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Plasma genotyping to predict treatment benefit in patients with NSCLC

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GENEVA, Switzerland, 15 April 2016 – The benefit of plasma genotyping to predict treatment benefit in patients with non-small-cell lung cancer (NSCLC) is confirmed in three studies presented today at the European Lung Cancer Conference (ELCC) 2016 in Geneva, Switzerland.1 Researchers however warned that plasma tests are unlikely to fully replace tissue biopsies.

Patients with NSCLC are tested for epidermal growth factor receptor (EGFR) mutations which indicate their suitability for targeted EGFR tyrosine kinase inhibitor (TKI) therapy. Tissue biopsies are the gold standard but are not possible in around 20% of NSCLC patients. Plasma is a potential alternative for EGFR mutation analysis through extraction of circulating tumour DNA (ctDNA).

The primary results of the ASSESS trial, presented at ELCC 20152, demonstrated that ctDNA is suitable and feasible for EGFR mutation analysis in real-world practice. The analysis presented today examined whether patient disease or demographic characteristics influenced the detection of EGFR mutations in plasma. There was increased sensitivity of EGFR mutation detection in plasma associated with increasing number and severity of metastases. EGFR mutation detection in plasma was also significantly higher in patients aged less than 65 years old compared with older patients. These findings were independently confirmed by the companion IGNITE study.

"Further studies are required to confirm these findings and identify potential underlying biological mechanisms – the age finding in particular is interesting," said Dr Nicola Normanno, chief of the Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy, author of one of the studies. "The increased ability to detect EGFR mutations in plasma from patients with a higher number of organs with metastases makes sense biologically, as these patients have higher tumour burden and we could expect more ctDNA to be released in the blood. The same could also be true for patients that have metastases to organs further away from the lungs (M1b)."

He continued: "The link with age is more difficult to understand. Evidence suggests that the biological features of certain tumours change with age. However, the specific biological mechanisms underlying the correlation between the success of plasma analysis and age will need to be investigated further."

Commenting on the implications of the findings for clinical practice, Normanno said: "If plasma testing is more reliable for some patients with certain characteristics, this may have implications in the way that we conduct mutation testing for patients with NSCLC, and ultimately impact upon treatment decisions. Our data suggests that for the majority of patients with metastatic disease a plasma test could be sufficient to determine EGFR mutation status particularly when a robust and reliable methodology is used. Due to the low sensitivity of plasma genotyping (60-70%), a biopsy will still be recommended in plasma negative cases."

Also presented today at the ELCC Conference is an analysis from the phase I AURA trial of osimertinib, a third generation T790M targeting EGFR inhibitor. Eligibility for the drug is currently determined through a positive biopsy test for T790M. The study evaluated the effectiveness of osimertinib, based on tumour results or plasma results, in patients with acquired resistance to first-line EGFR inhibitors who had the T790M mutation L858R or exon 19 deletion.

Positive T790M biopsies correlated with high response rates and long progression free survival (PFS), while those with T790M negative tumours had a low response rate and modest PFS. Patients with T790M positive plasma had high response rates and long PFS. But those with T790M negative plasma had mixed outcomes.

"The first conclusion is that a non-invasive blood test appears to have the ability to find T790M positive patients very effectively," said lead author Dr Geoffrey Oxnard, a thoracic cancer physician at the Dana-Farber Cancer Institute, Boston, US. "But the blood test only has a sensitivity of 70 or 80% so there are false negatives. In other words, if you have a negative result in the blood test it may be that the mutation was present but not detected."

Oxnard continued: "When we studied the tumour results on patients who were T790M negative in the blood we could differentiate those who do better or worse on osimertinib, meaning that a biopsy is an effective fall back to clarify who should and who shouldn't get the drug. We conclude that a two stage approach is needed, starting with the blood test. Patients who test positive for T790M on the blood test can receive osimertinib. Those who test negative should have a biopsy test to clarify their T790M status."

A surprising result was that some patients were T790M negative in the tumour but T790M positive in the blood test. "This suggests that the resistant mutation might be present in just a subset of the cells, or only in some sites of the tumour," said Oxnard. "A biopsy may not capture the cancer's resistance across all sites of disease but a blood test does. Patients with this apparent false negative tissue result did not respond as well to osimertinib as patients with a positive test. It could be that if T790M is only in a subset of resistance cells

there may be other resistance mechanisms hidden in the tumour which reduce the effect of the drug." A second study of osimertinib, limited to patients with an EGFR T790M mutation who had failed a previous EGFR inhibitor, found a high concordance between plasma positive and tissue positive tests. Patients with either positive test responded to the drug to a similar degree.

"The data demonstrates that the responses are equivalent, which hopefully will ultimately lead us to a point where we no longer have to do a biopsy in every patient," said one of the study authors Pasi Jänne, professor of medicine at the Dana-Farber Cancer Institute, Boston, US. "I think we will see more and more plasma testing for genetic alterations in lung cancer, where we are trying to treat a genetically defined patient population."

He added: "Blood can be drawn on every patient whereas biopsies are not feasible in everybody, so that opens up the spectrum of patients who can be tested. With a blood test you can isolate and analyse the DNA much faster than you can do a biopsy so eligibility for treatment could be determined more quickly."

Commenting on the findings of the three studies presented today, Dr Sanjay Popat, consultant thoracic medical oncologist at the Royal Marsden Hospital in London, UK, said: "These studies confirm the potential clinical utility of using ctDNA EGFR genotyping in routine practice and give information on the magnitude of false negatives. We now need validation of ctDNA EGFR genotyping in real world settings to better understand how it can be delivered. Analyses from clinical trial datasets are usually done retrospective to patient accrual in the trial which is very different to a patient waiting for the result in real time."

But he added: "Plasma testing will not routinely replace tissue biopsy for mutation testing which should still be regarded as the gold standard. It would be a complementary test, and may be a replacement in some patients, for example those in whom a tissue biopsy is not possible."

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References

1) 134O_PR: Plasma ctDNA analysis for detection of EGFR T790M mutation in patients (pts) with EGFR mutation-positive advanced non-small cell lung cancer (aNSCLC). S. Jenkins, UK. Friday 15th April 2016 – 10:00-10:15 NSCLC targeted therapy and circulating biomarkers Room C 135O_PR: Plasma genotyping for predicting benefit from osimertinib in patients (pts) with advanced NSCLC. G. Oxnard, US. Friday 15th April 2016 10:15-10:30 NSCLC targeted therapy and circulating biomarkers Room C 58O_PR: Clinical and demographic features that influence EGFR mutation detection in plasma from patients (pts) with aNSCLC: The ASSESS experience. N. Normanno, Italy. Friday 15th April 2016 – 9:45-10:00 NSCLC targeted therapy and circulating biomarkers Room C

2) http://www.esmo.org/Conferences/Past-Conferences/ELCC-2015-Lung-Cancer/News-Press-Releases/DNA-Blood-Test-Detects-Lung-Cancer-Mutations

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 http://www.esmo.org

About International Association for the Study of Lung Cancer

The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated solely to the study of lung cancer. Founded in 1974, the association's membership includes more than 5,000 lung cancer specialists in over 100 countries. IASLC members promote the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer and thoracic malignancies. IASLC brings scientists, members of the medical community and the public together from all over the world to share best practices and discover new and better ways to eliminate the health threat of thoracic cancers. Membership is open to any physician, scientist, nurse or allied health professional interested in lung cancer and other thoracic malignancies, including patients, survivors, caregivers and advocates. Visit http://www.iaslc.org for more information and follow us on Twitter @IASLC

Abstract 134O_PR

Plasma ctDNA analysis for detection of EGFR T790M mutation in patients (pts) with EGFR mutation-positive advanced non-small cell lung cancer (aNSCLC)

