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LAZCLUZE® (lazertinib)

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RYBREVANT, LAZCLUZE - COCOON Study

Last Updated: 12/08/2025

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, multicenter, randomized study evaluating the impact of enhanced (COCOON dermatologic management [DM] arm) vs standard (standard of care [SoC] DM arm) DM 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 intravenously (IV) plus LAZCLUZE orally (PO).The primary endpoint is the incidence of grade ≥2 dermatologic AEs of interest (DAEIs) in the first 12 weeks of RYBREVANT plus LAZCLUZE treatment.3-5
    • Interim analysis results were previously reported at a median follow-up of 4.2 months (data cutoff: November 13, 2024).5,6
    • At full enrollment, with a median follow-up of 7.1 months, grade ≥2 DAEIs in the first 12 weeks of treatment were reported in 42% (42/99) of patients in the COCOON DM arm and 75% (75/100) of patients in the SoC DM arm (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.13-0.45; P<0.0001). Grade ≥2 DAEIs with COCOON vs SoC DM were reported involving the scalp (10% vs 26%), face (15% vs 48%), body (20% vs 44%), and paronychia (21% vs 23%).5
    • Median time to the first occurrence of grade ≥2 DAEI was 3.5 months with COCOON DM and 1 month with SoC DM.5
    • The most common treatment-emergent adverse events (TEAEs) reported with COCOON DM vs SoC DM included paronychia (74% vs 69%), infusion-related reaction (61% vs 56%), hypoalbuminemia (60% vs 49%), and rash (48% vs 47%).7
    • Venous thromboembolism (VTE) was reported in 13% of patients in both the COCOON DM and SoC DM arms, with grade ≥3 VTEs reported in 5% and 3% of patients, respectively.5
    • In the COCOON DM vs SoC DM arm, dose reductions of any treatment (RYBREVANT or LAZCLUZE) due to DAEIs were reported in 15% vs 26% of patients, dose interruptions in 22% vs 33%, and discontinuations in 4% vs 4%.7
    • The investigator-assessed objective response rate (ORR) with COCOON DM vs SoC DM was 82% (95% CI, 73-89) vs 75% (95% CI, 65-83).5
    • Results for patient-reported outcomes (PROs) were reported in the analysis at full enrollment.5
  • An Asian subset analysis of COCOON evaluated the prophylactic management of dermatologic AEs with RYBREVANT plus LAZCLUZE treatment in EGFR-mutated NSCLC.8
    • The incidence of grade ≥2 DAEIs with COCOON DM vs SoC DM in the first 12 weeks of RYBREVANT plus LAZCLUZE treatment was 42% vs 77% (OR: 0.22; 95% CI:
      0.1-0.47; nominal P<0.0001).
    • The safety profile of RYBREVANT plus LAZCLUZE was consistent with the overall population, and no new safety signals were observed.
    • VTE was reported in 11% and 8% of patients in the COCOON DM and SoC DM arms, respectively.
    • In the COCOON DM vs SoC DM arm, dose reductions of RYBREVANT due to DAEIs were reported in 8 (12%) vs 12 (18%) patients, dose interruptions in 9 (14%) vs 18 (28%) patients, and discontinuations in 3 (5%) vs 2 (3%) patients, respectively.
  • A COCOON treatment substudy evaluated strategies for managing new-onset or persistent grade ≥2 DAEIs in patients continuing treatment with RYBREVANT plus LAZCLUZE.9
    • In stage 1 cohort B, 63% (5/8) of patients responded to tacrolimus treatment by demonstrating DAEI improvement and meeting the pre-specified threshold to initiate stage 2 enrollment, which is ongoing. The median time to DAEI improvement among responders was 2.3 weeks (95% CI, 2-4.3). No tacrolimus-related AEs were reported, and 38% (3/8) of patients reported complete resolution of DAEIs with tacrolimus.

PRODUCT LABELING

clinical study

COCOON Study

Study Design/Methods

  • Phase 2, ongoing, open-label, multicenter, randomized study designed to assess the impact of enhanced (COCOON DM arm) vs standard (SoC DM arm) DM 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.3-5
  • The study design is shown in Figure: COCOON Study Design.
  • The AE management strategy is shown in Figure: Preventing AEs with Amivantamab plus Lazertinib.

COCOON Study Design3-5

COCOON (ClinicalTrials.gov Identifier: NCT06120140); data cutoff: March 7, 2025.
Abbreviations: AE, adverse event; BID, twice daily; C, cycle; D, day; DAEI, dermatologic AE of interest; DM, dermatologic management; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; eGFR, estimated glomerular filtration rate; EORTC-QLQ-C30, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30; 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; PFS, progression-free survival; PGI-S, Patient’s Global Impression-Severity; PO, orally; PRO, patient-reported outcome; Q2W, twice a week; QD, once daily; ORR, overall response rate; QW, once a week; R, randomization; RDI, relative dose intensity; RECIST, Response Evaluation Criteria in Solid Tumors; SoC, standard of care; SPF, sun protection factor; TKI, tyrosine kinase inhibitor; UV, ultraviolet; VTE, venous thromboembolism; 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 DM.
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.
hA total of 200 patients (100 in each arm) were enrolled, providing approximately 82% power to detect a 35% treatment difference in DAEIs based on a 2-sided alpha level of 0.05.
iPatients used a digital health tool to monitor treatment compliance.
jAll patients received general skin prophylaxis instructions, including avoiding sunlight exposure, wearing UV protective clothing (including a hat and sunglasses), using broad-spectrum sunscreen (SPF ≥30), and avoiding alcohol-based topical agents; reactive treatment for skin toxicity was permitted per local practice.
k1050 mg (1400 mg if body weight ≥80 kg) QW in C1 (with the first dose split between C1D1 [350 mg] and C1D2 [700 mg if body weight <80 kg or 1050 mg if body weight ≥80 kg]) and then Q2W thereafter.
lSoC DM included general skin prophylaxis per local clinical practice and reactive treatment, such as topical corticosteroids and systemic antibiotics, with no standard preventive regimen.
mDAEIs included rash, dermatitis acneiform, pruritus, paronychia, skin fissures, acne, folliculitis, erythema, maculopapular rash, erythematous rash, macular rash, papular rash, pruritic rash, pustular rash, skin exfoliation, skin lesion, skin irritation, dermatitis, contact dermatitis, generalized exfoliative dermatitis, drug eruption, dyshidrotic eczema, asteatotic eczema, and eczema.
nAE severity per NCI CTCAE v5.0.
oAssessed using the Skindex-16 (a validated questionnaire that assesses the impact of skin conditions on quality of life using 3 subscales [functioning, emotional, and symptoms] and an average score of 0 [no impact] to 100 [impact experienced all the time]), PGI-S (a 4-point rating scale [none, mild, moderate, or severe symptoms] that assesses the severity of rash, skin condition, and nail infection over time), and EORTC-QLQ-C30 questionnaires.
pPer RECIST v1.1.

Preventing AEs with Amivantamab plus Lazertinib7

Abbreviations: AE, adverse event; BID, twice daily; IRR, infusion-related reaction; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolism.
aIncludes standard premedication (antihistamines, antipyretics, and glucocorticoids).
bProphylactic antibiotics: oral doxycycline or minocycline 100 mg BID; topical clindamycin lotion 1% on scalp daily before bedtime. Paronychia prophylaxis: chlorhexidine 4% on the fingernails and toenails daily. Skin moisturization: La Roche Posay Lipikar AP+M moisturizer on the body and face at least daily.
cLa Roche Posay Lipikar AP+M moisturizer was used in the COCOON study.

Results

Patient Characteristics
  • Of the 201 randomized patients, 199 who received ≥1 dose of RYBREVANT plus LAZCLUZE were included in the safety population (COCOON DM arm, n=99; SoC DM arm, n=100).5
  • The patient demographics and baseline characteristics are included in Table: Demographics and Baseline Disease Characteristics.

Demographics and Baseline Disease Characteristics5
Characteristic
COCOON DM
(n=99)
SoC DM
(n=100)a,b
Median age, years (range)
63 (34-80)
62.5 (28-83)
   <65 years, n (%)
56 (57)
56 (56)
   ≥65 to <75 years, n (%)
35 (35)
27 (27)
   ≥75 years, n (%)
8 (8)
17 (17)
Sex, n (%)
   Male
38 (38)
43 (43)
   Female
61 (62)
57 (57)
Race, n (%)
   Asian
66 (67)
65 (65)
   White
32 (32)
32 (32)
   American Indian or Alaska Native
1 (1)
0
   Black or African American
0
1 (1)
   Multiple
0
2 (2)
Median body weight, kg (range)
63 (29-97)
64.2 (39-106)
   <80 kg, n (%)
88 (89)
89 (89)
   ≥80 kg, n (%)
11 (11)
11 (11)
ECOG PS, n (%)
   0
40 (40)
45 (45)
   1
59 (60)
55 (55)
Median time from metastatic disease diagnosis, months (range)
1.15 (0.1-8.5)
1.15 (0.1-5.1)
History of brain metastases,c n (%)
32 (32)
43 (43)
Histologic type, n (%)
   Adenocarcinoma
94 (95)
97 (97)
   Squamous cell carcinoma
2 (2)
2 (2)
   Large cell carcinoma
1 (1)
0
   Other
2 (2)
1 (1)
Abbreviations: DM, dermatologic management; ECOG PS, Eastern Cooperative Oncology Group performance status; SoC, standard of care.
aTwo patients who did not meet the eligibility criteria at cycle 1 day 1 were excluded.
bIn the SoC DM arm, 28 (28%) patients received ≥1 prophylactic treatment, mainly consisting of sunscreen and moisturizing creams, within 14 days of initiating RYBREVANT + LAZCLUZE. Patients also received prophylactic antibiotics or antiseptics, including systemic doxycycline (2%; n=2), systemic minocycline (1%; n=1), topical doxycycline (1%; n=1), and chlorhexidine (3%; n=3).5,7
cBased on investigator-reported data recorded on electronic case report form page.
Primary Endpoint
  • At a median follow-up of 7.1 months, median duration of RYBREVANT and LAZCLUZE treatment, respectively, was 6.8 months (range, 0.3-11.6) and 7 months (range, 0.3-11.9) with COCOON DM and 6 months (range, 0.1-10.7) and 6.4 months (range, 0.3-11.3) with SoC DM.5
Grade ≥2 DAEIs in the First 12 Weeks of Treatment

