Safety Information for RYBREVANT FASPRO - Dermatologic Adverse Reactions

SUMMARY

• RYBREVANT FASPRO (amivantamab and hyaluronidase-lpuj) for subcutaneous (SC) administration is a coformulation of amivantamab with recombinant human hyaluronidase PH20 (rHuPH20).¹
• 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).²
• LAZCLUZE (lazertinib) is a third-generation EGFR tyrosine kinase inhibitor.³
• PALOMA-3 (NCT05388669) is a phase 3, open-label, international, randomized study evaluating the pharmacokinetics (PK), efficacy, and safety of RYBREVANT FASPRO plus LAZCLUZE (n=206) vs RYBREVANT plus LAZCLUZE (n=212) in patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R) locally advanced or metastatic NSCLC who experienced disease progression on or after osimertinib and platinum-based chemotherapy (N=418).^1,4
  • Rash was the leading cause of dose reductions in the RYBREVANT FASPRO plus LAZCLUZE and RYBREVANT plus LAZCLUZE groups (8% vs 4%), with the similar incidence of all-grade rash (46% vs 43%) and grade ≥3 rash (3% vs 4%) in both groups.¹
  • The median duration of rash was 31 days in the RYBREVANT FASPRO plus LAZCLUZE group and 44 days in RYBREVANT plus LAZCLUZE group.¹
  • The most common grade ≥3 adverse event (AE) was dermatitis acneiform, reported in 9% of patients in the RYBREVANT FASPRO plus LAZCLUZE group and 6% of patients in the RYBREVANT plus LAZCLUZE group.¹
• PALOMA-2 (NCT05498428) is an ongoing, phase 2, open-label, international, parallel-cohort study evaluating the efficacy and safety of RYBREVANT FASPRO with chemotherapy and/or LAZCLUZE combination therapy in patients with EGFR-mutated advanced NSCLC (N=520).^5,6
  • Paronychiawas the most common AE (all grades) reported in cohorts 1, 6, 2, 4, and 5 (72%, 70%, 68%, 44%, and 73%, respectively).^5,7-9
  • Updated results from cohort 1 showed that dermatologic AEs, including rash, paronychia, dermatitis acneiform, pruritus, and dry skin occurred more within the first 4 months of treatment.¹⁰ 
  • Updated results from cohorts 1, 5, and 6 showed that paronychia was the most commonly reported dermatologic AE (84%; all grades), followed by rash (70%), dermatitis acneiform (47%), and pruritus (38%).¹¹
  • In cohort 3b, paronychia was the most commonly reported (55%) dermatologic AE (all grades).¹²
• For medical management of dermatologic AEs in the PALOMA-3 study, refer to Guidelines for the Prevention, Monitoring, and Management of Dermatologic-Related Adverse Events in the PALOMA-3 Study.
• Please refer to RYBREVANT FASPRO, RYBREVANT, and LAZCLUZE product labeling for complete safety information, including dose modification guidelines for adverse reactions.
• Please refer to oncology supportive care guidelines for additional information.

PRODUCT LABELING

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

CLINICAL DATA

PALOMA-3 Study

Study Design/Methods

• Phase 3, randomized, open-label, international study designed to assess the PK, efficacy, and safety of RYBREVANT FASPRO plus LAZCLUZE (n=206) vs RYBREVANT plus LAZCLUZE (n=212) in patients with EGFR-mutated (Exon19del or Exon 21 L858R) locally advanced or metastatic NSCLC who experienced disease progression on or after osimertinib and platinum-based chemotherapy (N=418).^1,4
  • RYBREVANT FASPRO 1600 mg SC (2240 mg if body weight [BW] ≥80 kg) was administered once weekly (QW) for the first 4 weeks and then once every 2 weeks (Q2W) thereafter.
  • RYBREVANT 1050 mg intravenous (IV; 1400 mg if BW ≥80 kg) was administered QW for the first 4 weeks and then Q2W thereafter.
  • LAZCLUZE 240 mg orally (PO) was administered once daily.

Results

• At a median follow-up of 7 months (range, 0.1-14.4), the median duration of treatment was 4.7 months (range, 0.1-13.2) for RYBREVANT FASPRO plus LAZCLUZE and 4.1 months (range, 0-13.2) for RYBREVANT plus LAZCLUZE.¹
• Rash was the leading cause of dose reductions in the RYBREVANT FASPRO plus LAZCLUZE and RYBREVANT plus LAZCLUZE groups (8% vs 4%), with the similar incidence of all-grade rash (46% vs 43%) and grade ≥3 rash (3% vs 4%) in both groups.¹
• The median duration of rash was 31 days in the RYBREVANT FASPRO plus LAZCLUZE group and 44 days in RYBREVANT plus LAZCLUZE group.¹
• The most common grade ≥3 AE was dermatitis acneiform, reported in 9% of patients in the RYBREVANT FASPRO plus LAZCLUZE group and 6% of patients in the RYBREVANT plus LAZCLUZE group.¹
• The incidence of dermatologic AEs reported in the PALOMA-3 study is shown in the Table: PALOMA-3: Incidence of Dermatologic AEs.

