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1 Tumor Treating Fields (TTFields) A Novel Cancer Treatment Modality: Translating Preclinical Evidence and Engineering into a Survival Benefit with Delayed Decline in Health-Related Quality of Life R. Stupp 1*, M. Taphoorn 2,3, L. Dirven 2,3, S. Taillibert 4, J. Honnorat 5, T. Chen 6, J. Sroubek 7, S.H. Paek 8, J. Bruna Escuder 9, J. Easaw 1, C. David 11, C.Y. Kim 12, R. Desai 13, Y. Kew 14, A. Olivi 15, A. Hottinger 16, E.D. Kirson 17, G. Lavy-Shahaf 17, M.E. Hegi 18, Z. Ram 19 on behalf of the EF-14 Investigators 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University Feinberg School of Medicine, Chicago, IL, US; 2 Neurology, Leiden University Medical Center, The Hague, NL; 3 Department of Neurology, Leiden University Medical Center, Leiden, NL; 4 Neuro-oncology, Hôpital Universitaire Pitié-Salpêtrière, Paris, FR; 5 Neuro-oncology, Hospices Civils de Lyon, University Claude Bernard Lyon, Lyon, FR; 6 Neurosurgery, University of Southern California, Los Angeles, CA, US; 7 Neurosurgery, Na Homolce Hospital, Prague, CZ; 8 Neurosurgery, Seoul National University Hospital (SNUH), Seoul, KR; 9 Department of Neurology, Bellvitge Hospital Universitari, Barcelona, ES; 1 Medical Oncology, Tom Baker Cancer Centre, Calgary, CA; 11 Neurosurgery, Lahey Clinic, Burlington, MA, US; 12 Neurosurgery, Seoul National University Bundang Hospital, Bundang, KR; 13 Neurosurgery and Spine Assoc., Maine Medical Center (MMC), Scarborough, ME, US; 14 Neurology, Methodist Hospital, Houston, TX, US; 15 Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD, US; 16 Medical Oncology, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, CH; 17 Research and Development, Novocure, Haifa, IL; 18 Department of Neurosurgery BH-19/11, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, CH; 19 Neurosurgery, Tel Aviv Medical Center, Tel Aviv, IL *Contact: roger.stupp@northwestern.edu

2 Disclosures Consulting/advisory role to: Celgene Debiopharm Ipsen Merck KGaA/EMD Serono MSD/Merck & Co Novartis Roche/Genentech Spouse employee/stockholder of: Celgene Travel support received from: Novocure Ltd. All honoraria to institution 2

3 Tumor Treating Fields (TTFields): Mechanism of Action Alternating electric fields affect polar microtubules in dividing cells resulting in: Disruption of microtubule assembly Cell cycle arrest and prolongation of mitosis Apoptosis or aneuploidy 3 Giladi M et al. Sci Rep 215;5:1846.

4 EF-14 Trial: Treatment Schema and Study Design

5 Health-Related Quality of Life (HRQoL) Evaluation Analysis per EORTC QLQ-C3 and QLQ-BN2 at baseline, 3 and 6, and every 3 months until death Change from baseline and over time -free survival: Time to >1-point deterioration in scores from baseline, without a subsequent 1-point improvement in scores compared with baseline; progressive disease (PD); or death in the absence of a previous definitive deterioration before the next assessment Time to deterioration (TTD): Similar to deterioration-free survival, except the exclusion of PD as an event Nine domains Global Health Status Physical functioning Cognitive functioning Role functioning Social functioning Emotional functioning Itchy skin Pain Weakness of legs

6 Baseline Demographics of HRQoL Population Characteristics TTFields/TMZ (N=437) TMZ (N=22) Median age, years (range) 56. (19 83) 57. (19 8) Radiation therapy <57 Gy, n (%) 2 (4.6) 1 (5.) 6 Gy (standard; ±5%), n (%) 399 (91.3) 188 (93.1) >63 Gy, n (%) 15 (3.4) 3 (1.5) TTFields cycles, median (range) 8.3 ( 82) TMZ cycles, median (range) 6.2 ( 51) 5.5 ( 33) Extent of resection Biopsy only, % Partial/complete, % 34/53 35/53 Karnofsky Performance Score, median (range) 9 (6 1) 9 (7 1) Mini-Mental State Examination score, n (%) 429 (98.2) 194 (96.) TTFields adherence (first 3 months), % 74.8

7 Outcomes EF-14 Trial: TTFields/TMZ vs TMZ Progression-free survival (PFS) (primary) Overall survival (OS) (secondary)

8 Patient Flow and Compliance with Completing HRQoL Forms (in Surviving Patients) TTFields/TMZ Baseline HRQoL 3 Month HRQoL 6 Month HRQoL 9 Month HRQoL 12 Month HRQoL (n=466) (n=437) (n=35) (n=244) (n=156) (n=139) 94% 88% Intent-to-Treat Population (n=695) Compliance with HRQoL Forms (% Surviving Pts.) 68% 61% 58% 56% 47% 41% 42% 4% Baseline Month 3 Month 6 Month 9 Month 12 TMZ Alone (n=229) Baseline HRQoL (n=22) 3 Month HRQoL (n=126) 6 Month HRQoL (n=17) 9 Month HRQoL (n=78) 12 Month HRQoL (n=58)

9 Mean Changes in HRQoL Over Time in Predefined Scales/Items A. Global Health Status B. Physical functioning C. Cognitive functioning D. Role functioning E. Social functioning F. Emotional functioning TTFields/TMZ TMZ alone G. Itchy skin H. Pain I. Weakness of legs

10 Stable or Improved HRQoL During Progression-Free Period 1 Stable/improved from baseline (%) p=1 p<1 p=1 p=1 p=.389 n= Global Health Status Pain Physical functioning Weakness of legs Itchy skin TTFields/TMZ TMZ (N=138) (N=351)

11 HRQoL: -Free Survival Role functioning Social functioning Itchy skin -free survival: Time to >1-point deterioration in scores from baseline without a subsequent 1-point improvement in scores compared with baseline; progressive disease; or death in the absence of a previous definitive deterioration before the next assessment.

12 HRQoL: Time to (TTD) Global Health Status Physical functioning Cognitive functioning Role functioning Social functioning Emotional functioning Pain Itchy skin Weakness of legs 12 Time to deterioration (TTD): Similar to deterioration-free survival, with the exception that progressive disease was excluded as an event.

13 EF-14 HRQoL Analysis: Summary of Results Maintenance therapy with TTFields/TMZ significantly prolonged PFS and OS in patients with newly diagnosed GBM -free survival was significantly longer with TTFields/TMZ vs TMZ alone for global health, physical and emotional functioning, and leg weakness For non-progressive patients, no difference was seen in the TTD of HRQoL scales in patients treated with TTFields/TMZ vs TMZ alone, except: Itchy skin under the arrays (as expected) Pain was delayed in patients receiving TTFields/TMZ There was a higher overall percentage of patients with stable or improved HRQoL scales (predefined) in the TTFields/TMZ arm Carrying the TTFields delivery device continuously did not negatively influence the patient s HRQoL, except for local skin reaction Decline in quality of life was delayed due to prolongation of PFS and OS 13

14 EF-14 HRQoL Analysis: Conclusion The addition of TTFields to standard treatment for patients with newly diagnosed glioblastoma results in improved survival without a negative impact on HRQoL, except for more skin pruritus which was an expected consequence from the transducers arrays. 14

15 Acknowledgments Patients and families who participated in the trial Investigators, nurses, and data managers at 83 sites in 12 countries Collaborators, technicians, and staff of the CRO and the study sponsor 15