Osimertinib Combo Boosts PFS in EGFR/TP53+ NSCLC Trial

Data from the phase 3 TOP trial (NCT04695925) demonstrated a significant progression-free survival (PFS) improvement with osimertinib (Tagrisso) plus platinum-based chemothearpy vs osimertinib alone among those advanced non–small cell lung cancer (NSCLC) harboring concurrent EGFR and TP53 mutations, according to a presentation at the 2026 European Lung Cancer Congress.¹

The median PFS was 34.0 months (95% CI, 24.9-36.4) in the combination arm (n = 146) vs 15.6 months (95% CI, 13.0-18.3) in the monotherapy arm (n = 148; HR, 0.44; 95% CI, 0.32-0.60; P < .001). Median follow-up was 25.1 months (95% CI, 21.0-29.2) and 26.1 months (95% CI, 19.6-32.4) in the combination and monotherapy arms, respectively, and overall PFS maturity was 59.2%.

A consistent PFS benefit was observed with the combination vs the monotherapy, irrespective of sex, age, smoking history, method used for tissue testing, EGFR mutation type, ECOG performance status, presence or brain metastases, and presence of liver metastases.

“These findings provide key evidence to support a molecular risk–guided, individualized treatment strategy for EGFR-mutated advanced NSCLC,” lead study author Yunpeng Yang, MD, said in a presentation of the data. Yang is a member of the Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine in Guangzhou, China.

What was the rationale for evaluating osimertinib plus chemotherapy?

Osimertinib is an international frontline standard of care for patients with EGFR-mutant advanced NSCLC, retaining its indication since 2018.² However, acquired resistance with EGFR TKI monotherapy, especially in patients with concurrent TP53 mutations and other high-risk features, is common.¹ Although intensified regimens like that of osimertinib plus chemotherapy and lazertinib (Lazcluze) plus amivantamab-vmjw (Rybrevant) have shown improved overall survival (OS) and PFS vs EGFR TKI monotherapy, they bear added financial and physical toxicity.

“The central debate has shifted from establishing the efficacy of combination therapy to another question: Which patient population truly needs treatment intensification?” Yang said.

As such, investigators designed the TOP study to determine the safety and efficacy of an already-established combination regimen in a focused population of high-risk patients.

How was the study designed to test this hypothesis?

In this randomized, multicenter, open-label, phase 3 trial investigators enrolled previously untreated patients with stage IV or recurrent EGFR-mutant (exon 19 deletion or exon 21 L858R) nonsquamous NSCLC with concurrent TP53 mutations. Investigators also stipulated an ECOG performance status of 0 or 1, and patients with stable central nervous system metastases were permitted.

A total of 292 patients were randomly assigned 1:1 to receive osimertinib at 80 mg once daily plus 500 mg/m² of pemetrexed and carboplatin at area under the curve 5 every 3 weeks for 4 cycles, followed by osimertinib and pemetrexed maintenance; or osimertinib alone. Treatment was continued until disease progression or intolerable toxicity.

The primary end point was investigator-assessed PFS. Secondary end points included OS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), safety, and patient-reported outcomes.

Efficacy was also stratified according to EGFR mutation type (exon 19 deletion vs exon 21 L858R), presence of brain metastasis (yes vs no), and ECOG performance status (0 vs 1).

What was the patient disposition and baseline characteristics?

A total of 356 patients were screened, 294 randomly assigned, and 289 dosed. The latter two populations comprised the full analysis and safety analysis sets, respectively. At the November 11, 2025, data cutoff, 47% (n = 66) and 24% (n = 35) of patients remained on any therapy in the combination (osimertinib only, 14%; n = 20; osimertinib and pemetrexed, 33%; n = 46) and monotherapy arms, respectively.

In the combination arm, primary reasons for discontinuation of osimertinib, carboplatin, and pemetrexed, respectively, included progression (46%; 1%; 30%), patient decision (4%; 4%; 11%), and adverse effect ([AE] 2%; 11%; 26%). These reasons led to discontinuation in the osimertinib arm at respective rates of 71%, 2%, and 2%.

Within the combination arm, the median age was 57 years old (range, 29-79) and the minority were 65 years or older (21.9%). Most patients were female (52.1%), had an ECOG performance status of 1 (70.5%), had no history of smoking (74.7%), and had an exon 19 deletion (54.8%). Presence of extrathoracic metastases (87.7%) but not within the brain (50.7%) or liver (84.2%) were predominant. The median baseline tumor size was 47.0 mm (range, 11.2-151.0). Baseline characteristics were well balanced in both arms.

What was the statistical design of the study?

With a sample size of 292 patients and an expected number of PFS events of 170, investigators had 80% power to identify a HR of 0.65 for the risk reduction in disease progression or death by the long-rank test, at a 2-sided significance level of 0.05. This sample size would correspond with a difference in median PFS of at least 7 months, with an estimated 20 months in the investigational arm and 13 months in the control arm. Yang noted that the calculation accounted for a monthly dropout rate of 0.36% in each arm.

