For the Tox Check series, Gilberto Lopes, MD, of Sylvester Comprehensive Cancer Center at University of Miami, joined Rahul Gosain, MD, MS, and Rohit Gosain, MD, to discuss key adverse effects of afatinib, osimertinib, and amivantamab-lazertinib in patients with non–small cell lung cancer (NSCLC) harboring EGFR mutations.
Dr. Lopes began by describing the mechanisms of underlying toxicities seen across the class: When anti-EGFR agents impair keratinocytes, the resulting cell damage causes the immune system to release cytokines, triggering inflammation. The resulting inflammation creates an environment that allows commensal bacteria to grow and cause secondary infections.
Key toxicities seen across anti-EGFR agents in NSCLC include rash, diarrhea, paronychia, mucositis, pneumonitis, and cardiotoxicity. Although toxicities vary in severity by agent, the management strategies generally apply across the class.
Dr. Lopes highlighted that pneumonitis and interstitial lung disease events can happen with any anti-EGFR agent, though they are often asymptomatic. If patients develop symptoms such as shortness of breath, the standard approach is to pause anti-EGFR and treat with steroids.
“You always have to have a degree of suspicion because the only way to detect pneumonitis is on a [computed tomography] scan,” Dr. Lopes advised.
Management of Afatinib Toxicity in NSCLC
In today’s practice, with the emergence of agents like osimertinib and amivantamab-lazertinib, afatinib is typically reserved for patients who have NSCLC with uncommon EGFR mutations.
Afatinib is linked to more severe skin toxicities than other anti-EGFR inhibitors. As a result, patients are often started on antibiotics preemptively. However, Dr. Lopes noted that he is more concerned about diarrhea with afatinib. “Diarrhea happens for almost every single patient who gets the drug, especially at the full dose of 40 mg,” he said. “We also see grade 3 diarrhea, which is extremely rare with the other agents.”
When using afatinib, Dr. Lopes starts most patients with EGFR-mutated NSCLC at the standard 40-mg dose, with fairly aggressive dose reductions if he sees toxicity.
Adverse Effects of Osimertinib
Osimertinib involves many of the same class-wide adverse effects as afatinib, but skin toxicities don’t need to be managed as aggressively, Dr. Lopes said.
Regarding potential cardiac toxicities, electrocardiograms (ECGs) prior to treatment and for the first few months to monitor the QT interval are standard. For most patients, monitoring can eventually stop, but regular ECGs and echocardiograms should continue for high-risk patients.
Furthermore, “while you can see acute kidney injury with osimertinib, more often what happens is the drug blocks a pump in the kidney and serum creatinine begins to increase,” Dr. Lopes stated. He recommended reviewing patients’ cystatin C to monitor kidney function and glomerular filtration rate.
The doctors agreed that, despite the greater tolerability, the toxicities of osimertinib can greatly affect quality of life, and active management is key.
Amivantamab-Lazertinib Adverse Effects in Lung Cancer
The approval of amivantamab-lazertinib was a major shift for NSCLC with EGFR mutations, with clinical trials achieving meaningful increases in overall survival.
One major toxicity to consider is infusion-related reactions (IRRs), which occur in about 70% of patients. The SKIPPirr trial, which Dr. Lopes coauthored, found that administering 8 mg of dexamethasone 2 days, 1 day, and 1 hour before infusion reduced the risk of IRRs with amivantamab.
If IRRs do occur, Dr. Lopes noted, they happen only with the first infusion and typically aren’t a future concern for at least 95% of patients. A subcutaneous formulation of amivantamab, currently in development, may also reduce the risk of IRRs.
Amivantamab-lazertinib has also shown increased skin toxicity compared with osimertinib. However, the COCOON trial described a formal regimen for proactive management with oral antibiotics, daily ceramide-containing moisturizer, and a chlorhexidine skin wash. If that regimen doesn’t control skin toxicity, dose reduction or interruption is appropriate.
Oral retinoids have shown potential efficacy in managing skin toxicity, but topical retinoids exacerbated it, Dr. Lopes said, emphasizing that oncologists should always stop doxycycline before starting any retinoids.
Amivantamab-lazertinib is also associated with an increased risk of venous thromboembolism, primarily deep vein thrombosis and pulmonary embolism. Standard prevention involves anticoagulants for the first 4 months of anti-EGFR therapy.
Dr. Lopes prefers to reduce the amivantamab dose first and then lazertinib as needed when making dose adjustments, he said.
Overall, Dr. Rohit Gosain emphasized that, as new treatments improve survival in NSCLC with EGFR mutations, managing adverse effects is key for maximizing patients’ duration of therapy.
