EGFR-mutated locally advanced or metastatic NSCLC treated with first-line RYBREVANT plus LAZCLUZE. The primary endpoint is the incidence of grade ≥2 dermatologic AEs of interest in the first 12 weeks after treatment initiation.^14,15
  • Please refer to RYBREVANT, LAZCLUZE - COCOON Study for additional information.
• For medical management of rash-related AEs in the MARIPOSA, MARIPOSA-2, and PAPILLON studies, refer to Guidelines for the Prevention, Monitoring, and Management of Rash-Related AEs in the MARIPOSA, MARIPOSA-2, AND PAPILLON Studies.^16-18
• For medical management of rash-related AEs in the CHRYSALIS study, refer to Guidelines for the Prevention, Monitoring, and Management of Rash-Related AEs in the CHRYSALIS Study.¹⁹
• For best practices for preventing and managing dermatologic AEs, refer to Best Practices for Prevention and Management of Dermatologic AEs Reported in the Literature.^13,20
• Please refer to RYBREVANT and LAZCLUZE product labeling for complete dosage and safety information, including premedications and dose modification guidelines for adverse reactions.
• Please refer to product labeling for carboplatin and/or pemetrexed for complete prescribing information.
• Please refer to oncology supportive care guidelines for additional information.

PRODUCT LABELING

• RYBREVANT (amivantamab-vmjw) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT-pi.pdf.
• LAZCLUZE (lazertinib) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/LAZCLUZE-pi.pdf.

CLINICAL DATA

MARIPOSA Study

Study Design/Methods

• Phase 3, ongoing, randomized study designed to assess the efficacy and safety of RYBREVANT plus LAZCLUZE (open label, n=429) vs osimertinib (double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment in 1074 patients with EGFRmutated (Exon19del or L858R) locally advanced or metastatic NSCLC.^2-4
  • RYBREVANT 1050 mg intravenous (IV; 1400 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on cycle 1 day 1 (C1D1) and D2, followed by every 2 weeks thereafter.
  • LAZCLUZE 240 mg orally (PO) was administered once daily.
  • Osimertinib 80 mg PO was administered once daily.

Results

• The median duration of treatment was 18.5 months for RYBREVANT plus LAZCLUZE and 18 months for osimertinib.^2-4
• The incidence of dermatologic AEs reported in the MARIPOSA study is shown in the table MARIPOSA: Incidence of Dermatologic AEs.

• In the final OS analysis with a median follow-up of 37.8 months (range, 0-48.1), the incidence of dermatologic AEs reported is shown in Table: MARIPOSA Final OS Analysis: Incidence of Dermatologic AEs.⁵

Guidelines for prevention and management of dermatologic AEs throughout treatment were reported and are summarized below.

PAPILLON Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR Exon20ins mutations.^6,7
  • RYBREVANT 1400 mg IV (1750 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by RYBREVANT 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 (C3D1) until disease progression.
  • Pemetrexed 500 mg/m² IVwas administered every 3 weeks until disease progression.¹⁶
  • Carboplatin area under the curve (AUC) 5 IV was administered every 3 weeks for up to 4 cycles.

Results

• The median duration of treatment was 9.7 months (range, 0.1-26.9) for RYBREVANT plus chemotherapy and 6.7 months (range, 0-25.3) for chemotherapy alone.^6,7
• The incidence of dermatologic AEs reported in the PAPILLON study is shown in the table PAPILLON: Incidence of Dermatologic AEs.

Guidelines for prevention and management of dermatologic AEs throughout treatment were reported and are summarized below.

MARIPOSA-2 Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-LAZCLUZE-chemotherapy (n=263) and RYBREVANT-chemotherapy (n=131) vs chemotherapy alone (n=263) in 657 patients with EGFR-mutated locally advanced or metastatic NSCLC on or after osimertinib monotherapy (as the most recent line of therapy).^8,9
  • RYBREVANT 1400 mg IV (1750 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 (C3D1) until disease progression.
  • LAZCLUZE 240 mg PO was administered once daily.
  • Chemotherapy was administered every 3 weeks at the beginning of each cycle, with carboplatin at AUC 5 IV for the first 4 cycles, and pemetrexed at 500 mg/m² IV until disease progression.
• In the RYBREVANT-LAZCLUZE-chemotherapy arm, patients randomized before November 7, 2022, received LAZCLUZE on C1D1. Due to an increase in hematologic and gastrointestinal toxicities in the arm, the regimen was modified to start LAZCLUZE after carboplatin completion.⁹
  • An open-label, randomized, extension cohort will evaluate the efficacy and safety of the modified RYBREVANT-LAZCLUZE-chemotherapy regimen vs RYBREVANT-chemotherapy.