PALOMA-2 Study

Study Design/Methods

• Phase 2, ongoing, parallel-cohort, open-label, international study designed to assess the efficacy and safety of RYBREVANT FASPRO with chemotherapy and/or LAZCLUZE in patients with EGFR-mutated advanced NSCLC (N=520).^5,6
  • Cohorts 1 and 6: RYBREVANT FASPRO 1600 mg SC (2240 mg if BW ≥80 kg) was administered QW for the first 4 weeks and then Q2W thereafter. LAZCLUZE 240 mg PO was administered once daily.⁵
  • Cohort 2: RYBREVANT FASPRO 1600 mg SC (2240 mg if BW ≥80 kg) was administered on cycle 1 day 1, then 2400 mg (3360 mg if BW ≥80 kg) on days 8 and 15 of cycle 1, and then Q3W thereafter. Carboplatin area under the curve 5 (AUC5, for a maximum of 4 cycles) and pemetrexed 500 mg/m² until disease progression were administered on day 1 of each 21-day cycle.⁸
  • Cohort 3b: RYBREVANT FASPRO 1600 mg SC (2240 mg if BW ≥80 kg) was administered on cycle 1 day 1, then 2400 mg (3360 mg if BW ≥80 kg) on days 8 and 15 of cycle 1, and then Q3W thereafter. Carboplatin AUC5 (for a maximum of 4 cycles) and pemetrexed 500 mg/m2 until disease progression were administered on day 1 of each 21-day cycle.¹² 
  • Cohort 4: Of the 26 patients enrolled, 25 were switched from RYBREVANT to RYBREVANT FASPRO. Patients in cohort 4 previously received RYBREVANT for ≥8 weeks without dose reduction or evidence of progressive disease, as part of standard of care, an expanded access program, or rollover from a long-term extension study. RYBREVANT FASPRO 1600 mg SC (2240 mg if BW ≥80 kg) was administered on days 1 and 15 of each 28-day cycle with or without LAZCLUZE.⁷
  • Cohort 5: RYBREVANT FASPRO 1600 mg SC (2240 mg if BW ≥80 kg) was administered QW for the first 4 weeks, and then 3520 mg (4640 mg if BW ≥80 kg) Q4W thereafter (28-day cycles). LAZCLUZE 240 mg PO was administered once daily.⁹ 

Results

Cohorts 1 and 6 Interim Results

• The incidence of dermatologic AEs reported in the PALOMA-2 study is shown in the Table: PALOMA-2: Incidence of Dermatologic AEs in Cohort 1 and Cohort 6.

Cohort 1 Updated Results

• In cohort 1, no specified prophylactic dermatologic management was implemented (the COCOON regimen was not included).¹⁰ 
• The incidence of first-onset dermatologic AEs reported in cohort 1 is shown in the Table: PALOMA-2: Incidence of First-Onset Dermatologic AEs in Cohort 1.

Cohort 5 Interim Results

• The incidence of dermatologic AEs reported in the PALOMA-2 study is shown in the Table: PALOMA-2: Incidence of Dermatologic AEs in Cohort 5.
• No prophylactic measures for dermatologic AEs were recommended.⁹ 

Cohorts 1, 5, and 6 Updated Results

• The incidence of dermatologic AEs reported in the PALOMA-2 study is shown in Table: PALOMA-2: Incidence of Dermatologic AEs in Cohorts 1, 5, and 6.
• Prophylaxis for dermatologic AEs was not mandated.¹¹

Cohort 2

• The incidence of dermatologic AEs reported in the PALOMA-2 study is shown in the Table: PALOMA-2: Incidence of Dermatologic AEs in Cohort 2.

Cohort 3b

• The incidence of dermatologic AEs reported in the PALOMA-2 study is shown in the Table: PALOMA-2: Incidence of Dermatologic AEs in Cohort 3b.

Cohort 4

• The most common AE associated with EGFR inhibition was paronychia (44%).⁷
• The incidence of rash (grouped term, including rash, rash maculopapular, acne, dermatitis acneiform, rash pustular, and skin lesions) occurred in 10 (40%) patients, with grade ≥3 events reported in 3 (12%) patients.⁷
• The incidence of dermatologic AEs reported in the PALOMA-2 study is shown in the Table: PALOMA-2: Incidence of Dermatologic AEs in Cohort 4.

guidelines for the prevention, monitoring, and management of DERMATOLOGIC-related adverse events in the PALOMA-3 StudY

The information provided in this section summarizes interventions investigators in the PALOMA-3 study were instructed to perform to monitor and manage dermatologic AEs. These are not recommendations for individual patient care. Interventions should be based on patient presentation and the clinical judgment of the treating physician. Please refer to product labeling for complete safety information, including dose modification guidelines for adverse reactions.

