Tagrisso With Chemotherapy Improves Survival in EGFR+ NSCLC

People with EGFR-positive non–small cell lung cancer (NSCLC) whose disease spread outside the brain after treatment with Tagrisso lived longer when they kept taking Tagrisso along with chemotherapy, according to a phase 3 study shared at the 2025 World Conference on Lung Cancer.

The data, which were shared in a press briefing, indicated that the combination of Tagrisso and chemotherapy (49 patients) was linked with improved progression-free survival versus placebo plus chemotherapy (49 patients). The median progression-free survival in the respective arms was 8.4 months and 4.4 months. The data were at 76% maturity and the median follow-up in the Tagrisso and placebo arms was 5.4 months and 5.5 months, respectively.

In evaluable patients without baseline central nervous system metastases, the central nervous system progression-free survival with Tagrisso plus chemotherapy (38 patients) was longer, at 15.9 months, versus 8.6 months with placebo plus chemotherapy (37 patients). These data were at 43% maturity, and the median follow-up was 5.5 months and 5.6 months in the respective arms. Moreover, the Tagrisso combination was also linked with improved non–central nervous system progression-free survival versus chemotherapy alone. The median non–central nervous system progression-free survival in the respective arms was 8.4 months and 5.2 months. Data maturity was 73%, and the median follow-up was 3.6 months in both arms.

Moreover, with data at 55% maturity, the median overall survival was longer with Tagrisso plus chemotherapy versus placebo plus chemotherapy, at 15.9 months and 9.8 months, respectively. The median follow-up in the respective arms was 12 months and 11.1 months.

“These results indicate that resistance to first-line Tagrisso may be heterogeneous, and some tumor cells remain sensitive to continued therapy,” Giulia Pasello, MD, PhD, of the Veneto Institute of Oncology IOV-IRCCS and the University of Padova in Padova, Italy, said in a news release. “This trial supports Tagrisso as a backbone treatment strategy in this setting.”

In the Realm of EGFR-Mutated Non–Small Cell Lung Cancer, What Did the Phase 3 Study Examine?

The global, randomized, double-blind, phase 3 study enrolled patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer with or without central nervous system metastases. These patients were at least 18 years of age, experienced non–central nervous system progression on first-line Tagrisso, and had a World Health Organization performance score of 0 or 1; their EGFR mutations were exon 19 deletion or L858R.

Study participants (98 patients) were randomized 1:1 to receive placebo or 80 mg of Tagrisso once daily plus 75 mg/m2 of cisplatin or area under the curve 5 of carboplatin plus 500 mg/m2 of pemetrexed given every 3 weeks for 4 cycles followed by placebo or 80 mg of Tagrisso once daily plus 500 mg/m2 of pemetrexed every 3 weeks. Treatment continued until progressive disease or other discontinuation criteria were met. Patients were stratified by the presence of central nervous system metastases (yes versus no).

Imaging assessments of the chest and abdomen and the brain were done at baseline and every 6 weeks for the first 13 cycles; they were done every 12 weeks thereafter. The primary end point of the study was investigator-assessed progression-free survival, and key secondary end points comprised central nervous system progression-free survival according to baseline central nervous system metastases status, non–central nervous system progression-free survival, and overall survival.

A total of 98 patients were randomized, and 96 patients were dosed; 48 patients were randomized to the Tagrisso arm and 48 were randomized to the placebo arm; 15% and 8% of patients were still receiving Tagrisso or placebo at the time of data cutoff, which was October 28, 2024; 13% and 8% of patients in the respective arms were still receiving pemetrexed.

Across the Tagrisso and placebo arms, the median patient age was 62 years. Most patients were female (61%; 80%), never smokers (65%; 67%), and White (80%; 78%), and about half had an ECOG performance status of 1 (53%; 51%). Most patients had stage 4 disease by American Joint Committee on Cancer criteria at the time of study entry (100%; 98%). Central nervous system metastases were present in 22% of those in the Tagrisso arm versus 24% of those in the placebo arm. The more common EGFR mutation type was exon 19 deletions (65%; 55%). The median time on first-line Tagrisso in the respective arms was 21.3 months and 19.6 months.

What Else Is Known About the Efficacy of Tagrisso Plus Chemotherapy in this Setting?

The 6-month progression-free survival rate with Tagrisso plus chemotherapy was 64% versus 32% with placebo plus chemotherapy. The 6-month central nervous system progression-free survival rates were 87% and 63% in the respective arms, and the 6-month non–central nervous system progression-free survival rates were 65% and 35%, respectively. The 6-month overall survival rates were 67% and 47%.

The non–central nervous system objective response rate in the Tagrisso arm (49 patients) was 35% versus 29% in the placebo arm (49 patients). The median non–central nervous system duration of response was 8.2 months with Tagrisso versus 4.2 months without.

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

What is the Side Effect Profile of Tagrisso Plus Chemotherapy?

Safety data for the Tagrisso combination aligned with what has previously been reported for each drug. Any-grade side effects occurred in 98% of those in the Tagrisso and placebo arms; 63% and 46% of them were grade 3 or higher. Serious side effects were experienced by 38% and 31% of patients in the respective arms, and side effects proved fatal for 1 patient in each arm. Side effects led to discontinuation of Tagrisso or placebo, pemetrexed, or platinum for 13%, 19%, and 13% of patients in the Tagrisso arm; these respective rates were 2%, 2%, and 0% in the placebo arm.

The most common grade 3 side effects in the Tagrisso and placebo arms were anemia (13%; 13%), neutropenia (13%; 2%), decreased white blood cell count (10%; 4%), decreased neutrophil count (8%; 6%), decreased platelet count (6%; 2%), increased aspartate aminotransferase levels (4%; 0%), nausea (2%; 0%), increased alanine aminotransferase levels (2%; 2%), and decreased appetite (2%; 0%). The most common grade 4 events in the Tagrisso arm were neutropenia, increased alanine aminotransferase levels, decreased neutrophil count, and decreased white blood cell count (2% each). In the placebo arm, these were decreased platelet count (4%) and neutropenia (2%).

References

1. Pasello G, Zhao J, Tufman A, et al. COMPEL: Osimertinib + platinum-based chemotherapy in patients with EGFRm advanced NSCLC and progression on 1L osimertinib. Presented at: 2025 International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 1174.
2. COMPEL study shows continuing osimertinib treatment through progression with the addition of chemotherapy improves progression-free survival in EGFR-mutated NSCLC. News release. International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer. September 6, 2025. Accessed September 6, 2025. https://wclc.iaslc.org/
3. A study to evaluate chemotherapy plus osimertinib against chemotherapy plus placebo in patients with non-small cell lung cancer (NSCLC) (COMPEL). ClinicalTrials.gov. Updated July 10, 2025. Accessed September 6, 2025. https://clinicaltrials.gov/study/NCT04765059

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