S. Jenkins1, J. Yang2, S. Ramalingam3, K. Yu4, S. Patel5, S. Weston1, R. Lawrance6, M. Cantarini7, P. Jänne8, T. Mitsudomi9 1Personalised Healthcare and Biomarkers, AstraZeneca, Macclesfield, UK, 2Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 3Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA, 4Clinical Operations, Roche Molecular Systems, Inc., Pleasanton, CA, USA, 5Oncology Companion Diagnostics Unit, Personalised Healthcare and Biomarkers, AstraZeneca, Royston, UK, 6Biometrics and Informatics, AstraZeneca, Macclesfield, UK, 7Global Medicines Development, AstraZeneca, Macclesfield, UK,8Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 9Thoracic Surgery, Kinki University School of Medicine, Osaka, Japan

Background: Osimertinib is an irreversible EGFR-TKI that targets the T790M EGFR-TKI resistance mutation as well as common EGFR-TKI-sensitive mutant forms of EGFR. Pt selection for two single-arm Phase II registration studies (AURA extension, NCT01802632; AURA2, NCT02094261) was based on detection of the T790M mutation using the cobas® EGFR Mutation Test for use with formalin-fixed, paraffin-embedded tissue (cobas tissue test). Plasma samples were collected from screened pts and analysed retrospectively using the cobas® EGFR Mutation Test v2.0 (cobas plasma test; plasma claims not yet available in the US). Next generation sequencing (NGS) analysis was also performed on these plasma samples.

Methods: Agreement (positive and negative) between the cobas tissue test and the cobas plasma test, for detection of EGFR mutations, was calculated in the pooled Phase II analysis set. Agreement between the cobas plasma test and NGS analysis of plasma was calculated using samples from AURA2 pts.

Results: In the pooled analysis, the positive percentage agreement (PPA) and negative percentage agreement (NPA) between the cobas tissue test and plasma test were 61.4% and 78.6%, respectively for detection of T790M. In AURA2, the PPA and NPA between the cobas plasma test and NGS analysis of plasma were 91.5% and 91.1%, respectively. As of May 2015, comparable ORR was observed in the subset of pts with a positive T790M plasma test as for all patients selected using the cobas tissue test. Common sensitising mutations were also analysed. PPA and NPA between the cobas tissue test and plasma test were 75.6% and 98.1%, respectively, for the L858R mutation, and 85.1% and 98.0%, respectively, for exon 19 deletions.

Conclusions: Data indicate that approximately 60% of pts with T790M positive NSCLC, the biomarker against which treatment with osimertinib is targeted, could have avoided an invasive biopsy by use of a plasma test. However, for EGFR-TKI-resistant pts, without detectable T790M in plasma, a tissue-based test is advised to address the potential for false negative results from the plasma test. These results indicate the utility of both plasma- and tissue-based tests in the diagnostic setting.

Clinical trial identification: NCT01802632 and NCT02094261 (Release dates 25 February 2013 and 17 March 2014) Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca

Disclosure: S. Jenkins, S. Patel, S. Weston, R. Lawrance, M. Cantarini: Employee and shareholder: AstraZeneca J. Yang: Advisory boards: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, AstraZeneca, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene. S. Ramalingam: Consultancy fees: AstraZeneca, Boehringer Ingelheim, Celgene, Genentech, Novartis, Lilly, Merck, Bristol-Myers Squibb. K. Yu: Employee: Roche Molecular Systems, Inc. P. Jänne: Consultancy fees: AstraZeneca, Pfizer, Roche Research support: AstraZeneca, Astellas Pharmaceuticals Stock ownership: Gatekeeper Pharmaceuticals Other: Post marketing royalties on DFCI owned patent on EGFR mutations licensed to Lab Corp. T. Mitsudomi: Advisory board: AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer Honoraria: AstraZeneca, Chugai, Boehringer-Ingelheim, Pfizer Research fund: Boehringer-Ingelheim, Chugai, Pfizer.

