Practice Update: Haematology & Oncology

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EXPERT OPINION DR FRED HIRSCH Current concepts in anti- angiogenic therapy for non–small cell lung cancer Dr Haffizulla speaks with Dr Fred Hirsch, CEO of the International Association for the Study of Lung Cancer and Professor of Medicine at the University of Colorado in Denver, at ASCO.

NEWS First-line therapy with nivolumab + ipilimumab has demonstrated clinical activity and manageable safety in advanced non- small-cell lung cancer First-line therapy with nivolumab plus ipilimumab has demonstrated clinical activity and manageable safety in advanced non-small-cell lung cancer in the phase 1 CheckMate 012 trial, results reported at ASCO show. D r Scott Joseph Antonia, of the H. Lee Moffitt Cancer Center & Research Institute in Florida, explained that nivolumab + ipilimumab is approved for advanced melanoma and has demonstrated clinical activity and manageable safety in various solid tumours. CheckMate 012 is a phase 1 study of nivolumab monotherapy or combined with other therapies first line for advanced non-small-cell lung cancer. Dr Antonia and colleagues reported updated results, in- cluding tumour growth dynamic modelling, derived from nivolumab + ipilimumab dosing schedules with a view to optimising safety and permitting synergistic activity. One hundred forty-eight patients with any non-small-cell lung cancer histology received nivolumab + ipilimumab across four dose cohorts. The primary objective was safety. Secondary objectives were objective response rate (Response Evaluation Criteria in Solid Tumors v1.1) and 24-week progression-free survival rate. Exploratory endpoints were overall survival and efficacy by tu- mour programmed death ligand 1 (PD-L1) expression. The effect of nivolumab + ipilimumab dosing was assessed by tumour growth dynamic modelling generated using individual tumour assessments. Model-predicted tumour shrinkage at week 12 was compared across cohorts. Treatment-related adverse events and select treatment-related adverse events were manageable. Treatment-related adverse events leading to discontinuation were comparable to nivolumab alone (10%), with no treatment-related deaths. Across cohorts, objective response rates ranged from 13–39%. Median duration of response was not reached. Responses were noted regardless of PD-L1 expression, with a higher magnitude of benefit in tumours that expressed PD-L1. Tumour growth dynamic modelling predicted enhanced tumour shrinkage for nivolumab 3 mg per kilogram of body weight + ipili- mumab 1 mg/kg schedules compared with nivolumab alone or any nivolumab 1 mg/kg – containing schedule. Based on integrated efficacy, safety, and tumour growth dynamic data, nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks was proposed for further evaluation. Dr Antonia concluded that first-line therapy with nivolumab + ipilimumab demonstrated clinical activity and a manageable safety profile.

Dr Haffizulla: Dr Hirsch, revisiting the idea of anti-angio- genic therapy in the adjuvant setting in lung cancer, what is your opinion of some of the data that were presented? Dr Hirsch: We saw the data from the large ECOG study with adjuvant chemotherapy and bevacizumab, and, in princi- ple, it is a negative trial. 1 The data were also presented at the IASLC World Conference on Lung Cancer last year in Denver. They have updated the data, but the update doesn’t change the main message. Angiogenesis in lung cancer is certainly a target. I think the problem is we don’t

have a biomarker. We have tried so hard to find a biomarker for bevacizumab, and for other anti-angiogenic drugs, but we haven’t succeeded. And I think selection of patients is important when we are talking personalised therapy. The adjuvant trial from ECOG – of course, it was disap- pointing to see a negative trial, but it tells us something. It tells us, among other things, that such a trial has gone on for years. I don’t know if it’s 8 years or 10 years to come to these results. We need to find mechanisms for doing trials much faster. We cannot wait 10 years. The

science goes so fast, so we need to move into smaller trials where we can evaluate signals. We need adaptive design like the ALCHE- MIST study, which is a targeted approach. Dr Haffizulla: Absolutely. Well, speaking about non-small cell lung cancer, I know that we spoke about anti-angiogenic therapy; how will this affect the treatment paradigm for non-small cell disease? Dr Hirsch: Well, bevacizumab was approved many years ago, and, of course, it’s introduced in clinical practice. It’s not used all the time in all places for several reasons; however, it is approved and it is in the guidelines. Other angiogenic drugs are also approved in second line; ramucirumab is also in this category. I think the whole problem with angiogenic treatment is that we haven’t succeeded in getting a selection paradigm. References 1. Wakelee HA, Dahlberg SE, Keller SM, et al. Paper presented at: 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 8507. T790Mwas detected in plasma of 18 (31%). ORR and median PFS were similar in pa- tients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumour (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M- negative plasma had overall favourable outcomes (ORR, 46%; median PFS, 8.2 months), tumour genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months). CONCLUSION In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study sug- gests that, upon availability of validated plasma T790M assays, some patients could avoid a tumour biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyp- ing, those with T790M-negative plasma results still need a tumour biopsy to de- termine presence or absence of T790M. Association between plasma genotyp- ing and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016 Jun 27;[Epub ahead of print], Oxnard GR, Thress KS, Alden RS, et al.

JOURNAL SCAN Plasma genotyping and outcomes with osimertinib treatment in patients with advanced NSCLC Journal of Clinical Oncology Take-home message • This retrospective study was designed to evaluate the efficacy of cell-free plasma DNA genotyping as a biomarker in predicting the outcome with osimer- tinib in patients with advanced non-small cell lung cancer. Objective response rates and progression-free survival of patients with T790M-positive plasma were similar to those with T790M-positive tumours (63% and 9.7 months vs 62% and 9.7 months, respectively). Additionally, tumour genotyping allowed for differentiation of T790M-positive plasma patients with better outcomes and T790M-negative plasma patients with poor outcomes with osimertinib. • The analysis allows for the possibility of replacing invasive tumour biopsy with noninvasive T790M genotyping Dr Jeremy Jones

PracticeUpdate Editorial Team

Key data fromASCO: Immunotherapy for lung cancer INTERVIEW WITH DR FRED HIRSCH Dr Fred Hirsch, CEO of the International Association for the Study of Lung Cancer and Professor of Medicine at the University of Colorado

Abstract PURPOSE Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrat- ed potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. METHODS Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included

had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAM- ing. Plasma genotyping accuracy was assessed by using tumour genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analysed in all T790M-positive or T790M- negative patients. RESULTS Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumours,

in Denver, talks about key research in immuno- therapy for lung cancer.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY