Osimertinib given as First-Line Treatment May Alter Biology of EGFR Mutated Non-Small-Cell Lung Cancer

Presentation at the European Lung Cancer Conference (ELCC)

GENEVA, Switzerland, 14 April 2016 – The third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is effective in the first-line treatment of EGFR mutated non-small-cell lung cancer (NSCLC), according to a late-breaking abstract presented at the European Lung Cancer Conference (ELCC) 2016 in Geneva, Switzerland.¹ A second late-breaking abstract confirms the drug’s effectiveness in patients with the T790M mutation.

EGFR inhibition is the standard of care for NSCLC patients with EGFR activating mutations but nearly 50 to 60% develop resistance by developing a T790M mutation. Osimertinib is a potent inhibitor of the original EGFR mutations (exon 19 and exon 21) and the T790M. The study presented today investigated whether the use of osimertinib as first-line therapy for EGFR mutation positive NSCLC would result in favourable efficacy due to delayed T790M mediated resistance.

The study included 60 patients from two phase I expansion cohorts of the AURA trial that had locally advanced or metastatic EGFR mutated NSCLC. Thirty patients received 80 mg a day and 30 received 160 mg a day in the first-line setting. The median follow-up was 16.6 months.

The overall response rate was 77%. Median progression free survival (PFS) was 19.3 months for the 160 mg dose and has not yet been reached for the 80 mg dose. Median duration of response has not been reached. The drug was well tolerated with few adverse events, particularly at the approved 80 mg dose, where just 10% of patients required dose reduction to manage toxicities.

Prof Suresh Ramalingam, professor of haematology and medical oncology at Emory School of Medicine and deputy director of Winship Cancer Institute, Atlanta, Georgia, US, study author, said: “The overall response rate was among the best reported for first-line therapy of EGFR mutated NSCLC. The PFS results are exciting, well exceeding the historical control rates of 10 to 13 months with first or second generation drugs. Many of the patients have not had disease progression on the study and are still benefitting from treatment.”

Initial data suggests that patients who had disease progression did not have T790M mutation as the mechanism of resistance. “That tells us that we may be changing the biology of the disease with the use of first-line osimertinib,” said Ramalingam.

The findings will be further investigated in a phase III clinical trial in more than 500 patients comparing osimertinib to either erlotinib or gefitinib for front-line therapy. Results are expected in up to 18 months.

Commenting on the findings, Dr Enriqueta Felip, a medical oncologist at Vall d`Hebron University Hospital in Barcelona, Spain, not involved in the study, said: “The results with osimertinib in the first-line look promising. The ongoing randomised trial will define the role of osimertinib in the treatment of EGFR mutated patients who are treatment-naive.”

A second late-breaking abstract presented today reveals the mature results of two AURA studies that investigated osimertinib at the recommended 80 mg dose in EGFR mutated and T790M positive NSCLC patients who had progressed on previous EGFR TKI therapy. Response rates were 71% in the phase I dose expansion cohort of 63 patients and 66% in pooled results from two phase II studies of 411 patients. PFS was 9.7 and 11 months for the phase I cohort and phase II studies, respectively.

“We found a response rate and PFS that were consistent between the two studies and with earlier reports from the AURA studies,” said lead author Prof James Yang, director of the Department of Oncology and Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. “Adverse events such as interstitial lung disease and QT prolongation² were infrequent, with similar rates to our previous analyses.”

He concluded: “In this mature pooled analysis for T790M positive EGFR mutant patients who have progressed on prior EGFR TKI, we were able to show a high overall response rate, encouraging duration of response and good tolerability profile. PFS was long compared to the four to five months provided by chemotherapy. This is good news for patients with EGFR mutations who have failed EGFR TKI, for whom osimertinib is now standard of care. Molecular diagnosis for T790M must now be the standard as well.”

Commenting on the results, Felip said: “The study confirms the good results with osimertinib in this setting. Nowadays, in patients with EGFR mutation who progress after an EGFR TKI, there is a clear need for T790M testing since we now have a highly active agent, osimertinib, for this situation.”

Osimertinib recently received accelerated approval as the first indicated treatment for patients with EGFR T790M mutation positive metastatic NSCLC in the US, EU and Japan.

-END-

References
1. LBA1_PR: Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. S. Ramalingam, US. Thursday 14^th April 2016 – 15:30-15:45 New strategies for EGFR addicted NSCLC Room B
LBA2_PR: Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J. Yang, Taiwan. Thursday 14^th April 2016 – 15:45-16:00 New strategies for EGFR addicted NSCLC Room B
2. The QT interval is a measure of the electrical cycle of the heart. A prolonged QT interval indicates a risk of abnormal heart rhythms.

