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RYBREVANT, LAZCLUZE - COCOON Study

Last Updated: 04/14/2025

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
  • COCOON (NCT06120140) is an ongoing, phase 2, open-label, randomized study evaluating the impact of enhanced (COCCON dermatologic management [DM] arm) vs standard (standard of care [SoC] DM arm) dermatologic management on the incidence of dermatologic adverse events (AEs) among treatment-naïve patients with EGFR-mutated locally advanced or metastatic NSCLC treated with first-line RYBREVANT intravenous (IV) plus LAZCLUZE orally (PO).3-5 The primary endpoint is the incidence of grade ≥2 dermatologic AEs in the first 12 weeks after treatment initiation with RYBREVANT plus LAZCLUZE.3,4 Enrollment was planned for approximately 180 patients at 78 sites across 11 study locations worldwide.3
    • At the interim analysis with a median follow-up of 4.2 months, 138 patients had received ≥1 dose of RYBREVANT plus LAZCLUZE and had undergone ≥12 weeks of follow-up.4
      • The median duration of treatment was 4.2 months with COCOON DM and 4.1 months with SoC DM.
    • During the first 12 weeks of treatment, grade ≥2 dermatologic AEs were reported in 38.6% (27/70) of patients with COCOON DM vs 76.5% (52/68) of patients SoC DM (P<0.0001; odds ratio [OR], 0.19 [0.09-0.4]), and grade 3 dermatologic AEs were reported in 4.3% of patients with COCOON DM vs 8.8% of patients with SoC DM.4
    • Consistent reductions in grade ≥2 dermatologic AEs were observed across all subgroups.4
    • Discontinuation of RYBREVANT or LAZCLUZE due to dermatologic or any AEs was less frequent with COCOON DM than with SoC DM.4

PRODUCT LABELING

clinical study

COCOON Study

Study Design/Methods

  • Ongoing phase 2, open-label, randomized study evaluating the impact of enhanced (COCOON DM arm) vs standard (SoC DM arm) 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 IV plus LAZCLUZE PO.3-5 
  • The study design is shown in Figure: COCOON Study Design.

COCOON Study Design3-5

A screenshot of a computer screen AI-generated content may be incorrect.

COCOON (ClinicalTrials.gov Identifier: NCT06120140) enrollment period: February 2024 onwards; estimated study completion: March 31, 2026.
Abbreviations: AE, adverse event; BID, twice daily; DM, dermatologic management; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; eGFR, estimated glomerular filtration rate; Exon19del, Exon 19 deletion; ILD, interstitial lung disease; IV, intravenous; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NSCLC, non-small cell lung cancer; PO, orally; PRO, patient-reported outcome; Q2W, twice a week; QD, once daily; QW, once a week; R, randomization; SoC, standard of care; SPF, sun protection factor; TKI, tyrosine kinase inhibitor; W, week.
aPatients must have had all lesions treated as clinically indicated and any definitive local therapy completed ≥2 weeks prior to randomization and are receiving no more than prednisone 10 mg (or equivalent) for treatment.
beGFR >45 mL/min.
cIncluding, but not limited to, uncontrolled diabetes, ongoing/active infection, active bleeding diathesis, impaired oxygenation requiring continuous oxygen supplementation, and psychiatric illness or other circumstances that would limit compliance with study requirements.
dKnown allergy, hypersensitivity, or intolerance to the excipients of amivantamab or lazertinib; to tetracyclines, doxycycline, minocycline, or their excipients; or to any component of enhanced dermatologic management.
eIncluding, but not limited to, deep vein thrombosis or pulmonary embolism within 1 month prior to administration of the first dose of background anticancer treatment or other cardiovascular diseases within 6 months prior to administration of the first dose.
fAdjuvant/neoadjuvant therapy for stage I/II disease is allowed if administered >12 months prior to the development of locally advanced or metastatic disease.
gAdjuvant treatment with osimertinib is allowed if administered >12 months prior to the development of locally advanced or metastatic disease and all osimertinib toxicities are resolved prior to enrollment.
hPlanned enrollment of 200 participants was estimated to provide a power of 82% to detect a 35% difference in dermatologic AEs of interest. The study is now fully enrolled.
iPatients will use a digital health tool to monitor treatment compliance.
jSoC DM included general skin prophylaxis per local practice and reactive treatment, such as topical corticosteroids and systemic antibiotics.

kAll patients received general skin prophylaxis instructions including minimizing sunlight exposure, wearing UV protective clothing, using SPF ≥30 sunscreen, and avoiding alcohol-based skin agents.
l1050 mg (1400 mg if body weight ≥80 kg) QW for the first 4 weeks and Q2W thereafter.
mDermatologic AEs of interest included rash, dermatitis acneiform, pruritus, skin fissures, acne, folliculitis, erythema, eczema, maculopapular rash, skin exfoliation, skin lesion, skin irritation, dermatitis, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular, dermatitis contact, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema asteatotic, and paronychia.

nAE severity per NCI CTCAE v5.0.

Results

Patient Characteristics
  • At the interim analysis with a median follow-up of 4.2 months, 138 patients (COCOON DM arm, n=70; SoC DM arm, n=68) had received ≥1 dose of RYBREVANT plus LAZCLUZE and had undergone ≥12 weeks of follow-up.4
    • The median duration of treatment was 4.2 months with COCOON DM and 4.1 months with SoC DM.
  • Patient characteristics and baseline demographics are included in Table: Patient Characteristics and Demographics.

Patient Characteristics and Demographics4
Characteristic
COCOON DM
(n=70)a
SoC DM
(n=68)b
Median (range) age, years
62.5 (36-78)
62.5 (37-83)
Female, n (%)
42 (60)
37 (54)
Race,c n (%)
   Asian
52 (74)
49 (72)
   White
17 (24)
19 (28)
ECOG PS 1, n (%)
44 (63)
36 (53)
EGFR mutation type, n (%)
   Exon19del
35 (50)
37 (54)
   L858R
35 (50)
31 (46)
History of smoking, n (%)
24 (34)
21 (31)
History of brain metastases, n (%)
23 (33)
27 (40)
Abbreviations: DM, dermatologic management; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; L858R, Exon 21 L858R substitution; SoC, standard of care.
aIn the COCOON DM arm, 48 patients received doxycycline for a median duration of 2.7 months, and 24 patients received minocycline for a median duration of 2.8 months.bTwo patients randomized to SoC DM did not meet inclusion criteria at cycle 1 day 1 and discontinued the study prior to receiving RYBREVANT plus LAZCLUZE.
cOnepatient in COCOON DM was American Indian or Alaska Native.
Note: Percentages may not sum to 100 due to rounding.
Primary Endpoint
  • During the first 12 weeks of treatment, grade ≥2 dermatologic AEs were reported in 38.6% (27/70) of patients with COCOON DM vs 76.5% (52/68) of patients with SoC DM (P<0.0001; OR, 0.19 [0.09-0.4]); see Table: Dermatologic AEs.

Dermatologic AEs4
COCOON DM
(n=70)
SoC DM
(n=68)
Grade ≥2 dermatologic AEs, n (%)
27 (38.6)
52 (76.5)
   Grade 2 dermatologic AEs, %
34.3
67.6
   Grade 3 dermatologic AEs, %
4.3
8.8
Two or more different grade ≥2 dermatologic AEs, %
6
18
Abbreviations: AE, adverse event; DM, dermatologic management; SoC, standard of care.

Grade ≥2 Dermatologic AEs by Body Location4
Dermatologic AEs, n (%)
COCOON DM
(n=70)
SoC DM
(n=68)
Approximate % Reduction with
COCOON DM vs SoC DM
Facial/body (excluding scalp)
16 (23)
42 (62)
65
Scalp
6 (9)
20 (29)
70
Paronychia
11 (16)
14 (21)
25
Abbreviations: AE, adverse event; DM, dermatologic management; SoC, standard of care.

