Second-Line Sequencing After Osimertinib Progression in EGFR-Mutated Non-Small Cell Lung Cancer: COMPEL and MARIPOSA-2

Dr. Leal outlines her approach to second-line treatment selection following progression on frontline osimertinib monotherapy in EGFR-mutated NSCLC. She recommends repeat molecular testing at progression, particularly liquid biopsy for rapid, noninvasive results, ideally complemented by tissue biopsy to characterize resistance mechanisms and exclude histologic transformation such as small cell transformation. Common resistance mechanisms include C797S mutations and MET alterations. Clinical factors informing second-line selection include performance status, organ function (particularly renal function given platinum-based chemotherapy considerations), burden and sites of progression (with consideration of localized radiation for limited progression, including CNS-limited disease), social support, and patient preference regarding treatment intensity.

She reviews the COMPEL regimen (osimertinib plus chemotherapy versus chemotherapy alone after osimertinib progression), noting the study excluded patients with CNS progression and underwent a sample size reduction due to accrual challenges, but showed approximately 6-month PFS improvement and a trend toward OS benefit, making this treatment a reasonable option for appropriately selected patients.

She contrasts this with MARIPOSA-2, a randomized phase 3 trial demonstrating that amivantamab plus chemotherapy improved both PFS and OS compared to chemotherapy alone after osimertinib progression, including a notable intracranial PFS benefit, which is especially meaningful given the persistent risk of CNS progression in this population. She acknowledges greater toxicity burden with MARIPOSA-2 historically, though incorporation of subcutaneous amivantamab (demonstrated in COPERNICUS Cohort 2) is shifting this balance toward a more manageable side effect profile.