As part of the primary PFS analysis, investigators would perform a preplanned interim OS analysis. A final OS analysis would be conducted once approximately 60% of survival events had taken place.

What other efficacy end points were shared?

An interim look at OS with 30.6% maturity revealed a median of 48.4 months (95% CI, 42.7-not evaluable [NE]) in the combination arm vs 36.5 months (95% CI, 28.1-NE) in the monotherapy arm (HR, 0.57; 95% CI, 0.38-0.88). Median follow-up was 27.7 months (95% CI, 23.1-32.3) and 26.3 months (95% CI, 22.7-29.9) in the combination and monotherapy arms, respectively.

With respect to response, the ORR was 82.9% (95% CI, 75.8%-88.6%) in the combination arm, all of which were partial. Stable disease (SD) occurred in 8.9% and 3.4% of patients had progressive disease (PD); 4.8% were NE. The DCR was 91.8% (95% CI, 86.1%-95.7%) and median DOR was 32.7 months (95% CI, 26.0-35.6). In the monotherapy arm, the ORR was 71.6% (95% CI, 63.6%-78.7%) and all responses were partial; 12.8% had SD and 12.2% had PD; 3.4% of patients were NE. The DCR was 84.5% (95% CI, 77.6%-89.9%) and median DOR was 15.3 months (95% CI, 13.3-18.4).

Did the safety profile differ from prior reports of the combination?

“The safety profile in this study was consistent with that reported in the [phase 3] FLAURA2 study [NCT04035486], with no new safety signals,” Yang reported.

The median number of cycles of pemetrexed was 17 (range, 1-52) and most patients (n = 119; 84.4%) finished 4 cycles of carboplatin-based therapy. Longer median exposure to osimertinib was seen in the combination group vs the monotherapy group, at 20.3 months (range, 1.1-53.6) and 15.4 months (range, 0.5-53.9), respectively.

Treatment-related AEs (TRAEs) occurred in 97.9% (n = 138) and 94.6% (n = 140) of patients in the combination (n = 141) and monotherapy (n = 148) arms, respectively; 62.4% (n = 88) and 14.9% (n = 22) of events, respectively, were grade 3 or greater. Treatment-related serious AEs occurred in 10.6% (n = 15) and 1.4% (n = 2) of patients in the investigational and control arms, respectively, and TRAEs leading to death only occurred in 1 patient in the combination arm and resulted from decreased platelet counts.

TRAEs leading to treatment discontinuation, dose reduction, and dose interruption occurred in 26.2% (n = 37), 19.9% (n = 28), and 41.1% (n = 58) of patients in the combination arm, respectively, vs 1.4% (n = 2), none, and 8.8% (n = 13) of patients in the monotherapy arm.

TRAEs were presented in order of frequency and in the combination and monotherapy arms, respectively, included anemia (82.3%; 41.9%), decreased neutrophil count (43.3%; 24.3%), decreased white blood cell count (53.9%; 32.4%), decreased platelet count (39.7%; 18.9%), increased aspartate aminotransferase levels (62.4%; 28.4%), stomatitis (59.6%; 40.5%), decreased lymphocyte count (52.5%; 52.0%), increased blood creatinine phosphokinase levels (54.6%; 45.9%), rash (59.6%; 45.9%), diarrhea (56.1%; 47.3%), increased blood creatinine levels (58.2%; 44.6%), increased alanine aminotransferase levels (54.6%; 29.1%), decreased appetite (51.1%; 20.9%), hyponatremia (48.2%; 39.2%), hypoalbuminemia (44.7%; 21.6%), fatigue (39.7%; 16.2%), constipation (37.6%; 10.1%), nausea (33.4%; 14.2%), paronychia (32.6%; 23.0%), vomiting (25.5%; 12.8%), insomnia (22.7%; 8.8%), hypoesthesia (19.9%; 10.1%), alopecia (19.9%; 10.8%), increased blood cholesterol levels (17.0%; 4.7%), abnormal ST-T segment on electrocardiogram (16.3%; 11.5%), and pain (15.6%; 7.4%).

“The most common TRAEs in the combination group were hematologic toxicities, and the majority of non-hematologic TRAEs were grade 1 or 2. The most common TRAEs in the monotherapy group were lymphocyte count decrease and diarrhea,” Yang concluded.

Disclosures: Yang had no competing interests to disclose.

References

1. Yang Y, Zhou T, Gao F, et al. Osimertinib with or without chemotherapy as first-line treatment in EGFR-mutant advanced NSCLC with concurrent TP53 mutations (TOP study). Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 2O.
2. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. Updated April 19, 2028. Accessed March 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations