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Dr Margaret Shi, 02 Jan 2020

Tivozanib as third- or fourth-line therapy improves progression-free survival (PFS) compared with sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have received ≥2 previous systemic treatments, according to results of the phase III, randomized, controlled TIVO-3 trial.

Osimertinib improves OS vs older EGFR-TKIs in untreated advanced NSCLC

Prof. Suresh Ramalingam
Winship Cancer Institute of Emory University
Atlanta, Georgia, US
27 Nov 2019

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), significantly improves overall survival (OS) vs gefitinib or erlotinib in patients with EGFR mutated, advanced or metastatic non-small-cell lung cancer (NSCLC) who have not received prior systemic anticancer therapy or EGFR tyrosine kinase inhibitor (TKI) therapy, according to results of the FLAURA trial. These results, presented at the European Society for Medical Oncology (ESMO) Congress 2019, reinforce the importance of osimertinib as the first-line standard of care (SoC) for patients with EGFR mutated, advanced NSCLC.

The FLAURA trial

Until recently, the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR-TKI–sensitizing mutations consisted of monotherapy with a first- or second-generation EGFR-TKI, such as gefitinib or erlotinib. The phase III FLAURA trial evaluated the efficacy and safety of osimertinib vs gefitinib or erlotinib in the first-line treatment of patients with locally advanced or metastatic NSCLC with the EGFR Ex19del or L858R mutation. Patients with central nervous system (CNS) metastases were eligible if their condition was neurologically stable and did not require steroid for ≥2 weeks. [N Engl J Med 2018;378:113-125]

The trial included 556 patients (median age, 64 years) with WHO performance status of 0/1 enrolled from 132 sites in 29 countries. “In each group, 62–64 percent of patients were female, 62 percent were Asian, 63–65 percent were never-smokers, 63 percent had the EGFR Ex19del mutation, and 19–23 percent had CNS metastases at baseline,” said investigator Professor Suresh Ramalingam of the Winship Cancer Institute of Emory University, Atlanta, US.

Patients in the trial were randomized 1:1 to receive osimertinib (80 mg once daily; n=279) or a standard EGFR-TKI (gefitinib 250 mg once daily or erlotinib 150 mg once daily; n=277). Upon disease progression, patients in the comparator EGFR-TKI arm with post-progression documentation of the T790M mutation were allowed to cross over to receive open-label osimertinib as second-line therapy.

Primary endpoint results, reported previously, demonstrated significantly improved progression-free survival (PFS) with osimertinib vs gefitinib or erlotinib. At data cut-off in June 2017, median PFS was 18.9 months in the osimertinib arm vs 10.2 months in the comparator EGFR-TKI arm (hazard ratio [HR], 0.46; 95 percent CI, 0.37 to 0.57; p<0.001), with consistent benefit seen across predefined patient subgroups. These results led to US FDA approval of osimertinib as first-line treatment for patients with EGFR mutated metastatic NSCLC in April 2018.

Final results: Osimertinib improves OS

“Final results of the FLAURA trial demonstrated a statistically significant and clinically meaningful improvement in OS with osimertinib vs gefitinib or erlotinib, supporting osimertinib as the first-line SoC for patients with EGFR mutated advanced NSCLC,” reported Ramalingam. 

At data cut-off in June 2019, median OS was 6.8 months longer in the osimertinib vs comparator EGFR-TKI arm (median, 38.6 months vs 31.8 months; HR, 0.799; 95 percent confidence interval [CI], 0.641 to 0.997; p=0.0462). (Figure 1) [Ramalingam S, ESMO 2019, abstract LBA5_PR]

340mo1

“Osimertinib is the first EGFR-TKI monotherapy to demonstrate a statistically significant OS benefit vs another EGFR-TKI,” said Ramalingam.

“Of note, the median OS in the control group is the longest reported for gefitinib and erlotinib in this patient population. This is attributable to the fact that 31 percent of patients [n=85] in the control group crossed over to receive osimertinib after disease progression, which makes the OS improvement with osimertinib vs gefitinib and erlotinib even more noteworthy,” he commented.

The OS benefit with osimertinib was observed in all patient subgroups, with a larger magnitude of benefit seen in non-Asian patients (n=209) (HR, 0.542; 95 percent CI, 0.378 to 0.772) than in Asian patients (n=347) (HR, 0.995; 95 percent CI, 0.752 to 1.319).

“In Asian patients, the Kaplan-Meier curves demonstrated an OS benefit with osimertinib in the first 3 years. Thereafter, the high degree of censoring and small number of events call for caution in data interpretation,” Ramalingam noted.

Durability of benefit

Final results of the FLAURA trial also demonstrated durability of osimertinib’s treatment benefit, with the median time to first subsequent therapy or death being almost double in the osimertinib vs comparator EGFR-TKI arm (25.5 months vs 13.7 months; HR, 0.478; 95 percent CI, 0.393 to 0.581; p<0.0001). (Figure 2)

“At 36 months, 28 percent of patients in the osimertinib arm vs 9 percent of patients in the comparator EGFR-TKI arm remained on their allocated first-line study treatment,” said Ramalingam. (Figure 2)

340mo2revised

Following disease progression, 47 percent of patients in the osimertinib arm and 65 percent of those in the comparator EGFR-TKI arm received second-line treatment. (Figure 3) 

340mo3

“In the osimertinib arm, chemotherapy was the most commonly used second-line treatment [68 percent], but 22 percent of patients remained on osimertinib after disease progression,” said Ramalingam. 

Among patients in the comparator EGFR-TKI arm, only 31 percent (n=85) were eligible for second-line treatment with osimertinib. 

“In both groups, about 30 percent of patients were unable to receive subsequent therapy. The vast majority of them died before they could receive any second-line treatment,” Ramalingam noted.

Safety outcomes

The safety profile of osimertinib remained consistent with previous data from the FLAURA trial. 

“The median duration of treatment exposure was 20.7 months in the osimertinib arm vs 11.5 months in the comparator EGFR-TKI arm. Despite a longer median duration of exposure to osimertinib, rates of grade ≥3 possibly causally related adverse events [AEs] were lower with osimertinib vs gefitinib or erlotinib [18 percent vs 29 percent],” said Ramalingam. 

The most commonly reported AEs were diarrhoea (all grades, 60 percent for osimertinib vs 58 percent for comparator EGFR-TKI; grade 3/4, 3 percent vs 3 percent), rash and acne (all grades, 59 percent vs 79 percent, grade 3/4, 1 percent vs 7 percent), nail effects (all grades, 39 percent vs 34 percent; grade 3/4, 1 percent vs 1 percent), and dry skin (all grades, 38 percent vs 37 percent; grade 3/4, <1 percent vs 1 percent). 

Rates of liver enzyme elevations were lower with osimertinib vs comparator EGFR-TKI (aspartate transaminase elevation: all grades, 10 percent vs 25 percent; grade 3/4, 1 percent vs 4 percent) (alanine transaminase elevation: all grades, 7 percent vs 27 percent; grade 3/4, 1 percent vs 8 percent).

Impact on clinical practice

“The final OS analysis of the FLAURA trial reinforces the importance of using osimertinib as the first-line SoC for patients with EGFR mutated advanced NSCLC,” Ramalingam concluded.

“FLAURA’s OS results are practice-changing. In fact, clinical practice in the US has already changed with the PFS data,” said invited discussant Dr Pasi Jänne of the Dana-Farber Cancer Center in Boston, Massachusetts, US. 

Based on these results, Jänne advised against using an older-generation EGFR-TKI in the first-line treatment of patients with EGFR mutated advanced NSCLC. “In FLAURA patients who were first treated with gefitinib or erlotinib, only 31 percent were able to receive subsequent osimertinib therapy upon disease progression, and 30 percent received no subsequent therapy,” he explained. 

“With the final results of FLAURA, we should be done with single-agent EGFR-TKI comparisons and shift focus to strategies that could further enhance the efficacy of osimertinib,” Jänne suggested.

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Most Read Articles
Dr Margaret Shi, 02 Jan 2020

Tivozanib as third- or fourth-line therapy improves progression-free survival (PFS) compared with sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have received ≥2 previous systemic treatments, according to results of the phase III, randomized, controlled TIVO-3 trial.