TP53 Status and Time Toxicity Shape Sequencing Decisions in EGFR-Mutated NSCLC

With TP53 comutation status now recognized as a meaningful prognostic signal in EGFR-mutated non–small cell lung cancer (NSCLC), the question facing thoracic oncologists has moved from whether to intensify frontline therapy to how confidently that decision can be made and what to do once resistance sets in.

"[I] do lean towards combination strategies for most patients. Regardless of their TP53 mutational status, the only situation [in which I would not use a combinatorial approach] would be [due to] patient preference or [for] someone who's frail or who doesn't have comutation and has 1 or 2 sites of metastatic disease where I could do local consolidative therapy," Arthi Sridhar, MD, an assistant professor in the Department of Medicine at UT Southwestern Medical Center in Dallas, said during a recent OncLive® Scientific Interchange and Workshop.

As part of the workshop, faculty went over a single evolving patient case, from diagnosis through post-progression sequencing, to unpack how TP53 mutation status, brain metastases, and the growing antibody-drug conjugate (ADC) landscape are reshaping treatment selection in EGFR-mutated NSCLC.¹

Does TP53 comutation status support frontline treatment intensification in EGFR-mutated NSCLC?

The panel's index case was a 59-year-old, TP53-comutated patient with EGFR L858R mutations and symptomatic, bilateral brain metastases. Faculty showed unanimous support for combination systemic therapy over osimertinib (Tagrisso) monotherapy in this case, although opinions were split between using osimertinib plus platinum-pemetrexed vs amivantamab (Rybrevant) plus lazertinib (Lazcluze).

The phase 3 TOP trial (NCT04695925) evaluated osimertinib plus platinum-pemetrexed against osimertinib monotherapy in a TP53-mutated population and showed a near-doubling of investigator-assessed progression-free survival (PFS) with the combination (n = 146) vs osimertinib monotherapy (n = 148; HR, 0.44; 95% CI, 0.32-0.60). An early, favorable signal for overall survival (OS) was observed (HR, 0.57; 95% CI, 0.38-0.88), although the data are immature.²

Additionally, the TP53-altered patient subgroup in the phase 3 FLAURA2 (NCT04035486) trial showed a PFS HR of 0.57 (95% CI, 0.29-1.12) and an OS HR of 0.71 (95% CI, 0.40-1.27) for osimertinib plus chemotherapy vs osimertinib alone, while the TP53-altered subgroup in the phase 3 MARIPOSA trial (NCT04487080) showed a statistically significant PFS benefit with amivantamab plus lazertinib over osimertinib monotherapy (HR, 0.65; 95% CI, 0.48-0.87; P = .003).^3-5

Panelists noted that the TOP trial enrolled a Chinese-only population with a higher-than-typical smoking history for an EGFR-mutated cohort; this limitation should be considered when weighing how directly the data should inform practice in the United States (US).

What is the optimal sequencing of second-line therapy after progression on frontline osimertinib-based regimens?

Following progression on frontline treatment with the FLAURA2 regimen with new liver, spleen, and bone metastases but stable central nervous system disease after a 12-month chemotherapy-free interval, the panel weighed 3 second-line strategies: platinum-pemetrexed rechallenge alongside continued osimertinib, datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), and amivantamab plus chemotherapy.

An exploratory FLAURA2 analysis found that patients rechallenged with platinum-based chemotherapy after progression on osimertinib plus chemotherapy had a 77% 3-year OS rate; 88% of rechallenged patients had a pemetrexed-free interval exceeding 6 months, with a median pemetrexed-free interval of 19.8 months (range, 0.5-42.3).⁶

"I really like the data [supporting] rechallenge,” said Chul Kim, MD, the director of thoracic oncology at MedStar Georgetown University Hospital and an associate professor at Georgetown University in Washington, DC. “Eighty-eight percent of patients [were] chemotherapy-free for 6 months, which is still really good. I was not considering rechallenging as much before [I saw these data.”

Pooled data from the phase 3 TROPION-Lung01 (NCT04656652) and phase 2 TROPION-Lung05 (NCT04484142) trials showed an objective response rate (ORR) of 42.7% (95% CI, 33.6%-52.2%) and median PFS of 5.8 months (95% CI, 5.4-8.2) with dato-DXd in EGFR-mutated NSCLC (n = 117).⁷ Data from a resistance-mechanism subgroup analysis of the phase 3 MARIPOSA-2 trial (NCT04988295) showed that amivantamab plus chemotherapy improved median PFS over chemotherapy alone in patients with baseline TP53 co-mutations (5.6 vs 4.1 months; HR, 0.63; 95% CI, 0.44-0.92; P = .014).⁸ Several panelists cited antibody-drug conjugate (ADC) trial eligibility as a practical constraint on sequencing, since deruxtecan-payload ADCs share overlapping targets that can exclude patients from subsequent investigational ADC trials.