Grade ≥2 DAEIs in the First 12 Weeks of Treatment5,7
DAEIs
COCOON DM
(n=99)
SoC DM
(n=100)
OR (95% CI); P-Value
Grade ≥2 DAEIs, n (%)
42 (42)
75 (75)
0.24 (0.13-0.45); P<0.0001
   Grade 2 DAEIs, n (%)
36 (36)
68 (68)
-
   Grade 3 DAEIs, n (%)
6 (6)
7 (7)
-
   Grade 4 or 5 DAEIs, %
0
0
-
Abbreviations: CI, confidence interval; DAEI, dermatologic adverse event of interest; DM, dermatologic management; OR, odds ratio; SoC, standard of care.

Grade ≥2 DAEIs in the First 12 Weeks of Treatment by Body Location5
DAEIs
COCOON DM
(n=99)
SoC DM
(n=100)
OR (95% CI);
P-Value
Grade ≥2 DAEIs involving skin (including scalp, face, and body; excluding paronychia), n (%)
27 (27)
62 (62)
P<0.0001a
   Grade 2 DAEIs, %
24
55
-
   Grade 3 DAEIs, %
3
7
-
Grade ≥2 DAEIs involving scalp, n (%)
10 (10)
26 (26)
0.32 (0.15-0.71); P=0.005a
   Grade 2 DAEIs, %
9
21
-
   Grade 3 DAEIs, %
1
5
-
Grade ≥2 DAEIs involving face, n (%)
15 (15)
48 (48)
0.19 (0.1-0.38); P<0.0001a
   Grade 2 DAEIs, %
14
42
-
   Grade 3 DAEIs, %
1
6
-
Grade ≥2 DAEIs involving body, n (%)
20 (20)
44 (44)
0.32 (0.17-0.61); P=0.0004a
   Grade 2 DAEIs, %
18
37
-
   Grade 3 DAEIs, %
2
7
-
Grade ≥2 DAEIs involving paronychia, n (%)
21 (21)
23 (23)
0.9 (0.46-1.76); P=0.7613a
   Grade 2 DAEIs, %
18
23
-
   Grade 3 DAEIs, %
3
0
-
Abbreviations: CI, confidence interval; DAEI, dermatologic adverse event of interest; DM, dermatologic management; OR, odds ratio; SoC, standard of care.
aNominal P-value; this endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.

Grade ≥2 DAEIs in the First 12 Weeks of Treatment Across Predefined Subgroups5
Subgroup
Events/N (%)
OR (95% CI)
COCOON DM
SoC DM
All patients
42/99 (42)
75/100 (75)
0.25 (0.13-0.45)
Age
   <65 years
25/56 (45)
41/56 (73)
0.3 (0.13-0.65)
   ≥65 years
17/43 (40)
34/44 (77)
0.19 (0.08-0.49)
Sex
   Female
28/61 (46)
41/57 (72)
0.33 (0.15-0.71)
   Male
14/38 (37)
34/43 (79)
0.15 (0.06-0.41)
Racea
   Asian
28/66 (42)
50/65 (77)
0.22 (0.1-0.47)
   Non-Asian
14/33 (42)
25/35 (71)
0.3 (0.11-0.81)
Weight
   <80 kg
37/88 (42)
65/89 (73)
0.27 (0.14-0.5)
   ≥80 kg
5/11 (45)
10/11 (91)
0.08 (0.01-0.9)
ECOG PS
   0
20/40 (50)
38/45 (84)
0.18 (0.07-0.51)
   1
22/59 (37)
37/55 (67)
0.29 (0.13-0.63)
EGFR mutation typea
   Exon19del
23/50 (46)
41/54 (76)
0.27 (0.12-0.62)
   Exon 21 L858R
19/49 (39)
34/46 (74)
0.22 (0.09-0.54)
History of dermatologic disease
   No
35/88 (40)
69/93 (74)
0.23 (0.12-0.43)
   Yes
7/11 (64)
6/7 (86)
0.29 (0.03-3.37)
Abbreviations: CI, confidence interval; DAEI, dermatologic adverse event of interest; DM, dermatologic management; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; OR, odds ratio; SoC, standard of care.
aBased on investigator-reported data.
Secondary Endpoints
Two or More Different Grade ≥2 DAEIs
  • In the first 12 weeks of treatment, ≥2 different grade ≥2 DAEIs were reported in 10% vs 25% of patients with COCOON vs SoC DM.5
Grade ≥2 DAEIs in the First 6 Months of Treatment