Keywords: osimertinib, AZD9291, T790M, EGFR-TKI

Abstract 135O_PR

Plasma genotyping for predicting benefit from osimertinib in patients (pts) with advanced NSCLC

G.R. Oxnard1, K.S. Thress2, R.S. Alden1, R. Lawrance3, C.P. Paweletz4, M. Cantarini5, C. Barrett2, J. Yang6, P. Jänne1 1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 2IMED Oncology Translational Sciences, AstraZeneca, Waltham, MA, USA, 3Biometrics and Informatics, AstraZeneca, Macclesfield, UK, 4Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,5Global Medicines Development, AstraZeneca, Macclesfield, UK, 6Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Background: Osimertinib (AZD9291) is a selective, irreversible EGFR-TKI recently approved by the FDA for the treatment of pts with EGFR T790M positive metastatic NSCLC who have progressed on/after EGFR-TKI therapy. In the Phase I AURA trial (NCT01802632), plasma was collected for analysis to determine whether genotyping of plasma DNA could identify pts who gain clinical benefit from osimertinib.

Methods: Pre-treated NSCLC pts from the trial (20 mg-240 mg dosing cohorts) were included if they had a common EGFR-sensitising (sens) mutation and central-lab confirmed tumour and/or exploratory plasma genotyping (BEAMing) T790M result (n=308). Objective response rate (ORR) and median progression-free survival in months (mPFS) were assessed, dividing pts based on either tumour or plasma genotyping. Data cut-off was 1 May 2015.

Results: In 216 pts with both plasma and tumour genotyping results, concordance for T790M was 70%. Concordance improved to 80% limiting to 137 cases with a sens mutation detected in plasma. Outcomes were robust in 179 pts T790M+ in tumour (62% ORR, 9.7 mPFS) or in 167 pts T790M+ in plasma (63% ORR, 9.7 mPFS). Outcomes were unexpectedly favourable in 104 pts T790M- in plasma (46% ORR, 8.2 mPFS) compared with 58 pts T790M- in tumour (26% ORR, 3.4 mPFS). Using detection of the plasma sens mutation as a control, plasma T790M- cases could be differentiated into a 'T790M undetected' group (T790M-/sens+) with poorer outcomes (38% ORR, 4.4 mPFS) and a 'plasma uninformative' group (T790M-/sens-) with better outcomes (64% ORR, 15.2 mPFS).

Conclusions: Plasma genotyping can identify pts with T790M resistance, therefore avoiding an invasive biopsy for tumour T790M. In contrast, the ORR observed in pts with T790M- plasma genotyping likely reflects false negative results. For EGFR-TKI-resistant pts without detectable T790M in plasma, a tissue-based test is therefore advised to identify T790M+ candidates for osimertinib therapy. Testing for a plasma sens mutation may serve as a control to inform the likelihood of falsely negative plasma T790M results. These data support the investigation of a new paradigm for resistance management, with rapid plasma genotyping as a test option prior to undergoing a biopsy for T790M.

Clinical trial identification: NCT01802632 (Release date 23 February 2013)

Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca

Disclosure: G.R. Oxnard: Advisory board/consulting: AstraZeneca, Boehringer-Ingelheim, Clovis, Genentech, Sysmex. K.S. Thress, R. Lawrance, M. Cantarini, C. Barrett: Employee and shareholder: AstraZeneca. C.P. Paweletz: Honoraria: BioRad, Clovis Oncology. J. Yang: Advisory boards: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Astrazeneca, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene. P. Jänne: Consultancy fees: AstraZeneca, Pfizer, Roche Research support: AstraZeneca, Astellas Pharmaceuticals Stock ownership: Gatekeeper Pharmaceuticals Other: Post marketing royalties on DFCI owned patent on EGFR mutations licensed to Lab Corp. All other authors have declared no conflicts of interest.