Results

• At a median follow-up of 8.7 months, the median duration of treatment was 5.8 months for RYBREVANT-LAZCLUZE-chemotherapy, 6.3 months for RYBREVANT-chemotherapy, and 3.7 months for chemotherapy alone.^8,9
• The incidence of dermatologic AEs reported in the MARIPOSA-2 study is shown in the table MARIPOSA-2: Incidence of Treatment-Emergent Dermatologic AEs.

Guidelines for prevention and management of dermatologic AEs throughout treatment were reported and are summarized below.

CHRYSALIS Study

The results of the CHRYSALIS study are also included in the RYBREVANT product labeling. The incidence of adverse reactions described below may vary from that in the RYBREVANT product labeling due to the evaluation of different patient populations for safety analyses, contributing to differences in reported percentages. The summary below describes safety results from patients with metastatic or unresectable NSCLC and EGFR Exon20ins mutations with disease progression during or after platinum-based chemotherapy who received RYBREVANT at the RP2D and all patients treated at the RP2D.

Study Design/Methods

• Phase 1, ongoing, open-label, multicenter, dose escalation and dose expansion study evaluating the safety, efficacy, and pharmacokinetics of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR mutations who had disease progression during or after previous SOC treatment.¹⁰
  • RYBREVANT monotherapy was administered at the RP2D: 1050 mg IV (1400 mg IV for body weight ≥80 kg) every week for C1, with the initial dose as a split infusion on C1D1 and D2, and every 2 weeks thereafter until disease progression or unacceptable toxicity.
  • A total of 114 patients with metastatic or unresectable NSCLC and EGFR Exon20ins mutations with disease progression during or after platinum-based chemotherapy were evaluated for safety, and 81 evaluable patients were assessed for efficacy.

Results

• The median follow-up for safety was 5.1 months (range, 0.2-29.3 months).¹⁰
• The incidence of dermatologic AEs reported in the CHRYSALIS study is shown in the table CHRYSALIS: Incidence of Dermatologic AEs in Patients Treated at the RP2D.

• Treatment-related grade ≥3 AEs were reported in 18 (16%) patients, including rash (n=4, 4%).¹⁰
• Treatment-related serious AEs included single reports each of cellulitis, infected dermal cyst, rash, and toxic epidermal necrolysis (TEN).¹⁰
• Treatment-emergent rash (grouped term) typically occurred within the first treatment cycle, with the median time to first onset being 11 days (range: 1-99).²¹
  • The 4 grade 3 treatment-emergent rash events had a median onset of 28.5 days after the first dose of RYBREVANT.
• Among the 98 patients with treatment-emergent rash, the rash resolved on treatment for 19 (19.4%) patients, with the median time to resolution of all reported rash AEs of 92 days (range: 8-737).²¹
• Among 15 (13%) patients who had a treatment-related AE that resulted in a reduction of the RYBREVANT dose, rash was the most common leading to a dose reduction in 11 (10%) patients.¹⁰
• Treatment-emergent AEs that resulted in RYBREVANT dose interruption among 40 (35.1%) patients included dermatitis acneiform (n=4, 3.5%), rash (n=2, 1.8%) and rash maculo-papular (n=2, 1.8%).²¹
• Discontinuation due to rash occurred in 2 (1.8%) patients.^10,21
  • One patient discontinued treatment due to dermatitis acneiform.
  • One patient discontinued treatment due to TEN. This patient had a history of rash on nivolumab and started treatment with RYBREVANT with an ongoing grade 1 rash.
• In a long-term analysis of patients in CHRYSALIS cohort D with a median follow-up of 19.2 months, the incidence of dermatologic AEs reported are shown in the table CHRYSALIS Long-Term Analysis: Incidence of Dermatologic AEs in Patients Treated at the RP2D.¹¹

Guidelines for prevention and management of dermatologic AEs throughout treatment were reported and are summarized below.

Additional Analysis

Singh-Kandah et al (2024)¹² reported results from a post hoc analysis of the CHRYSALIS study on the incidence, severity, time to first onset, and management of rash and paronychia in patients receiving RYBREVANT at the RP2D (N=380).