Grade ≥2 DAEIs in the First 6 Months of Treatment5
DAEIs
COCOON DM
(n=80)
SoC DM
(n=78)
P-Value
Grade ≥2 DAEIs, n (%)
53 (66)
65 (83)
0.015a
   Grade 2 DAEIs, %
58
71
-
   Grade 3 DAEIs, %
9
13
-
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
aNominal P-value; this endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.

Grade ≥2 DAEIs in the First 6 Months of Treatment by Body Location5
DAEIs
COCOON DM
(n=80)
SoC DM
(n=78)
P-Value
Grade ≥2 DAEIs involving skin (including scalp, face, and body; excluding paronychia), n (%)
33 (41)
59 (76)
<0.0001a
   Grade 2 DAEIs, %
36
63
-
   Grade 3 DAEIs, %
5
13
-
Grade ≥2 DAEIs involving scalp, n (%)
13 (16)
27 (35)
0.009a
   Grade 2 DAEIs, %
15
25
-
   Grade 3 DAEIs, %
1
10
-
Grade ≥2 DAEIs involving face, n (%)
20 (25)
45 (58)
<0.0001a
   Grade 2 DAEIs, %
21
46
-
   Grade 3 DAEIs, %
4
12
-
Grade ≥2 DAEIs involving body, n (%)
27 (34)
44 (56)
0.005a
   Grade 2 DAEIs, %
30
45
-
   Grade 3 DAEIs, %
4
12
-
Grade ≥2 DAEIs involving paronychia, n (%)
35 (44)
29 (37)
0.401a
   Grade 2 DAEIs, %
40
37
-
   Grade 3 DAEIs, %
4
0
-
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
aNominal P-value; this endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
Any-Grade DAEIs
  • The incidence of any-grade DAEIs with COCOON vs SoC DM is included in Table: Any-Grade DAEIs.

Any-Grade DAEIs7
DAEIs, n (%)
COCOON DM
(n=99)
SoC DM
(n=100)
Any-grade DAEIs
93 (94)
98 (98)
   Grade 1 DAEIs
29 (29)
11 (11)
   Grade 2 DAEIs
52 (53)
74 (74)
   Grade 3 DAEIs
12 (12)
13 (13)
   Grade 4 DAEIs
0
0
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
Time to First Occurrence of Grade ≥2 DAEI

Reactive Management Medications for Treating DAEIs (≥10%)7
Medication, n (%)
COCOON DM
(n=99)
SoC DM
(n=100)
Patients with ≥1 reactive medications
83 (84)
98 (98)
   Topical corticosteroids
56 (57)
83 (83)
   Topical antibiotics and chemotherapeutics
52 (53)
67 (67)
   Systemic antibacterials
35 (35)
61 (61)
      Tetracyclines
25 (25)
54 (54)
   Antiseptics and disinfectants
28 (28)
38 (38)
   Systemic antihistamines
20 (20)
37 (37)
   Topical antifungals
16 (16)
20 (20)
   Emollients and protectives
14 (14)
38 (38)
   Other topical preparations
14 (14)
15 (15)
   Anti-acne preparations
13 (13)
28 (28)
   Ophthalmologicals
13 (13)
9 (9)
   Systemic corticosteroids
8 (8)
15 (15)
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
Summary of AEs
  • The incidence of the most common TEAEs reported across the COCOON and SoC DM arms is included in Table: Summary of AEs.

