NEW IN SOLEIL RESEARCH™
A biomarker-defined phase 3 trial has tested whether adding platinum-pemetrexed chemotherapy to first-line osimertinib can improve disease control in a high-risk subgroup of advanced EGFR-mutated non–small cell lung cancer (NSCLC). The result is clinically important—but the benefit must be interpreted alongside a substantial increase in treatment toxicity and still-immature overall-survival data.
Plain-Language Summary
The TOP trial enrolled 294 adults with previously untreated stage IV or recurrent nonsquamous NSCLC whose tumors carried both a sensitizing EGFR mutation and a concurrent TP53 mutation. Patients were randomly assigned to osimertinib alone or osimertinib plus carboplatin and pemetrexed, followed by maintenance osimertinib plus pemetrexed.
Median progression-free survival—the time before cancer progression or death—was 34.0 months with the combination and 15.6 months with osimertinib alone. The hazard ratio was 0.44 (95% CI, 0.32–0.60; P<.001), indicating a substantially lower rate of progression or death during follow-up in the combination group.
That improvement came with considerably more severe treatment-related toxicity. Grade 3 or higher treatment-related adverse events occurred in 62.4% of patients receiving the combination compared with 14.9% receiving osimertinib alone. Overall-survival data were still immature, so the trial has not yet established that the combination helps patients live longer.
What the TOP Trial Tested
TOP was a multicenter, randomized, open-label phase 3 trial conducted at 17 centers in China. Between March 2021 and July 2024, investigators enrolled 294 treatment-naive adults with stage IV or recurrent nonsquamous NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation together with a TP53 mutation. Participants had an ECOG performance status of 0 or 1. Patients with asymptomatic, stable brain metastases were eligible.
Participants were randomized 1:1. The combination group received osimertinib 80 mg daily plus pemetrexed and carboplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed. The control group received osimertinib 80 mg daily alone. The prespecified primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival, response, safety, and quality of life.
Main Findings
At the November 11, 2025 data cutoff, median follow-up was 25.1 months in the combination group and 26.1 months in the osimertinib-alone group. Median progression-free survival was 34.0 months versus 15.6 months, an absolute median difference of 18.4 months (95% CI, 9.9–22.3). The hazard ratio for progression or death was 0.44 (95% CI, 0.32–0.60; P<.001).
The objective response rate was 82.9% with the combination and 71.6% with osimertinib alone. The PFS benefit was reported as consistent across prespecified subgroups, including patients with brain metastases and those with L858R mutations.
Overall survival, however, had reached only 30.6% maturity. Although the investigators reported a favorable trend, a trend is not a demonstrated survival advantage. Longer follow-up is required before concluding that the combination prolongs life.
Safety and Treatment Burden
The efficacy gain was accompanied by a marked increase in severe toxicity. Grade 3 or higher treatment-related adverse events occurred in 62.4% of patients in the combination group versus 14.9% with osimertinib monotherapy. The JAMA research summary also reports one death from thrombocytopenia in the combination group.
This tradeoff is central to interpretation. A longer PFS can be clinically meaningful, but it should not be discussed independently of toxicity, treatment intensity, intravenous chemotherapy exposure, maintenance pemetrexed, and the absence—so far—of a proven overall-survival benefit.
Methodological Quality
Soleil Research assessment: HIGH — randomized phase 3 evidence in a biomarker-defined population, with important ascertainment and generalizability caveats.
The randomized, multicenter phase 3 design provides strong internal evidence that the treatment strategy caused the observed PFS difference within the population studied. The comparator was a clinically established first-line targeted therapy, the trial was prospectively registered, and the primary endpoint was prespecified.
At the same time, the trial was open-label and the primary endpoint was investigator-assessed PFS. Because knowledge of treatment assignment can influence the timing or interpretation of progression assessment, some ascertainment bias cannot be completely excluded. The magnitude of the observed PFS difference makes this limitation unlikely to explain the entire result, but it remains methodologically relevant.
Strengths
- Prospective, randomized phase 3 design.
- Multicenter enrollment across 17 sites.
- Clear molecular eligibility requiring sensitizing EGFR plus concurrent TP53 mutations.
- Clinically relevant first-line comparison against osimertinib monotherapy.
- Large PFS effect with a narrow confidence interval and prespecified subgroup analyses.
- Prospective registration and prespecified efficacy, safety, and quality-of-life outcomes.
Limitations and Cautions
- Overall survival is immature. TOP establishes a PFS advantage, not a proven survival advantage.
- The trial was open-label. The primary endpoint was investigator-assessed, leaving some risk of assessment bias.
- Generalizability is narrower than the headline. All participating centers were in China, and patients had ECOG performance status 0–1, nonsquamous disease, qualifying sensitizing EGFR mutations, and concurrent TP53 mutations.
- Severe toxicity was substantially higher. The combination cannot be evaluated on efficacy alone.
- TP53 should not automatically be treated as a universally validated predictive biomarker. TOP randomized only patients with TP53-mutant disease. It therefore demonstrates benefit within that biomarker-defined population, but it does not by itself prove a treatment-by-TP53 interaction relative to TP53-wild-type disease.
- Symptomatic brain metastases were excluded. Results should not be generalized to that population without additional evidence.
Funding and Conflicts of Interest
JAMA reports funding from AstraZeneca, the Noncommunicable Chronic Diseases–National Science and Technology Major Project, and the National Natural Science Foundation of China.
The PubMed conflict-of-interest statement reports that Dr Li Zhang received grants from Eli Lilly, Novartis, Roche, Hansoh, and Bristol Myers Squibb outside the submitted work, as well as consulting fees from MSD, BeiGene, and Xiansheng Pharma. No other disclosures were reported. These relationships do not invalidate a randomized trial, but they should remain visible when interpreting the evidence and reinforce the value of mature follow-up and external validation.
Soleil Insight
Precision oncology can help define where treatment intensification is worth testing—but benefit and burden must be judged together. In TOP, adding platinum-pemetrexed chemotherapy to osimertinib produced a large progression-free survival gain in selected patients with advanced EGFR/TP53-mutant NSCLC, while markedly increasing grade 3 or higher toxicity. Until overall-survival data mature, the evidence supports a more effective disease-control strategy in the studied population—not a universal mandate for combination therapy.
Original Publication
Zhou T, Zhou H, Gao F, et al. Osimertinib With or Without Chemotherapy in Advanced Non–Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial. JAMA. 2026;336(10):838–847. Published online August 10, 2026. DOI: 10.1001/jama.2026.10599. Trial registration: NCT04695925.
Featured image: Mikael Häggström, MD, via Wikimedia Commons, CC0 1.0. The histopathology image is illustrative and is not from the TOP trial or specific to an EGFR/TP53-mutant study specimen.
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