Select cases of advanced EGFR-mutated NSCLC with different disease burden treated with first-line osimertinib plus chemotherapy

Case 1: Patient with co-mutations
Presentation and investigation
A 65-year-old male with good past health presented in June 2024 with a 1-month history of cough.

Chest X-ray (CXR) and CT scan showed a mass in the right lower lobe, which was confirmed to be lung carci­noma by bronchoscopy with transbron­chial biopsy. PET-CT scan revealed right lower lobe tumour (5.5 x 5.1 x 6.8 cm; SUV_max, 8.5) with pleural involvement. (Figure 1) Brain MRI showed no evi­dence of central nervous system (CNS) metastases. Genetic testing revealed the presence of EGFR exon 21 L858R mutation, TP53 mutation, and PIK3CA amplification, but he did not have any circulating EGFR mutations in plas­ma. He was diagnosed with advanced EGFR-mutated non-small-cell lung can­cer (NSCLC) and co-mutations.

Treatment and response
Following a discussion regarding the potential progression-free survival (PFS) benefit of the FLAURA2 regimen during a follow-up appointment, the patient agreed to initiate the first-line combi­nation therapy with osimertinib 80 mg QD and chemotherapy (pemetrexed 500 mg/m² plus carboplatin [pharma­cologically guided dose]). The decision took into account his tumour and pa­tient factors, including EGFR exon 21 L858R and TP53 co-mutations and his fitness for chemotherapy, indicated by a baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0.

His cough had subsided within the first month of treatment. Reassessment PET-CT scan after 9 months showed very good partial response (VGPR). The tumour shrank to dimensions of 2.9 x 2.3 x 3.3 cm (SUV_max, 2.5) and the pleural involvement had improved. (Figure 1B)

He tolerated the combination treat­ment well, and experienced grade 1 neutropenic fever, which was resolved with antibiotics. His ECOG PS remained at 0 during the treatment.

Last seen in April 2025, the patient remained on osimertinib 80 mg QD and pemetrexed maintenance therapy 500 mg/m² Q3W. He had been on com­bination therapy for 10 months.

Case 2: Patient with extensive CNS metastases and high tumour burden
Presentation and investigation
The patient was a 49-year-old seden­tary female with a history of obesity, im­paired fasting glucose, and dyslipidaemia.

She presented in early March 2024 with a cough lasting 3–4 months, progressive shortness of breath (SoB) for 1 month, and blood-stained sputum and anorexia for the past 1–2 weeks. Although the patient’s baseline ECOG PS was 1, she was hospitalized due to persistent high output from pleural drain (1L/day) and ongoing oxygen therapy at 2L/min.

CXR showed a near “white out” of the right lung. Right pleural fluid cytol­ogy and pleural biopsy both confirmed lung adenocarcinoma. PET-CT scan revealed a mass in the right lower lobe measuring 6.8 x 6.4 x 6.3 cm (SUV_max, 18.4), consolidation in the right up­per lobe, and a large right hydropneu­mothorax. (Figure 2) Moreover, there were left lung nodules measuring up to 0.7 cm and bilateral adrenal nodules measuring up to 1.1 cm (SUV_max, 8.9).

PET-CT scan also showed multiple liver metastases up to 2.4 x 1.8 cm (SUV_max, 19.4). Brain MRI on 20 March 2024 revealed hypointense signal on T1W images and hyperintense signal on T2W images. There were multiple diffuse lesions measuring up to 1.7 cm throughout the brain parenchyma, in­volving bilateral cerebral hemispheres, cerebellar hemispheres, and the brain­stem. (Figure 2) In addition, there were extensive bone and nodal metastases.

In addition to EGFR exon 19 dele­tion, next-generation sequencing re­vealed PIK3CA and TP53 mutations. The findings led to a diagnosis of EGFR-mutated metastatic NSCLC, with CNS, liver and bone metastases.

Treatment and response
Upfront osimertinib plus chemo­therapy was planned for the patient due to her high tumour volume, CNS involvement, and poor prognostic TP53 and PIK3CA mutations. However, given her compromised respiratory function, prolonged hospital stays, and comor­bid obesity, the patient was advised to undergo rehabilitation and CT coronary angiography to rule out coronary heart disease before starting chemotherapy.

Osimertinib 80 mg QD was start­ed. After 10 days of treatment, she was weaned off oxygen, and the chest drain was removed, as pleural fluid output had markedly reduced from 1 L/day to approximately 100 mL/day. Her ECOG PS improved from 1 to 0, with a marked reduction in respiratory symptoms.

The patient started chemotherapy with pemetrexed and carboplatin to pro­long PFS and better control CNS me­tastases. After 1 month of combination treatment, reassessment PET-CT scan showed VGPR of the lung with residual pleural effusion. Notably, the metastat­ic lesions in the brain and liver showed near-complete to complete responses. (Figure 2) PET-CT scan of the bone showed stable disease.

Her carcinoembryonic antigen (CEA) level decreased from 402 to 3 ng/mL in January 2025 and has re­mained stable since.

She developed grade 1 acneiform rash, which resolved with topic antibi­otics, and grade 1 thrombocytopenia in cycles 3–4. No neutropenia was ob­served throughout treatment.

Last seen on 15 April 2025, she had been on the combination treatment for over 1 year, and her ECOG PS was 0.

Discussion
Despite the robust efficacy of front­line treatment with osimertinib mono­therapy demonstrated in the phase III FLAURA trial, almost all patients with EGFR-mutated advanced NSCLC will eventually have disease progression.^1,2

Osimertinib is a highly potent, se­lective third-generation EGFR-TKI, whereas chemotherapy has a non-selective antitumour effect. Combining EGFR-TKI with chemotherapy may work synergistically to prevent acquired resis­tance and effectively target and eliminate diverse tumour cell populations (eg, both EGFR-TKI–sensitive and EGFR-TKI– resistant subclones), thereby prolonging patients’ PFS in the first-line setting.^1,3

The two cases illustrate the pre­ferred candidates for first-line osimerti­nib plus chemotherapy (the FLAURA2 regimen), including co-mutations (eg, EGFR exon 21 L858R, TP53, and PIK­3CA mutations) in both cases, as well as extensive CNS metastases in case 2. These patients may not respond as well to osimertinib monotherapy and might benefit most from upfront chemother­apy plus osimertinib to further prolong their PFS.^1,3

The use of osimertinib plus chemo­therapy in our two patients with poor prognostic factors are based on FLAU­RA2 and its analyses. FLAURA2 is a phase III, international, open-label trial which randomized 557 treatment-naïve patients with EGFR-mutated (exon 19 deletion or L858R mutation) ad­vanced NSCLC 1:1 to receive either osimertinib 80 mg QD with intravenous chemotherapy (pemetrexed [500 mg/ m²] plus either cisplatin [75 mg/m²] or carboplatin [pharmacologically guided dose, defined as an area under the con­centration-time curve of 5 mg/mL/min) on day 1 of 21-day cycles for four cycles, or osimertinib monotherapy 80 mg QD.¹

The median prolongation in PFS with osimertinib plus chemotherapy vs osimertinib monotherapy was 9.5 months according to central review (median, 29.4 vs 19.9 months; HR, 0.62; 95 percent CI, 0.48–0.80).¹ Our patients have been on the combina­tion therapy ranging from 10 months (case 1) and >1 year (case 2) and have not exhibited any signs of disease progression.

