Pharmacy Practice in Focus: Oncology
Amivantamab with lazertinib emerges as a promising frontline therapy for EGFR-mutated metastatic NSCLC, enhancing overall survival and treatment tolerability.
The use of amivantamab (Rybrevant; Johnson & Johnson), an EGFR-MET bispecific monoclonal antibody, in combination with lazertinib (Lazcluze; Johnson & Johnson), a third-generation EGFR tyrosine kinase inhibitor, has emerged as a frontline treatment option for patients with EGFR exon 19 deletion or exon 21 L858R–mutated, metastatic non–small cell lung cancer (NSCLC).
Recent updates for overall survival (OS) data from the phase 3 MARIPOSA trial (NCT04487080)1 further support the use of amivantamab plus lazertinib over osimertinib (Tagrisso; AstraZeneca) monotherapy in the front-line setting for this patient population.2 Additionally, interest is growing in subcutaneous amivantamab administration along with new evidence-based supportive care techniques, reinforcing the need for oncology teams to assess the best ways to incorporate this regimen into clinical practice.
The current mainstays of treatment for patients with newly diagnosed, EGFR-mutated, metastatic NSCLC include osimertinib monotherapy, osimertinib plus systemic chemotherapy, and, most recently, amivantamab plus lazertinib. Single-agent osimertinib may be a preferred agent in patients with multiple comorbidities, those who are frail, or those who are older. The use of a single agent may prevent the increased risk of adverse effects that could occur in a multiagent regimen. Conversely, younger patients who have more bulky or aggressive disease with a high tumor burden may benefit from osimertinib plus systemic chemotherapy or the combination of amivantamab plus lazertinib.2 Patient comorbidities, supportive care measures, and additional patient-centered factors should be at the forefront to help guide treatment selection.
MARIPOSA investigators recently reported updated OS results showing that, at a median follow-up of about 37.8 months, the amivantamab plus lazertinib group had an HR of 0.75 compared with the osimertinib group (95% CI, 0.61-0.92; P < .005). The median OS had not yet been reached for patients who received amivantamab plus lazertinib; however, the lower boundary of the CI was about 42.9 months. Assuming an exponential distribution of OS in both arms, amivantamab plus lazertinib is expected to extend median OS by at least 12 months vs osimertinib, a clinically significant difference.2,3
Author Bios
Kevin Leffers, PharmD, is an oncology pharmacy resident at Florida Cancer Specialists & Research Institute in Fort Myers.
Nicole Bentivegna, PharmD, BCOP, is a clinical pharmacy services manager at Florida Cancer Specialists & Research Institute in Fort Myers.
Although the MARIPOSA data are promising, certain precautions must still be taken when administering amivantamab plus lazertinib. Amivantamab is associated with the risk of infusion-related reactions (IRRs), interstitial lung disease, skin reactions, ocular reactions, and fetal toxicity. Lazertinib has the additional risk of venous thromboembolism, requiring anticoagulation prophylaxis while on therapy for at least the first 4 months of therapy.4,5
IRRs have an onset of around 1 hour after initiation of amivantamab infusion, with the most common being fever, hypotension, and dyspnea. While investigators were learning the kinetics and characteristics of amivantamb in the early stages of the trial, managing infusion-like reactions was an evolving process to identify the optimal prophylaxis regimen for patients. With the known onset time of IRRs, close monitoring should be implemented during the infusion. A common practice before administering amivantamab-based regimens includes dexamethasone 8 mg orally twice daily for 2 days prior to infusion, followed by 8 mg orally on the day of infusion, and then 10 mg intravenously (IV) plus oral antihistamines and antipyretics 1 hour before infusion.6
Supporting evidence for this regimen was observed in the phase 2 SKIPPirr clinical trial (NCT05663866)7, which aimed to identify the most effective prophylactic practices to mitigate IRRs. The trial had 4 cohorts: dexamethasone 4 mg orally twice daily (cohort 1); dexamethasone 8 mg orally twice daily (cohort 2); 10 mg montelukast (Singulair; Organon & Co, cohort 3); or subcutaneous methotrexate prior to infusion (cohort 4). Cohort 2 was the only group to make it to the expansion stage, with the lowest IRR rates, none of which were above grade 2.6,7
Given the evidence of IRRs as a common occurrence with amivantamab, another phase 3 trial, PALOMA-3 (NCT05388669),8 evaluated a subcutaneous formulation of amivantamab as an effective alternative for patients. The results showed noninferior efficacy and pharmacokinetics for subcutaneous amivantamab compared with IV administration. At a median follow-up of about 7 months, overall response rates were approximately 30% and 33% for the subcutaneous and IV arms, respectively. Administration time for subcutaneous amivantamab was reduced from about 5 hours with an IV to 5 minutes across 2 days and showed a 5-fold reduction in IRRs.6,8-10
As previously mentioned, skin toxicities are also a common reaction when amivantamab and lazertinib are given together. In the phase 2 COCOON trial (NCT06120140),11 the goal was to provide insight into preventive dermatologic adverse event management for patients receiving amivantamab plus lazertinib.12 This study evaluated treatment-naive patients on the same regimen used in MARIPOSA with and without advanced dermatologic support protocols. Researchers aimed to establish improved efficacy in an enhanced prophylactic regimen vs standard dermatologic care. Prophylaxis included systemic antibiotics (doxycycline or minocycline) once daily for 3 months, along with 1% clindamycin lotion for the scalp, 4% topical chlorhexidine for nails, and ceramide-based moisturizers for general skin areas.
The study found a significant reduction (~50%) in skin toxicities when advanced prophylaxis was provided compared with standard care.1,12 These results highlight the necessity of routine practice of dermatologic protocols for patients receiving amivantamab-based therapy. The COCOON trial findings have been shown to be applicable in clinical practice, providing evidence for extensive prophylactic regimens that can improve patient outcomes and treatment tolerability.12
Amivantamab plus lazertinib offers a promising new frontline option for EGFR-mutated metastatic NSCLC, based on updated MARIPOSA trial data showing a significant OS benefit over osimertinib. Although the regimen comes with challenges, such as IRR and skin toxicities, emerging practices, such as subcutaneous administration and improved supportive care protocols, can improve tolerability. As this combination becomes more widely used in practice, it is essential to consider individual patient factors and to provide consistent adverse effect management to optimize patient outcomes.
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