First-line osimertinib plus chemotherapy further extends PFS in advanced EGFR-mutated NSCLC
12 Jun 2025
byDr. James Ho , Specialist in Respiratory Medicine, Hong Kong
The third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib, is preferred over earlier-generation EGFR TKIs as the first-line agent in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). In an interview with MIMS Oncology, Dr James Ho, Specialist in Respiratory Medicine in Hong Kong, discussed the positive survival outcomes associated with first-line treatment with osimertinib plus chemotherapy together in patients with advanced EGFR-mutated NSCLC, and shared which patients may benefit from this upfront combination treatment strategy.
Unmet need in EGFR-mutated NSCLC
Despite osimertinib’s established efficacy as monotherapy in EGFR-mutated NSCLC in the phase III FLAURA trial vs first-generation EGFR TKIs, almost all patients eventually experience disease progression due to intrinsic tumour heterogeneity and diverse acquired resistance mechanisms. [N Engl J Med 2020;382:41-50; N Engl J Med 2023;389:1935-1948; Crit Rev Oncol Hematol 2024;196:104295; Br J Cancer 2019;121:725-737]
“Even with osimertinib’s potency, resistance and concomitant disease progression are inevitable,” noted Ho. “Tumour factors such as TP53 co-mutations or high baseline tumour burden often predict poorer outcomes with osimertinib monotherapy.” [Crit Rev Oncol Hematol 2024;196:104295; Br J Cancer 2019;121:725-737; Biomedicines 2022;10:2109]
The phase III open-label FLAURA2 trial addressed this unmet need by combining osimertinib with platinum-based chemotherapy in the first-line setting to further improve outcomes in patients with advanced EGFR-mutated NSCLC. [N Engl J Med 2023;389:1935-1948]
FLAURA2 trial results
In FLAURA2, patients with treatment-naïve EGFR-mutated (exon 19 deletion or L858R mutation) advanced NSCLC were randomized to receive either osimertinib 80 mg QD with chemotherapy (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin [pharmacologically guided dose]), or osimertinib 80 mg QD monotherapy. [N Engl J Med 2023;389:1935-1948]
PFS and potential OS benefits
Results showed significantly longer investigator-assessed progression-free survival (PFS) in the osimertinib plus chemotherapy group vs osimertinib monotherapy (25.5 vs 16.7 months; hazard ratio [HR], 0.62; 95 percent confidence interval [CI], 0.49–0.79; p<0.001). (Figure)
FLAURA2 also demonstrated a trend of overall survival (OS) benefit favouring osimertinib plus chemotherapy vs osimertinib monotherapy (79 vs 73 percent) at 24 months. [N Engl J Med 2023;389:1935-1948] Second interim analysis (41 percent maturity) showed that median OS was not reached in the osimertinib plus chemotherapy group vs 36.7 months in the osimertinib monotherapy group (HR, 0.75; 95 percent CI, 0.57–0.97). [Valdiviezo Lama NI, et al, ELCC 2024, abstract 4O]
Consistent results in subgroups
“FLAURA2 also demonstrated consistent results in prespecified subgroups,” noted Ho.
Central nervous system (CNS) metastases are common in patients with EGFR-mutated NSCLC, occurring in up to 50 percent of patients within 5 years of diagnosis. [Lung Cancer 2015;88:108-111; J Clin Oncol 2024;42:808-820] In FLAURA2, osimertinib plus chemotherapy improved CNS efficacy vs osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. [J Clin Oncol 2024;42:808-820]
Although TP53 co-mutation is one of the poor prognostic factors in advanced NSCLC, in an exploratory analysis of FLAURA2, the combination of osimertinib plus chemotherapy demonstrated PFS benefit, regardless of baseline TP53 alterations. [Clin Transl Oncol 2024;26:3236-3245; Yang JC, et al, WCLC 2024, abstract MA12.03]
FLAURA2 also assessed PFS by baseline tumour burden (ie, the number of metastatic anatomical locations and extent of distant metastases at study entry). For patients with high baseline tumour burden (ie, ≥3 metastatic anatomical locations), osimertinib plus chemotherapy was associated with a 43 percent lower risk of disease progression or death vs osimertinib monotherapy (median PFS, 24.9 vs 16.4 months; HR, 0.57; 95 percent CI, 0.43 0.77). Osimertinib plus chemotherapy was also associated with a clinical benefit vs osimertinib monotherapy regardless of baseline brain, liver, or bone metastasis. [Valdiviezo N, WCLC 2024, abstract MA12.04]
No new safety signals
Combining osimertinib and chemotherapy did not raise new safety signals, and adverse events (AEs) were manageable with standard handling. The rate of grade ≥3 AEs was higher with osimertinib plus chemotherapy vs osimertinib monotherapy (64 vs 27 percent), but these were primarily chemotherapy-related. [N Engl J Med 2023;389:1935-1948]
“In patients receiving osimertinib plus chemotherapy, we monitor blood counts closely and find that most patients tolerate the regimen well with supportive care,” noted Ho.
Patient selection
“The mechanistic rationale of combining osimertinib plus chemotherapy up front is that it leverages two distinct mechanisms of action, potentially improving efficacy over either treatment alone,” explained Ho. “Osimertinib targets EGFR-mutant cancer cells, while chemotherapy broadly attacks rapidly dividing cells. This dual approach helps address tumour heterogeneity by targeting both EGFR-TKI–sensitive and –resistant subclones, potentially improving treatment effectiveness.” [N Engl J Med 2023;389:1935-1948]
“I may also opt for upfront combination treatment in those with TP53 co-mutations at baseline, since this indicates poorer prognosis and these patients may not do as well with osimertinib monotherapy,” he added.
This is consistent with FLAURA2’s results, which showed that patients with advanced EGFR-mutated NSCLC with high-risk features (ie, CNS metastasis, high baseline tumour burden, or exon 21 L858R or TP53 co-mutations) may derive greater benefit from first-line osimertinib plus chemotherapy. [N Engl J Med 2023;389:1935-1948; J Clin Oncol 2024;42:808-820; Valdiviezo N, WCLC 2024, abstract MA12.04; Yang JC, et al, WCLC 2024, abstract MA12.03]
“Practical considerations supporting first-line use of osimertinib plus chemotherapy include poor prognostic factors at baseline [eg, presence of TP53 mutation, EGFR L858R mutation, and co-mutations as well as detectable plasma EGFR], good baseline performance status [ie, WHO performance status 0–1] and organ function, which are critical for chemotherapy tolerance,” said Ho. [N Engl J Med 2023;389:1935-1948; Yang JC, et al, WCLC 2024, abstract MA 12.03] “Patients’ preferences should also be considered, especially after trade-offs between efficacy and toxicity are discussed.”
Guideline recommendations
“FLAURA2 results have led to regulatory approval of osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC in the US, Europe, and recently, Hong Kong,” noted Ho. [www.fda.gov/drugs/ resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung cancer; www.ema.europa.eu/en/medicines/human/EPAR/tagrisso]
“This combination therapy has also been endorsed by the American Society of Clinical Oncology [ASCO] and the National Comprehensive Cancer Network [NCCN],” Ho added. [J Clin Oncol 2024;42:e72-e86; NCCN Clinical Practice Guidelines in Oncology, Non-Small Cell Lung Cancer, version 3.2025]
Conclusions
Clinicians now have treatment flexibility (osimertinib with or without chemotherapy) in the first-line setting for advanced EGFR-mutated NSCLC, including patients with poor prognostic factors at baseline. Results from FLAURA2 have expanded therapeutic options and enhanced the clinical utility of osimertinib, especially in patients presenting with high-risk features.
“For eligible patients, starting with osimertinib plus chemotherapy maximizes the upfront benefit, delays resistance and preserves future treatment options,” concluded Ho.
