Osimertinib new SoC for EGFR-mutated advanced NSCLC?

Elvira Manzano
Roshini Claire Anthony
18 Jan 2018

Osimertinib significantly improved progression-free survival (PFS) over standard first-line therapy in the phase III FLAURA trial and experts say it could be the next standard of care (SoC) for advanced non-small cell lung cancer (NSCLC) harbouring EGFR mutation (EGFRm).

“Definitely, osimertinib is the new SoC for first-line treatment of EGFRm advanced NSCLC,” said lead author Dr Yuichiro Ohe from the National Cancer Center Hospital in Tokyo, Japan. “However, we should await the overall survival (OS) data, which is immature at the time of the analysis, with caution to find out if patients treated with osimertinib actually live longer.”

Overall results of the FLAURA trial presented at ESMO Asia 2017 (and previously at ESMO 2017) showed a median PFS of 18.9 months with osimertinib vs 10.2 months for SoC, with a hazard ratio (HR) of 0.46 (p<0.0001). The PFS benefit was consistent across all subgroups, even in patients with or without central nervous system (CNS) metastases at study entry. [ESMO Asia 2017, abstract 4130; N Engl J Med 2017;doi:10.1056/NEJMoa1713137]

Of note, the median duration of response was two-fold higher with osimertinib (17.2 vs 8.5 months for SoC) while overall response rate (ORR) was 80 and 76 percent, respectively. Interim OS results also appeared to favour osimertinib (HR, 0.63; p=0.0068) but were not statistically significant at 25 percent maturity (p<0.0015 is required to establish significance). Osimertinib safety profile was comparable to SoC, with lower rates of ≥grade 3 adverse events (34 percent vs 45 percent for SoC).

“First- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) are the recommended first-line treatment for EGFRm advanced NSCLC,” said Ohe. “However, despite high response rates and beneficial PFS, half of patients on EGFR inhibitors invariably develop EGFR T790M-mediated resistance.”

Osimertinib, a third-generation EGFR-TKI, is approved for advanced NSCLC and T790M resistance mutations.

Osimertinib benefits extend to Asian NSCLC patients

The FLAURA investigators compared osimertinib with standard first-line therapy erlotinib or gefitinib in untreated NSCLC patients with EGFR exon 19 or 21 mutations. PFS was the primary endpoint and 556 patients from Asia, Europe, and North America were randomized in a 1:1 ratio to osimertinib or SoC.

A subset analysis of 322 Asian patients (46 Chinese, 120 Japanese, and 156 from other parts of Asia) with EGFRm NSCLC, results of which were presented at ESMO Asia 2017 in Singapore, also showed improved PFS with osimertinib, putting to halt questions on whether race had an impact on the treatment outcomes.

PFS was longer with osimertinib vs SoC (median 16.5 vs 11.0 months). As in the overall FLAURA population, osimertinib was associated with a 46 percent reduced risk for progression or death [HR], 0.54; p<0.0001) and a doubling of the median duration of response vs SoC (18 vs 9 months; odds ratio [OR], 2.19; p=0.0002) in Asian NSCLC patients. [ESMO Asia 2017, abstract LBA6_PR]

Patients in the Asian subset had locally advanced or metastatic NSCLC (median age 64 years) with WHO performance status 0–1 and harbouring EGFR Ex19del or L858R and were randomized to osimertinib 80 mg once daily or SoC erlotinib (150 mg once daily) or gefitinib (250 mg once daily).

ORR was comparable between osimertinib and SoC (80 percent vs 75 percent, respectively; OR, 1.33; p=0.2918). OS data are yet immature, though results point to “an interesting trend towards improved OS with osimertinib compared with SoC” (HR, 0.65; p=0.0609), said lead author Professor Byoung Chul Cho from the Yonsei Cancer Center in Seoul, Korea, who presented the Asian subset results at ESMO Asia 2017.

Fewer patients on osimertinib than on SoC experienced grade ≥3 adverse events (AEs; 40 percent vs 48 percent) or discontinued treatment due to any AEs (15 percent vs 21 percent).

Dermatitis acneiform, and AST and ALT increases were less frequent with osimertinib vs with SoC (30 percent vs 53 percent, 12 percent vs 36 percent, and 7 percent vs 36 percent, respectively), while more patients on osimertinib experienced QT prolongation (15 percent vs 5 percent) and interstitial lung disease (6 percent vs 2 percent).  

“Asian patients had similar toxicities with osimertinib as the overall FLAURA population,” said Cho. “Data from this analysis support osimertinib as a new [SoC] for first-line therapy in Asian patients with EGFRm advanced NSCLC.”

Professor James Yang from the National Taiwan University College of Medicine in Taipei, Taiwan, meanwhile called for further studies to ascertain if Asian and non-Asian patients with EGFRm have distinct responses to EGFR-TKIs, which he said “might be due to variations in clinical practice rather than biology.”

CNS responses with osimertinib

Treatment with osimertinib also resulted in a nominally statistically significant and clinically meaningful improvement in the CNS PFS over SoC, said Dr Johann Vansteenkiste, a respiratory oncologist at the University Hospital KU in Leuven, Belgium. He presented the CNS data from the FLAURA study at ESMO Asia 2017.

“Osimertinib reduced the risk of CNS progression or death by 52 percent (hazard ratio [HR], 0.48; nominal p=0.014). Fewer patients experienced CNS progression with osimertinib and fewer progressed due to new CNS lesions,” he added. [ESMO Asia 2017, abstract LBA5]

The CNS objective response rate (ORR) was also higher with osimertinib at 66 percent vs 43 percent with standard EGFR TKI therapy (erlotinib or gefitinib). “The CNS responses, I should say, were durable,” said Vansteenkiste.

The subgroup analysis included 128 patients (61 treated with osimertinib and 67 with SoC) with at least 1 measurable and/or nonmeasurable CNS lesion at baseline.

“CNS metastases, including brain metastases, are a common and very disabling complication of advanced EGFRm–positive NSCLC. They are notoriously difficult to treat, as existing oral therapies are often unable to effectively cross the blood-brain barrier,” said Vansteenkiste. “The CNS efficacy seen with osimertinib as a first-line treatment in patients with EGFRm advanced NSCLC suggests improved clinical outcomes in an area of great unmet medical need.” 

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