Clinical Benefit Across Predefined Subgroups4
Subgroup
Events/n
OR (95% CI)b
COCOON DM
SoC DM
All patientsa
27/70
52/68
0.19 (0.09-0.4)
Age
   <65 years
17/41
28/39
0.28 (0.11-0.71)
   ≥65 years
10/29
24/29
0.11 (0.03-0.375)
Sex
   Female
19/42
26/37
0.35 (0.14-0.89)
   Male
8/28
26/31
0.08 (0.02-0.27)
Weight
   <80 kg
25/63
46/61
0.215 (0.1-0.46)
   ≥80 kg
2/7
6/7
0.07 (0.005-0.97)
Race
   Asian
20/52
38/49
0.18 (0.08-0.43)
   Non-Asian
7/18
14/19
0.23 (0.06-0.915)
ECOG PS
   0
11/26
26/32
0.17 (0.05-0.55)
   1
16/44
26/36
0.22 (0.085-0.57)
EGFR mutation type
   Exon19del
13/35
29/37
0.16 (0.06-0.46)
   L858R
14/35
23/31
0.23 (0.08-0.66)
History of dermatologic disease
   No
24/63
49/64
0.19 (0.09-0.41)
   Yes
3/7
3/4
0.25 (0.02-3.77)
Abbreviations: CI, confidence interval; DM, dermatologic management; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; L858R, Exon 21 L858R substitution; OR, odds ratio; SoC, standard of care.aSafety analysis set.bUnadjusted OR.
Secondary Endpoints
Dose Modifications Due to AEs
  • Discontinuation of RYBREVANT or LAZCLUZE due to dermatologic or any AEs was less frequent with COCOON DM than with SoC DM; see Table: Dose Modifications of RYBREVANT/LAZCLUZE Due to AEs.
  • Venous thromboembolism was observed in 6% of patients with COCOON DM vs 7% of patients with SoC DM.

Dose Modifications of RYBREVANT/LAZCLUZE Due to AEs4
COCOON DM
(n=70)
SoC DM
(n=68)
Dermatologic AEs, n (%)
   Dose interruption
11 (16)
23 (34)
   Dose reduction
5 (7)
13 (19)
   Discontinuation
1 (1)
3 (4)
Any AEs, n (%)
   Dose interruption
35 (50)
37 (54)
   Dose reduction
15 (21)
21 (31)
   Discontinuation
8 (11)
13 (19)
Abbreviations: AE, adverse event; DM, dermatologic management; SoC, standard of care.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 24 March 2025.

References

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1 Moores SL, Chiu ML, Bushey BS, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res. 2016;76(13):3942-3953.  
2 Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small cell lung cancer. Future Oncol. 2022;18(6):639-647.  
3 Cho BC, Girard N, Sauder MB, et al. Enhanced vs standard dermatologic management with amivantamab-lazertinib in advanced NSCLC: phase 2 COCOON study. Poster presented at: International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC); September 7-10, 2024; San Diego, CA.  
4 Girard N, Li W, Spira AI, et al. Preventing moderate to severe dermatologic adverse events in first-line EGFR-mutant advanced NSCLC treated with amivantamab plus lazertinib: early success of the COCOON trial. Oral Presentation presented at: European Lung Cancer Congress (ELCC); March 26-29, 2025; Paris, France.  
5 Janssen Research & Development, LLC. A phase 2, open-label, randomized trial evaluating the impact of enhanced versus standard dermatologic management on selected dermatologic adverse events among patients with locally advanced or metastatic EGFR-mutated NSCLC treated first-line with amivantamab + lazertinib. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 March 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT06120140 NLM Identifier: NCT06120140.