Osimertinib Improves Progression-free Survival in Patients with EGFR Mutated Lung Cancer

LUGANO-MADRID – Osimertinib improves progression-free survival by 54% compared to standard first line therapy in patients with EGFR mutated non-small-cell lung cancer (NSCLC), according to late-breaking results from the FLAURA trial presented today at the ESMO 2017 Congress in Madrid. (1)

EGFR mutations are present in around 15% of NSCLC in Western populations, rising to 35% in Asian populations. EGFR inhibitors are superior to chemotherapy in the first line treatment of these patients. However, despite high response rates and good progression-free survival, patients invariably develop resistance to drugs such as erlotinib and gefitinib. In the majority of patients this resistance is mediated by a T790M mutation.

“We hypothesised that a drug which targets EGFR sensitising mutations and the T790M resistance mutation would be associated with a better outcome,” said principal investigator Professor Suresh Ramalingam, MD, Deputy Director, Winship Cancer Institute of Emory University, Atlanta, Georgia, US.

Osimertinib is a third generation EGFR-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR and T790M resistance mutations. A preliminary study in 60 treatment naive patients with EGFR mutations found that the median progression-free survival with osimertinib was 20.5 months, which was almost two-fold higher than results achieved with erlotinib or gefitinib.

FLAURA was a randomised phase III clinical trial comparing osimertinib to standard of care erlotinib or gefitinib as first line therapy in NSCLC patients with EGFR exon 19 or 21 mutations. The primary endpoint was progression-free survival. A total of 556 patients from Asia, Europe, and North America were randomised 1:1 to treatment with osimertinib or standard of care.

The median progression-free survival was 18.9 months with osimertinib compared to 10.2 months for the standard therapy, with a hazard ratio of 0.46 (95% confidence interval, 0.37–0.57; p<0.0001). The benefit in progression-free survival was consistent across all subgroups, including patients with and without brain metastases at the start of the study.

The median duration of response was two-fold higher for patients treated with osimertinib (17.2 months) versus standard of care (8.5 months). The overall response rate was 80% with osimertinib compared to 76% with standard of care treatment.

Overall survival appeared to favour osimertinib with a hazard ratio of 0.63 although this was not statistically significant at the interim overall survival analysis (25% maturity). (2) Median overall survival was not reached. The incidence of grade 3 or higher toxicities was lower for osimertinib (34%) than the standard treatment (45%).

Ramalingam said: “Osimertinib was clearly superior to standard first line treatment in patients with EGFR mutated NSCLC. 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.”

Regarding toxicities, Ramalingam said: “The safety profile of osimertinib was more favourable despite longer treatment duration (16.2 months) compared to standard of care (11.5 months).”

Commenting on the results for ESMO, Dr Enriqueta Felip, Head, Thoracic and H&N Cancer Group, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, said: “Osimertinib reduced the risk of cancer progression by 54% compared with standard of care and extended the median time to progression by about nine months. The drug was well tolerated and it has activity in the brain. Based on these results, osimertinib should be considered a new first line treatment option for patients with EGFR mutations.”

“Overall survival data is not yet mature and there is a clear need to continue follow-up to see if those treated with osimertinib live longer,” she added.

Regarding the need for further research, Felip said: “More data is needed on the mechanisms of acquired resistance in patients treated with osimertinib in the first line setting.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

1. Abstract LBA2_PR ‘Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA’ will be presented by Dr Suresh Ramalingam during Presidential Symposium I on Saturday 9 September 2017, 16:30 to 18:00 (CEST) in the Madrid Auditorium.
2. The p value for overall survival (OS) was p=0.0068. This was not statistically significant because a p value of 0.0015 was required for statistical significance at the current OS maturity.

