Estelamari Rodriguez, MD, MPH

Siddhartha Devarakonda, MD, of Providence Swedish Cancer Institute describes what it takes to deliver combination therapy for epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC) outside a trial, crediting financial advocates, social workers, nurses and pharmacists.

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center presents a 74-year-old woman with epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), no central nervous system involvement, limited mobility, osteoporosis and rheumatoid arthritis, who lives alone an hour from the cancer center and depends on others for transportation.

Siddhartha Devarakonda, MD, of Providence Swedish Cancer Institute says he tries not to push patients with asymptomatic brain metastases from epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC) toward local therapy, calling whole brain radiation the wrong step for this patient and noting that another consultation costs the patient time.

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center presents a 68-year-old woman with newly diagnosed metastatic lung adenocarcinoma, an epidermal growth factor receptor (EGFR) exon 19 deletion with a concurrent TP53 co-mutation, multiple small asymptomatic brain metastases on staging magnetic resonance imaging, disease confined to lung and brain, and good performance status with support at home.

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center presents long-term resistance data from the phase 3 MARIPOSA study in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), where amivantamab plus lazertinib reduced acquired MET amplification approximately fourfold and secondary EGFR resistance mutations approximately fivefold compared with osimertinib.

Siddhartha Devarakonda, MD, of Providence Swedish Cancer Institute says he sees no remaining role for intravenous amivantamab in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), with subcutaneous administration taking 10 to 15 minutes and easing chair time and scheduling.

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center describes COPERNICUS, a pragmatic study of first-line subcutaneous amivantamab plus lazertinib with protocol-directed supportive care in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), which was open at her own site.

Matthew Gumbleton, MD, PhD, of Huntsman Cancer Institute rejects the idea that a TP53 co-mutation points toward chemotherapy in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC).

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center contrasts central nervous system (CNS) imaging in the phase 3 MARIPOSA and FLAURA2 studies of epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), noting that one scanned every patient on a set schedule while the other continued imaging mainly in patients with baseline brain metastases.

Siddhartha Devarakonda, MD, of Providence Swedish Cancer Institute pushes back on the high-risk label in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), noting that when 89% of patients with analyzable circulating tumor DNA in the phase 3 MARIPOSA study carry at least 1 high-risk feature, the term loses meaning.

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center presents the final overall survival data from the phase 3 FLAURA2 study of osimertinib plus chemotherapy in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC), at more than 47.5 months versus approximately 38 months for osimertinib alone, and asks how the panel handles cross-trial comparison.

Matthew Gumbleton, MD, PhD, of Huntsman Cancer Institute and Siddhartha Devarakonda, MD, of Providence Swedish Cancer Institute discuss how they translate grade 3 or higher adverse event rates into a conversation a patient can actually use in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC).

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center walks through the mature overall survival data from the phase 3 MARIPOSA study of amivantamab plus lazertinib in epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC).

Estelamari Rodriguez, MD, MPH, of Sylvester Comprehensive Cancer Center opens this CancerNetwork Around the Practice discussion on first-line therapy for epidermal growth factor receptor (EGFR)-mutated advanced non–small cell lung cancer (NSCLC) with panelists Matthew Gumbleton, MD, PhD, of Huntsman Cancer Institute, and Siddhartha Devarakonda, MD, of Providence Swedish Cancer Institute.

Two clinical scenarios illustrated shared decision-making in practice: a 58-year-old woman with TP53 mutation, L858R, and asymptomatic brain metastases drew unanimous consensus for treatment intensification with either FLAURA2 or MARIPOSA, given her high-risk features and flexible schedule.

The debate examined whether amivantamab-lazertinib or osimertinib-chemotherapy more favorably reshapes resistance biology, with the MARIPOSA team citing data showing lower rates of MET amplification (7.3% vs. 13.1%) and secondary EGFR mutations (1.4% vs. 7.6%) compared to osimertinib monotherapy, alongside a potential immune-activating effect of amivantamab and a possible curve-flattening signal suggesting disease course modification.

Panelists agreed that subcutaneous amivantamab represents meaningful progress over the IV formulation, nearly eliminating infusion reactions, reducing dosing frequency to every four weeks, and lowering high-grade dermatologic toxicity, although grade 1-2 rash and the burden of the COCOON prophylaxis regimen remain relevant considerations for patients.

The debate centered on CNS efficacy comparisons between MARIPOSA and FLAURA2, with the key distinction being that MARIPOSA mandated serial brain MRIs for all patients, enabling full intracranial PFS analysis across all 429 participants, whereas FLAURA2 only required serial imaging in patients with baseline CNS metastases, limiting the robustness of its CNS data.

The TOP trial, a phase three study focused exclusively on TP53-mutant EGFR-mutant non-small cell lung cancer, validated the FLAURA2 findings in this high-risk subset, showing a striking PFS benefit of 34.0 versus 15.6 months (HR 0.44) for osimertinib plus chemotherapy over monotherapy, with a favorable duration of response of 32.7 versus 15.9 months, though overall survival data remain immature.

The FLAURA2 phase three trial demonstrated that adding platinum-based chemotherapy to osimertinib significantly improved outcomes over osimertinib monotherapy in first-line EGFR-mutant non-small cell lung cancer, with a median PFS of 29.4 versus 19.9 months and a statistically significant overall survival benefit of 47.5 versus 37.6 months.

The COPERNICUS study, an ongoing phase two trial, evaluated amivantamab-based regimens in EGFR-mutant non-small cell lung cancer across two cohorts, first-line and post-osimertinib progression, with a key focus on implementing mandatory prophylactic skin and DVT regimens, resulting in dramatically lower rash rates (4% grade 3+) compared to the original MARIPOSA trial.

Panelists discuss the pivotal MARIPOSA trial, which examined combining amivantamab with lazertinib versus osimertinib monotherapy, showing improvements in progression-free survival (23.7 vs. 16.6 months), overall survival, CNS efficacy, and particularly strong benefits in high-risk subgroups such as TP53-mutant patients. Safety data from the trial highlighted the importance of prophylactic measures, especially for rash and other adverse events, noting that with current prophylaxis protocols, serious toxicity rates have been significantly reduced compared to the original study.

Estelamari Rodriguez, MD, MPH, presents a case of a 50-year-old African American woman, non-smoker, with pleural metastases; the panel discusses interstitial lung disease management, the use of antibody-drug conjugates, disease timing, and strategies for providing symptomatic relief, specifically considering drug holds if steroids only offer partial relief.

Christine Bestvina, MD, presents a case of a 34-year-old non-smoker diagnosed with Stage IIIA NSCLC after presenting with chest wall pain; the panel then explores their approaches to managing toxicities, including rashes and sores, by employing dose reductions and steroids to control adverse reactions.

Alexander Spira, MD, PhD, FACP, presents a case of a 45-year-old male with stage IV NSCLC, bone and liver metastases, and an EGFR exon 20 insertion; the panel then discusses their approach to treating brain metastases using stereotactic radiosurgery radiation therapy.

The panelists explore the importance of communicating with patients, nurses, and caregivers about potential adverse reactions and injection site reactions, while emphasizing the need to offer ongoing reassurance and support throughout the treatment journey.