Keywords: osimertinib, EGFR T790M, cell-free DNA, plasma genotyping

Abstract 58O_PR

Clinical and demographic features that influence EGFR mutation detection in plasma from patients (pts) with aNSCLC: The ASSESS experience

N. Normanno1, H. Brown2, V. Haddad3, M. Ratcliffe2, R. McCormack2, S. Tjulandin4, K. Hagiwara5, B. Han6, M. Reck7 1Dept. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori – I.R.C.C.S – Fondazione Pascale, Naples, Italy, 2Personalised Healthcare and Biomarkers, AstraZeneca, Macclesfield, UK, 3Biostatistics & Information Sciences, AstraZeneca, Royston, UK, 4Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Centre, Moscow, Russian Federation, 5Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan, 6Department of Respiratory Medicine, Shanghai Chest Hospital, Jiao Tong University, Shanghai, China,7Department of Thoracic Oncology, LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), Grosshansdorf, Germany Background: Mutation detection from circulating free tumour-derived DNA (ctDNA) in plasma offers a minimally invasive alternative when biopsy is not possible. Despite continuous improvement in detection methods, the sensitivity of EGFR mutation-positive detection remains lower in plasma compared with tumour tissue. The large non-interventional study ASSESS (NCT01785888) offers the ability to investigate if clinical characteristics of disease and/or pt demographics influence the ability to detect mutations in plasma.

Methods: The accuracy of EGFR mutation-positive detection in plasma compared with tumour (sensitivity, specificity, concordance) was reported and analysed by the Coughlin method for the following covariates: gender, age, ethnicity, smoking status, disease stage, World Health Organization (WHO) performance status (PS), time since diagnosis, metastases and number of organs with metastases, in 1162 pts from Europe and Japan.

Results: Of those pts with EGFR mutation-positive tumours, EGFR mutation-positive detection in plasma was higher in pts aged

Conclusions: These data suggest that pt age significantly influences the ability to detect EGFR mutation-positive from plasma; detection is also more likely when pts have a higher metastatic tumour burden. Further studies are required to confirm these findings/identify underlying biological mechanisms.

Characteristic Subgroup Tumour and plasma evaluable N (%) EGFR mutation-positive by tumour Sensitivity (95% CI) Specificity (95% CI) Interaction with tumour tissue p-value

Total – 1162 189 46.03 (38.8, 53.4) 97.43 (96.2, 98.3) – Age >=65 680 (58.52) 126 37.3 (28.9, 46.4) 96.39 (94.5, 97.8) =3 195 (16.78) 36 69.44 (51.9, 83.7) 96.23 (92.0, 98.6) 0.2114 Time since diagnosis 0.66 months 579 (50.04) 96 46.88 (36.6, 57.3) 97.52 (95.7, 98.7) 0.7023

Concordance >79%. NC, non-calculable Clinical trial identification: NCT01785888

Legal entity responsible for the study: AstraZeneca

Funding: AstraZeneca

Disclosure: N. Normanno: Received grants/research support from, and been a Consultant for, AstraZeneca, Qiagen and Roche Diagnostics. H. Brown, V. Haddad, M. Ratcliffe, R. McCormack: Employee of AstraZeneca and holds shares in AstraZeneca. S. Tjulandin: Member of the speakers' bureau for AstraZeneca, Pfizer and Sanofi-Aventis. K. Hagiwara: Member of the speakers' bureau for AstraZeneca, Chugai Pharmaceuticals and Pfizer and holds a patent with LSI Medience. B. Han: Member of the speakers' bureau for AstraZeneca and Roche and a Consultant for AstraZeneca and Pfizer. M. Reck: Member of speakers' bureau for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Hoffmann-La Roche, Lilly and Pfizer; Consultant for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Hoffmann-La Roche, Lilly, MSD and Pfizer.

Keywords: plasma, ctDNA, EGFR mutation, NSCLC

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