• As of the March 2021 data cutoff, the median treatment duration was 4.1 months, and the median follow-up was 7.6 months.¹²
• A total of 296/380 (78%) patients experienced treatment-related rash and/or paronychia.¹²
• A rash of grade 2 or more was reported in male patients (74/143; 52%) more frequently than in female patients (68/237; 29%).¹²
• A majority of the 164 patients with paronychia also experienced rash (143/164; 87%).
• Grade 3 events reported in >1% of patients were paronychia (7/380; 2%) and rash (5/380; 1%). No grade 4 events were reported.¹² A summary of dermatologic treatment-emergent AEs and time to first occurrence are shown in the table CHRYSALIS Post Hoc Analysis: Incidence of Treatment-Emergent Dermatologic AEs in Patients Treated at the RP2D.

• Rash typically occurred prior to paronychia, with a median onset of 15 and 68.5 days, respectively.¹²
  • Median onset of acne, rash, dermatitis acneiform, erythema, and rash maculopapular was within the first 22 days of treatment.
  • Scalp rash appeared later in treatment, with a median onset of 40 days.
• During treatment, rash was reported by patients within the first cycle, while onset of paronychia was spread across cycles.¹²
  • After 3 treatment cycles, grade ≥3 events of rash and paronychia were less frequent.
  • The frequency of grade 1 or 2 rash events was low and stable from third treatment cycle onward.
  • Rash instances reported after 4 treatment cycles were generally recurrences.
• Dose reductions due to rash or paronychia occurred in 21/380 (6%) and 10/380 (3%) patients, respectively.¹²
• Treatment discontinuation due to rash or paronychia occurred in 1/380 (0.3%) and 2/380 (0.5%) patients, respectively.¹²
• Concomitant medications received by patients with rash or paronychia after therapy initiation to mitigate symptoms are summarized in the table Most Common Concomitant Medications Used for Rash and Paronychia in CHRYSALIS.

Other relevant literature

• Guidelines for the prevention and treatment of cutaneous AEs associated with RYBREVANT treatment were published based on a retrospective case series of 7 patients from the CHYRSALIS study.²²
• A case series of 6 patients with dermatologic AEs associated with RYBREVANT reported continuation of cancer therapy with AE management and RYBREVANT dose reduction.²³
• Case reports of pityriasis amiantacea and linear immunoglobulin A (IgA) bullous dermatosis, and skin lesions in patients treated with RYBREVANT were published.^24-26

guidelines for the prevention, monitoring, and management of rash-related aes in the MARIPOSA, MARIPOSA-2, AND PAPILLON Studies

The information provided in this section summarizes interventions investigators in the MARIPOSA, MARIPOSA-2, and PAPILLON studies were instructed to perform to monitor and manage rash. These are not recommendations for individual patient care. Interventions should be based on patient presentation and the clinical judgment of the treating physician.

Prophylactic Measures

The prophylactic regimen can be managed according to local practice and guidelines; however, these should include the following^16-18:

• Avoid exposure to sunlight.
• Wear protective clothing (including hat, sunglasses, etc.).
• Use broad-spectrum sunscreen (containing titanium dioxide and/or zinc oxide) with a skin protection factor (SPF) ≥30 and reapply as necessary. Ultraviolet A light can penetrate glass; therefore, sunscreen should also be worn indoors and in vehicles if exposed to direct sunlight.
• Apply alcohol-free emollient cream or ointments (eg, glycerin, cetomacrogol, or ceramide-based cream) or skin moisturizer on dry areas of the body. Topical agents can be applied on a daily basis starting on day 1 of treatment, and more often as needed. The ideal time for application is after bathing. Creams and ointments are preferred over gels, lotions, and oils.

Additional Prophylactic Measures in MARIPOSA and MARIPOSA-2 Studies

In the MARIPOSA and MARIPOSA-2 studies, a more proactive management of rash is warranted for patients receiving RYBREVANT plus LAZCLUZE, given the anticipated increase in anti-EGFR activity^17,18:

• Alcohol-based (eg, gel formulations) topical agents such as steroids, antibiotics, or hand sanitizers can dry the skin and should be avoided.
• Patients should have prescriptions (preferably already filled) for topical antibiotics, oral antibiotics, and topical steroids at the time of initial dosing, to minimize any delay in reactive management once rash is observed.
• Strongly consider initiating antibiotic therapy on C1D1 and continuing antibiotic therapy for the first 8 weeks: either a topical antibiotic (clindamycin, mupirocin, or fusidic acid) on sun-exposed skin, or an oral antibiotic (such as doxycycline 100 mg once daily, minocycline 100 mg once daily, or cephalexin 500 mg once daily).
• A topical corticosteroid of medium to low potency twice daily on the face and chest (such as alclometasone 0.05% or desonide 0.05% cream) may also be considered.

