Osimertinib Plus Chemo Reduces Progression in EGFR-Positive NSCLC With Central Nervous System Metastases

Osimertinib (Tagrisso) plus chemotherapy reduced the risk for central nervous system (CNS) progression in patients with EGFR-mutated non-small cell lung cancer (NSCLC) with CNS metastases, according to findings from the phase 3 FLAURA2 trial (NCT04035486) presented at the 2023 ESMO Congress.¹

Ultimately, patients who received osimertinib with chemotherapy had an estimated 9% risk of developing a CNS lesion at 24 months (95% CI, 4-16) whereas those who received osimertinib alone had an estimated 23% risk (95% CI, 14-33).

Also, compared with osimertinib alone, adding chemotherapy to the EGFR tyrosine kinase inhibitor (TKI) contributed to a higher CNS objective response rate (ORR) and better complete response (CR) rate with durable responses, all with a tolerable and manageable safety profile.

“These data support the addition of platinum-pemetrexed to osimertinib as a new firstline treatment option for patients with an EGFR mutated, advanced non-small cell lung cancer, including those with brain [metastases],” David Planchard, MD, PhD, thoracic oncologist and head of the thoracic pathology committee at Institut Gustave Roussy in Paris, France, said during the presentation of the findings.

David Planchard, MD, PhD

Thoracic Oncologist and Head of the Thoracic Pathology Committee

Institut Gustave Roussy

Paris, France

Prior reports have demonstrated that firstline osimertinib plus chemotherapy significantly improved progression-free survival (PFS) over osimertinib alone—this was consistent across all subgroups, including those with brain metastases.

In the FLAURA2 trial, researchers enrolled patients with pathologically confirmed, EGFR-mutated, advanced NSCLC who had not undergone previous treatments. These patients had an ECOG performance status of either 0 or 1 and were at least 18 years old. Of note, the trial also permitted patients who had asymptomatic CNS metastases that either did not require steroids or were stable for at least 2 weeks after receiving definitive treatment or steroids.

A total of 557 patients were randomly assigned 1:1 to receive either firstline osimertinib with chemotherapy (n = 279) or frontline osimertinib alone (n = 278). Both arms received the assigned treatment until progression or treatment discontinuation.

Brain imaging was performed on all patients at baseline. It was also performed if, and when, disease progression occurred, although patients with CNS metastases at baseline underwent additional-to-scheduled assessments until progression. Each CNS scan in this trial was assessed by a neuroradiologist using modified RECIST guidelines.

CNS-related endpoints were assessed by modified RECIST1.1 and included ORR, PFS, and duration of response (DOR). Safety was assessed in both groups via the Common Terminology Criteria for Adverse Events (CTCAE) v5. The data cutoff for this trial was April 3, 2023.

Researchers performed 2 analysis sets. The first was a CNS blinded independent central review (BICR) full analysis set and included patients with 1 or more measurable or non-measurable lesions; this set included 118 patients receiving osimertinib plus chemotherapy and 104 patients receiving osimertinib alone. The second set was a CNS evaluable for response set, which included patients with 1 or more measurable lesions; this set included 40 patients receiving osimertinib plus chemotherapy and 38 patients receiving osimertinib alone.

Findings From the Full Analysis (Measurable and Non-Measurable Lesions)

In the CNS-BICR full analysis set, the ORR was 73% (95% CI, 64-81) in the osimertinib plus chemotherapy group and 69% (95% CI, 59-78) in the osimertinib monotherapy group. Of note, 59% (n = 70) of patients assigned osimertinib plus chemotherapy achieved a CR to therapy compared with 43% (n = 45) of those assigned monotherapy.

The median CNS DOR in this analysis was not reached (NR) in the osimertinib plus chemotherapy group (95% CI, 23.8-not calculable [NC]) compared with 26.2 months (95% CI, 19.4-NC) in the osimertinib only group.

Ultimately, the addition of chemotherapy reduced the risk of CNS-related disease progression or death by 42% (HR, 0.58; 95% CI, 0.33-1.01) in this population.² At 12 months, the rates of PFS were 87% vs 83% between the combination and monotherapy groups, respectively. At 24 months, the rates were 74% vs 54%.

Results Among Those With Measurable Lesions

For the CNS evaluable for response set, the CNS ORR was 88% (95% CI, 73%-96%) among patients assigned osimertinib plus chemotherapy and 87% (95% CI, 72%-96%) among patients receiving osimertinib monotherapy. Complete responses were achieved by 48% (n = 19) vs 16% (n = 40) of patients, respectively.

The median CNS DOR in this set was not reached in the osimertinib plus chemotherapy group (95% CI, 21.6-NC) and 20.9 months in the osimertinib alone group (95% CI, 12.6-NC).

In this population, the addition of chemotherapy reduced the risk of progression or death by 60% (HR, 0.40; 95% CI, 0.19-0.84). At 12 months, the PFS rates were 89% vs 73%. At 24 months, the rates were 65% vs 37%.

Safety Analysis

According to Planchard, the safety profiles were consistent with what investigators had expected.

Of note, more grade 3 or worse adverse events were reported in the dual therapy arm. Hematological toxicities were the most reported. Regarding interstitial lung disease, 9 patients (3%) and 10 patients (4%) reported this event in the combination and monotherapy groups. Toxicities were most frequent and severe during the induction period and were reported to gradually recede over time.

“Osimertinib has proven ability to cross the blood-brain barrier and improve outcomes for patients with lung cancer and CNS metastases, who often face a poorer prognosis than patients whose disease has not spread to the brain,” said in a press release from AstraZeneca, the manufacturer of osimertinib. “In FLAURA2, the addition of chemotherapy to osimertinib led to a complete response and the disappearance of these tumors in the brain in more than half of these patients.”

^References

^{1. Planchard D, Janne PA, Cheng Y, et al. FLAURA2: Safety and CNS outcomes of first-line (1L) osimertinib (osi) ± chemotherapy (CTx) in EGFRm advanced NSCLC. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA68.}

^{2. Tagrisso (osimertinib) plus chemotherapy reduced the risk of disease progression in the brain by 42% in patients with EGFR-mutated advanced lung cancer and brain metastases at baseline. News release. AstraZeneca. October 21, 2023. Accessed October 21, 2023. https://tinyurl.com/44rda6ym}