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Best Practices in lung cancer – November 2017 Vol 8

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Tyrosine Kinase Inhibitors

Osimertinib Improves Progression-Free Survival in Patients with EGFR-Mutated Lung Cancer

Osimertinib improves progression-free survival by 54% compared with standard first-line therapy in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to late-breaking results from the FLAURA trial presented at the ESMO 2017 Congress in Madrid.1

EGFR mutations are present in approximately 15% of NSCLC in Western populations, rising to 35% in Asian populations. EGFR inhibitors are superior to chemotherapy in the first-line treatment of these patients. However, despite high response rates and good progression-free survival, patients invariably develop resistance to drugs such as erlotinib and gefitinib. In the majority of patients this resistance is mediated by a T790M mutation.

“We hypothesized that a drug which targets EGFR-sensitising mutations and the T790M resistance mutation would be associated with a better outcome,” said principal investigator Suresh Ramalingam, MD, of the Winship Cancer Institute, Emory University in Atlanta, GA.

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that potently and selectively inhibits both EGFR and T790M resistance mutations. A preliminary study in 60 treatment-naive patients with EGFR mutations found that the median progression-free survival with osimertinib was 20.5 months, which was almost 2-fold higher than results achieved with erlotinib or gefitinib.

FLAURA was a randomized phase 3 clinical trial comparing osimertinib with standard of care erlotinib or gefitinib as first-line therapy in NSCLC patients with EGFR exon 19 or 21 mutations. The primary end point was progression-free survival. A total of 556 patients from Asia, Europe, and North America were randomized 1:1 to treatment with osimertinib or standard of care.

The median progression-free survival was 18.9 months with osimertinib compared with 10.2 months for the standard therapy, with a hazard ratio of 0.46 (95% CI, 0.37-0.57; P <.0001). The benefit in progression-free survival was consistent across all subgroups, including patients with and without brain metastases at the start of the study.

The median duration of response was 2-fold higher for patients treated with osimertinib (17.2 months) versus standard of care (8.5 months). The overall response rate was 80% with osimertinib compared with 76% with standard-of-care treatment.

Overall survival appeared to favor osimertinib with a hazard ratio of 0.63, although this was not statistically significant at the interim overall survival analysis (25% maturity).* Median overall survival was not reached. The incidence of grade 3 or higher toxicities was lower for osimertinib (34%) than for the standard treatment (45%).

Regarding toxicities, Dr Ramalingam said, “The safety profile of osimertinib was more favorable despite longer treatment duration (16.2 months) compared to standard of care (11.5 months).”

Commenting on the results for ESMO, Enriqueta Felip, MD, PhD, Head, Thoracic and H&N Cancer Group, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain, said, “Osimertinib reduced the risk of cancer progression by 54% compared with standard of care and extended the median time to progression by about 9 months. The drug was well tolerated, and it has activity in the brain. Based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations.”

“Overall survival data are not yet mature, and there is a clear need to continue follow-up to see if those treated with osimertinib live longer,” she added.

Regarding the need for further research, Dr Felip said: “More data are needed on the mechanisms of acquired resistance in patients treated with osimertinib in the first-line setting.”

*The P value for overall survival was P = .0068. This was not statistically significant because a P value of .0015 was required for statistical significance at the current overall survival maturity.

Reference

  1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Paper presented at: European Society for Medical Oncology 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA2_PR.

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