High-Risk Features Could Guide Treatment Intensification in First-Line EGFR-Mutated NSCLC

Although frontline osimertinib (Tagrisso) remains the standard of care for patients with non–small cell lung cancer (NSCLC) whose disease harbors classical EGFR mutations, treatment intensification with chemotherapy plus osimertinib or amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) can improve outcomes in patients with higher-risk features, according to Lyudmila A. Bazhenova, MD.

“We currently have 3 FDA-approved [treatment] options: osimertinib, osimertinib plus chemotherapy, and amivantamab plus lazertinib,” Bazhenova said during a presentation at the 26th Annual International Lung Cancer Congress.¹ “The last 2 [options] belong to the [treatment] intensification era.”

Bazhenova is the director of the Hematology Oncology Training Program, the leader of the Lung Cancer Unit, a thoracic oncologist, and a clinical professor of medicine at the University of California, San Diego Moores Cancer Center.

Elucidating Optimal Candidates for Treatment Intensification

Bazhenova began her presentation by noting that treatment intensification can delay disease resistance to therapy. Treatment intensification can also ensure that the most effective therapy is given in the first line, she added. However, the decision to intensify treatment is not straightforward because the improvement in efficacy is also accompanied by increased toxicity, she said.

To determine which patients are good candidates for treatment intensification, Bazhenova focused on data from the phase 3 FLAURA2 (NCT04035486) and phase 3 MARIPOSA (NCT04487080) trials. The studies examined osimertinib plus chemotherapy and amivantamab plus lazertinib, respectively, in patients with untreated EGFR-mutated NSCLC.^2,3 Both studies included an osimertinib monotherapy arm.

Bazhenova noted that baseline characteristics between the 2 studies were similar, with comparable percentages of female patients, Asian patients, mutation types, and incidence of brain metastases. She then homed in on 5 patient subgroups for whom treatment intensification could be suitable: those with brain metastases, circulating tumor DNA (ctDNA) positivity, TP53 mutations, high disease burden at baseline, and leptomeningeal disease.

Subset Analyses of FLAURA2 and MARIPOSA

Data from FLAURA2 revealed that patients with baseline central nervous system (CNS) metastases who received osimertinib plus chemotherapy (n = 116) achieved a median progression-free survival (PFS) of 24.9 months (95% CI, 22.0-not calculable [NC]) compared with 13.8 months (95% CI, 11.0-16.7) among patients who received osimertinib monotherapy (n = 110; HR, 0.47; 95% CI, 0.33-0.66).² Patients without baseline CNS metastases in the investigational (n = 163) and control (n = 168) arms experienced a median PFS of 27.6 months (95% CI, 24.7-NC) and 21.0 months (95% CI, 16.7-30.5), respectively (HR, 0.75; 95% CI, 0.55-1.03).

In MARIPOSA, patients with a history of brain metastases who received amivantamab plus lazertinib (n = 178) achieved a median PFS of 18.3 months (95% CI, 16.6-23.7) vs 13.0 months (95% CI, 12.2-16.4) in the osimertinib arm (n = 172; HR, 0.69; 95% CI, 0.53-0.92).⁴ Patients without a history of brain metastases in the combination (n = 251) and monotherapy (n = 257) arms experienced a median PFS of 27.5 months (95% CI, 22.1-not evaluable [NE]) and 19.9 months (95% CI, 16.6-22.9), respectively (HR, 0.69; 95% CI, 0.53-0.89).

“It is clear that the PFS curve separates more widely in FLAURA2 in patients with CNS metastases vs those with no CNS metastases,” Bazhenova said. “In MARIPOSA, the separation is identical in both of the [subgroups] and this is reflected in the hazard ratios. There is more separation in FLAURA2 compared with MARIPOSA, probably owing to the fact that pemetrexed has a reasonable CNS penetration.”

In terms of ctDNA analysis, patients with EGFR mutations detected in the plasma at baseline who received the combination in FLAURA2 (n = 147) experienced a median PFS of 24.8 months (95% CI, 19.6-27.9) compared with 13.9 months (95% CI, 13.6-16.6) in the monotherapy arm (n = 161; HR, 0.60; 95% CI, 13.6-16.6).⁵ Patients without baseline plasma EGFR mutations in the investigational (n = 65) and monotherapy (n = 48) arms experienced a median PFS of 33.3 months (95% CI, 23.8-NC) and 30.3 months (95% CI, 25.0-NC), respectively (HR, 0.93; 95% CI, 0.51-1.72).