What is the outlook for ADCs in EGFR-mutated NSCLC?

Reactions to the ADC data were mixed. "I think I'm going to be the Debbie Downer here. I'm not excited about any of the ADCs in the post-EGFR setting. I don't know that TROP2 is the right target for ADCs in this. When you look at the adverse effect profiles, we're just adding chemotherapy, and sometimes worse chemotherapy than platinum pemetrexed," said Angel Qin, MD, a clinical associate professor of internal medicine at the University of Michigan Rogel Medical School in Ann Arbor.

Others, such as Abdul Naqash, MD, director of immuno-oncology and an associate professor at the University of Oklahoma Stephenson Cancer Center in Oklahoma City, saw a clear rationale for moving ADCs earlier in the treatment course to limit downstream subclonal resistance.

What unmet needs did the panel identify?

Time toxicity emerged as a recurring theme. "We tend to forget the time toxicity of treatments,” Naqash said. “One of the discussions I try to have with my patients is what [a given] treatment looks like for [them] in terms of PFS and OS, but also in terms of the time that they'll spend within the health care system, whether [because of] toxicities or infusions. A lot of my patients are from rural Oklahoma, so they have to travel 2 to 3 hours [by car] to n National Cancer Institute–designated cancer center.”

Panelists also flagged repeat tissue biopsy at progression as a frequently missed step in community practice. Kim described a patient sequenced through osimertinib, then MARIPOSA-2, then Dato-DXd, who was later found to have an undetected BRAF fusion. "I recently saw a patient [who was treated with] osimertinib, then MARIPOSA-2, then Dato-DXd. I couldn't enroll him in any of the ADC trials because they were excluded. The patient was found to have BRAF fusion last year, and that was not acted upon,” he said.

Ultimately, one common thread emerged from the panel discussion: TP53 co-mutation is a useful prognostic signal supporting intensification, but validated predictive biomarkers to choose between regimens and prospective data on optimal ADC sequencing remain unmet needs in EGFR-mutated NSCLC.

References

1. Beyond the standard: individualizing care in EGFR-mutated NSCLC from first-line intensification to post-progression sequencing. An OncLive Scientific Interchange and Workshop. OncLive. May 31, 2026. Accessed July 1, 2026.
2. 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.
3. Yang JC, Robichaux J, Planchard D, et al. FLAURA2: resistance, and impact of baseline TP53 alterations in patients treated with 1L osimertinib ± platinum-pemetrexed. J Thorac Oncol. 2024;19(10):S101-S102. doi:10.1016/j.jtho.2024.09.184
4. Janne PA, Plancard D, Kobayashi K, et al. FLAURA2: Exploratory overall survival (OS) analysis in patients (pts) with poorer prognostic factors treated with osimertinib (osi) ± platinum-pemetrexed chemotherapy (CTx) as first-line (1L) treatment (tx) for EGFR-mutated (EGFRm) advanced NSCLC. Ann Oncol. 2025;36(suppl 2):S1618-S1619. doi:10.1016/j.annonc.2025.09.091
5. Felip E, Cho BC, Gutierrez V, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: a secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol. 2024;42(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504
6. Escriu C, Janne PA, Planchard D, et al.Chemotherapy (chemo) rechallenge in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC who discontinued 1L osimertinib (osi) + platinum–pemetrexed (plat–pem) due to progression (PD): FLAURA2 exploratory analysis. ESMO Open. 2026;11(suppl 3):106334. doi:0.1016/j.esmoop.2026.106334
7. Ahn MJ, Sands J, Lisberg AE, et al. Efficacy and safety of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously-treated EGFR-mutated advanced non-small cell lung cancer (NSCLC): A pooled analysis of TROPION-Lung01 and TROPION-Lung05. Ann Oncol. 2024;35(suppl 4):S1630-S1631. doi:10.1016/j.annonc.2024.10.656
8. Califano R, Passaro A, Tan JL, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Outcomes by osimertinib resistance mechanisms in MARIPOSA-2. J Clin Oncol. 2025;43(suppl 16):8639. doi:0.1200/JCO.2025.43.16_suppl.8639