Central nervous system (CNS) metastases are a common and severe complication in patients with EGFR-mutated non-small cell lung cancer (NSCLC). These metastases are associated with a poorer prognosis and have a significant negative impact on the quality of life of these patients. EGFR-mutated NSCLC has a higher tendency for CNS metastases, with up to 45% of patients developing brain metastases during their disease course1. The blood-brain barrier limits the effectiveness of many systemic therapies, making treatment challenging. However, EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib, which can penetrate the blood-brain barrier, have yielded promising intracranial responses.
Several studies have demonstrated that osimertinib, both alone and in combination with chemotherapy, significantly improves progression-free survival (PFS) and response rates in the CNS 2,3. In November 2023, the phase III FLAURA-2 study demonstrated an improvement in PFS with first-line osimertinib plus 4 cycles of platinum-pemetrexed, followed by maintenance pemetrexed compared to osimertinib monotherapy in patients with EGFR-mutated advanced NSCLC2. More recently, follow-up results presented at the 2024 European Lung Cancer Congress in Prague, Czech Republic, showed the addition of chemotherapy to osimertinib in first-line also demonstrated a favorable trend toward overall survival (OS) at 2 years.
In a preplanned subgroup analysis of the FLAURA-2 study, Pasi Jänne and colleagues assessed the CNS efficacy of the combination therapy versus osimertinib monotherapy as first-line treatment in patients with EGFR-mutated NSCLC according to baseline CNS metastases status4.
In the study, all randomly assigned patients had mandatory brain scans at baseline, performed predominantly using MRI. Blinded independent central review (BICR) by neuro-radiologists enabled an accurate reflection of the proportion of patients with baseline CNS metastases. A significant number of patients had CNS disease at baseline (approximately 40% in each treatment arm). Of note, brain radiotherapy prior to enrollment in the study was allowed. Sixteen patients (14%) in the combination arm and 18 (17%) in the monotherapy arm received prior brain radiotherapy, of whom four and seven patients, respectively, were CNS evaluable-for-response.
Although many analyses did not show clear statistical superiority, the data suggest that the addition of chemotherapy to osimertinib in the first-line setting improves both the depth of CNS response as well as CNS PFS with a 42% reduction in the risk of CNS progression or death. Notably, 59% of patients in the combination arm achieved a complete intra-cranial response (CR) compared to 43% in the monotherapy arm. None of the patients with a CNS CR had received prior brain radiotherapy. The analysis of CNS PFS was limited by low data maturity (27%); there were low numbers at risk after 24 months in both treatment arms (combination arm, 32 patients; monotherapy arm, 15 patients).
The overall adverse event (AE) rates were similar between the patients in this sub analysis compared to the overall FLAURA2 study population. Although the investigators of the FLAURA-2 study state that the combination therapy was generally well tolerated and that reported AEs were manageable with standard medical practice, it is important to realize that the incidence of grade 3-5 adverse events was high with 64% in the combination arm versus 27% with osimertinib monotherapy. In addition, the combination arm was associated with double the rate of fatal events (7% vs. 3%). Furthermore, the proportion of patients who discontinued treatment because of an adverse event was 48% with combination treatment compared to 6% with osimertinib monotherapy.
In the combination arm, AEs led to pemetrexed discontinuation in 119 patients (43%) and to carboplatin/cisplatin discontinuation in 46 patients (17%). It is not apparent which AE was mainly responsible for discontinuation of pemetrexed maintenance therapy. One could assume it was due to renal function impairment; however, no grade 3 blood creatinine increases were reported in patients with combination treatment. Previous studies have supported the efficacy and safety of pemetrexed continuation maintenance strategy after 4 cycles of platinum doublet5. However, due to the high rate of discontinuation of pemetrexed maintenance therapy, one might consider continuing osimertinib alone after 4 cycles of cisplatin/carboplatin-pemetrexed without pemetrexed maintenance therapy.
The findings of this study underscore the potential of the combination of osimertinib and platinum doublet chemotherapy to significantly improve CNS-related outcome in patients with EGFR-mutated advanced NSCLC, and thereby offer a new first-line treatment option for patients with CNS metastases. However, in light of the toxicity profile and the currently immature survival data, osimertinib plus chemotherapy may not be the best standard of care for all patients. The challenge remains to identify the patients that are more likely to benefit from combination treatment. Hopefully further analysis of FLAURA-2 data and other future studies will give us more direction. It is clear, however, that better treatment strategies are needed and that it is essential to identify combinations that will better address both primary and acquired resistance in EGFR-mutated NSCLC and thereby further improve outcome for our patients.
References
- 1. Shin, J., et al., Prognostic Impact of Newly Proposed M Descriptors in TNM Classification of Non-Small Cell Lung Cancer. J Thorac Oncol, 2017. 12(3): p. 520-528.
- 2. Planchard, D., et al., Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med, 2023. 389(21): p. 1935-1948.
- 3. Soria, J.C., et al., Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2018. 378(2): p. 113-125.
- 4. Janne, P.A., 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, 2024. 42(7): p. 808-820.
- 5. Scagliotti, G.V., et al., Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials. Lung Cancer, 2014. 85(3): p. 408-14.