In MARIPOSA, patients with detectable ctDNA at baseline who received the combination (n = 231) or osimertinib monotherapy (n = 240) achieved a median PFS of 20.3 months (95% CI, 16.6-24.0) and 14.8 months (95% CI, 12.9-16.5), respectively (HR, 0.68; 95% CI, 0.86; P = .002).⁴ Patients in the investigational (n = 105) and control (n = 96) without detectable ctDNA at baseline experienced a median PFS of 27.7 months (95% CI, 22.1-NE) and 21.9 months (95% CI, 16.6-NE), respectively (HR, 0.72; 95% CI, 0.47-1.10; P = .132).

In patients with wild-type TP53 at baseline in FLAURA2, the median PFS was NR in both arms; the HR for PFS was NC.⁶ Patients with altered TP53 in the combination (n= 41) and monotherapy arms (n = 38) experienced a median PFS of 27.6 months (95% CI, 24.7-NC) and 27.6 months (95% CI, 13.9-30.3), respectively (HR, 0.57; 95% CI, 0.29-1.12).

At a median follow-up of 22.0 months, patients with wild-type TP5 treated with amivantamab plus lazertinib in MARIPOSA (n = 117) achieved a median PFS of 22.1 months (95% CI, 18.5-NE) compared with 19.9 months (95% CI, 14.8-23.9) in the osimertinib arm (n = 130; HR, 0.75; 95% CI, 0.52-1.07; P = .114).⁴ Those with TP53 comutations in the combination (n = 149) and monotherapy (n = 144) arms experienced a median PFS of 18.2 months (95% CI, 15.3-22.1) and 12.9 months (95% CI, 11.1-14.7), respectively (HR, 0.65; 95% CI, 0.48-0.87; P = .003).

“Even though I personally try to intensify treatment for patients with TP53 mutations, the data here are a bit less clear and I don’t see a significant differential in the HRs,” Bazhenova commented.

Specifically in FLAURA2, patients with a high disease burden at baseline (≥ 3 metastatic sites) who received osimertinib plus chemotherapy (n = 151) had a median PFS of 24.9 months (95% CI, 21.9-27.6) compared with 16.4 months (95% CI, 13.6-19.2) in the monotherapy arm (n = 169; HR , 0.57; 95% CI, 0.43-0.77).⁷ Patients with less than 3 metastatic sites at baseline in the combination (n = 128) and monotherapy (n = 109) arms experienced a median PFS of 27.9 months (95% CI, 24.7-NC) and 30.5 months (95% CI, 16.6-NC), respectively (HR, 0.75; 95% CI, 0.51-1.11).

Finally, Bazhenova highlighted data from FLAURA2 showing that patients with leptomeningeal disease who received osimertinib plus chemotherapy (n = 13) achieved a CNS response rate of 69%, including a CNS complete response (CR) rate of 38%.⁸ Comparatively, patients who received osimertinib monotherapy (n = 5) experienced a CNS response rate of 40% and a CNS CR rate of 20%.

“We don’t talk a lot about patients with leptomeningeal disease,” Bazhenova noted. “[These data] show that patients with leptomeningeal disease have better outcomes if you intensify treatment with chemotherapy.”

References

• Bazhenova LA. Classical EGFR mutations: how I choose first-line therapy. Presented at: 26th Annual International Lung Cancer Congress; July 25-26, 2025; Huntington Beach, CA.
• Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
• Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
• Felip E, Cho RC, Gutiérrez 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;41(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504
• Jänne PA, Kobayashi K, Robichaux J, et al. FLAURA2: exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi) ± platinum-pemetrexed. Cancer Res. 2024;84(suppl 7):CT017. doi:10.1158/1538-7445.AM2024-CT017
• Yang JCH, Robichaux J, Planchard D, et al. FLAURA2: Resistance, and impact of baseline TP53 alterations in patients treated with first-line osimertinib with or without platinum-pemetrexed. Presented at: 2024 World Conference on Lung Cancer; September 7-10, 2024. San Diego, CA.
• Valdiviezo N, Gray JE, Jänne PA, et al. FLAURA2: impact of tumor burden on outcomes of first-line osimertinib ± chemotherapy in patients with EGFR-mutated advanced NSCLC. Presented at: 2024 World Conference on Lung Cancer; September 7-10, 2024. San Diego, CA.
• Jänne PA, Planchard D, Kobayashi K, et al. CNS efficacy of osimertinib with or without chemotherapy in epidermal growth factor receptor–mutated advanced non–small-cell lung cancer. J Clin Oncol. 2023;42(7):808-820. doi:10.1200/JCO.23.02219