Reactive Management

It is strongly recommended that patients who develop rash/skin toxicities receive evaluations for management on the specific AE. Consider consultation with a dermatologist, especially if the rash is grade 3, atypical in appearance or distribution, or does not improve within 2 weeks (for grade 2 rash). Consultation with a dermatologist is required if the rash is grade 4. The following were suggested regimens for reactive management^16-18:

• Initiate a topical corticosteroid (cream or ointment) twice daily.
  • Examples to use for face: betamethasone valerate 0.05%, hydrocortisone valerate 0.2% or desonide 0.05%
  • Examples to use for body: betamethasone valerate 0.1%, triamcinolone acetonide 0.1%
• If not already initiated for prophylaxis, initiate systemic antibiotic (such as doxycycline 100 mg twice daily, minocycline 100 mg twice daily, or cephalexin 500 mg twice daily), or increase the dosing if already administered.
• If an associated skin infection is suspected, obtain bacterial and fungal cultures followed by adjustment of antibiotic or antifungal therapy, based upon culture and susceptibility determination.
• For reactive management of pruritic lesions, the use of cool compresses and oral antihistamine agents may be helpful.
• For skin fissures, use of Monsel’s solution (ferric subsulfate solution), silver nitrate, or zinc oxide cream is recommended.
• For xerosis, fragrance-free moisturizing creams or sprays are recommended.
• For desquamation, emollients and mild soap are recommended.
• For paronychia, antiseptic soaks and topical potent corticosteroids in addition to oral antibiotics are recommended and, if no improvement is seen, a dermatology or surgery consultation is recommended.
• After the rash is controlled, consider gradually tapering the antibiotic. In the MARIPOSA study, it was recommended to consider de-escalating broad spectrum antibiotics and continuing or resuming prophylactic antibiotics.

Consider the following algorithms described in Table: Suggested Algorithm for Management of Rash in Patients Receiving RYBREVANT in the MARIPOSA Study, Table: Suggested Algorithm for Management of Rash in Patients Receiving RYBREVANT-Chemotherapy in the MARIPOSA-2 Study, Table: Suggested Algorithm for Management of Rash in Patients Receiving RYBREVANT-LAZCLUZE-Chemotherapy in the MARIPOSA-2 Study, and Table: Suggested Algorithm for Management of Rash in Patients Receiving RYBREVANT in the PAPILLON Study in a stepwise manner:

Scalp Rash

Atypical scalp rash and associated infection may develop over time with the use of EGFR inhibitors. Treatment options include^16-18:

• A topical steroid shampoo (eg, clobetasol 0.05%), or an antidandruff shampoo with anti-inflammatory, antibacterial, and antifungal properties (eg, ketoconazole, selenium sulfide [Selsun^®], zinc pyrithione [Head and Shoulders^®], or Ciclopirox). These shampoos should be used twice/week, massaging into scalp, leaving on for 2-5 minutes, and then rinsing.
• Application of a steroid lotion may also be effective (eg, betamethasone valerate 0.1% lotion, mometasone furoate 0.1% lotion, or betamethasone dipropionate 0.05% lotion).
• Initiation of a systemic antibiotic (eg, doxycycline 100 mg twice daily, minocycline 100 mg twice daily) may also be used to treat acute scalp infection.
• In the MARIPOSA study, topical acetic acid 0.25% solution irrigation was also recommended.

Of note, while wearing hats to avoid sun damage to the scalp is suggested in a prophylactic setting, avoiding any headwear for a patient with established scalp rash is strongly recommended to prevent further spread of the rash.

Reactive Management of Pruritus in the MARIPOSA and MARIPOSA-2 Studies

Grade 1 Pruritus^17,18

• Apply topical low to moderate strength steroid cream (eg, hydrocortisone 2.5%, desonide 0.05%, or betamethasone valerate 0.05%), topical calcineurin inhibitor (eg, tacrolimus or pimecrolimus), or topical antipruritic containing numbing agent (eg, pramoxine) and menthol.

Grade 2 Pruritus^17,18

• Apply topical moderate to high strength steroid cream (eg, betamethasone valerate 0.1%, triamcinolone acetate 0.1%) or topical antipruritic containing numbing agent (eg, pramoxine) and menthol.
• Initiate an oral antipruritic (eg, cetirizine, fexofenadine, rupatadine, bilastine) one dose twice daily. If still pruritic after 2-5 days, may increase to double dose twice daily.

Grade 3 Pruritus^17,18

• Initiate an oral antipruritic (as above for grade 2 pruritus).
• Initiate oral pregabalin or gabapentin.
• Initiate an oral corticosteroid (eg, prednisone 0.5-1.0 mg/kg/day or equivalent for 5 days).

guidelines for the prevention, monitoring, and management of rash-related AEs in the CHRYSALIS Study

The information provided in this section summarizes interventions investigators in the CHRYSALIS study were instructed to perform to monitor and manage rash. These are not recommendations for individual patient care. Interventions should be based on patient presentation and the clinical judgment of the treating physician.

General Considerations in Rash Management¹⁹:

• Patients were instructed to avoid unnecessary exposure to sunlight.
• Employed a proactive approach (ie, prophylactic measures; see below for examples).
• Consider consultation with a dermatologist, especially for severe rash, atypical appearance, or distribution, or lack of improvement within 2 weeks of treatment.
• If patients developed rash, see steps outlined under Reactive Management below.
• Special measures were undertaken for patients receiving combination treatments and are noted below. These patients should have prescriptions for topical antibiotics, oral antibiotics, and topical steroids at the time of initial dosing, in order to minimize any delay in reactive management once rash is observed.

Prophylactic Measures

The following were suggested regimens for prophylaxis¹⁹:

• Broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin protection factor (SPF) ≥30.
• Thick, alcohol-free emollient cream (eg, glycerin and cetomacrogol cream) on dry areas of the body.
• Topical agents can be applied on a daily basis starting on day 1 of study treatment, and more often as needed.
• For patients receiving combination treatments: Initiate topical antibiotics (such as clindamycin 1% gel or similar preparation) to sun-exposed skin starting on day 1.

Reactive Management

It is strongly recommended that patients who develop rash/skin toxicities receive evaluations for management on the specific AE. The following were suggested regimens for reactive management¹⁹:

• Topical corticosteroids (eg, hydrocortisone 2.5% cream).
• Topical clindamycin (1% gel) or systemic antibiotics (eg, doxycycline 100 mg twice daily or minocycline 100 mg twice daily).
• For patients receiving combination treatments, transition to oral antibiotics (such as doxycycline 100 mg twice daily, minocycline 100 mg twice daily, or cephalexin 500 mg twice daily) and initiate topical steroids (such as hydrocortisone 2.5% gel) to affected areas at the initial onset of rash, regardless of toxicity grade.
• For pruritic lesions, cool compresses and oral antihistamine agents could be helpful.
• For fissuring, the use of Monsel’s solution (ferric subsulfate solution), silver nitrate, or zinc oxide cream was advised.
• For desquamation, thick emollients and mild soap were recommended.
• For paronychia, antiseptic soaks and local potent corticosteroids in addition to oral antibiotics were advised and, if no improvement was seen, a dermatology or surgery consultation was recommended.
• For infected lesions, bacterial and fungal culturing followed by the appropriate culture-driven systemic or topical antibiotics were indicated.

Consider the following algorithm described in table: Suggested Algorithm for Management of Rash in Patients Receiving RYBREVANT Monotherapy in the CHRYSALIS Study in a stepwise manner:

Best practices for prevention and management of dermatologic AEs reported in the literature

The information provided in this section includes best practices for prevention and management of dermatologic toxicities (non-scalp rash, scalp rash, pruritus, alopecia, and dry skin) reported in the literature.^13,20 These are not recommendations for individual patient care. Interventions should be based on patient presentation and the clinical judgment of the treating physician.

• Discuss lifestyle modifications, which include avoiding the following¹³:
  • Manicures, pedicures, and artificial nails
  • Drying agents in soaps and makeup (eg, alcohol)
  • Skin irritants
  • Hot showers and baths
  • Gardening
  • Being outdoors and/or sun exposure
• Patients should be encouraged to incorporate the following lifestyle changes²⁰: 
  • Moisturize daily.
  • Apply SPF >30 broad-spectrum sunscreen after moisturizer.
  • Wear gloves when cleaning or gardening.
  • Use gentle emollients or soap substitutes.
• Dermatology should be consulted early in treatment for dermatologic toxicities and when initial interventions are not successful or severe cases are observed.¹³
• Patients should notify their healthcare team as soon as they encounter AEs to enable prompt treatment.²⁰ 
• Consider the following described in table: Prevention and Treatment of Non-Scalp Rash, Scalp Rash, Pruritus, Alopecia, and Dry Skin.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 06 October 2025. The information included in this response is limited to relevant data from the registrational studies for RYBREVANT.