1. SOCCAR a Phase II Trial of Sequential Versus Concurrent Chemotherapy and Radiotherapy Using an Accelerated Hypofractionated Radiation Schedule in Stage III NSCLC J Maguire, R McMenamin, N O’Rourke, C Peedell, M Snee, S McNee, V Kelly

2. overview development of SOCCAR chemo- radiotherapy regimen SOCCAR trial where next………….?

3. SWOG 88 - 05 45 Gy CDDPCDDP CDDP CDDP VP16 Platinum 50 mg/m 2 days 1, 8, 29, 36 Etoposide 50 mg/m 2 days 1-5, 29-33 Albain KS, Rushi VW et al JCO 1995

4. Problems with concurrent chemo-radiotherapy in NSCLC TOXICITY – radical radiotherapy and full dose chemotherapy at the same time oesophagitis, pneumonitis, sepsis initial US studies reported 10% treatment related mortality PATIENT SELECTION CRITICAL

5. Accelerated Repopulation is a major cause of local treatment failure radical RT in 28 days may ↓ effects 55Gy/20f/26-28d a standard UK regimen

6. Liverpool 1996 - 2004 Concurrent Chemo-RT - development 20 fractions in 4 weeks initially CDDP 20 mg/m 2 1-5, 16-20 dose escalation 45, 47.5, 50, 52.5, 55 Gy weekly Vinorelbine added 2003

7. PS 0-1 (78.8%) PS 2 (18.8%) PS 3 (2.4%) ChemoRT (Liverpool, not SOCCAR) Performance Status

8. IIIB (74.5%) IIIA (7%) IIB (12.8%)IV (3.2%) IB (2.5%) Stage ChemoRT (Liverpool, not SOCCAR)

9. Liverpool (not SOCCAR) Stage III NSCLC PS 0-1 concurrent chemoRT Survivalby RT dose (not randomised) Months 55Gy/2052.5Gy/20<52.5Gy/20 n= 64 37 17 Med. 30.3 m 15.5 m 19.4 m 1 year 72.4% 62.2% 64.7% 2 year 57.4% 43.2% 29.4% 3 year 46% 40.5% 23.5% 55 Gy/20 52.5 Gy/20 <52.5Gy/20 %

10. concurrent ChemoRT adjuvant chemo vs no adjuvant chemo Stage 3PS 0-1 (Liverpool, not SOCCAR, non-randomised) months % chemo no chemo chemono chemo median26.6 m14.6 m 1 yr84% 75% 2 yr52.4% 43.7% 3 yr43.3% 43.7% 5 yr31.9% 31.2% p= NS

11. Liverpool Lung Cancer Unit 1997 - 2004 68 patients Toxicity oesophagitisG148.4% G227.4% G36.5% neutropenic sepsis5 treatment related deaths0

13. Pulmonary function after Chemo-RT Patients FEV 1

14. SOCCAR - Aims 1. Provide definitive answer to question: is concurrent Chemo-RT superior? 2. Enable UK centres to gain experience with concurrent Chemo-RT in controlled setting of phase III multicentre trial

15. trial funding and disclosure Funding: CRUK Sponsor: University College London Trial administration: UCL cancer trials centre Supported by British Thoracic Oncology Group Maguire, J: research support and speakers honoraria: Pierre Fabre, Astra Zeneca; advisory boards: Eli Lilly McMenamin,R: speakers honoraria: Pfizer; advisory boards: Bayer, GSK; support for meetings: GSK, Ibt, Ferring, Boeringer O’Rourke, N: support for meeting Roche Peedell, C: nil Snee, M nil McNee, S nil Kelly, V: support for meeting Pierre Fabre Cancer Research UK & UCL Cancer Trials Centre

16. SOCCAR Endpoint Survival at 2 years Secondary endpoints QOL Local control Health economics

17. SOCCAR – patient selection PERFORMANCE STATUS activities in past few days no allowance for age activity diary and review if equivocal

18. SOCCAR – patient selection 2 Staging CT + PET scans required - one within 4 weeks of randomisation Use additional techniques if you have them e.g. US guided neck node bx 4D radiotherapy planning

