The landscape of treatment options following osimertinib resistance in EGFR-mutant non-small cell lung cancer (NSCLC) is rapidly evolving, with emerging data highlighting the critical importance of understanding underlying resistance mechanisms to guide therapeutic selection. At the 26th Annual International Lung Cancer Congress, experts emphasized that personalized treatment approaches based on specific mutations and patient characteristics are becoming essential as the field moves away from one-size-fits-all strategies.
"As we move away from the era where one size fits all for first-line EGFR-mutant NSCLC, we now have at least 3 sizes and probably more to come. That's going to complicate what you do next, because what you do first, of course, has a big impact on that," stated Heather Wakelee, MD, professor of medicine and chief of the Division of Oncology at Stanford University School of Medicine.
MET Amplification Drives Targeted Combination Strategies
MET amplification remains the central driver of resistance in EGFR-mutant NSCLC, with clinical data supporting MET inhibition in the setting of acquired osimertinib resistance. The phase 2 SAVANNAH trial demonstrated significant progression-free survival (PFS) benefits with savolitinib plus osimertinib, achieving a median PFS of 8.3 months (95% CI, 5.8-15.1) versus 3.6 months (95% CI, 1.4-5.7) with savolitinib plus placebo (HR, 0.27; 95% CI, 0.13-0.57). The median duration of response was 9.9 months.
These findings were reinforced by the phase 3 SACHI trial, where the median PFS with savolitinib plus osimertinib was 8.2 months (95% CI, 6.9-11.2) versus 4.5 months (95% CI, 3.0-5.4) with chemotherapy (HR, 0.34; 95% CI, 0.23-0.49; P <.0001). Median overall survival was 22.9 months (95% CI, 16.8-not evaluable) with the combination versus 17.7 months (95% CI, 14.9-26.3) with chemotherapy.
"With MET, we're often dealing with expression levels, amplification or protein levels, not just mutations. We all know about MET mutations in the setting of drug resistance, it's not so much the mutations as those higher levels of expression," Wakelee noted, highlighting the complexity of MET alterations in resistance mechanisms.
Chemotherapy-Based Combinations Show Promise
Beyond investigational MET inhibitors, FDA-approved amivantamab represents a relevant treatment option as a bispecific antibody targeting both EGFR and MET. Data from the MARIPOSA-2 trial demonstrated that amivantamab plus chemotherapy significantly improved PFS compared with chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64; P < .001) after progression on osimertinib.
Updated analyses showed that amivantamab plus chemotherapy improved PFS in patients with detectable ctDNA at baseline (HR, 0.49; 95% CI, 0.36-0.68; P < .0001) and those harboring TP53 co-mutations (HR, 0.63; 95% CI, 0.44-0.92; P = .014), suggesting biomarker-driven efficacy patterns.
Antibody-Drug Conjugates Emerge as Viable Options
The antibody-drug conjugate landscape has shown mixed but promising results in the post-osimertinib setting. Telisotuzumab vedotin demonstrated an overall response rate of 58% in patients with MET-overexpressing, EGFR-mutant NSCLC, though it carries distinct toxicities including ocular effects and peripheral edema.
Datopotamab deruxtecan (Dato-DXd) has shown particularly robust efficacy. A pooled analysis of the TROPION-Lung05 and TROPION-Lung01 trials reported a confirmed overall response rate of 42.7% (95% CI, 33.6%-52.2%) in previously treated patients with advanced EGFR-mutated NSCLC, including a 4.3% complete response rate. The median duration of response was 7.0 months (95% CI, 4.2-9.8), median PFS was 5.8 months (95% CI, 5.4-8.2), and median overall survival was 15.6 months (95% CI, 13.1-19.0).
These findings supported the FDA's decision to grant accelerated approval to Dato-DXd for adult patients with locally advanced or metastatic, EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy in June 2025.
In contrast, patritumab deruxtecan showed more modest results. The phase 3 HERTHENA-Lung02 trial demonstrated a median PFS of 5.8 months compared with 5.4 months with chemotherapy (HR, 0.77; 95% CI, 0.63-0.94; P = .011), but median overall survival was essentially equivalent at 16.0 versus 15.9 months (HR, 0.98; 95% CI, 0.79-1.22). Based on these modest OS benefits, the biologics license application for patritumab deruxtecan was subsequently withdrawn.
Precision Medicine Approaches Guide Treatment Selection
The phase 2 ORCHARD trial represents a precision medicine approach to addressing osimertinib resistance, evaluating targeted combination therapies based on patients' specific resistance biology. Patients are assigned to treatment groups based on molecular profiling after first-line osimertinib progression, with Group A evaluating patients with protocol-determined biomarkers treated with novel osimertinib combinations.
"One of the most common resistance mutations that we see is MET amplification. That has been associated with first-line EGFR-directed therapy," noted Sandip P. Patel, MD, professor of medicine at UC San Diego Health and conference cochair. He emphasized that detection methods often determine how MET amplification is identified, with tissue-based FISH testing being most sensitive, though many oncologists use cell-free DNA approaches.
Treatment Sequencing Considerations
Treatment selection following first-line osimertinib should be guided by underlying resistance mechanisms. For patients with MET amplification, multiple targeted therapies are available. In cases of histologic transformation to small cell lung cancer, platinum plus etoposide remains standard. For resistance mutations such as EGFR C797S, earlier-generation EGFR TKIs may be considered depending on allelic configuration.
The optimal sequencing of therapies remains less clear for patients who have progressed after receiving patritumab deruxtecan or bispecific antibodies like amivantamab. Questions also persist about whether to rechallenge with osimertinib plus chemotherapy if patients previously received this combination.
Despite the emergence of novel targeted approaches, conventional chemotherapy remains an essential backbone for patients who have exhausted targeted therapies or lack identifiable resistance mechanisms. "Plain old, vanilla chemotherapy is still very effective," Wakelee concluded, emphasizing the continued importance of traditional approaches in the treatment armamentarium.
