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Pharmacy Updates 1L Treatment for EGFRm NSCLC
Pharmacy Updates and the Evolving First-Line Treatment Landscape for Patients With EGFR-Mutated NSCLC 

Released: September 29, 2025

Nicole Bentivegna
Nicole Bentivegna, PharmD, BCOP
Frank Scimeca
Frank Scimeca, PharmD, MBA, BCOP
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Key Takeaways
  • Thorough genetic testing on tumor tissue to detect actionable mutations including various EGFR mutations helps to streamline drug authorization by pharmacists and enhance patient care.
  • First-line therapy options for EGFR-mutated advanced non-small-cell lung cancer have recently expanded to include the combination regimens of amivantamab plus lazertinib and osimertinib plus chemotherapy that have demonstrated improved overall survival outcomes.
  • Specialty and clinical pharmacists are uniquely positioned to prevent, mitigate, and manage toxicities associated with these combination regimens to maximize patient benefit.

Introduction
As drug therapy experts, pharmacists must continuously adapt to address clinical care gaps and improve patient outcomes. Specialty pharmacists play a central role in coordinating complex, multimodal therapy that exists in the clinical care of patients with cancer. Beyond dispensing, specialty oncology pharmacists require knowledge of genomic testing methods, premedication strategies, supportive care, and adverse event (AE) management. The acquisition and delivery of therapies to improve patient care requires collaboration among pharmacy strategists, pharmaceutical distributors, financial coordinators, and hospital administrators, which was emphasized at the 2025 Asembia meeting earlier this year.

Education is another major cornerstone for optimizing the care of patients with cancer. Pharmacists have a central role in preparing patients and the multidisciplinary care team to anticipate, recognize, and manage treatment-related toxicities. For example, the treatment landscape for EGFR-mutated non-small-cell lung cancer (NSCLC) is evolving rapidly, with regimens containing bispecific antibodies and tyrosine kinase inhibitors (TKIs) that are reshaping the frontline standard of care. These new agents and combinations present a range of clinical challenges that must be mitigated. Clinical and specialty pharmacists remain pivotal in the AE management process. This commentary outlines ways that professionals are adapting to this landscape.

Genetic Testing Guides Treatment Decisions for NSCLC
Although EGFR has been a target of therapy in NSCLC since the first approval of gefitinib, nuances in genetic alterations, deletions, substitutions and secondary mutations arising from drug resistance have created a more complicated treatment environment. Therefore, timely and comprehensive next-generation sequencing (NGS) is a foundation of care for patients with NSCLC. Genetic testing is recommended for resectable (stage IB to IIIC) and unresectable advanced NSCLC. Without adequate testing, patients could miss the opportunity for an optimized treatment approach and associated outcome.

EGFR is a receptor tyrosine kinase normally found on the surface of epithelial cells where it aids the routine maintenance of skin regeneration and cardiovascular functioning. When the EGFR gene harbors alterations like exon 19 deletions, exon 21 L858R mutations, or exon 20 insertions, it becomes a driver of lung cancer. Although these genetic alterations facilitate carcinogenesis, they can also help guide therapy selection. For example, exon 19 and 21 mutations predict responsiveness to oral EGFR TKIs and occur in approximately 10% of White patients and up to 50% of Asian patients with NSCLC.

Specialty pharmacists are a critical part of the care team because their assistance streamlines the authorization process and decreases the time to therapy initiation. These professionals play a critical role in ensuring genetic test results are available in a timely manner. They also review patient results to help guide therapeutic decision-making in collaboration with the multidisciplinary oncology team by interpreting NGS data and flagging clinically relevant information.

New Combination Regimens With EGFR-Targeting TKIs
Recently, 2 additional first-line treatment options for newly diagnosed metastatic NSCLC with a specific EGFR alteration became designated as Category 1 treatment options by the National Comprehensive Cancer Network guidelines for NSCLC. The first option for tumors with an EGFR exon 19 deletion or exon 21 L858R mutation is the combination of osimertinib plus systemic chemotherapy. The FLAURA2 trial update demonstrated that first-line osimertinib plus chemotherapy significantly improved overall survival compared to osimertinib monotherapy. The second option is the combination of amivantamab, an EGFR-MET bispecific antibody, with lazertinib, another third-generation EGFR TKI. Results from the phase III MARIPOSA trial demonstrated superior progression-free survival and, more recently, improved overall survival vs osimertinib monotherapy.

Treatment selection in the first-line setting should be patient specific and reflect comorbidities. For example, osimertinib monotherapy is favored for frail or older patients, individuals with multiple comorbidities, or individuals facing infusion or access barriers. By contrast, younger patients with aggressive or bulky disease may benefit more from 1 of the previously mentioned combination drug regimens. Pharmacists can also offer patient-specific intervention strategies by proactively counseling patients and incorporating toxicity monitoring into refill calls.