Rash

The prevention and management of EGFR inhibitor-induced rash-related treatment-emergent adverse events (TEAEs) can be conducted in accordance with local institutional guidelines or according to the recommendations below.¹³

Prophylactic Measures

The prophylactic regimen can be managed according to local practice and guidelines; however, it should include the following¹³:

• Avoid exposure to sunlight.
• Wear protective clothing (including hat, sunglasses, etc.).
• Use broad-spectrum sunscreen with a sun protection factor (SPF) of ≥30 and reapply as necessary. Ultraviolet (UV) A light can penetrate glass; therefore, sunscreen should also be worn indoors and in vehicles if exposed to direct sunlight. Recommended active sunscreen ingredients are zinc oxide and/or titanium dioxide.
• 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, and more often as needed. The ideal time for application is after bathing. Creams and ointments are preferred over gels, lotions and oils.
• Avoid alcohol-based (eg, gel formulations) topical agents such as steroids, antibiotics, or hand sanitizers which can dry the skin.
• A proactive approach is recommended, given the anticipated increase in anti-EGFR activity¹³:
  • Patients should have prescriptions (preferably already filled) for topical antibiotics, PO antibiotics, and topical steroids at the time of initial dosing, to minimize any delay in reactive management once rash is observed.
  • Strongly consider initiation of antibiotic therapy on cycle 1 day 1 and continuation of antibiotic therapy for the first 8 weeks: either a topical antibiotic (clindamycin, mupirocin, or fusidic acid) on sun-exposed skin, or an PO 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.¹³

• Consult 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).¹³
• Initiate a topical corticosteroid (cream or ointment) twice daily¹³
  • Examples for face: betamethasone valerate 0.05%, hydrocortisone valerate 0.2% or desonide 0.05%
  • Examples 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.¹³
• 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.¹³
• For skin fissures, use of Monsel’s solution (ferric subsulfate solution), silver nitrate, zinc oxide cream, or cyanoacrylate sealant is recommended.¹³
• For xerosis, fragrance-free moisturizing creams or sprays are recommended.¹³
• For desquamation, emollients and mild soap are recommended.¹³
• After the rash is controlled, consider gradually tapering the antibiotic.¹³

Consider the following algorithm described in Table: Suggested Algorithm for Management of Rash in Patients Receiving RYBREVANT FASPRO or RYBREVANT in the PALOMA-3 Study.

Pruritus

Reactive Management

Grade 1 Pruritus

• 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.¹³

Grade 2 Pruritus

• 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.¹³
• Initiate an PO antipruritic (eg, cetirizine, fexofenadine, rupatadine, bilastine) one dose twice daily. If still pruritic after 2-5 days, may increase to double dose twice daily.¹³

Grade 3 Pruritus

• Initiate an PO antipruritic (as above for grade 2 pruritus).¹³
• Initiate PO pregabalin or gabapentin.¹³
• Initiate an PO corticosteroid (eg, prednisone 0.5-1.0 mg/kg/day or equivalent for 5 days).¹³

Paronychia

Paronychia is a well-recognized toxicity associated with anti-EGFR therapeutics. As a result, there are recommendations that should be followed to prevent or minimize patient discomfort associated with this toxicity.¹³

Prophylactic Measures

• Avoid skin irritants.¹³
• Cushion affected areas.¹³
• Wear gloves and comfortable shoes.¹³
• Apply moisturizer to nails.¹³

Reactive Management

Grade 1 Paronychia

• Use antimicrobial soaks once or twice daily: warm bowl of water plus 5 mL of bleach (sodium hypochlorite) or vinegar (DO NOT USE BOTH TOGETHER); soak for 5 minutes, rinse, pat dry, and then apply either emollient or topical treatments below.¹³
• Apply topical antiseptic (povidone-iodine 10% solution) twice daily.¹³
• Apply a topical steroid ointment (eg, betamethasone valerate 0.1% or clobetasol) or topical calcineurin inhibitor (eg, tacrolimus 0.1%) twice daily. If using topical steroid, once resolved, switch to topical calcineurin inhibitor daily or decrease to twice per week to maintain.¹³

Grade 2 or 3 Paronychia

• In addition to the guidance for grade 1 paronychia above¹³:
  • Apply topical antibiotic/antifungal agent (eg, mupirocin, fusidic acid, clotrimazole, or miconazole) twice daily.
  • Initiate PO antibiotic for at least 14 days (eg, doxycycline 100 mg twice daily, minocycline 100 mg twice daily, or cephalexin 500 mg twice daily).
  • Consult a dermatologist or podiatrist.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 11 September 2026. The information included in this response is limited to relevant data from the PALOMA-3 and PALOMA-2 studies.