How To Manage Side Effects of EGFR Inhibitors in NSCLC

Azam Farooqui, MD Ironwood Cancer and Research Centers | Joshua Sabari, MD NYU Langone Health | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Anti-EGFR tyrosine kinase inhibitors (TKIs) are mainstay treatments for non-small cell lung cancer (NSCLC) with EGFR mutations, especially in the metastatic setting.

• Cutaneous and gastrointestinal (GI) events are common side effects seen across anti-EGFR TKIs.

• The combination of amivantamab and lazertinib is associated with more severe cutaneous toxicities and other distinct toxicities that require dedicated prophylactic strategies.

• Data support that dose holds and reductions can be done to manage many toxicities without compromising efficacy outcomes with these agents.

Managing Side Effects of Afatinib, Osimertinib, and Lazertinib

Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with two thoracic medical oncologists—Joshua Sabari, MD, of NYU Langone Health, and Azam Farooqui, MD, of Ironwood Cancer and Research Centers—to discuss how to manage side effects of three EGFR inhibitors used in NSCLC: afatinib, osimertinib, and lazertinib. Broadly, cutaneous toxicities like rash and pruritus are the most common side effects shared by the EGFR inhibitor class. 

Afatinib Toxicities in Metastatic NSCLC

Afatinib is an oral, second-generation EGFR inhibitor approved for metastatic, non-resistant EGFR–mutated NSCLC. The full dose of afatinib is 40 mg once daily, and the dose can be reduced to 30 mg, followed by 20 mg. Dr. Sabari noted that he often starts patients at 30 mg, which historical data support has comparable efficacy to the full dose. 

Dermatologic, ocular, gastrointestinal (GI), pulmonary, hematologic, and ear, nose, and throat side effects are associated with afatinib. The most common side effects are cutaneous toxicities and diarrhea, the latter of which is the primary driver of dose reductions. Interstitial lung disease (ILD) is an uncommon side effect that must also be monitored. 

In the current era, afatinib has largely been supplanted by combination regimens for frontine therapy in patients with NSCLC with common EGFR mutations, and it is typically only used in patients with atypical EGFR mutations. 

Potential Side Effects of Osimertinib

Osimertinib is an oral, third-generation EGFR inhibitor approved for EGFR–mutated NSCLC in both the adjuvant and first-line metastatic treatment settings. The full dose of osimertinib is 80 mg once daily, which can be reduced to 40 mg. Osimertinib is associated with dermatologic, ocular, cardiac, pulmonary, and electrolyte side effects. Some patients also experience hematologic toxicities like anemia. While rates of cardiac toxicity are low with osimertinib, if a patient experiences recurring cardiac toxicity despite dose holds and reductions, switching to lazertinib may be appropriate, said Dr. Sabari. 

When using osimertinib, the doctors recommended monitoring for QTc prolongation and cardiomyopathy with electrocardiograms and echocardiograms every few months. Osimertinib also requires proactive monitoring for ILD, although oncologists should consider if ILD events are related to previous radiation therapy or the underlying disease burden rather than osimertinib before changing therapy, said Dr. Farooqui. 

Osimertinib monotherapy is used less frequently after first-line combination regimens were approved based on the FLAURA2 and MARIPOSA trials. However, single-agent osimertinib may still be a viable option for patients who can’t tolerate chemotherapy or amivantamab plus lazertinib. 

Amivantamab Plus Lazertinib Toxicities and Prophylactic Strategies

Lazertinib is an oral, third-generation EGFR inhibitor used in combination with amivantamab, a bispecific antibody against EGFR and MET. The combination was approved as first-line therapy for metastatic NSCLC based on the MARIPOSA trial. The full dose of lazertinib is 240 mg once daily, which can be reduced to 160 mg and then 80 mg. The amivantamab dose is based on baseline body weight and is given weekly for the first 5 weeks, followed by every other week starting Week 7.

The combination of amivantamab and lazertinib is associated with dermatologic, ocular, pulmonary, and cardiac toxicities, as well as infusion-related reactions (IRRs) and electrolyte derangement. Many side effects are more prominent in the first few months of therapy, and reduce over time. Due to the dual inhibition of EGFR, cutaneous toxicities are more pronounced with amivantamab and lazertinib compared with single-agent TKI therapy.

When using amivantamab and lazertinib, three prophylactic strategies are needed to manage cutaneous and cardiac toxicities and IRRs. Firstly, the COCOON regimen is a combination of antibiotics, antiseptics, and moisturizers that was shown to significantly reduce the rate of dermatologic adverse events. Secondly, a prophylactic-dose anticoagulant is given for the first 4 months of treatment to reduce the risk of venous thromboembolism. Lastly, pre-infusion dexamethasone is given to reduce the rate of IRRs based on the SKIPPirr trial. Notably, a subcutaneous formulation of amivantamab was recently approved, which is associated with substantially lower rates of IRRs.

Even if patients are not experiencing significant cutaneous toxicities during treatment, oncologists should stress the importance of continuing the prophylactic COCOON regimen to prevent side effects from developing that may interrupt treatment, said Dr. Farooqui.

Closing the discussion, the doctors emphasized that prophylactic strategies, proactive monitoring, and appropriate dose holds or modifications to manage side effects of EGFR inhibitors in lung cancer are paramount to keep patients on treatment long-term and derive the most efficacy possible while maintaining quality of life. In addition, trial data and additional analyses support that dose holds or reductions with these agents can alleviate toxicities without sacrificing efficacy.