Managing and Mitigating AEs
Although data from the MARIPOSA trial are promising, important precautions should be taken when administering the combination of amivantamab with lazertinib. Amivantamab is associated with infusion-related reactions (IRRs), interstitial lung disease, skin and ocular toxicities, and fetal risk. Lazertinib carries a similar safety profile, with the added risk of venous thromboembolism (VTE), for which anticoagulation prophylaxis is recommended during the first 4 months of therapy. As an example, prophylactic anticoagulation led to 2-fold reduction in the incidence of VTE in the MARIPOSA trial (20.0% vs 11.4%).

IRRs typically occur within the first hour of amivantamab infusion, most often presenting as fever, hypotension, and dyspnea. Given the predictable onset, close monitoring is essential during administration. A premedication regimen includes dexamethasone 8 mg PO BID for 2 days before infusion, 8 mg PO on the day of infusion, then 10 mg IV dexamethasone plus oral antihistamines and antipyretics 1 hour prior. Evidence for this approach was established in the phase II SKIPPirr trial, which evaluated prophylactic strategies to mitigate IRRs. With the objective of further reducing the risk of IRRs compared with the intravenous formulation of amivantamab, the PALOMA-3 trial investigated a subcutaneous formulation of amivantamab, which demonstrated noninferior efficacy and pharmacokinetics to intravenous dosing. With the subcutaneous formulation, administration time is reduced from 5 hours over 2 days to approximately 5 minutes, and there was a 5-fold reduction in IRRs. The subcutaneous formulation is currently under FDA review and, if approved, could significantly reduce chair time for patients while minimizing toxicities. 

Dermatologic toxicities are common with EGFR-targeted therapies given that EGFR is involved in skin and hair follicle development. These toxicities are generally manageable with topical steroids and antibiotics, but dermatology consult can also be considered. The phase II COCOON trial evaluated enhanced dermatologic prophylaxis for patients receiving amivantamab with lazertinib. The regimen included systemic antibiotics (doxycycline or minocycline for 3 months), clindamycin 1% lotion for the scalp, 4% topical chlorhexidine for nails, and ceramide-based moisturizers. Compared with standard dermatologic care, this approach reduced skin toxicities, supporting the integration of prophylactic dermatologic protocols into routine practice to improve tolerability and patient outcomes.

Hematologic toxicities like anemia, neutropenia, and thrombocytopenia are some of the most frequent toxicities experienced by patients treated with osimertinib plus chemotherapy. In addition, gastrointestinal effects like diarrhea, nausea, and vomiting may also occur. Although osimertinib-specific events like rash, nail changes, and rare interstitial lung disease remain possible, the main incremental burden comes from chemotherapy-related myelosuppression and constitutional symptoms. Data from FLAURA2 showed higher rates of grade ≥3 AEs with the combination (64%) compared to osimertinib alone (27%) but most were manageable with supportive care, dose modifications, and proactive monitoring.

As illustrated, regimens with EGFR inhibitors are associated with challenges such as IRRs, dermatologic toxicities, and increased risk of VTE events. However, innovations like subcutaneous administration and proactive supportive care protocols can significantly improve tolerability. As this treatment option becomes more widely adopted, careful patient selection and consistent AE management remain essential to optimizing outcomes.

Closing Thoughts
As frontline EGFR-targeted therapy shifts toward mixed modality regimens that combine intravenous therapies with oral targeted therapies, clinical and specialty pharmacists serve as the hub of integrated cancer care. They must stay well versed in emerging data to help balance efficacy, safety, access, and adherence in real-world practice. Their responsibilities extend well beyond dispensing and include reviewing genomic testing results, synchronizing infusion and oral workflows, implementing premedication and supportive care strategies, and ensuring appropriate VTE event prophylaxis when indicated. Leaning on pharmacy practice professionals can help unite clinical expertise with practical care coordination, ensuring that patients with EGFR-mutated NSCLC receive not only safe and effective therapy but also the support needed to achieve better outcomes and improved quality of life.

Your Thoughts
What are your biggest challenges in the care of your patients with EGFR-mutated NSCLC? Please answer the polling question and join the conversation by posting a comment in the discussion section.

For more information on the current management of patients with EGFR-mutated NSCLC, be sure to watch our website for an upcoming program specifically developed by pharmacists for pharmacists: “Personalized Treatment in EGFR-Mutated NSCLC: Applying the Latest Clinical Evidence to Address Barriers and Improve Quality of Care”.

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In your current practice, which of the following treatment options do you use as first-line therapy for patients with EGFR-mutated advanced NSCLC?

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