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[This article belongs to Volume - 71, Issue - 3]
Published on : 2026-03-29 18:46:49
Article Code: AMJ-29-03-2026-12372
Title : Osimertinib with platinum–pemetrexed versus oismertinib monotherapy in EGFR-mutated non-small-cell lung cancer with concurrent tumor suppressor gene alterations: A randomized, double-blind, placebo-controlled phase 3 trial (BRAZIL-TSG)
Author(s) : Carlos A. Silva, MD, PhD, Maria G. Santos, MD
Abstract :
Background: Third-generation epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are standard
first-line therapy for EGFR-mutated non-small-cell lung cancer (NSCLC). However, co-existing tumor suppressor gene
(TSG) alterations (e.g., TP53, RB1) are associated with inferior outcomes. The ACROSS2 trial demonstrated improved
progression-free survival (PFS) with aumolertinib plus chemotherapy versus monotherapy in this population, but was
limited by an open-label design and immature overall survival (OS) data [10]. We aimed to confirm these findings
with a double-blind, placebo-controlled design and powered OS analysis.
Methods: BRAZIL-TSG was a multicenter,
double-blind, phase 3 trial conducted across 14 centers in Brazil and Latin America. Patients with untreated,
EGFR-mutated (exon 19 deletion or L858R) stage IIIB/IV non-squamous NSCLC and concurrent TSG alterations (TP53,
RB1, PTEN, or ARID1A) confirmed by central next-generation sequencing (NGS; 500-gene panel) were randomized
(1:1) to oismertinib (80 mg orally once daily) plus pemetrexed (500 mg/m²) and carboplatin (AUC 5) every 3 weeks
for 4 cycles, followed by oismertinib plus pemetrexed maintenance, or oismertinib plus placebo. The primary
endpoint was investigator-assessed PFS. Secondary endpoints included OS, objective response rate (ORR), and safety.
Results: Between March 2022 and August 2024, 342 patients were randomized (171 per arm). At a median follow-up
of 32.4 months, median PFS was 26.4 months (95% CI, 22.1–30.8) with combination therapy versus 17.8 months
(95% CI, 14.2–20.1) with monotherapy (hazard ratio [HR], 0.48; 95% CI, 0.36–0.64; p<0.001). Landmark PFS rates at
24 months were 58.3% versus 38.7%, respectively. Mature OS data showed a median OS of 48.2 months versus 36.5
months (HR, 0.62; 95% CI, 0.45–0.86; p=0.003). The benefit was consistent across all subgroups, including patients
with TP53-only mutations (HR, 0.44) and those with concurrent TP53/RB1 alterations (HR, 0.71). Grade ≥3 adverse
events occurred in 42% of patients in the combination arm versus 19% in the monotherapy arm, primarily
hematologic toxicities. No unexpected safety signals were observed.
Conclusions: In patients with EGFR-mutated
NSCLC and concurrent TSG alterations, first-line oismertinib plus platinum–pemetrexed provided statistically
significant and clinically meaningful improvements in both PFS and OS compared with oismertinib alone, establishing
a new standard of care for this high-risk population.