Final FLAURA Results Demonstrate Overall Survival Benefit with Osimertinib Over TKIs in Advanced NSCLC

Exploratory analysis of FLAURA data demonstrates that longitudinal ctDNA monitoring can provide early detection of disease progression and/or resistance in advanced NSCLC

First-line treatment with osimertinib provided improved overall survival (OS) over standard treatment with a comparator tyrosine kinase inhibitor (TKI) in patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer (NSCLC).

In addition, FLAURA investigators demonstrated the utility of circulating tumour DNA (ctDNA) in identifying patients with advanced NSCLC who are likely to experience disease progression. These findings from two presentations regarding the phase III FLAURA trial were reported at the ESMO Congress 2019 in Barcelona, Spain.

Osimertinib is a third generation, irreversible, oral EGFR-TKI that inhibits both EGFR mutations and EGFR T790M resistance mutations.

Final results show overall survival is prolonged with osimertinib compared to either gefitinib or erlotinib

Suresh S. Ramalingam, Haematology and Medical Oncology, Emory University, Winship Cancer Institute in Atlanta, United States of America, reported the final OS results from an analysis done at 58% maturity of OS data from the phase III FLAURA study (NCT02296125). He noted that previously reported results form FLAURA demonstrated significantly improved progression-free survival (PFS) compared to an EGFR-TKI (hazard ratio [HR] 0.46, p < 0.001), thus meeting the study primary endpoint. However, OS data were at 25% maturity at that time.

FLAURA enrolled treatment naive patients aged ≥18 years (≥20 in Japan) with Ex19del/L858R EGFR-mutated advanced NSCLC, and WHO performance status 0–1; patients having stable CNS metastases that did not require steroids for ≥2 weeks were allowed. Following 1.1 randomisation, 279 patients were treated with oral osimertinib at 80 mg once daily and 277 patients received either gefitinib at 250 mg daily or erlotinib 150 mg orally per day. Patients were stratified according to mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover to osimertinib was allowed for patients in the comparator EGFR-TKI arm upon central confirmation of disease progression (PD) and T790M positivity.

The primary endpoint was investigator-assessed PFS by RECIST v1.1, and OS was a secondary endpoint. Data cut-off was 25 June 2019.

Crossover to osimertinib upon PD was reported for 70 (25%) patients in the comparator arm.

OS favoured osimertinib over the comparator EGFR-TKI

Despite crossover by one-fourth of the patients in the comparator arm, OS was prolonged with osimertinib versus the comparator. Median OS was 38.6 months (95.05% confidence interval [CI], 34.5-41.8) versus 31.8 months (95.05% CI, 26.6, 36.0), respectively (HR 0.799; 95.05% CI, 0.641-0.997; p = 0.0462).

The 12-month, 24-month, and 36-month OS rates were 89% versus 83%, 74% versus 59%, and 54% versus 44% with osimertinib versus comparator, respectively.

The median follow-up for OS in the patients overall was 35.8 months with osimertinib versus 27.0 months with comparator and the medium follow-up for censored patients was 43.1 months in both treatment arms.

During follow-up, 155 (56%) deaths occurred in the osimertinib arms versus 166 (60%) in the comparator arm.

Adverse events (AEs; any cause) per investigator occurred in 98% of patients in both cohorts; of these 42% were grade ≥3 with osimertinib and 47% with comparator EGFR-TKI. AEs leading to discontinuation occurred in 15% of patients on osimertinib versus 18% of patients on comparator EGFR-TKI.

ctDNA data from FLAURA reflect disease progression

Using data from the FLAURA trial, Jhanelle E. Gray, Department of Thoracic Oncology, H. Lee Moffitt Cancer Centre and Research Institute, Tampa, United States of America and collegues established ctDNA as a valid indicator of PD. The investigators used plasma samples that were collected during FLAURA on days 1, 8, 15, followed by every 21 days during weeks 3 to 18, and every 6 weeks thereafter. Samples from patients at disease progression and/or treatment discontinuation were evaluated using ctDNA droplet digital PCR (ddPCR; Biodesix) for EGFR mutations (Ex19del, L858R, and T790M) at all available time points, as well as C797S at all post-week 6 time points. C797S and T790M were the only resistance mutations assayed. ctDNA progression was defined with respect to the nadir ctDNA result and its proximity to the ddPCR detection and quantification limits.

This ctDNA progression analysis included 122 (22%) patients having valid longitudinal monitoring ddPCR data and PD per RECIST at the first data cut-off of 12 June 2017. Consistent ctDNA results were observed in both treatment arms; in 80 (66%) patients with median PFS of 9.5 months that experienced PD, ctDNA progression preceded or co-occurred with PD with 2.7 months median lead time.

Acquired C797S or T790M was detected in 57 (47%) patients showing ctDNA progression; of these C797S was detected in 4 (8%) osimertinib patients and T790M was detected in 53 (74%) patients on comparator. The median time to detection was 16.7 and 8.4 months with osimertinib and comparator, respectively, which reflected the observed median PFS.

In 106 patients demonstrating both ctDNA progression and PD, acquired T790M and C797S could be detected either at the same time as, or earlier than PD in 41 (38%) patients; of these 2 (5%) were in the osimertinib and 39 (58%) were in the comparator arm. The median lead-time was 1.4 months.

Discussant points

Pasi A. Jänne of the Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, USA who discussed the FLAURA findings said that the results are clinically meaningful with median OS improvement of almost 7 months and 28% vs. 9% of patients receiving study therapy at 36 months. The outcomes were consistent across subgroups, but magnitude of benefit varies in subgroups. The study findings are practice changing; however, osimertinib is already approved for EGFR T790M in 87 countries worldwide and furthermore, it is approved for first-line treatment in 78 countries worldwide. But barriers to first-line use are cost and/or lack of reimbursement.

Conclusions

Regarding OS findings,the investigators concluded thatfront-line osimertinib provided a statistically significant and clinically meaningful improvement in OS versus the comparator EGFR-TKI in patients with EGFR-mutated advanced NSCLC. In addition, the safety profile appeared consistent with previously reported data. 

The investigators performing the ctDNA monitoring concluded that this technique may allow earlier identification of patients who progress on first-line EGFR-TKI therapy and also early detection of EGFR-mediated resistance mechanisms prior to PD in patients with EGFR-mutated NSCLC. They commented that they intend to explore early detection of non-EGFR-mediated resistance.

 

Disclosure

This FLAURA study was funded by AstraZeneca.

References

LBA5_PR – Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis.

LBA85 – Gray JE, Peled N, Markovets A, et al. Longitudinal circulating tumour DNA (ctDNA) monitoring for early detection of disease progression and resistance in advanced NSCLC in FLAURA.