Tagrisso (osimertinib)

EGFR tyrosine kinase inhibitors (TKIs) have transformed management, with first-line osimertinib demonstrating a median progression-free survival (PFS) of 18.9 months and overall survival (OS) of 38.6 months in the FLAURA trial...Understanding these mechanisms is critical for optimizing patient outcomes and guiding personalized therapeutic approaches. This review discusses current strategies to delay or overcome resistance and highlights emerging therapeutic avenues with the potential to reshape the management of EGFR-mutant NSCLC.

This study supports the real-world effectiveness and tolerability of first-line osimertinib. Oligoprogression was associated with longer OS compared with systemic progression, and the integration of LATs in carefully selected patients with oligoprogression may be associated with prolonged osimertinib treatment duration and favorable post-progression outcomes.

Durvalumab plus etoposide-platinum demonstrated a modest treatment response in neuroendocrine-transformed EGFR-mutated NSCLC. AEs were concordant with the known safety profiles of the combination, and no new safety signals were observed.

TP53 GOF mutations define a biologically and clinically distinct subtype of EGFR-mutant NSCLC characterized by early resistance to osimertinib.

P2, N=348, Not yet recruiting, Akeso

Clinical courses were heterogeneous: one patient achieved a durable partial response using combined osimertinib and crizotinib. A second patient, intolerant to dual TKI therapy due to QTc prolongation and grade 3 edemas, achieved a sustained partial response with platinum-pemetrexed chemotherapy...However, its biological significance, driver versus passenger role, and therapeutic relevance remain uncertain. Combined EGFR and ROS1 inhibition may be considered in selected cases, but further validation is required.

In pooled analyses from TROPION-Lung01 and TROPION-Lung05, Dato-DXd achieved an objective response rate of ~45% and a median duration of response of 6.5 months, which compares favorably with historical outcomes with docetaxel. Dato-DXd is being evaluated in combination with osimertinib in the first-line and post-osimertinib settings, following encouraging activity in the phase II ORCHARD platform trial evaluating therapeutic strategies for EGFR-TKI-resistant disease...Current research aims to elucidate the mechanisms underlying these toxicities and to identify modifiable risk factors to further improve tolerability. The biological mechanisms contributing to the differential efficacy of Dato-DXd are also under investigation and may further inform its clinical role.Expert opinion: Determining how best to integrate Dato-DXd within existing treatment sequences has the potential to meaningfully address persistent unmet needs in EGFR-mutated NSCLC.

These findings suggest that osimertinib crosses the placenta with a moderate tissue uptake, while alectinib and its metabolite M4 do not appear to be transferred to the fetus but accumulate significantly within the placental tissue. Further studies are needed to guide treatment selection for NSCLC in pregnant women.

Recent clinical trials have led to US Food and Drug Administration approval of osimertinib and alectinib as adjuvant treatments for resected pathologic stage II/III EGFR and ALK-mutated NSCLC; their use in the neoadjuvant setting remains subject to trials. These questions are the subject of two ongoing National Clinical Trials Network trials: CTIU2317-A082304-S2402-Perioperative versus Adjuvant Systemic Therapy in Patients with Resectable NSCLC (PROSPECT-Lung; ClinicalTrials.gov Identifier: NCT04267848)-and S2414-A Randomized Phase III Trial Incorporating Pathologic Response in Participants with Early-Stage NSCLC to Optimize Immunotherapy in the Adjuvant Setting (INSIGHT; ClinicalTrials.gov Identifier: NCT06498635). We discuss why there is sufficient equipoise to justify seeking answers to these two extremely important, patient-centered questions.

The mOS of the EGFR-TP53 co-mutant group who received second-line TKIs combined with platinum-containing double-drug chemotherapy and bevacizumab after the progression of first-line single-drug TKIs was 27.0 months versus 6.0 months compared with those who did not receive second-line therapy (P = .019). In first-line EGFR-TKIs monotherapy in patients with EGFR-TP53 co-mutation, osimertinib was clearly superior to gefitinib. In first-line EGFR-TKIs monotherapy progression, TKIs combined with chemotherapy and antiangiogenesis therapy could prolong patients' survival.