Adjuvant therapy of NSCLC: where to go from here?

Transcription

1 SAMO Winter Workshop on Chest Tumours Adjuvant therapy of NSCLC: where to go from here? J Vansteenkiste Dept Pulmonology Leuven Lung Cancer Group

2 > adjuvant therapy ± 1,200,000 lung cancers worldwide >80% non-small cell lung cancer ± 20 to 30% resectable 5-year survival 40 to 50% post resection A majority of resected patients are potential candidates for effective adjuvant strategies Adjuvant radiotherapy: no proven benefit on overall survival

3 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

4 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

5 Early stage NSCLC > recurrence after curative resection First author (Year) Locoregional Brain Systemic Mountain (1980) - squamous - non-squamous Feld (1984) - squamous - non-squamous 24% 17% % 83% 39% 20% 41% 25% 25% 50% Holmes (1986) 17% 17% 66% Lad (1988) - squamous - non-squamous 24% 16% 19% 26% 57% 58% Ohta (1993) 20% - 80%

6 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

7 > meta-analysis analysis Results for cisplatin-based adjuvant chemotherapy o hazard ratio 087 (95%CI ) (P=008)( o 13% decrease in risk of death o 5% improvement in 5-yr 5 survival (47% to 52 Consequence (1994) o adjuvant chemotherapy not a standard o hypothesis generator of modern trials 52%) NSCLC collaborative group,, Br Med J 311: , 909, 1995

8 > meta-analysis analysis statistics are like striptease, you don t learn much, but it gives you ideas A French scientific statement

9 > modern studies: IALT 1,867 patients Chemo Control Participating countrie 148 centers 33 countries Update in 2002 for >98% patients Median follow-up 56 months

10 > modern studies: IALT 1,867 patients Chemo Control Participating countrie 148 centers 33 countries Update in 2002 for >98% patients Median follow-up 56 months

11 1,00 0,80 0,60 0,40 0,20 Early stage NSCLC > IALT outcome (survival) HR 086 [ ] 098] (P<003) 445% 404% Chemotherapy (n=932) No Chemotherapy (n=935) 0, Follow-up (years ears) IALT investigators, N Engl J Med 350: , 2004

12 > IALT relapse patterns Local relapse Distant relapse Combined relapse Death without relapse CT Control IALT investigators, N Engl J Med 350: , 2004

13 > IALT covariate interaction (f) N status (p-int=080, p-trend=056) p N0 164/ /427 N1 144/ /267 N2 161/ /241 (g) Stage (p-int=041, p-trend=021) p Stage I 115/ /348 Stage II 123/ /222 Stage III 231/ / chemo better control better

14 > IALT perspective Benefit in 5-year 5 survival o IALT: 41% o small cell lung cancer (chemoradio vs chemo): 5% o breast cancer (adjuvant CMF): 32% o breast cancer (adjuvant hormones): 36% o colon cancer (adjuvant chemotherapy): 5%

15 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

16 > modern studies: overview Stage N Adjuvant 5Y survival HR (P)( Interpretation Meta,, 1995 I-IIIAIIIA 1394 cis based 52 vs (008) Hypothesis generator IALT, 2004 I-III III 1867 cis doublet 445 vs (003) Positive ALPI, 2003 I-IIIAIIIA 1209 MVP 50 vs (059) Negative CALGB, 2004 IB 504 carbo-pacli 71 vs 59* 062 (003) Positive (early stop) NCI-C, C, 2005 IB-II II 482 cis-vino 69 vs (001) Positive BLT, 2004 I-IIIAIIIA 381 cis based NR 102 (098 ) Underpowered ANITA, 2005 IB-IIIA IIIA 840 cis-vino 51 vs (001) Positive

17 > modern studies: : ALPI Scagliotti et al, J Natl Cancer Inst 95: , 1461, 2003

18 > which adjuvant chemotherapy? Choose according to existing adjuvant data o Cis-Etoposide patients o Cis-Vinorelbine patients o no direct comparative studies Choose according to abundant comparative studies in advanced NSCLC o large body of evidence with Cis-Gemcitabine

19 #7007 phase 3 CALGB study: update Completely resected NSCLC stage IB R Adjuvant: 4 cycles Carbo-Paclitaxel Observation only 1 5Y overall survival: 60% vs 57% (P=032)( o DFS better with adjuvant: : HR 074 [ ] 096] ; P=0027 o better 3YS: 79% vs 70% (P=0045)( o T >4cm: HR 062 [ ] 089] ; P=001 data not mature (131/150 required events), DFS and 3YS support continued consideration of CP in stage IB

