Beyond 1L Therapy: Optimal Sequencing Strategies and Rationale

The discussion around optimal sequencing of therapies beyond first-line treatment in EGFR-mutant lung cancer remains complex and somewhat controversial. Although the goal is to select the best initial therapy for patients, the choice inevitably influences subsequent treatment options and outcomes. Some clinicians emphasize the continued relevance of single-agent therapies for certain patient populations, highlighting the importance of quality of life and the benefits of oral regimens with limited toxicity. There is recognition that platinum-doublet chemotherapy combined with immunotherapy still offers flexibility, especially in adjusting treatment based on response and tolerability over time. However, the lack of crossover in some clinical trials challenges the interpretation of survival benefits, raising questions about the real-world applicability of certain regimens.

When comparing different first-line approaches, including combination therapies, the focus shifts to ensuring patients can access a broad range of effective treatments over the disease course. Combination regimens may limit sequencing flexibility for some patients, but they also provide a more aggressive up-front approach that could improve outcomes for the majority. Emerging therapies such as antibody-drug conjugates and novel chemotherapy combinations are expanding the arsenal of options available in later lines, although insurance coverage and approval status can complicate access. The sequencing challenge lies in balancing the immediate efficacy of first-line treatment with preserving opportunities for effective second- and third-line therapies.

There is ongoing debate about whether all patients require exposure to every class of therapy to maximize overall survival. Some evidence suggests that repeated use of previously effective agents, such as chemotherapy or immunotherapy, may still be beneficial upon disease progression. At the same time, evolving clinical trial data are beginning to shed light on strategies for maintaining disease control post progression, including continuing third-generation tyrosine kinase inhibitors or reintroducing chemotherapy. These decisions are further complicated by insurance barriers and the need for individualized patient-centered care. Ultimately, the field is evolving rapidly, with treatment paradigms adapting as new evidence emerges and therapeutic options broaden.