Meeting NewsPerspective

Osimertinib extends PFS in EGFR-positive lung cancer

MADRID — First-line osimertinib prolonged PFS by 54% compared with standard therapy among patients with EGFR-positive advanced non-small cell lung cancer, according to results of the FLAURA trial presented at the European Society for Medical Oncology Congress.

Although interim OS results did not show a statistically significant difference between groups, they suggest “a strong and promising survival trend” in favor of osimertinib, Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University in Atlanta, said during a press conference.

“Osimertinib should be considered as a new standard of care for first-line therapy for EGFR-mutated advanced NSCLC,” Ramalingam said.

Incidence of EGFR mutations in patients with NSCLC range from approximately 15% in Western countries to 35% in Asia.

EGFR inhibitors such as erlotinib (Tarceva; Genentech, Astellas) and gefitinib (Iressa, AstraZeneca) have proven more effective than chemotherapy for first-line treatment of this population. These agents induce high response rates and confer an encouraging PFS benefit; however, patients almost always develop resistance. In more than half of cases, this resistance is mediated by a T790 mutation.

Ramalingam and colleagues hypothesized that osimertinib (Tagrisso, AstraZeneca) — a third-generation EGFR inhibitor approved for treatment of advanced NSCLC and T790M-mediated acquired resistance — may be a more effective first-line option.

Data from a preliminary study that included 60 treatment-naive patients with EGFR-mutated disease showed osimertinib-treated patients achieved a median PFS of 20.5 months, nearly double the median PFS for patients treated with erlotinib or gefitinib.

In the double-blind, randomized phase 3 FLAURA trial, Ramalingam and colleagues compared osimertinib to standard care with erlotinib or gefitinib as first-line therapy for patients with NSCLC who harbored EGFR exon 19 or exon 21 mutations.

The analysis included 556 adults from North America, Europe and Asia. Researchers assigned patients 1:1 to osimertinib or standard of care.

The 279 patients assigned osimertinib received 80 mg orally daily. The 277 patients assigned standard care received either gefitinib 250 mg orally daily or erlotinib 150 mg orally daily.

The osimertinib and standard-of-care groups were balanced for baseline characteristics, including sex (64% vs. 62%), race (62% Asian in each group), exon 19 deletion (57% vs. 56%), L858R mutation (35% vs. 32%) and central nervous system metastases (19% vs. 23%).

Patients assigned standard of care could cross over to osimertinib upon confirmed progression and positivity for T790M mutation.

PFS served as the primary endpoint. Secondary endpoints included objective response rate, duration of response, disease control rate, depth of response, OS, patient-reported outcomes and safety.

Osimertinib-treated patients achieved significantly longer median PFS (18.9 months vs. 10.2 months; HR= 0.46; 95% CI, 0.37-0.57). Researchers observed the PFS benefit across all subgroups, including patients who had central nervous system metastases at study entry (15.2 months vs. 9.6 months; HR = 0.47; 95% CI, 0.3-0.74) and those who did not have central nervous system metastases at study entry (19.1 months vs. 10.9 months; HR = 0.46; 95% CI, 0.36-0.59).

“Osimertinib was clearly superior to standard first line treatment in patients with EGFR-mutated NSCLC,” Ramalingam said in a press release. “The progression-free survival benefit for patients with and without brain metastases was almost identical, suggesting that osimertinib is active in the brain, as well as in systemic sites. This is important because brain metastasis is a common problem in EGFR-mutated patients.”

Results also showed longer median duration of response (17.2 months vs. 8.5 months) and higher overall response rate (80% vs. 76%) in the osimertinib group.

At data cutoff, 58 (21%) patients assigned osimertinib and 83 (30%) patients assigned standard of care had died.

Interim OS analysis showed a trend in favor of osimertinib (HR = 0.63; P = .0068); however, the difference did not reach the P value of .0015 required for statistical significance at the current 25% OS maturity. Median OS had not been reached in either treatment group.

Despite longer treatment duration with osimertinib than standard of care (16.2 months vs. 11.5 months), researchers reported lower incidence of grade 3 or higher toxicities in the osimertinib group (34% vs. 45%).

Enriqueta Felip Font, MD, PhD, head of the thoracic and head and neck cancer group at Vall d’Hebron University Hospital at Vall d’Hebron Institute of Oncology in Barcelona, agreed the results support osimertinib as 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,” Flip said. “More data [are] needed on the mechanisms of acquired resistance in patients treated with osimertinib in the first-line setting.” – by Mark Leiser

 

Reference:

Ramalingam S, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

 

Disclosures: Astra Zeneca funded this study. Ramalingam reports advisory board roles with AstraZeneca, Bristol-Myers Squibb, Genentech and Boehringer-Ingelheim. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

MADRID — First-line osimertinib prolonged PFS by 54% compared with standard therapy among patients with EGFR-positive advanced non-small cell lung cancer, according to results of the FLAURA trial presented at the European Society for Medical Oncology Congress.

Although interim OS results did not show a statistically significant difference between groups, they suggest “a strong and promising survival trend” in favor of osimertinib, Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University in Atlanta, said during a press conference.

“Osimertinib should be considered as a new standard of care for first-line therapy for EGFR-mutated advanced NSCLC,” Ramalingam said.

Incidence of EGFR mutations in patients with NSCLC range from approximately 15% in Western countries to 35% in Asia.

EGFR inhibitors such as erlotinib (Tarceva; Genentech, Astellas) and gefitinib (Iressa, AstraZeneca) have proven more effective than chemotherapy for first-line treatment of this population. These agents induce high response rates and confer an encouraging PFS benefit; however, patients almost always develop resistance. In more than half of cases, this resistance is mediated by a T790 mutation.

Ramalingam and colleagues hypothesized that osimertinib (Tagrisso, AstraZeneca) — a third-generation EGFR inhibitor approved for treatment of advanced NSCLC and T790M-mediated acquired resistance — may be a more effective first-line option.

Data from a preliminary study that included 60 treatment-naive patients with EGFR-mutated disease showed osimertinib-treated patients achieved a median PFS of 20.5 months, nearly double the median PFS for patients treated with erlotinib or gefitinib.

In the double-blind, randomized phase 3 FLAURA trial, Ramalingam and colleagues compared osimertinib to standard care with erlotinib or gefitinib as first-line therapy for patients with NSCLC who harbored EGFR exon 19 or exon 21 mutations.

The analysis included 556 adults from North America, Europe and Asia. Researchers assigned patients 1:1 to osimertinib or standard of care.

The 279 patients assigned osimertinib received 80 mg orally daily. The 277 patients assigned standard care received either gefitinib 250 mg orally daily or erlotinib 150 mg orally daily.

The osimertinib and standard-of-care groups were balanced for baseline characteristics, including sex (64% vs. 62%), race (62% Asian in each group), exon 19 deletion (57% vs. 56%), L858R mutation (35% vs. 32%) and central nervous system metastases (19% vs. 23%).

Patients assigned standard of care could cross over to osimertinib upon confirmed progression and positivity for T790M mutation.

PFS served as the primary endpoint. Secondary endpoints included objective response rate, duration of response, disease control rate, depth of response, OS, patient-reported outcomes and safety.

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Osimertinib-treated patients achieved significantly longer median PFS (18.9 months vs. 10.2 months; HR= 0.46; 95% CI, 0.37-0.57). Researchers observed the PFS benefit across all subgroups, including patients who had central nervous system metastases at study entry (15.2 months vs. 9.6 months; HR = 0.47; 95% CI, 0.3-0.74) and those who did not have central nervous system metastases at study entry (19.1 months vs. 10.9 months; HR = 0.46; 95% CI, 0.36-0.59).

“Osimertinib was clearly superior to standard first line treatment in patients with EGFR-mutated NSCLC,” Ramalingam said in a press release. “The progression-free survival benefit for patients with and without brain metastases was almost identical, suggesting that osimertinib is active in the brain, as well as in systemic sites. This is important because brain metastasis is a common problem in EGFR-mutated patients.”

Results also showed longer median duration of response (17.2 months vs. 8.5 months) and higher overall response rate (80% vs. 76%) in the osimertinib group.

At data cutoff, 58 (21%) patients assigned osimertinib and 83 (30%) patients assigned standard of care had died.

Interim OS analysis showed a trend in favor of osimertinib (HR = 0.63; P = .0068); however, the difference did not reach the P value of .0015 required for statistical significance at the current 25% OS maturity. Median OS had not been reached in either treatment group.

Despite longer treatment duration with osimertinib than standard of care (16.2 months vs. 11.5 months), researchers reported lower incidence of grade 3 or higher toxicities in the osimertinib group (34% vs. 45%).

Enriqueta Felip Font, MD, PhD, head of the thoracic and head and neck cancer group at Vall d’Hebron University Hospital at Vall d’Hebron Institute of Oncology in Barcelona, agreed the results support osimertinib as 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,” Flip said. “More data [are] needed on the mechanisms of acquired resistance in patients treated with osimertinib in the first-line setting.” – by Mark Leiser

 

Reference:

Ramalingam S, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

 

Disclosures: Astra Zeneca funded this study. Ramalingam reports advisory board roles with AstraZeneca, Bristol-Myers Squibb, Genentech and Boehringer-Ingelheim. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

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    Perspective

    The results, in my opinion, are clinically meaningful given osimertinib reduced risk for disease progression by 54%. The drug was well tolerated, and the duration of response also was longer with osimertinib. There are a number of questions to be addressed, such as determining what the mechanism of acquired resistance is for these patients. But I would agree this should be considered a new standard first-line treatment for patients who have these mutations.

    • Enriqueta Felip Font, MD, PhD
    • Vall d’Hebron University Hospital Vall d’Hebron Institute of Oncology Barcelona, Spain

    Disclosures: Felip Font reports honoraria from, speaker's bureau/lecture fees from, or advisory board/consultant roles with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer and Roche.

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