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Data from the COMPEL trial support extending osimertinib (Tagrisso, AstraZeneca) therapy to patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) who progress on first-line treatment with the drug.

In patients who experienced non-central nervous system (CNS) progression after first-line therapy, continuing the third-generation EGFR tyrosine kinase inhibitor alongside platinum-based chemotherapy prolonged progression-free survival by about 4 months and overall survival by about 6 months.

Overall, the combination therapy led to a 57% reduction in the risk of disease progression or death.

"These results indicate that resistance to first-line osimertinib may be heterogeneous, and some tumor cells remain sensitive to continued therapy," lead investigator Giulia Pasello, MD, PhD, medical oncologist, Veneto Institute of Oncology, Padova, Italy, said in a statement. 

Pasello presented the findings during a press briefing on September 6 at the World Conference on Lung Cancer (WCLC) 2025 in Barcelona, Spain.

Benefits Beyond First Line 

Osimertinib is a preferred first-line treatment for EGFR-mutated advanced NSCLC, offering protection against CNS progression. However, most patients eventually experience disease progression and move on to platinum-based chemotherapy, Pasello explained. 

The COMPEL trial evaluated whether continuing osimertinib following progression, when paired with chemotherapy, could extend patient survival.

Ninety-eight patients with non-CNS progression on first-line osimertinib were randomized (1:1) to receive either osimertinib 80 mg or placebo once daily. Both groups also received platinum-pemetrexed chemotherapy (cisplatin 75 mg/m² or carboplatin AUC5 alongside pemetrexed 500 mg/m² every 3 weeks for 4 cycles), followed by maintenance pemetrexed (500 mg/m² every 3 weeks) until disease progression or discontinuation. 

Randomization was stratified by the presence of CNS metastases at baseline (22% in the osimertinib group and 24% in the placebo group). The primary endpoint was progression-free survival and secondary endpoints were CNS progression-free survival (according to CNS metastases status at baseline), non-CNS progression-free survival, and overall survival.

Overall, 96 patients received treatment — 48 in each group. Continuing osimertinib alongside chemotherapy was associated with improved progression-free survival (hazard ratio [HR], 0.43) and longer overall survival (HR, 0.71) in patients with non-CNS progression on first-line osimertinib. 

Median overall survival was 15.9 months with osimertinib vs 9.8 months without it. Median progression-free survival was 8.4 months with osimertinib vs 4.4 months with placebo. 

The 6-month overall survival rates were 67% with osimertinib plus chemotherapy and 47% with placebo plus chemotherapy, and the 6-month progression-free survival rate was 64% vs 32%, respectively.

Osimertinib plus chemotherapy was also associated with longer CNS progression-free survival in patients without CNS involvement at baseline (15.9 vs 8.6 months with placebo; HR, 0.56), adding to the established evidence supporting osimertinib's protective effect in the CNS, Pasello said. The 6-month CNS progression-free survival rates in these patients were 87% with osimertinib and 63% with placebo.

Fewer patients on osimertinib than placebo had new brain lesions during follow-up (5 vs 13 patients).

Improvement in non-CNS progression-free survival was also observed with osimertinib plus chemotherapy (8.4 vs 5.2 months; HR, 0.43), suggesting that the benefit of this combination extends beyond the CNS. The 6-month non-CNS progression-free survival rates were 65% and 35%, respectively.

New lesions were reported in 37% of patients on osimertinib vs 51% of those in the placebo arm, with fewer patients in the osimertinib group experiencing new brain lesions (10% vs 27%).

The safety findings of the osimertinib plus chemotherapy regimen were consistent with the known safety profiles for each drug. In the osimertinib group, 63% experienced a grade 3 or higher adverse event and 38% experienced serious adverse events compared to 46% and 31%, respectively, in the placebo group. Overall, six patients in the osimertinib group discontinued drug treatment compared to one patient in the placebo group. 

"Results from COMPEL support continuing osimertinib as a backbone treatment for EGFRm advanced NSCLC through lines of therapy," Pasello told the briefing. 

The COMPEL study was funded by AstraZeneca, Cambridge, UK. No disclosure information was provided.