Enhanced Dermatologic AE Prophylaxis Is Effective in EGFR-Mutated Advanced NSCLC

Image Credit: © Sebastian Kaulitzki – stock.adobe.com

Prophylactic enhanced dermatologic management significantly reduced the incidence of grade 2 or higher dermatologic adverse effects (AEs) vs standard dermatologic management within the first 12 weeks of first-line amivantamab-vmjw (Rybrevant)/lazertinib (Lacluze) treatment in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), meeting the primary end point of the first preplanned interim analysis of the phase 2 COCOON trial (NCT06120140).1

Findings, which were presented at the 2025 European Lung Cancer Congress, showed that within the first 12 weeks of treatment with amivantamab plus lazertinib, the rate of grade 2 or higher dermatologic AEs was 38.6% among evaluable patients who received enhanced dermatologic management (n = 70; COCOON DM arm) vs 76.5% among those who received standard-of-care (SOC) dermatologic management (n = 68; SOC DM arm; OR, 0.19 [95% CI, 0.09-0.40; P < .0001]). A 2-fold reduction in the rate of grade 3 dermatologic AEs was observed in the COCOON DM arm (4.3%) vs the SOC DM arm (8.8%); the rates of grade 2 dermatologic AEs in these respective arms were 34.3% and 67.6%, respectively. Additionally, investigators saw a 3-fold reduction in the proportion of patients who reported at least 2 different grade 2 or higher dermatologic AEs in the COCOON DM arm (6%) vs the SOC DM arm (18%). Notably, consistent reductions in grade 2 or higher dermatologic AEs favoring the COCOON DM arm were observed across all prespecified subgroups.

A Glance at Amivantamab/Lazertinib’s Role in EGFR-Mutated NSCLC

The combination of amivantamab plus lazertinib was approved by the FDA in August 2024 for the frontline treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.2 This regulatory decision was supported by findings from the phase 3 MARIPOSA trial (NCT04487080), in which, at a median follow-up of 37.8 months, the median overall survival was not reached (NR; 95% CI, 42.9 months-NR) with the combination vs 36.7 months (95% CI, 33.4-41.0) with osimertinib (Tagrisso; HR, 0.75; 95% CI, 0.61-0.92; P < .005).1

Notably, the first onset of dermatologic AEs—including rash, paronychia, dermatitis acneiform, pruritus, and dry skin—with the MARIPOSA regimen typically occurs within the first 4 months of treatment. The COCOON investigators noted that early management of these AEs may help patients remain on amivantamab/lazertinib treatment longer.

COCOON Trial Design

COCOON enrolled patients with locally advanced or metastatic NSCLC who had received no prior treatment for advanced disease, had documented EGFR exon 19 deletions or L858R mutations, and had an ECOG performance status of 0 or 1. Stratification factors included race (Asian vs non-Asian) and age (< 65 years vs ≥ 65 years). A total of 201 patients were randomly assigned 1:1 to receive amivantamab plus lazertinib with enhanced (n = 99; COCOON DM regimen) or standard (n = 102; SOC DM regimen) dermatologic management.

The COCOON DM regimen consisted of oral doxycycline or minocycline for 12 weeks at 100 mg twice daily followed by 1% topical clindamycin lotion on the scalp daily from week 13 onward; 4% chlorhexidine on the fingernails and toenails daily for 12 months; and ceramide-based moisturizer on the face at least daily for 12 months. The SOC DM regimen included general skin prophylaxis based on local practice, as well as reactivate treatment like topical corticosteroids and systemic antibiotics. Venous thromboembolism (VTE) prophylaxis was mandatory for all patients in the trial during the first 4 months.

The primary end point was the incidence of grade 2 or higher dermatologic AEs in the first 12 weeks after the initiation of amivantamab plus lazertinib. Key secondary end points included the number of grade 2 or higher dermatologic AEs per patient; the incidence and severity of paronychia; the incidence and severity of scalp rash; and the frequency of dose reductions, interruptions, and discontinuations due to AEs. The interim primary analysis was planned for when approximately 70% of patients had completed week 12 assessments.

