First-line treatment with osimertinib plus platinum-based chemotherapy achieved a statistically significant and clinically meaningful progression-free survival improvement compared with osimertinib alone in patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC), according to the findings of the phase III FLAURA2 study. These results were presented by Pasi A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, at the 2023 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer.1
In patients with advanced EGFR-mutated NSCLC, median progression-free survival was improved by 38% using the combination of osimertinib and platinum-based chemotherapy vs osimertinib monotherapy. The absolute improvement in progression-free survival was 8.8 months favoring the combination over monotherapy according to investigator assessment and by 9.5 months based on blinded independent central review.
“Results from this study demonstrate a remarkable improvement in progression-free survival with the osimertinib-plus-chemotherapy approach, showcasing a significant reduction in disease progression risk compared to osimertinib monotherapy,” stated Dr. Jänne.
Further analysis of FLAURA2 and future studies will refine which patients are most likely to respond to the combination [osimertinib plus platinum/pemetrexed].— Pasi A. Jänne, MD, PhD
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“These findings mark a significant advancement in the management of advanced EGFR-mutated NSCLC. The FLAURA2 study supports osimertinib combined with platinum-pemetrexed as a new and promising first-line treatment option, poised to make a profound impact on patient outcomes in this challenging disease setting,” he added. “This is a first-line option.”
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor with activity in the central nervous system. Unlike earlier-generation EGFR tyrosine kinase inhibitors, osimertinib can inhibit both sensitizing and resistant EGFR mutations.
These findings come on the heels of the double-blind, phase III FLAURA study, showing superior overall survival with osimertinib vs comparator EGFR tyrosine kinase inhibitors (gefitinib or erlotinib) in advanced EGFR-mutated NSCLC.2 The absolute overall survival benefit was about 8 months for the osimertinib-treated group.
Treatment with osimertinib was also found to be superior to placebo in another phase III trial—ADAURA—in completely resected stage II–IIIA EGFR-mutated NSCLC.3 In that setting, the 2-year disease-free survival rate was 89% with osimertinib vs 52% with placebo. A further analysis of that trial showed improved overall survival in those patients, with a 5-year overall survival rate of 88% with osimertinib vs 78% with placebo, representing a 51% lower risk of death for those treated with osimertinib.4
Prior studies suggested that osimertinib compared with first- and second-generation EGFR tyrosine kinase inhibitors yielded a benefit in EGFR-mutated NSCLC. FLAURA2 was designed to evaluate whether osimertinib plus standard platinum-based chemotherapy would lead to superior outcomes compared with osimertinib monotherapy in patients with advanced EGFR-mutated NSCLC.
FLAURA2 enrolled 557 patients and randomly assigned them 1:1 to two treatment arms: osimertinib plus chemotherapy or osimertinib monotherapy. In the arm given combination therapy, osimertinib at 80 mg/d was paired with pemetrexed plus either cisplatin or carboplatin. Patients had to have advanced NSCLC with EGFR mutations exon 19 del and L858R on exon 21. Stratification factors were race, EGFR mutation status, and performance status according to the World Health Organization classification.
At baseline, about 38% of patients were female, with a median age of about 61; about 35% were non-Asian, and 32% were former smokers. Almost all tumors (99%) were adenocarcinomas, 95% had metastatic disease, and 53% had extrathoracic visceral metastasis. Stable central nervous system (CNS) metastases were allowed. All patients had brain scans at baseline.
Investigator-assessed median progression-free survival was 25.5 months with the combination therapy vs 16.7 months with osimertinib monotherapy, representing a significant 38% improvement for the combination arm (P < .0001). At 2 years, the progression-free survival rates for the two treatment arms were 57% and 41%, respectively. Progression-free survival rates were similar according to blinded independent central review.