In the final OS analysis of FLAURA2, osimertinib plus chemotherapy resulted in a statistically significant and clinically meaningful improvement in OS vs osim­ertinib monotherapy.⁴

The combination therapy leverag­es two distinct mechanisms of action, potentially improving treatment out­comes.¹ In an updated plasma analysis of FLAURA2, fewer patients had de­tectable acquired genomic alterations with osimertinib plus chemotherapy vs osimertinib monotherapy, and no new acquired resistance mechanisms were observed.⁵

The PFS benefit with osimerti­nib plus chemotherapy appeared to be consistent across subgroups with poor prognosis, including patients with L858R mutation (case 1) or CNS metas­tases (case 2).¹

In FLAURA2, 41 percent of patients had baseline CNS metastases and 38 percent had L858R mutation. The PFS benefit with osimertinib plus chemother­apy vs osimertinib alone was observed in patients with (median, 24.9 vs 13.8 months; HR, 0.47; 95 percent CI, 0.33– 0.66) or without CNS metastases at baseline (median, 27.6 vs 21.0 months; HR, 0.75; 95 percent CI, 0.55–1.03) and among those with L858R mutation (24.7 vs 13.9 months; HR, 0.63; 95 percent CI, 0.44–0.90).¹

Notably, patient 2’s brain lesions achieved a complete response after 2 months of combination therapy, which is consistent with the preplanned anal­ysis of FLAURA2. In patients with base­line CNS metastases, osimertinib plus chemotherapy demonstrated a higher CNS complete response rate (59 vs 43 percent) and a clinically meaningful im­provement in the risk of CNS progres­sion or death (HR, 0.58; 95 percent CI, 0.33–1.01) vs osimertinib alone. CNS metastases may enhance the pene­tration of chemotherapy into the brain by disrupting the blood-brain barrier, thereby potentially contributing to the observed synergistic effect on CNS ef­ficacy.⁶

In patients with high baseline tumour burden (≥3 metastatic anatomical loca­tions), osimertinib plus chemotherapy significantly extended median PFS (24.9 vs 16.4 months; HR, 0.57; 95 percent CI, 0.43–0.77) vs osimertinib monother­apy in a subgroup analysis of FLAURA2. (Figure 3) Osimertinib plus chemother­apy was also associated with a clinical benefit vs osimertinib monotherapy, re­gardless of baseline CNS, liver or bone metastases.⁷

TP53 mutations are the most prev­alent alterations detected in 54.6–68.8 percent of EGFR-mutant NSCLC, in­cluding our two patients, and are often linked to poor prognosis.⁸ Of note, PFS Kaplan-Meier curves showed a separa­tion in favour of osimertinib plus chemo­therapy vs osimertinib alone, regardless of baseline TP53 status, in preliminary baseline tissue analyses.⁵

The safety profile of osimertinib plus chemotherapy was consistent with the established profiles of its components, without new safety signals. Although not experienced by our two patients, the incidence of ≥grade 3 adverse events (AEs) from any cause was higher with the combination therapy vs monothera­py (64 vs 27 percent), primarily driven by chemotherapy-related AEs.¹

In addition to the PFS and OS ben­efits, practical discussion points sup­porting first-line use of osimertinib plus chemotherapy include poor prognostic factors at baseline (eg, co-mutations, TP53 mutation, EGFR exon 21 L858R mutation, detectable plasma EGFR, ex­tensive CNS metastases, and high tu­mour burden).

During the evaluation of initiating osimertinib plus chemotherapy, it is important to consider the trade-offs between efficacy and toxicity. Patients’ preferences should be considered. Good physical fitness (ie, ECOG PS 0–1) and organ function are critical for che­motherapy tolerance. As demonstrated in case 2, in the sedentary patient with multiple metabolic comorbidities who relies on a pleural drain (and thus faces a heightened risk of infection), it is still feasible to use the combination therapy after undergoing rehabilitation and ruling out coronary heart disease.

The FLAURA2 regimen further pro­longs PFS in the first-line treatment of advanced EGFR-mutated NSCLC, and is particularly beneficial in patients with poor prognosis.1 This combination ther­apy is endorsed by the American Soci­ety of Clinical Oncology (ASCO) and the National Comprehensive Cancer Net­work (NCCN) guidelines, and it is now available in the Hospital Authority.^9,10

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