20 Pooling of individual patient data from ALPI, IALT, NCI-C, C, BLT and ANITA Pooled HR 089 [ ]; 096]; P<0005; 5YS 43 ->49% Variation with stage Early stage NSCLC #7008 LACE* meta-analysis analysis o IA: 141 [ ]; IB: 093 [ ] o II: 083 [ ]; 094]; III: 083 [ ] 095] No significant variation with o 2 nd drug: vinorelbine marginally better than older drugs (P=004), but these patients also had a higher cisplatin dose * Lung Adjuvant Cisplatin Evaluation

21 Early stage NSCLC #7009 NCI-C: C: elderly subanalysis (Dr Pepe) Completely resected NSCLC stages IB II R 1 Adjuvant: 4 cycles Cis-Vinorelbine Observation only 5Y overall survival: 69% vs 54% (P=001)( o retrospective analysis of <65Y (n=327) vs >65Y (n=155) o survival prospects <65Y slightly better than >65Y (P=008)( o elderly benefit from adj chemo: HR 061 [ ]; 098]; P=004 o elderly have more dose reduction / omission therapy should not be withheld because of age Winton et al, N Engl J Med 352: , 2005

22 > surgery + adjuvant chemo standard? YES! But,, for which patient, which stage, which drugs? o age group as well o the platinum is cisplatin o stage IB << stages II / IIIA But balance effect / tolerance is an issue o NNT: : 10 (20) treatments needed for one extra cure o about 50% cannot receive adjuvant therapy (postop complications or PS does not allow timely start)

23 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

24 > LLCG guidelines (wwwllcgbe)

25 Stage IA Early stage NSCLC > LLCG guidelines (wwwllcgbe) o surgery o if medically inoperable o either radical radiotherapy o if feasible, wedge excision by VATS or limited thoracotomy Stage IB, II and IIIA (only( T3N1) o consider induction protocol o surgery, followed by adjuvant chemo in fit patients o if medically inoperable o radiotherapie if radical dose feasible Stadium IIIA (only( T1-3 unforeseenn2 N2) o surgery, followed by adjuvant chemo in fit patients o value of adjuvant radiotherapy unclear

26 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

27 > future issues alive and well afer surgery alive and well afer surg + chemo death of relapse death co- morbididty death of relapse death co- morbididty

28 > compliance adjuvant chemotherapy Trial IALT ALPI CALGB NCI-C BLT ANITA1 N cycles 3-44 cycles 3 cycles 4 cycles 4 cycles 3 cycles Compliance 74% 69% 85% 50% 64% 4 cycles NR * median number vinorelbine doses 10/16

29 > future issues Improve alive and tolerability well afer better surgery chemotherapy targeted agents induction chemotherapy death of relapse death co- morbididty alive and well afer surg + chemo death of relapse death co- morbididty

30 > future issues * Trial in Refinement of Early stages Adjuvant Therapy Improve alive and tolerability well afer better surgery chemotherapy targeted agents induction chemotherapy TREAT*: death of cis-alimta vs cis-vinorelbine relapse less toxic adjuvant treatments death co- morbididty alive and well afer surg + chemo death of relapse death co- morbididty

31 ABSTRACT 7019 Multi center, double blind, blind, randomized, placebo controlled controlled phase II study to assess the recombinant MAGE A3 A3 compound as adjuvant therapy in completely resected stages IB/II II MAGE A3 A3 positive NSCLC J Vansteenkiste 1, M Zielinski 2, J Dahabre 3, A Linder 4, W Malinowski 5, J Jassem 6, E Esteban 7, M Lopez Brea 8, B Passlick 9, F Lehmann 10, V G Brichard 10 1 UZ Gasthuisberg, Leuven Lung Cancer Group, Belgium; 2 Szpital Chorob Pluc, Zakopane, Poland; 3 Medical Centre, Athens, Greece; 4 LungenKlinik, Hemer, Germany; 5 Szpital Kopernika, Tusznin, Poland; 6 Klinika Onkologii Radiotherapii, Gdansk, Poland; 7 Hospital Central de Asturias, Oviedo,, Spain; 8 Hospital Marques de Valdecilla, Santander, Spain; 9 Asklepios Klinik, Gauting, Germany; 10 GlaxoSmithKline Biologicals, Rixensart,, Belgium

32 Study rationale About half of the patients with completely resected early stage NSCLC will relapse Activity and safety of MAGE A3 A3 treatment was demonstrated in melanoma 1 About 35% of stages IB II II express MAGE A3 A3 2 Post operative operative MAGE A3 A3 immunization might be a targeted, well tolerated,, and effective treatment 1 Marchand et al, Eur J Cancer 39:70 77, 77, 2003 Kruit et al, Int J Cancer 117: , 604, Sienel et al, Eur J Cardiothorac Surg 25: , 134, 2004

