Meeting NewsPerspective

Front-line osimertinib improves OS in EGFR-mutated lung cancer

BARCELONA, Spain — Osimertinib significantly extended OS compared with standard epidermal growth factor receptor tyrosine kinase inhibitors as front-line treatment for EGFR-mutated advanced non-small cell lung cancer, according to late-breaking results of the randomized phase 3 FLAURA study presented at European Society for Medical Oncology Congress.

“Osimertinib is very different than all the other EGFR inhibitors,” Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University, said during his presentation. “It’s highly selective and has a much better safety profile. It also has a much higher penetration in the brain and, therefore, is able to create responses in 70% to 90% of patients with brain metastases, which is a common problem for EGFR lung cancer. It also blocks the T790M pathway, which is the most common resistance mechanism for patients treated with first and second generation EGFR inhibitors.”

Previous results from the FLAURA trial showed osimertinib (Tagrisso, AstraZeneca), a third-generation, irreversible EGFR TKI that targets EGFR-sensitizing and EGFR T790M resistance mutations, significantly improved PFS among this patient population compared with gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva; Astellas Oncology, Genentech).

The final OS analysis, with OS data at 58% maturity, included 556 treatment-naive patients with exon 19 deletion or L858R EGFR-mutated advanced NSCLC who were randomly assigned 80 mg once-daily osimertinib (n = 279) or a comparator EGFR TKI (n = 277), including 250 mg once-daily gefitinib or 150 mg once-daily erlotinib.

One-quarter (n = 70) of patients in the comparator group switched to osimertinib during the study.

Median follow up was 35.8 months for the osimertinib group and 27 months for the comparator group.

Results showed significantly longer median OS among patients who received osimertinib vs. a comparator EGFR TKI (38.6 months vs. 31.8 months; HR = 0.79; 95% CI, 0.64-0.99).

Osimertinib-treated patients were more likely to be alive at 12 months (89% vs. 83%), 24 months (74% vs. 59%), and 36 months (54% vs. 44%).

Adverse events led to treatment discontinuation by 15% of patients in the osimertinib group and 18% of patients in the comparator group.

The safety profile appeared consistent with previous results.

“[This study] showed a statistically significant and a clinically beneficial OS result in front-line treatment of stage IV EGFR-mutated NSCLC,” Ramalingam said. “I will also point out that osimertinib is the first TKI to show improvement in OS over another TKI in the treatment of advanced-stage cancer.” – by John DeRosier

Reference:

Ramalingam SS, et al. Abstract LBA5_PR; Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

Disclosures: AstraZeneca funded this study. Ramalingam reports honoraria, consultant roles or research funding from Advaxis, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo Oncology, Merck, Takeda and Tesaro. Please see the abstract for all other authors’ relevant financial disclosures.

BARCELONA, Spain — Osimertinib significantly extended OS compared with standard epidermal growth factor receptor tyrosine kinase inhibitors as front-line treatment for EGFR-mutated advanced non-small cell lung cancer, according to late-breaking results of the randomized phase 3 FLAURA study presented at European Society for Medical Oncology Congress.

“Osimertinib is very different than all the other EGFR inhibitors,” Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University, said during his presentation. “It’s highly selective and has a much better safety profile. It also has a much higher penetration in the brain and, therefore, is able to create responses in 70% to 90% of patients with brain metastases, which is a common problem for EGFR lung cancer. It also blocks the T790M pathway, which is the most common resistance mechanism for patients treated with first and second generation EGFR inhibitors.”

Previous results from the FLAURA trial showed osimertinib (Tagrisso, AstraZeneca), a third-generation, irreversible EGFR TKI that targets EGFR-sensitizing and EGFR T790M resistance mutations, significantly improved PFS among this patient population compared with gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva; Astellas Oncology, Genentech).

The final OS analysis, with OS data at 58% maturity, included 556 treatment-naive patients with exon 19 deletion or L858R EGFR-mutated advanced NSCLC who were randomly assigned 80 mg once-daily osimertinib (n = 279) or a comparator EGFR TKI (n = 277), including 250 mg once-daily gefitinib or 150 mg once-daily erlotinib.

One-quarter (n = 70) of patients in the comparator group switched to osimertinib during the study.

Median follow up was 35.8 months for the osimertinib group and 27 months for the comparator group.

Results showed significantly longer median OS among patients who received osimertinib vs. a comparator EGFR TKI (38.6 months vs. 31.8 months; HR = 0.79; 95% CI, 0.64-0.99).

Osimertinib-treated patients were more likely to be alive at 12 months (89% vs. 83%), 24 months (74% vs. 59%), and 36 months (54% vs. 44%).

Adverse events led to treatment discontinuation by 15% of patients in the osimertinib group and 18% of patients in the comparator group.

The safety profile appeared consistent with previous results.

“[This study] showed a statistically significant and a clinically beneficial OS result in front-line treatment of stage IV EGFR-mutated NSCLC,” Ramalingam said. “I will also point out that osimertinib is the first TKI to show improvement in OS over another TKI in the treatment of advanced-stage cancer.” – by John DeRosier

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Reference:

Ramalingam SS, et al. Abstract LBA5_PR; Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

Disclosures: AstraZeneca funded this study. Ramalingam reports honoraria, consultant roles or research funding from Advaxis, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo Oncology, Merck, Takeda and Tesaro. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Nicholas Rohs

    Nicholas Rohs

    I consider this practice-reaffirming data. In my opinion, osimertinib had already proven itself a preferred first-line option with the known PFS benefit, good brain penetration and favorable tolerance. To have the OS benefit just solidifies that for me. These data also come with a 47% crossover rate among patients receiving subsequent therapy. It’s also impressive that 22% of patients are still on osimertinib at 3 years. We can't ignore the large cost difference between osimertinib and first- or second-generation TKIs, but with approximately one-third of patients in each arm not receiving subsequent therapy, I think it makes sense to lead with the most effective and tolerated therapy. FLAURA also highlights the really diverse landscape of resistance mechanisms after osimertinib therapy, many of which are actionable. We’re seeing very varied subtypes of resistance that may be amenable to completely different types of targeted therapy or otherwise confirming the need for chemotherapy. It highlights the need for re-genotyping these patients either via liquid or tissue biopsy at progression, and to design clinical trials to evaluate the best way to approach these patients with either sequential or concurrent targeted therapies. However, I think the two next data sets I am most interested in seeing is osimertinib in combination with anti-angiogenesis antibodies or chemotherapy.  Given the data we have seen with other TKIs, I believe this could be practice changing, but we will have to see what the cost in side effect profile will be.

    • Nicholas Rohs, MD
    • Mount Sinai

    Disclosures: Rohs reports a consultant role with AstraZeneca.

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