SOCCARa 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

overview

• development of SOCCAR chemo- radiotherapy regimen

• SOCCAR trial

• where next………….?

SWOG 88 - 05

45 Gy

CDDP CDDP CDDP CDDP

VP16 VP16

Platinum 50 mg/m2 days 1, 8, 29, 36Etoposide 50 mg/m2 days 1-5, 29-33

Albain KS, Rushi VW et alJCO 1995

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

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

Liverpool 1996 - 2004

Concurrent Chemo-RT - development

• 20 fractions in 4 weeks

• initially CDDP 20 mg/m2 1-5, 16-20

• dose escalation 45, 47.5, 50, 52.5, 55 Gy

• weekly Vinorelbine added 2003

PS 0-1 (78.8%)

PS 2 (18.8%)

PS 3 (2.4%)

ChemoRT (Liverpool, not SOCCAR)

Performance Status

IIIB (74.5%)

IIIA (7%)

IIB (12.8%)IV (3.2%)

IB (2.5%)

Stage

ChemoRT (Liverpool, not SOCCAR)

Liverpool (not SOCCAR)Stage III NSCLC PS 0-1 concurrent chemoRT

Survival by RT dose (not randomised)

Months

55Gy/20 52.5Gy/20 <52.5Gy/20n= 64 37 17Med. 30.3 m 15.5 m 19.4 m1 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

%

concurrent ChemoRT adjuvant chemo vs no adjuvant chemo

Stage 3 PS 0-1 (Liverpool, not SOCCAR, non-randomised)

160140120100806040200

1.0

.8

.6

.4

.2

0.0

months

%

chemo

no chemo

chemo no chemomedian 26.6 m 14.6 m1 yr 84% 75%2 yr 52.4% 43.7%3 yr 43.3% 43.7%5 yr 31.9% 31.2%

p= NS

Liverpool Lung Cancer Unit

1997 - 2004 68 patients

Toxicity oesophagitis G1 48.4%

G2 27.4% G3 6.5%

neutropenic sepsis 5

treatment related deaths 0

Pulmonary function after Chemo-RT

Patients

FEV 1

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

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

SOCCAR

Endpoint Survival at 2 years

Secondary endpoints

QOLLocal controlHealth economics

SOCCAR – patient selection

• PERFORMANCE STATUS

activities in past few days no allowance for age activity diary and review if

equivocal

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

SOCCAR - chemotherapy

• Cisplatinum/vinorelbine

anti-emetics as per local practice

antibiotics required days 9 - 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

pathologically confirmed

NSCLC stage III , PS 0-1,

CT± mediastinoscopy, PET-CT

unsuitable for surgeryCONCURRENT ARM SEQUENTIAL ARM

cisplatinum 80mg/m2 day 1

vinorelbine 25mg/m2 day 1,

8 4 cycles

55Gy/20f/4weeks

cisplatinum 80mg/m2 weeks

1,4

vinorelbine 15mgs/m2

weekly

cisplatinum 80mg/m2 day 1

vinorelbine 25mg/m2 d 1, d 8

2 cycles

4 weeks

55Gy/20f/4weeks

4 weeks

SOCCAR Trial Design

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

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

problems at the start……

• introducing a new technology

• European Clinical Trials Directive

• “adverse publicity”

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)

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

SOCCAR NSCLC Stage III PS 0 - 1

Months

CON SEQ n 67 59median 27.4 m 18.6 m1 year 73.1% 83.1%2 year 54% 42%3 year 38% 27%5 year 33.6% NR

Local PD 10% 22%

Con

Seq

%

Concurrent Schedules ComparedCancer Research UK & UCL Cancer Trials Centre

• Trial %2ys RT CT %TRM G3/4oes • pts Gy/f

SOCCAR 2010 70 54 55/20 cis/vin 4 17%

Jeremic 1996 65 43 69.6/58/6w carbo/etop 0 8Belderbos 2006 66 39 66/24 daily cis 1.5 17 Fournel 2005 100 39 66/33 cis/etop 10 32 Curran 2003 201 37 60/30 cis/vbl 3 25 Huber 2006 99 36 60/30 wkly taxol 0 13 Furuse 1999 156 34.6 56/28spli cis/vind 0.6 3 Zatloukal 2004 51 34 60/30 cis/vin 0 18 Belani 2005 92 29 66/33 carbo/tax ? 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

SOCCAR Concurrent ChemoRT

n=67median 27.4 mth1 year 73.1%2 yr 54%3 year 38%5 year 33.6%

Months

%

Liverpool 55Gy/20 + chemo Pre-SOCCAR

n=65median 35.5m1 year 79.5%2 yr 61.2%3 year 49%5 year 33.7%7 year 29.5%

Months

%

Pre-SOCCAR Pilot study (excluding Liverpool) 55 Gy/20 + concurrent cis/vin

Survival

Months

n= 61 median 26.8 m1 ye ar 64.9%2 yea r 52.1%3 year 43.3%

%

Concurrent ChemoRT 55Gy / 20 f with cisplatinum and vinorelbine

Months

%

SOCCAR

Liverpool

Pilot exc.

Liverpool SOCCAR Pilotn 65 67 61median 35.5 m 27.4 m 26.8 m 1 year 79.5% 74% 64.9%2 year 61.2% 54% 52.1%3 year 49% 38% 43.3%5 year 33.7% 33.6%7 year 29.5%

what next………?

• needs to be relevant internationally

• ? relevance of individualised dose escalation for some patients (but tumour size critical)

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

RTOG 0617 – interim analysis ASTRO October 2011

survival 60Gy 74Gy

one year 81% 70.4%

median 21.7m 20.7m p= 0.02

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

BIG LUNG TRIAL: PROPOSAL 2012Patient 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

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:

1 1

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

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)

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

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!