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Patients with EGFR-mutated non–small cell lung cancer (NSCLC) who experienced non–central nervous system (CNS) progression on frontline osimertinib (Tagrisso) derived survival benefits from continuing osimertinib treatment plus platinum-based chemotherapy, according to findings from the phase 3 COMPEL study (NCT04765059) presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.^1,2

The data, which were shared in a press briefing, indicated that the combination of osimertinib and chemotherapy (n = 49) was linked with improved progression-free survival (PFS) vs placebo plus chemotherapy (n = 49). The median PFS in the respective arms was 8.4 months (95% CI, 5.7-11.8) and 4.4 months (95% CI, 3.5-5.6), translating to a 57% reduction in the risk of disease progression or death (HR, 0.43; 95% CI, 0.27-0.70. The data were at 76% maturity and the median follow-up in the osimertinib and placebo arms was 5.4 months (range, <0.1-24.9) and 5.5 months (range, <0.1-11.1), respectively.

In evaluable patients without baseline CNS metastases, the CNS PFS with osimertinib plus chemotherapy (n = 38) was longer, at 15.9 months (95% CI, 7.9-18.6), vs 8.6 months (95% CI, 5.6-19.4) with placebo plus chemotherapy (n = 37; HR, 0.56; 95% CI, 0.27-1.13). These data were at 43% maturity, and the median follow-up was 5.5 months (range, <0.1-23.6) and 5.6 months (range, <.01-13.8) in the respective arms. Moreover, the osimertinib combination was also linked with improved non-CNS PFS vs chemotherapy alone. The median non-CNS PFS in the respective arms was 8.4 months (95% CI, 5.7-11.8) and 5.2 months (95% CI, 3.5-5.8), respectively (HR, 0.43; 95% CI, 0.26-0.71). 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 (OS) was longer with osimertinib plus chemotherapy vs placebo plus chemotherapy, at 15.9 months (95% CI, 12.4-20.8) and 9.8 months (95% CI, 8.4-17.2), respectively (HR, 0.71; 95% CI, 0.42-1.23. The median follow-up in the respective arms was 12.0 months (range, 4.2-36.0) and 11.1 months (range, 0.8-34.5).

“These results indicate that resistance to first-line osimertinib 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.² “This trial supports osimertinib as a backbone treatment strategy in this setting.”

In the Realm of EGFR-Mutated NSCLC, What Did the Phase 3 COMPEL Study Examine?

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

Study participants (n = 98) were randomized 1:1 to receive placebo or 80 mg of osimertinib 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 osimertinib 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 CNS metastases (yes vs 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 PFS, and key secondary end points comprised CNS PFS according to baseline CNS metastases status, non-CNS PFS, and OS.

A total of 98 patients were randomized, and 96 patients were dosed; 48 patients were randomized to the osimertinib arm and 48 were randomized to the placebo arm; 15% and 8% of patients were still receiving osimertinib 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 osimertinib and placebo arms, the median patient age was 62 years (range, 37-88). 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, if not all, of the patients had stage IV disease by American Joint Committee on Cancer criteria at the time of study entry (100%; 98%). CNS metastases were present in 22% of those in the osimertinib arm vs 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 osimertinib in the respective arms was 21.3 months (range, 3.2-51.3) and 19.6 months (range, 7.4-52.3).

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

The 6-month PFS rate with osimertinib plus chemotherapy was 64% vs 32% with placebo plus chemotherapy. The 6-month CNS PFS rates were 87% and 63% in the respective arms, and the 6-month non-CNS PFS rates were 65% and 35%, respectively. The 6-month OS rates were 67% and 47%.

The non-CNS objective response rate (ORR) in the osimertinib arm (n = 49) was 35% (95% CI, 22%-50%) vs 29% (95% CI, 17%-43%) in the placebo arm (n = 49). The median non-CNS duration of response was 8.2 months (95% CI, 4.4-12.2) with osimertinib vs 4.2 months (95% CI, 3.1-7.6) without.

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

What is the Toxicity Profile of Osimertinib Plus Chemotherapy?

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

The most common grade 3 AEs in the osimertinib 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 (AST) levels (4%; 0%), nausea (2%; 0%), increased alanine aminotransferase (ALT) levels (2%; 2%), and decreased appetite (2%; 0%). The most common grade 4 events in the osimertinib arm were neutropenia, increased ALT 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%).

Editor’s Note: No disclosures were listed.

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