Patient Characteristics and Additional Trial Findings

Baseline characteristics were well balanced between the 2 arms. In the COCOON DM arm (n = 70), patients had a median age of 62.5 years (range, 36-78), and most were female (60%), Asian (74%), and had an ECOG performance status of 1 (63%). In total, 34% of patients had a history of smoking, and 33% of patients had a history of brain metastases. Fifty percent of patients each had EGFR exon 19 deletions and L858R mutations.

In the SOC DM arm (n = 68), patients had a median age of 62.5 years (range, 37-83), and most were female (54%), Asian (72%), and had an ECOG performance status of 1 (53%). In total, 31% of patients had a history of smoking, and 40% of patients had a history of brain metastases. Fifty-four percent of patients had EGFR exon 19 deletions, and 46% of patients had EGFR L858R mutations.

At a median follow-up of 4.2 months, 138 patients had received at least 1 dose of amivantamab plus lazertinib (comprising the safety analysis set) and had at least 12 weeks of follow-up. The median duration of amivantamab plus lazertinib treatment was 4.2 months in the COCOON DM arm vs 4.1 months in the SOC DM arm.

Within the first 12 weeks of treatment, patients in the COCOON DM arm had reduced rates of grade 2 or higher dermatologic AEs on various body locations compared with those in the SOC DM arm. The rates of facial/body dermatologic AEs were 23% in the COCOON DM arm vs 62% in the SOC DM arm. The rates of scalp dermatologic AEs were 9% and 29% in these respective arms, and the rates of paronychia were 16% and 21% in these respective arms.

Patients in the COCOON DM arm had lower rates of amivantamab or lazertinib discontinuations due to any AEs compared with those in the SOC DM arm, at 11% vs 19%. Dose interruptions due to any AEs occurred in 50% vs 54% of patients in these respective arms, and dose reductions due to any AEs occurred in 21% vs 31% of patients, respectively. The rates of dose interruption, dose reduction, and treatment discontinuations due to dermatologic AEs were also all lower in the COCOON DM arm vs the SOC DM arm, at 16%, 7%, and 1%, respectively, vs 34%, 19%, and 4%, respectively. Notably, 6% of patients in the COCOON DM arm had VTE vs 7% of those in the SOC DM arm.

The COCOON Regimen’s Context in the Paradigm

The investigators explained that the COCOON regimen fits into the paradigm alongside other prophylactic regimens used to prevent AEs associated with amivantamab plus lazertinib. The phase 2 SKIPPirr trial (NCT05663866) infusion-related reaction prophylactic regimen is recommended for use prior to amivantamab/lazertinib treatment and consists of oral dexamethasone twice daily at 8 mg 2 days and 1 day prior to amivantamab/lazertinib administration, as well as an additional 8-mg dose 1 hour before the first amivantamab/lazertinib infusion. At the time of amivantamab/lazertinib initiation, patients should begin VTE prophylaxis outlined in the phase 3 PALOMA-2 (NCT01740427) and PALOMA-3 (NCT05388669) trials, which consists of oral anticoagulants per National Comprehensive Cancer Network or local guidelines; the COCOON regimen is also designed to be initiated at this point in the treatment course.

Both arms of the trial are now fully enrolled, comprising a total trial population of 201 patients. Additional findings from COCOON are planned to be presented at upcoming congresses.

References

1. Girard N, Li W, Spira A, et al. 10MO: 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. J Thorac Oncol. 2025;20(suppl 1):S14-S16. doi:10.1016/S1556-0864(25)00205-9
2. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. August 20, 2024. Accessed April 10, 2025. https://www.investor.jnj.com/news/news-details/2024/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-approved-in-the-U.S.-as-a-first-line-chemotherapy-free-treatment-for-patients-with-EGFR-mutated-advanced-lung-cancer/default.aspx