19. SOCCAR - chemotherapy Cisplatinum/vinorelbine anti-emetics as per local practice antibiotics required days 9 - 20

20. SOCCAR - radiotherapy conformal GTV + min. 1.5cm circumferential, 1.5 cm sup-inf. margins V20 lung ≤ 30% no more than 12 cm oesophagus in PTV

21. 21 pathologically confirmed NSCLC stage III, PS 0-1, CT± mediastinoscopy, PET-CT unsuitable for surgery CONCURRENT ARMSEQUENTIAL ARM cisplatinum 80mg/m 2 day 1 vinorelbine 25mg/m 2 day 1, 8 4 cycles 55Gy/20f/4weeks cisplatinum 80mg/m 2 weeks 1,4 vinorelbine 15mgs/m 2 weekly cisplatinum 80mg/m 2 day 1 vinorelbine 25mg/m 2 d 1, d 8 2 cycles 4 weeks 55Gy/20f/4weeks 4 weeks SOCCAR Trial Design

22. SOCCAR - inclusion criteria histological or cytological confirmation staging by CT±mediastinoscopy, PET-CT judged inoperable by thoracic surgeon PS 0 – 1 v20 ≤ 30%, ≤ 12cm oesophagus in PTV FEV1 ≥ 1L, TLCO ≥ 50% conformal or 4D RT planning

23. starting position (2006) historically poor UK lung cancer survival minimalist and over-conservative approach to treatment long diagnosis to treatment times limited experience with concurrent chemoradiation 3/12 centres pre trial use of con regimen

24. problems at the start…… introducing a new technology European Clinical Trials Directive “adverse publicity”

27. demographics 130 patients, median age 62 (range 39 - 77) 61% male, 39% female 64% sq, 27% adeno 3 excluded (2 stage IV, 1 too extensive ) wt loss > 5% 16% con, 20% seq N3 8.6% con, 10% seq >70yrs 8pts con, 10pts seq acceptable toxicity (O’Rourke et al WLC 2011)

28. toxicities SAEs 46% vs 47% 15 grade 4 toxicities (8 con vs 7 seq) G3 oesophagitis: 8 con vs 1 seq (no grade 4 oesophagitis) confirmed treatment related deaths 2 con vs 1 seq deaths in first 6/12 3 con, 2 seq

29. SOCCAR NSCLC Stage III PS 0 - 1 Months CON SEQ n 67 59 median 27.4 m 18.6 m 1 year 73.1% 83.1% 2 year 54% 42% 3 year 38% 27% 5 year 33.6% NR Local PD 10% 22% Con Seq %

30. Concurrent Schedules Compared Cancer Research UK & UCL Cancer Trials Centre Trial %2ys RT CT %TRM G3/4oes pts Gy/f SOCCAR 201070 54 55/20 cis/vin 4 17% Jeremic 199665 43 69.6/58/6w carbo/etop 0 8 Belderbos 200666 39 66/24 daily cis 1.5 17 Fournel 2005100 39 66/33 cis/etop 10 32 Curran 2003201 37 60/30 cis/vbl 3 25 Huber 200699 36 60/30 wkly taxol 0 13 Furuse 1999156 34.656/28spli cis/vind 0.6 3 Zatloukal 200451 34 60/30 cis/vin 0 18 Belani 200592 29 66/33 carbo/tax ? 31

31. conclusions Cancer Research UK & UCL Cancer Trials Centre 55Gy/20f/26-28d with concurrent cisplatinum and vinorelbine is a highly effective treatment for stage III NSCLC, PS 0-1 2 year survival in concurrent group > 50% In comparison of 16 RCTs, 1733 patients treated on concurrent CTRT, this treatment ranks top on survival with comparable tolerability

32. SOCCAR Concurrent ChemoRT n=67 median27.4 mth 1 year73.1% 2 yr54% 3 year38% 5 year33.6% Months %

33. Liverpool 55Gy/20 + chemo Pre-SOCCAR n=65 median35.5m 1 year79.5% 2 yr 61.2% 3 year49% 5 year33.7% 7 year29.5% Months %