Summary of AEs7
Most Common (≥10% in Either Arm) TEAEsa
COCOON DM
(n=99)
SoC DM
(n=100)
Paronychia, n (%)
74 (74)
69 (69)
   Grade 1, %
30
27
   Grade 2, %
39
41
   Grade 3, %
5
1
IRR, n (%)
60 (61)
56 (56)
Hypoalbuminemia, n (%)
59 (60)
49 (49)
Rash, n (%)
48 (48)
47 (47)
   Grade 1, %
30
17
   Grade 2, %
15
22
   Grade 3, %
3
8
Increased ALT, n (%)
42 (42)
40 (40)
Peripheral edema, n (%)
35 (35)
30 (30)
Stomatitis, n (%)
33 (33)
42 (42)
Dermatitis acneiform, n (%)
32 (32)
42 (42)
   Grade 1, %
22
11
   Grade 2, %
7
28
   Grade 3, %
3
3
Increased AST, n (%)
31 (31)
31 (31)
Nausea, n (%)
22 (22)
19 (19)
Anemia, n (%)
22 (22)
14 (14)
Hypocalcemia, n (%)
21 (21)
16 (16)
Decreased appetite, n (%)
20 (20)
24 (24)
Diarrhea, n (%)
19 (19)
28 (28)
Dizziness, n (%)
19 (1)
7 (7)
Hypokalemia, n (%)
18 (18)
16 (16)
Constipation, n (%)
17 (17)
18 (18)
Mouth ulceration, n (%)
17 (17)
9 (9)
Dry skin, n (%)
16 (16)
12 (12)
   Grade 1, %
10
9
   Grade 2, %
5
3
   Grade 3, %
1
0
Pruritus, n (%)
16 (16)
21 (21)
   Grade 1, %
11
16
   Grade 2, %
5
5
   Grade 3, %
0
0
Paresthesia, n (%)
16 (16)
11 (11)
Skin fissures, n (%)
14 (14)
12 (12)
   Grade 1, %
7
6
   Grade 2, %
7
6
   Grade 3, %
0
0
Hyponatremia, n (%)
13 (13)
12 (12)
Thrombocytopenia, n (%)
13 (13)
12 (12)
Fatigue, n (%)
13 (13)
9 (9)
Increased blood alkaline phosphatase, n (%)
12 (12)
12 (12)
Headache, n (%)
12 (12)
11 (11)
Hypotension, n (%)
12 (12)
7 (7)
Gingival bleeding, n (%)
11 (11)
8 (8)
Hemorrhoids, n (%)
11 (11)
10 (10)
Vomiting, n (%)
11 (11)
10 (10)
Asthenia, n (%)
10 (10)
18 (18)
Hyperbilirubinemia, n (%)
10 (10)
1 (1)
Epistaxis, n (%)
9 (9)
11 (11)
Myalgia, n (%)
8 (8)
10 (10)
Rash maculopapular, n (%)
7 (7)
13 (13)
   Grade 1, %
2
4
   Grade 2, %
4
5
   Grade 3, %
1
4
Conjunctivitis, n (%)
7 (7)
10 (10)
Dry eye, n (%)
3 (3)
10 (10)
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DM, dermatologic management; IRR, infusion-related reaction; SoC, standard of care; TEAE, treatment-emergent adverse event.
aOther than paronychia and conjunctivitis, infections were reported in <10% of patients.
  • No differences in the incidence of infections or liver toxicity were observed between arms.5
  • In the COCOON DM arm, treatment-related AEs (TRAEs) led to discontinuation of doxycycline or minocycline in 1 (1%) patient, dose reduction in 3 (3%) patients, and dose interruption in 7 (7%) patients; TRAEs led to dose interruption of clindamycin in 1 (1%) patient.5,7
    • No discontinuation of clindamycin, chlorhexidine, or ceramide-based skin moisturizer due to TRAEs was reported.
Summary of VTE
  • VTE occurred in 13% of patients in both the COCOON and SoC DM arms.5
    • Grade ≥3 VTEs were reported in 5% of patients in the COCOON DM arm and 3% in the SoC DM arm.
  • Among all study patients, the VTE incidence was 5% (9/199) from 0-4 months and 11% (18/170) from 5-8 months of treatment.5
  • Any-grade TEAEs related to VTE prophylaxis were reported in 27 (27%) patients in the COCOON DM arm and 20 (20%) patients in the SoC DM arm.7
    • Grade ≥3 TEAEs related to VTE prophylaxis were reported in 3 (3%) patients in the COCOON DM arm and 1 (1%) patient in the SoC DM arm.7
Dose Reductions, Interruptions, and Discontinuations of Treatment Due to DAEIs
  • At the data cutoff of March 7, 2025, the frequency of dose modifications and discontinuations of RYBREVANT or LAZCLUZE due to DAEIs with COCOON vs SoC DM is included in Table: Dose Reductions, Interruptions, and Discontinuations of Treatment Due to DAEIs.
    • The frequency of dose interruption (RYBREVANT or LAZCLUZE) due to DAEIs with COCOON vs SoC DM was 10% vs 23% in the first 12 weeks and 22% vs 33% throughout the study duration (clinical cutoff).7

