Adding chemotherapy to first-line osimertinib more than doubled median progression-free survival in patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC) harboring concurrent TP53 mutations. The findings come from a phase III randomized trial led by Zhou et al and published in JAMA. Median progression-free survival was 34 months with osimertinib plus chemotherapy vs 15.6 months with osimertinib alone.
Osimertinib is a standard first-line treatment for advanced NSCLC with EGFR-sensitizing mutations, but acquired resistance remains a challenge. Concurrent TP53 mutations occur in approximately half of EGFR-mutated NSCLC cases and are associated with poorer treatment response and shorter progression-free survival. Combination strategies may delay resistance and improve outcomes, but their greater toxicity has fueled debate over which patients with EGFR-mutated NSCLC should receive intensified first-line treatment.
Study Details
The multicenter, open-label trial enrolled 294 patients at 17 centers in China with treatment-naive stage IV or recurrent nonsquamous NSCLC harboring both an EGFR-sensitizing mutation and a TP53 mutation. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and nearly half had brain metastases at baseline.
Patients were randomly assigned 1:1 to osimertinib plus chemotherapy (n = 146) or osimertinib alone (n = 148). Combination therapy consisted of osimertinib at 80 mg once daily plus pemetrexed and carboplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed. Patients in the monotherapy group received osimertinib at 80 mg once daily.
The primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival, objective response rate, duration of response, disease control rate, safety, and quality of life. Median age was 57 years, 54.1% of patients were women, and 48.6% had brain metastases at baseline.
Key Findings
At a median follow-up of 25.1 months in the combination group and 26.1 months in the monotherapy group, median progression-free survival was 34 months with osimertinib plus chemotherapy vs 15.6 months with osimertinib alone (HR = 0.44; P < .001). The progression-free survival benefit was consistent across prespecified subgroups, including patients with brain metastases and those with EGFR L858R mutations.
The objective response rate was 82.9% with combination therapy vs 71.6% with osimertinib alone. The median duration of response was more than twice as long in the combination group as in the monotherapy group, at 32.7 months vs 15.3 months.
An overall survival benefit was also observed at the prespecified interim analysis, although the survival data remained immature (30.6% maturity). Median overall survival was 48.4 months with osimertinib plus chemotherapy vs 36.5 months with osimertinib alone (HR = 0.57). The investigators cautioned that longer follow-up is needed to confirm the survival benefit.
The added toxicity with combination therapy was notable. Grade 3 or higher treatment-related adverse events occurred in 62.4% of patients receiving osimertinib plus chemotherapy compared with 14.9% receiving osimertinib alone. The most common grade 3 or higher events with combination therapy were decreased neutrophil counts, leukopenia, decreased platelet counts, and anemia. Serious treatment-related adverse events occurred in 10.6% vs 1.4% of patients, respectively.
One patient in the combination group died from treatment-related severe thrombocytopenia that led to pulmonary hemorrhage. Interstitial lung disease or pneumonitis occurred in 5% of patients receiving combination therapy and 6.8% receiving osimertinib alone.
Study Implications
The investigators said the findings also highlight the potential value of using TP53 status to guide treatment intensity. They noted that nearly half of patients with wild-type TP53 may achieve comparable outcomes with osimertinib alone, potentially sparing them the added toxicity of chemotherapy.
“These findings provide key evidence to support a molecular risk-guided, individualized treatment strategy for EGFR-mutated advanced NSCLC,” they concluded.
The authors noted that the study was conducted in a single region and that validation in other populations is warranted. Other limitations included the relatively short follow-up for overall survival and the open-label design, which may have introduced bias in investigator-assessed outcomes.
Hongyun Zhao, MD, Yunpeng Yang, MD, and Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, are the corresponding authors of the article.
DISCLOSURE: The study was funded by AstraZeneca, which also provided osimertinib, and was partly supported by the Noncommunicable Chronic Diseases–National Science and Technology Major Project and the National Natural Science Foundation of China. Dr. Zhang reported relationships with several pharmaceutical companies; no other disclosures were reported. For full disclosures of the study authors, visit jama.com.