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Abstract LBA2_PR

Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA

S. Ramalingam¹, T. Reungwetwattana², B. Chewaskulyong³, A. Dechaphunkul⁴, K.H. Lee⁵, F. Imamura⁶, N. Nogami⁷, Y. Ohe⁸, Y. Cheng⁹, B.C. Cho¹⁰, E.K. Cho¹¹, J.F. Vansteenkiste¹², P.J. Voon¹³, C. Zhou¹⁴, J. Gray¹⁵, R. Hodge¹⁶, Y. Rukazenkov¹⁷, J-C. Soria^18 
1Winship Cancer Institute, Emory University, Atlanta, GA, USA, ²Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, ³Oncology Unit, Department of Medicine, Chiang Mai University, Chiang Mai, Thailand, ⁴Internal Medicine, Division of Medical Oncology, Prince of Songkla University, Hat-Yai, Thailand, ⁵Division of Medical Oncology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea, ⁶Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan, ⁷Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan, ⁸Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan, ⁹Medical Oncology, Jilin Cancer Hospital, Jilin, China, ¹⁰Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Yonsei, Republic of Korea, ¹¹Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Inchon, Republic of Korea, ¹²Respiratory Oncology Unit (Pulmonology), University Hospital KU Leuven, Leuven, Belgium, ¹³Radiotherapy and Oncology, Hospital Umum Sarawak, Kuching, Malaysia, ¹⁴Department of Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China, ¹⁵Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA, ¹⁶Biostatistics and Informatics, AstraZeneca, Cambridge, UK, ¹⁷Research and Development, AstraZeneca, Cambridge, UK, ¹⁸Department of Drug Development, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif, France

Background: Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. Pre- and early clinical data suggest osimertinib may also be effective as initial therapy for EGFRm advanced NSCLC. FLAURA (NCT02296125) is a PhIII, double-blind, randomised study assessing efficacy and safety of osimertinib vs SoC EGFR-TKI in first-line pts with EGFRm advanced NSCLC.

Methods: Eligible pts: ≥18 years, no prior EGFR-TKI/systemic anti-cancer therapy for advanced disease, with Ex19del/L858R EGFRm advanced NSCLC. Neurologically stable pts with CNS mets were allowed, provided definitive treatment/steroids were completed for ≥2 weeks. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Primary endpoint: progression-free survival (PFS) by RECIST v1.1, by investigator. Data cut-off: 12 June 2017.

Results: Globally, 556 pts were randomised to treatment. Baseline characteristics were balanced across arms (osimertinib/SoC): female 64/62%; Asian 62/62%, Ex19del 57/56%, L858R 35/32%, CNS mets 19/23%.

* Median PFS with 95% confidence intervals calculated from Kaplan Meier method. ^†A p-value of 0.0015 was required for statistical significance at the current OS maturity. Final OS analysis will be completed at approximately 60% maturity.

PFS benefit was consistent across all subgroups, including pts with/without CNS mets at study entry. Median total treatment duration (range): 16.2 (0.1–27.4) months with osimertinib; 11.5 (0–26.2) with SoC. All causality adverse events (AEs), by investigator: osimertinib, 98% (Gr ≥3, 34%); SoC, 98% (Gr ≥3, 45%). AEs leading to discontinuation: osimertinib, 13%; SoC, 18%. Most common all causality AEs with osimertinib: diarrhoea (58% [Gr ≥3, 2%]), dry skin (32% [<1%]); SoC: diarrhoea (57% [3%]), dermatitis acneiform (48% [5%]).

Conclusions: Osimertinib demonstrated a superior risk/benefit over SoC as first-line therapy in pts with advanced EGFRm NSCLC.

Clinical trial identification: NCT02296125

Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca

Disclosure:S. Ramalingam: Advisory Board Meeting for: Astra Zeneca, Bristol-Myers Squibb, Genentech, Boehringer Ingelheim.
F. Imamura: Research fund and honoraria from AstraZeneca.
N. Nogami: Funding from Astrazeneca.
Y. Ohe: Honorarium/ Consultant/ Expert Testimony/ Research Funding (Institution); AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer, Bayer, Pfizer, MSD, Taiho, Clovis, Sanofi, Novartis, Kyorin, Dainippon-Sumitomo, Merck.
J.F. Vansteenkiste: Grants/research support: AstraZeneca Honoraria/consultation fees: AstraZeneca, Novartis, MSD, Boehringer Ingelheim, Eli-Lilly, Roche.
C. Zhou: Lecture honorarium: Eli Lily, AstraZeneca, Roche, Pfizer, Sanofi, Boehringer Ingelheim, Henrui Advisory Board: Roche, Boehringer Ingelheim, AstraZeneca.
J. Gray: Consultant/Advisory Boards: AstraZeneca, Celgene, Eli Lilly, Janssen, Boehringer-Ingelheim, Clovis. Research Funding: Array, AstraZeneca, Merck, Trovagene.
R. Hodge, Y. Rukazenkov: Employee of, and shareholder in, AstraZeneca.
J-C. Soria: Consultancy fees for AstraZeneca, Roche.
All other authors have declared no conflicts of interest.