34. Pre-SOCCAR Pilot study (excluding Liverpool) 55 Gy/20 + concurrent cis/vin Survival Months n= 61 median26.8 m 1 ye ar64.9% 2 yea r52.1% 3 year 43.3% %

35. Concurrent ChemoRT 55Gy / 20 f with cisplatinum and vinorelbine Months % SOCCAR Liverpool Pilot exc. Liverpool SOCCAR Pilot n 6567 61 median35.5 m27.4 m 26.8 m 1 year79.5%74% 64.9% 2 year61.2%54% 52.1% 3 year49% 38% 43.3% 5 year33.7%33.6% 7 year29.5%

36. what next………? needs to be relevant internationally ? relevance of individualised dose escalation for some patients (but tumour size critical)

37. improving efficacy concurrent chemoRT: dose escalation and cetuximab? RTOG 0617: four arm study Arm A 60Gy + carbo/taxol Arm B 74Gy + carbo/taxol Arm C 60Gy + carbo/taxol+ cetuximab Arm D 74Gy + carbo/taxol + cetuximab

38. RTOG 0617 – interim analysis ASTRO October 2011 survival 60Gy 74Gy one year 81% 70.4% median 21.7m 20.7m p= 0.02

40. What next? eligible patients should have concurrent chemoradiotherapy next UK study should have SOCCAR regimen standard arm vs conventional fractionation national agreement to compare 55Gy/20f with 64Gy/32f with concurrent cisplatinum/vinorelbine

41. BIG LUNG TRIAL: PROPOSAL 2012 Patient with inoperable stage II/III NSCLC suitable for radical treatment Fit for concurrent treatment Fit for sequential treatment Clinician judgement CARSON Randomised phase III comparison of SOCCAR 55Gy/20 fractions vs 66/33 + concurrent Cis/Vinorelbine ASCaN Randomised phase II pick the winner comparison of CHART-ED, IDEAL, I-START, ISO-A-IMRT v standard sequential treatment (cisplatin chemo x 4 followed by 55Gy in 20 fractions) - ASCaN - A Randomised Phase II study of Accelerated Sequential Chemo- radiotherapy in NSCLC CI: Mathew Hatton -CARSoN - Conventional Against Reduced Fractionation of Sensitised Radiotherapy in NSCLC CI: Joe Maguire

42. CARSON - DESIGN fit for concurrent chemoRT SOCCAR regimen 55 Gy in 20 fractions + concurrent Cis/Vinorelbine 66 Gy in 33 fractions + concurrent Cis/Vinorelbine Randomisation ratio: 11

43. CARSON - DESIGN Randomised phase III non-inferiority trial Aims to rule out the possibility that the SOCCAR regimen increases the death rate by more than 17.5% relative to 66Gy in 33 fractions this corresponds approximately to retaining half the benefit of going from sequential to concurrent treatment 2.5% 1-sided level of statistical significance 580 patients (80% power) Final selection between arms based on toxicity/HE

44. CARSON - DESIGN Aims to rule out the possibility that the SOCCAR regimen increases the death rate by more than 17.5% relative to 66Gy in 33 fractions Rule out reducing median OS by >3 months (assuming 20 months median on standard) The design assumes that the SOCCAR regimen will actually reduce the death rate by at least 10% Assumes median OS on SOCCAR will be 22.2 months compared to 20 months on standard (actual median in SOCCAR 27 months)

45. CARSON - DESIGN Other design options Superiority in terms of OS – but the SOCCAR regimen perhaps has advantages even if OS is the same Standard non-inferiority design in terms of OS – but this is very large and probably undeliverable. If SOCCAR has a small survival advantage this is overpowered. Use HE as a primary end-point – difficult to design and also demonstrating non-inferiority in terms of OS was crucial

46. conclusions 55Gy/20f/26-28d with concurrent cisplatinum and vinorelbine is a feasible and effective treatment for stage III NSCLC, PS 0-1 2 year survival in concurrent group > 50% SOCCAR confirms the value of an accelerated hypofractionated radiotherapy schedule as a therapeutic approach in NSCLC major opportunity for follow on trial now!