Notes to Editors

Disclaimer
Information contained in this press release was provided by the lecture authors. It does not necessarily express ESMO’s or IASLC’s point of view.

About the European Lung Cancer Conference (ELCC) 2016
The European Lung Cancer Conference (ELCC) has become the reference event in Europe for professionals treating lung cancers. It is organized by the European Society for Medical Oncology and the International Association for the Study of Lung Cancer, in collaboration with the partner societies ESTRO, ESTS and ETOP.

ELCC provides a comprehensive multidisciplinary overview of the latest as well as of the state-of-the-art knowledge in thoracic malignancies, covering different aspects such as prevention, screening, diagnosis, treatment modalities and the results of basic, clinical and translational research, presented by top international academic experts. Around 2,000 attendees are expected from throughout Europe and the rest of the world.

About the European Society for Medical Oncology
ESMO is the leading professional organisation for medical oncology. With more than 14,000 members representing oncology professionals from over 130 countries, ESMO is the society of reference for oncology education and information.

ESMO’s educational resources support an integrated, multi-professional approach to cancer care. We have European roots and a global reach: we welcome oncology professionals from around the world and we seek to erase boundaries in cancer care as we pursue our mission across oncology, worldwide.

To learn about ESMO, visit www.esmo.org

About the International Association for the Study of Lung Cancer
The International Association for the Study of Lung Cancer (IASLC) is the only global organisation dedicated to the study of lung cancer. Founded in 1974, the association’s membership includes more than 3,500 lung cancer specialists in 80 countries.

To learn more about IASLC please visit www.iaslc.org

Abstract LBA 1_PR

OSIMERTINIB AS FIRST-LINE TREATMENT FOR EGFR MUTATION-POSITIVE ADVANCED NSCLC: UPDATED EFFICACY AND SAFETY RESULTS FROM TWO PHASE I EXPANSION COHORTS

Ramalingam¹, J.C.-H. Yang², C.K. Lee³, T. Kurata⁴, D.-W. Kim⁵, T. John⁶, N. Nogami⁷, Y. Ohe⁸, P.A. Jänne⁹

¹Department Of Hematology And Medical Oncology, Winship Cancer Institute of Emory University, Atlanta/UNITED STATES OF AMERICA, ²Department Of Oncology, National Taiwan University Hospital, Taipei/TAIWAN, ³Medical Oncology, St George Hospital, Kogarah/AUSTRALIA, ⁴Department Of Thoracic Oncology, Kansai Medical University Hirakata Hospital, Osaka/JAPAN, ⁵Department Of Internal Medicine, Seoul National University Hospital, Seoul/KOREA, REPUBLIC OF, ⁶Medical Oncology, Austin Health/ Olivia Newton-John Cancer Research Institute, Heidelberg/AUSTRALIA, ⁷Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama/JAPAN, ⁸Department Of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa-City/JAPAN, ⁹Lowe Center For Thoracic Oncology, Dana Farber Cancer Institute, Boston/UNITED STATES OF AMERICA

Background: Osimertinib (AZD9291) is a potent, irreversible EGFR-TKI selective for EGFR‑TKI-sensitising (EGFRm) and T790M resistance mutations. We present updated efficacy and safety results from two Phase I expansion cohorts who received osimertinib 80 mg or 160 mg as first-line treatment for advanced EGFRm NSCLC in the AURA study (NCT01802632).
Methods: Treatment-naïve patients (pts) with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily. The objectives were to investigate the efficacy and safety of osimertinib in a first-line setting. EGFRm status was confirmed via local testing and / or central laboratory testing (cobas^® EGFR Mutation Test). Key eligibility criteria included measurable disease, a WHO performance status of 0 / 1 and acceptable organ function. Pts with stable asymptomatic brain metastases were eligible.
Results: Overall, 60 pts were enrolled at two dose levels (80 mg, n=30; 160 mg, n=30): 75% female; 72% Asian; 40% with EGFR exon 19 deletion, 42% L858R mutation; five pts were EGFR T790M positive by central test at entry. At the 4^th January 2016 data cut‑off, median follow‑up was 16.6 mths. The confirmed overall objective response rate (ORR) (95% CI) was 77% (64, 87). The ORR was 67% (47, 83) in the 80 mg cohort and 87% (69, 96) in the 160 mg cohort. Median duration of response was not reached (95% CI 12.5, not calculable [NC]) overall. Median progression-free survival (PFS) was 19.3 mths (95% CI 13.7, NC) overall, not yet reached in the 80 mg cohort (95% CI 12.3, NC) and 19.3 mths (95% CI 11.1, 19.3) in the 160 mg cohort. The proportion of pts progression free at 18 mths was 55% overall, 57% in the 80 mg cohort and 53% in the 160 mg cohort. The disease control rate was 97% overall (95% CI 88.5, 99.6). Dose reduction to manage adverse events (AEs) was required in 10% (3/30) and 47% (14/30) of pts at 80 mg and 160 mg, respectively. The most common AEs (% [Grade ≥3]) were diarrhoea (80 mg, 60% [0]; 160 mg, 87% [7%]), stomatitis (80 mg, 43% [0]; 160 mg, 50% [3%]) and paronychia (80 mg, 30% [0]; 160 mg, 53% [7%]).
Conclusions: First-line osimertinib for advanced EGFRm NSCLC results in a high ORR, promising PFS and manageable tolerability profile.
Clinical trial identification: NCT01802632 (25 February 2013)

Keywords: EGFR-TKI, AZD9291, osimertinib, first-line

Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca

Abstract LBA 2_PR

OSIMERTINIB (AZD9291) IN PRE-TREATED PTS WITH T790M-POSITIVE ADVANCED NSCLC: UPDATED PHASE 1 (P1) AND POOLED PHASE 2 (P2) RESULTS

Yang¹, S.S. Ramalingam², P.A. Jänne³, M. Cantarini⁴, T. Mitsudomi⁵

¹Department Of Oncology, National Taiwan University Hospital, Taipei/TAIWAN, ²Department Of Hematology And Medical Oncology, Winship Cancer Institute of Emory University, Atlanta/UNITED STATES OF AMERICA, ³Lowe Center For Thoracic Oncology, Dana Farber Cancer Institute, Boston/UNITED STATES OF AMERICA, ⁴Global Medicines Development, AstraZeneca, Macclesfield/UNITED KINGDOM,⁵Thoracic Surgery, Kinki University Faculty of Medicine, Osakasayama/JAPAN

Background: Osimertinib is a potent, oral, irreversible EGFR-TKI with efficacy in pts with EGFR-TKI sensitising (EGFRm) and T790M mutation positive advanced NSCLC. We present updated data from a P1 dose expansion cohort (AURA P1, NCT01802632) and a pre-planned pooled analysis of two P2 studies (AURA extension, NCT01802632 and AURA2, NCT02094261) that investigated osimertinib at the recommended 80 mg daily dose.
Methods: Pts with EGFRm and T790M-positive advanced NSCLC who had progressed following EGFR-TKI therapy received osimertinib 80 mg once daily. T790M-positive status was confirmed via central testing of biopsy samples (cobas® EGFR Mutation Test). Pts had measurable disease, WHO performance status 0 / 1 and acceptable organ function; stable brain metastases were allowed. Objective response rate (ORR) was the primary endpoint; duration of response (DoR) and progression-free survival (PFS) were secondary endpoints.
Results: Results are from a 4 Jan 2016 data cut-off for AURA P1 80mg treated T790M positive population and 1 Nov 2015 for AURA pooled P2. A total of 63 pts and 411 pts were assigned to treatment in AURA P1 (80 mg T790M positive population only) and AURA pooled P2, respectively. In AURA P1, investigator assessed ORR was 71% (43/61; 95% CI 57, 82), median DoR was 9.6 months (95% CI 7.7, 15.6) and median PFS was 9.7 months (95% CI 8.3, 13.6). In the AURA pooled P2, by blinded independent central review (BICR), ORR was 66% (262/397; 95% CI 61, 71), median DoR was 12.5 months (95% CI 11.1, not calculable), median PFS was 11.0 months (95% CI 9.6, 12.4) and the proportion of pts progression free at 12 months was 47.5% (95% CI 42.4, 52.5). In AURA P1 the most common causally-related adverse events (AEs) were rash grouped terms (37% [no Grade 3 (G3)]) and diarrhoea (35% [2%]). Rash grouped terms and diarrhoea were also the most common causally-related AEs in AURA pooled P2 (41% [G3 1%] and 38% [G3 1%], respectively).
Conclusions: In these updated analyses, the AURA pooled P2 results by BICR were found to confirm the findings of AURA P1. Osimertinib provides a high ORR, with encouraging DoR and PFS, and a manageable tolerability profile.
Clinical trial identification: Trial protocol number (NIH or European equivalent) and release date (where applicable): NCT01802632 (23 February 2013) and NCT02094261 (17 March 2014)

Keywords: osimertinib, T790M, EGFR-TKI, AZD9291

Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca