Front-line osimertinib improves overall survival in EGFR-mutation positive NSCLC

Barcelona, Spain, 28 September 2019 – First-line osimertinib significantly lengthens overall survival compared to older generation EGFR-TKIs in patients with Ex19del/L858R EGFR mutated advanced non-small cell lung cancer (NSCLC), according to late breaking results of the FLAURA trial presented at the ESMO Congress 2019 in Barcelona, Spain. (1,2)

The primary endpoint of progression free survival (PFS) was previously reported. (3) Survival data are now mature: the median overall survival with osimertinib was 38.6 months versus 31.8 months with first generation EGFR-TKIs, with a hazard ratio of 0.799 (p=0.0462). More than half (54%) of patients in the osimertinib group were alive at three years compared to 44% in the standard care group.

“The survival results are both statistically significant and clinically meaningful with first-line osimertinib for EGFR mutated patients,” said study author Prof Suresh Ramalingam, Winship Cancer Institute of Emory University, Atlanta, US. “This is the first time a TKI has proven to extend survival relative to another TKI in lung cancer therapy.”

Ramalingam noted that after disease progression, 31% of patients in the control group crossed over to the osimertinib arm, representing 47% of patients in the control group that received post-study therapy. “That is consistent with what we would expect in the real-world setting, since only about 50% of patients develop the T790M mutation and will be candidates for osimertinib,” he said.

Ramalingam concluded: “FLAURA met both its primary and key secondary endpoints and showed a favourable safety profile for osimertinib. The results further reinforce the clinical utility and superiority of osimertinib in the front-line setting. Based on these data, osimertinib should be the preferred front-line therapy for EGFR-mutated lung cancer patients.”

Commenting on the data, Dr Pilar Garrido, Ramon y Cajal University Hospital, Madrid, Spain said the results with osimertinib in the first-line setting are good news for patients. She added that the magnitude of benefit in overall survival is also relevant for the debate about the best sequence of treatment since osimertinib is the only TKI approved for second-line treatment in patients who develop resistance due to T790M. She said: “If osimertinib is used as first-line therapy, there is no TKI available when the disease progresses. Patients should be told that osimertinib offers an overall survival advantage and is well tolerated, but when the treatment fails, the only option is chemotherapy. Maximising the duration of chemotherapy-free treatment is important for many patients, but if we want to know the most effective sequence of TKIs we need studies specifically designed for that.”

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References

1 LBA5_PR ‘Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis’ will be presented by Suresh S. Ramalingam during the Presidential Symposium I on Saturday, 28 September, 16:30 to 18:20 (CEST) in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019

2 https://www.esmo.org/Conferences/ESMO-Congress-2019?hit=ehp

3 Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that targets both EGFR sensitising and EGFR T790M resistance mutations. It was approved for front-line use by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) after FLAURA met its primary endpoint of progression free survival. The primary results were presented at the ESMO Congress 2017 and subsequently published in the New England Journal of Medicine: Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378:113-125. doi:10.1056/NEJMoa1713137.

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LBA5_PR – Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis

S.S. Ramalingam1, J.E. Gray2, Y. Ohe3, B.C. Cho4, J. Vansteenkiste5, C. Zhou6, T. Reungwetwattana7, Y. Cheng8, B. Chewaskulyong9, R. Shah10, K.H. Lee11, P. Cheema12, M. Tiseo13, T. John14, M.C. Lin15, F. Imamura16, R. Hodge17, Y. Rukazenkov17, J.-C. Soria18, D. Planchard19

1 Hematology And Medical Oncology, Emory University, Winship Cancer Institute, Atlanta, United States of America, 2Thoracic Oncology, H. Lee Moffitt Cancer Center University of South Florida, Tampa, United States of America, 3Department Of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan, 4Medical Oncology Dept, Yonsei University, Seoul, Korea, Republic of, 5Oncology, University Hospital KU Leuven, Leuven, Belgium, 6Department Of Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China, 7Oncology, Ramathibodi Hospital, Bangkok, Thailand, 8Division Of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China, 9Oncology Unit, Department Of Medicine, Chiang Mai University, Chiang Mai, Thailand, 10Oncology, Kent Oncology Centre, Maidstone, United Kingdom, 11Medical Oncology, Chungbuk National University Hospital, Cheongju, Korea, Republic of, 12William Osler Health System, University of Toronto, Toronto, Canada, 13Medical Oncology Unit, University Hospital of Parma, Parma, Italy, 14Department Of Medical Oncology, Austin Health, Melbourne, Australia, 15Division Of Pulmonary And Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, 16Department Of Thoracic Oncology, Osaka International Cancer Institution, Osaka, Japan, 17Oncology R&d, AstraZeneca, Cambridge, United Kingdom, 18, Medimmune, Gaithersburg, United States of America, 19Medical Oncology, Gustave Roussy Institut de Cancerologie, Villejuif, France

Background: Osimertinib is a 3rd-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-mutated (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in NSCLC CNS metastases. In the Phase III FLAURA study (NCT02296125), osimertinib resulted in significant progression-free survival (PFS) benefit (primary endpoint; data cut off [DCO] 12 June 2017) over comparator EGFR-TKI (HR 0.46, p

Methods: Eligible patients (pts): greater than or equal to 18 years (Japan: greater than or equal to 20), treatment-naive with Ex19del/L858R EGFRm advanced NSCLC; WHO performance status 0-1. Pts with stable CNS metastases not requiring steroids for greater than or equal to 2 weeks were allowed. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or comparator EGFR-TKI (gefitinib 250 mg qd/erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover was allowed for pts in the comparator EGFR-TKI arm upon central confirmation of progression and T790M positivity. Primary endpoint: PFS by RECIST v1.1, per investigator. OS was a secondary endpoint. DCO 25 June 2019.

Results: Globally, 556 pts were randomised to osimertinib (n=279) or comparator EGFR-TKI (n=277). Per study protocol, 70 (25%) pts crossed over from comparator EGFR-TKI to osimertinib. Osimertinib significantly improved OS vs comparator EGFR-TKI. All causality AEs, per investigator: osimertinib, 98% (grade greater than or equal to 3, 42%); comparator EGFR-TKI, 98% (grade greater than or equal to 3, 47%). AEs leading to discontinuation: osimertinib, 15%; comparator EGFR-TKI, 18%. The safety profile appears consistent with previously reported data.

Conclusions: Osimertinib provided a statistically significant and clinically meaningful improvement in OS vs comparator EGFR-TKI in first-line pts with EGFRm advanced NSCLC.

Clinical trial identification: ClinicalTrials.gov NCT02296125

Editorial acknowledgement: We thank Natalie Griffiths, PhD, from iMed Comms, an Ashfield Company, who provided medical writing support funded by AstraZeneca.

Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca

Disclosure: S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda.

J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Celgene, Takeda; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb.

Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion, Kissei, Amgen, Janssen, ROXO.

B.C. Cho: Honoraria (institution), Advisory / Consultancy: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer-Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc..

J. Vansteenkiste: Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Roche; Speaker Bureau / Expert testimony: AstraZeneca, BMS, MSD, Roche.

C. Zhou: Honoraria (self): Roche, Eli Lilly, Boehringer Ingelheim, Merck, Hengrui and Qiru.

B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca.

R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca.

P. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Merck, Takeda, Novartis, Genomic Health, Pfizer.

M. Tiseo: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca.

T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer.

F. Imamura: Honoraria (self), Research grant / Funding (institution): AstraZeneca.

R. Hodge: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.

Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.

J. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Shareholder / Stockholder / Stock options: AstraZeneca, Gritstone; Full / Part-time employment: AstraZeneca.

D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Abbvie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck,Novartis, prIME Oncology, Pfizer.