FLAURA2 trial.(PFS), according to interim results from the
Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.
However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.
Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.
Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.
The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.
But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.
To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.
The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.
Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.
The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.
At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.
Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.
Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.
The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.
The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).
Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.
Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.
The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.
Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.
Mohana Roy, MD,she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.
Christian Rolfo, MD, PhD, MBA,that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.
The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.
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