Dose Reductions, Interruptions, and Discontinuations of Treatment Due to DAEIs7
n (%)
COCOON DM
(n=99)
SoC DM
(n=100)
Dose reductions of any study treatment due to DAEIs
15 (15)
26 (26)
   RYBREVANT
11 (11)
18 (18)
   LAZCLUZE
8 (8)
15 (15)
Dose interruptions of any study treatment due to DAEIs
22 (22)
33 (33)
   RYBREVANT
16 (16)
30 (30)
   LAZCLUZE
13 (13)
23 (23)
Discontinuations of any study treatment due to DAEIs
4 (4)
4 (4)
   RYBREVANT
4 (4)
4 (4)
   LAZCLUZE
3 (3)
3 (3)
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
  • At the data cutoff, in the COCOON vs SoC DM arm, 8 (8%) vs 7 (7%) patients completed treatment and 77 (78%) vs 71 (71%) patients remained on treatment.7
Efficacy
  • At a median follow-up of 7.1 months, the investigator-assessed ORR and best responses with COCOON vs SoC DM are included in Table: Efficacy Outcomes.
  • Median progression-free survival and duration of response with COCOON vs SoC DM were not reached.5

Efficacy Outcomes5
Response
COCOON DM
(n=99)
SoC DM
(n=100)
Investigator-assessed ORR,% (95% CI)
82 (73-89)
75 (65-83)
Best response,a n (%)
    PR
79 (82)
74 (74)
    SD
10 (10)
17 (17)
Abbreviations: CI, confidence interval; DM, dermatologic management; ORR, objective response rate; PR, partial response; SD, stable disease; SoC, standard of care.
aBased on the number of patients with measurable disease at baseline (COCOON DM, n=96; SoC DM, n=100).
PROs
  • Overall, 97% of patients in the COCOON DM arm and 98% in the SoC DM arm were compliant with skin condition assessments at baseline, with rates remaining >85% through cycle 7 day 1 (C7D1).5
  • Changes from baseline in the Skindex-16 total score in the first 12 months of treatment are included in Table: Changes From Baseline in the Skindex-16 Total Score.

Changes From Baseline in the Skindex-16 Total Score5,a
COCOON DM
(n=99)
SoC DM
(n=100)
P-Value
Mean (SE) total score at baseline
4.05 (1.01)
4.05 (1.02)
-
LS mean (95% CI) change from baseline at C1D15
7.4 (2.7-12)
25.2 (20.8-29.7)
<0.001b
LS mean (95% CI) change from baseline at C6D1
20.4 (14.8-26.1)
29.2 (23.3-35.1)
0.031b
Abbreviations: C, cycle; CI, confidence interval; D, day; DM, dermatologic management; LS, least squares; SE, standard error; SoC, standard of care.
aChanges in the Skindex-16 scores were evaluated using mixed models for repeated measures.
bNominal P-value; this endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.

Patients Reporting Dermatologic Symptoms on PGI-S7 
Patients Reporting Symptoms, %
COCOON DM
(n=99)
SoC DM
(n=100)
C3D15
C7D1
C3D15
C7D1
Rash
   None
23
27
14
12
   Mild
49
44
44
59
   Moderate
25
26
35
22
   Severe
4
3
8
7
Skin condition
   None
25
17
11
10
   Mild
44
56
48
54
   Moderate
26
26
35
31
   Severe
5
2
6
5
Nail infection
   None
29
17
20
10
   Mild
43
43
43
53
   Moderate
23
33
29
32
   Severe
6
7
9
5
Abbreviations: C, cycle; D, day; DM, dermatologic management; PGI-S, Patient Global Impression of Severity; SoC, standard of care.
  • No substantial differences in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) global health status and quality of life (QoL) scores were detected for the COCOON and SoC DM arms, with both arms maintaining the QoL from baseline throughout the treatment duration.5

Li et al (2025)8 reported the results from COCOON Asian subset analysis evaluating the prophylactic management of dermatologic AEs with RYBREVANT plus LAZCLUZE treatment in EGFR-mutated NSCLC.

Results

Patient Characteristics
  • A total of 131 patients of self-reported Asian race were included in the subset analysis.8
  • At the clinical data cutoff of March 7, 2025, with a median follow-up of 7.4 months, 81% of patients remained on the study.8
  • Baseline demographic and clinical characteristics were balanced between both arms.8 The patient demographics and baseline characteristics of the Asian subset are included in Table: Demographics and Baseline Disease Characteristics.

Demographics and Baseline Disease Characteristics8
Characteristic
COCOON DM
(n=66)
SoC DM
(n=65)
Median age, years (range)
63 (36-78)
61 (28-83)
Female, n (%)
38 (58)
33 (51)
Country of enrollment, n (%)
   China
25 (38)
21 (32)
   Malaysia
18 (27)
14 (22)
   Taiwan
11 (17)
11 (17)
   Republic of Korea
8 (12)
14 (22)
   United States
4 (6)
4 (6)
   France
0
1 (2)
ECOG PS 1, n (%)
39 (59)
40 (62)
History of brain metastases, n (%)
20 (30)
32 (49)
History of smoking, n (%)
15 (23)
19 (29)
EGFR mutation type, n (%)
   Exon19del
33 (50)
33 (51)
   Exon 21 L858R
33 (50)
32 (49)
Abbreviations: DM, dermatologic management; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; SoC, standard of care.
Primary Endpoint
Grade ≥2 DAEIs in the First 12 Weeks of Treatment