In patients with CNS metastasis at baseline, the median progression-free survival rate was 24.9 months vs 13.8 months, respectively, with osimertinib plus chemotherapy and osimertinib monotherapy. Among patients without baseline CNS metastasis, median progression-free survival was 27.6 months vs 21 months, respectively. The combination was beneficial vs monotherapy across all predefined subgroups, including age, smoking status, EGFR status, presence or absence of baseline metastasis, gender, and race.
Combination therapy was generally well tolerated, according to the investigators, and adverse events were reported to be manageable with standard medical practice.
“In the combination arm, as not unanticipated, more adverse events were causally related to combination treatment than monotherapy with osimertinib. Fortunately, the adverse events leading to death were very few,” Dr. Jänne noted.
Among all patients, adverse events of any type were experienced by 100% of those on the combination arm and 97% of those on the osimertinib monotherapy arm. Any adverse event of grade 3 or higher occurred in 64% and 27%, respectively. Adverse events leading to death were reported in 7% and 3%, respectively. Any serious adverse event occurred in 38% and 19%, respectively. The percentages of patients who discontinued treatment because of an adverse event were 48% and 6%, respectively.
Treatment-related adverse events were reported in 97% and 88%, respectively. Grade 3 or higher treatment-related adverse events were observed in 53% and 11%, respectively. Serious treatment-related adverse events occurred in 19% and 5%, respectively. All grade 4 adverse events in the combination arm were hematologic and associated with chemotherapy. No common grade 4 adverse events were reported in the osimertinib monotherapy arm.
Ongoing analysis of FLAURA2 data includes CNS response, CNS disease progression, endpoints after disease progression, subsequent therapy, and circulating tumor DNA (ctDNA) analysis.
During the question-and-answer session after Dr. Jänne’s presentation at a press conference, reporters raised two issues: the implication of additional mutations in a patient with EGFR-mutated NSCLC and of the presence of EGFR mutations on ctDNA after treatment with osimertinib.
Dr. Jänne offered the following responses: “FLAURA2 included the common mutations for which there is approval for osimertinib. We know from other studies that other genetic alterations arise concomitantly and may modulate the efficacy of EGFR inhibition. We will be looking at that in future analysis of the data.”
Dr. Jänne continued: “If EGFR mutation is still present in the blood as detected by ctDNA after 3 to 4 weeks of treatment osimertinib, that tends to predict for shorter progression-free survival. Those data will be presented in the future.”
“We are studying the clinical and molecular features of individuals who are most likely to benefit from the combination of chemotherapy and osimertinib,” he commented. “The study shows the combination is of benefit in all-comers. Further analysis of FLAURA2 and future studies will refine which patients are most likely to respond to the combination,” he explained.
DISCLOSURE: FLAURA2 was funded by AstraZeneca. Dr. Jänne has served as a consultant to Mirati Therapeutics, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Araxes Pharma, Ignyta, Takeda Oncology, Voronoi, Novartis, SFJ Pharmaceuticals, Biocartis, Loxo Oncology, Sanofi, Transcenta, AstraZeneca, and Daiichi Sankyo; owns stock in Gatekeeper Pharmaceuticals and Loxo Oncology; and receives postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations licensed to LabCorp.
1. Jänne P, Planchard D, Cheng, et al: Osimertinib with/without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). 2023 World Conference on Lung Cancer. Abstract PL03.13. Presented September 11, 2023.
2. Ramalingam S, Vansteenkiste J, Planchard D, et al: Overall survival with osimertinib in untreated EGFR-mutated advanced NSCLC. N Engl J Med 382:41-50, 2020.
3. Wu YL, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.
4. Herbst RS, Tsuboi M, John T, et al: Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with EGFR-mutated stage IB–IIIA non-small cell lung cancer. 2023 ASCO Annual Meeting. Abstract LBA3. Presented June 4, 2023.
Roy S. Herbst, MD, PhD, cautioned that although FLAURA2 is a positive result, most patients will still develop drug resistance. “The result is really good and clearly positive, but if you look at the survival curves, there is still early overlap in a way that makes it unlikely this combination will ...