Grade ≥2 DAEIs in the First 12 Weeks of Treatment8
DAEIs
COCOON DM
(n=66)
SoC DM
(n=65)
OR (95% CI); P-Value
Grade ≥2 DAEIs, n (%)
28 (42)
50 (77)
0.22 (0.1-0.47); P<0.0001a
   Grade 2 DAEIs, %
39
71
-
   Grade 3 DAEIs, %
3
6
-
Abbreviations: CI, confidence interval; DAEI, dermatologic adverse event of interest; DM, dermatologic management; OR, odds ratio; SoC, standard of care.
aNominal P-value; this endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
  • Consistent with the overall population, the incidence of grade ≥2 DAEIs in the first 12 weeks was reduced on the scalp, face, and body with COCOON DM compared with SoC DM.8 The incidence of grade ≥2 DAEIs in the first 12 weeks by body location among Asian patients is included in Table: Grade ≥2 DAEIs in the First 12 Weeks of Treatment by Body Location.

Grade ≥2 DAEIs in the First 12 Weeks of Treatment by Body Location8
DAEIs
COCOON DM
(n=66)
SoC DM
(n=65)
P-Value
Grade ≥2 DAEIs involving scalp, n (%)
3 (5)
20 (31)
P=0.0006a
   Grade 2 DAEIs, %
5
26
-
   Grade 3 DAEIs, %
0
5
-
Grade ≥2 DAEIs involving face, n (%)
7 (11)
29 (45)
P<0.0001a
   Grade 2 DAEIs, %
9
38
-
   Grade 3 DAEIs, %
2
6
-
Grade ≥2 DAEIs involving body, n (%)
14 (21)
28 (43)
P=0.0083a
   Grade 2 DAEIs, %
21
37
-
   Grade 3 DAEIs, %
0
6
-
Grade ≥2 DAEIs involving paronychia, n (%)
17 (26)
19 (29)
P=0.6563a
   Grade 2 DAEIs, %
24
29
-
   Grade 3 DAEIs, %
2
0
-
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
aNominal P-value; this endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
Note: Percentages may not sum to total value due to rounding.
Secondary Endpoints
Safety
  • The safety profile of RYBREVANT plus LAZCLUZE among Asian patients was consistent with the overall population, and no new safety signals were observed.8
  • Similar rates of liver function alterations were reported in both arms, indicating that prolonged tetracycline use with COCOON DM was safe.8
  • The most common prophylactic dermatologic interventions in the SoC arm were sunscreen and moisturizing creams (23%). The most common reactive DAEI management treatments included corticosteroids (80%), topical anti-infectives (71%), and systemic antibacterials (52%; mostly tetracyclines [43%]).8
Summary of VTE
  • VTE was reported in 11% and 8% of patients in the COCOON DM and SoC DM arms, respectively.8
    • The VTEs were mostly grades 1 or 2.
Dose Reductions, Interruptions, and Discontinuations of Treatment Due to DAEIs

Dose Reductions, Interruptions, and Discontinuations of Treatment Due to DAEIs8
n (%)
COCOON DM
(n=66)
SoC DM
(n=65)
Dose reductions of RYBREVANT due to DAEIs
8 (12)
12 (18)
Dose interruptions of RYBREVANT due to DAEIs
9 (14)
18 (28)
Discontinuations of RYBREVANT due to DAEIs
3 (5)
2 (3)
Abbreviations: DAEI, dermatologic adverse event of interest; DM, dermatologic management; SoC, standard of care.
PROs
  • Based on Skindex-16 total scores and PGI-S, patients in the COCOON DM arm reported a lower impact of anticancer treatment on dermatologic symptoms and QoL compared to the SoC DM arm through the median follow-up of 7.4 months.8

Spira et al (2025)9 reported the first results from the treatment substudy of COCOON evaluating the strategies for managing new-onset or persistent grade ≥2 DAEIs.

Study Design/Methods

  • Patients with EGFR-mutated advanced NSCLC from all arms in COCOON who experienced new-onset or persistent grade ≥2 DAEIs (excluding paronychia) and continued RYBREVANT plus LAZCLUZE treatment were enrolled in the substudy.9
    • Persistent DAEIs were defined as sustained moderate-to-severe skin toxicities despite prophylactic or treatment measures.
  • A 2-stage group sequential design was used to evaluate treatments that were applied for up to 12 weeks in 2 independently assessed cohorts9:
    • Stage 1:
      • Cohort A (n=8): ruxolitinib for up to 12 weeks
      • Cohort B (n=8): 0.1% tacrolimus ointment topical twice daily for up to 12 weeks
    • Stage 2: If ≥3/8 patients achieve DAEI improvement, proceed to stage 2 (enroll 8 patients in each cohort).
    • Expansion stage: If ≥9/16 patients achieve DAEI improvement, proceed to expansion stage (enroll upto ~24 patients in each cohort).
  • The exploratory endpoint was response to ruxolitinib or tacrolimus treatment, defined as an improvement in DAEIs by ≥1 level according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 grading within 12 weeks.9

Results

Patient Characteristics
  • As of 11 September 2025, 8 patients were enrolled in stage 1 of Cohort B (COCOON DM, n=2; SoC DM, n=6).9
  • At a clinical cutoff date of October 28, 2025, the median duration of RYBREVANT plus LAZCLUZE treatment was 15.9 months (range, 12.9-18.4), and the combination treatment is ongoing.9
    • RYBREVANT: 15.9 months (range, 12-18.4)
    • LAZCLUZE: 15.2 months (range, 6.9-18.4)
  • The patient demographics and baseline characteristics are included in Table: Demographics and Baseline Disease Characteristics.

Demographics and Baseline Disease Characteristics9
Characteristic
Cohort B
(n=8)
Median age, years (range)
57 (48-68)
Male, n (%)
5 (63)
Race, n (%)
   Asian
6 (75)
   White
2 (25)
ECOG PS, n (%)
   0
6 (75)
   1
2 (25)
History of brain metastases, n (%)
3 (38)
History of smoking, n (%)
4 (50)
EGFR mutation type, n (%)
   Exon19del
4 (50)
   Exon 21 L858R
4 (50)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion
Incidence of new-onset or persistent grade ≥2 skin DAEIs
  • The most common new-onset (n=1) or persistent (n=7) grade ≥2 skin DAEIs by preferred term, resulting in substudy enrollment, were dermatitis acneiform (50%) and rash (38%).9

New-onset or Persistent Grade ≥2 Skin DAEIs9
Skin DAEI (preferred term),a n (%)
Cohort B
(n=8)
Dermatitis acneiform
4 (50)
Rash
3 (38)
Rash maculopapular
1 (13)
Pruritic rash
1 (13)
Abbreviation: DAEI, dermatologic adverse events of interest.
aOne patient had 2 index DAEIs (maculopapular rash and pruritic rash) that resulted in treatment substudy enrollment.
Response to tacrolimus treatment
  • In stage 1, 5 of 8 (63%) patients responded to tacrolimus demonstrating DAEI improvement.9
    • All patients had not yet completed 12 weeks of treatment; therefore, the number of patients responding to tacrolimus may increase upon reaching the 12-week timepoint.
    • The pre-specified threshold (≥3/8) for proceeding to stage 2 was met, and stage 2 enrollment is ongoing.
  • At the current follow-up, the median duration of tacrolimus treatment was 12.3 weeks (range, 2.2-16.1), with treatment ongoing in 2 (25%) patients.9
    • A total of 3 (38%) patients completed tacrolimus treatment, and 3 (38%) patients discontinued treatment.
      • Reasons for discontinuation of tacrolimus treatment were lung cancer disease progression, patient withdrawal, and no reported clinical response (n=1 for each).
  • Median time to DAEI improvement among responders was 2.3 weeks (95% CI,
    2-4.3).9
  • Complete resolution of DAEIs was reported in 3 of 8 (38%) patients.9
  • No tacrolimus-related AEs were reported.9

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 05 December 2025.

 

References

Show
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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 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 December 05]. Available from: https://clinicaltrials.gov/ct2/show/NCT06120140 NLM Identifier: NCT06120140.  
5 Cho BC, Li W, Spira AI, et al. Enhanced versus standard dermatologic management with amivantamab-lazertinib in EGFR-mutated advanced NSCLC: the COCOON global randomized controlled trial. J Thorac Oncol. 2025;20(10):1517-1530.  
6 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.  
7 Cho BC, Li W, Spira AI, et al. Supplementary appendix for: Enhanced versus standard dermatologic management with amivantamab-lazertinib in EGFR-mutated advanced NSCLC: the COCOON global randomized controlled trial. J Thorac Oncol. 2025;20(10):1517-1530.  
8 Li J, Cho BC, Voon PJ, et al. Prophylactic management of dermatologic adverse events with amivantamab + lazertinib treatment in 1L EGFR-mutated NSCLC: COCOON Asian subset analysis. Oral Presentation presented at: European Society for Medical Oncology (ESMO) Asia Congress; December 5-7, 2025; Singapore.  
9 Spira AI, Sauder MB, Feldman J, et al. First results from the COCOON treatment substudy in managing moderate to severe dermatologic adverse events in participants with EGFR-mutated advanced NSCLC treated with first-line amivantamab-lazertinib. Poster presented at: North America Conference on Lung Cancer (NACLC); December 5-7, 2025; Chicago, Illinois.