33 NSCLC p stage IB (T2N0) and stage II (T1 2N1, T3N0) MAGE A3 A3 + by RT PCR Complete resection Recovered (PS 0 1) 0 Stratified Stage IB vs II Squamous vs non squam squam LN sampling vs dissection Study design R 2 1 MAGE A3 A3 administration 300 μg im Induction: q3w x 5 Maintenance: q3m x 8 Total 27 months Placebo same schedule Primary endpoint: : time to recurrence

34 Study flow Screened: : N=1089 (1( st informed consent before surgery) [01/ /2004] 05/2004] MAGE A3 A3 +: : N=363 (35% in stage IB/II) Enrolled: : N=182 (2( nd IC) Incorrect eligibility criteria Incorrect p stagep No (timely( timely) ) action Patient refusal Others MAGE A3: A3: N=122 Placebo: N=60

35 Study still blinded Safety 182 patients / 1609 treatment administrations Overall well tolerated Mild grade 1 or 2 local or systemic reactions, < 24 hours 29 grade 3 or 4 adverse events in 21 distinct patients Three grade 3 adverse events possibly related to treatment Leading to withdrawal of 2 patients (local pain, COPD exacerbation)

36 Efficacy: recurrence rate Stage Group N N recurr All MAGE A3 A3 Placebo = 114% TE = 27% [ 9[ 9 ; 51] 417 p = 0138 Median follow up 21 mo relapse rate (%)

37 Efficacy: recurrence rate Stage Group N N recurr All MAGE A3 A3 Placebo = 114% TE = 27% [ 9[ 9 ; 51] p = 0138 IB MAGE A3 A Placebo TE = 9% p = 0835 II MAGE A3 A3 Placebo TE = 48% p = 0055 Median follow up 21 mo relapse rate (%)

38 Cox regression analysis Stage All IB II Group N N recurr MAGE 3 Placebo MAGE Placebo MAGE 3 Placebo p = 0121 p = 0572 p = Hazard ratio

39 Perspective: NSCLC adjuvant therapy Evidence since % death risk reduction by platinum based adjuvant chemotherapy, but tolerability of concern 1 Toronto retrospective review: 59% patients referred for, 35% actually received adjuvant chemotherapy 2 MAGE A3 A3 promising activity In combination with postop chemotherapy? MAGE A3 A3 well tolerated For patients who cannot tolerate postop chemo? 1 IALT investigators,, N Egl J Med 350: , 360, 2004 Winton et al, N Engl J Med 352: , 2597, Kassam et al, J Clin Oncol 23:674S, 2005 (abstract)

40 > future issues alive and well afer surgery alive and well afer surg + chemo death of Target those who benefit: relapse prognostic factors death co- morbididty death of relapse death co- morbididty

41 > future issues high SUV on PET #7026 alive Lung and well mutagene model : : gene expression afer surgery profiles predict recurrence alive and well afer surg + chemo Potti et al, N Engl J Med 355: , 2006 death of Target those who benefit: relapse prognostic factors death co- morbididty death of relapse death co- morbididty

42 PET in lung cancer : prognosis > LLCG study : survival acc to SUV 1 Cumulative survival SUV < 7 SUV > Vansteenkiste et al, J Clin Oncol, 17: , 1999 Follow-up (months( months)

43 > future issues Soria et al, ASCO 2006 Bepler et al, J Clin Oncol 24: , 2006 alive and well afer surgery death of relapse death co- morbididty Enlarge benefit: better chemotherapy alive and well combine afer with surg biologicals + chemo induction chemotherapy predictive factors death of relapse death co- morbididty

44 > future issues Soria et al, ASCO 2006 Bepler et al, J Clin Oncol 24: , 2006 alive and well afer surgery death of relapse death co- morbididty Enlarge benefit: better chemotherapy alive and well combine afer with surg biologicals + chemo induction chemotherapy predictive factors death of relapse pharmacogenomics death co- morbididty

45 IALT-BIO = molecular program on resection specimens from IALT Excision Repair Cross Complementing 1 protein Early stage NSCLC > ERCC1 predictive value o nuclease excision repair system essential for repair of DNA-abberations (eg adducts caused by cisplatin) ERCC1 prognostic factor o untreated group: : ERCC1+ do better (HR 065, P<0008) ERCC1 predictive factor o ERCC1+ patients (n=335): HR 118 [ ] ; P=029 o ERCC1- patients (n=426): HR 067 [ ] 089] ; P<0006 Olaussen et al, N Engl J Med 355: , 2006

46 > #7051 beta-tubulin tubulin III predictive value Biological studies in the adjuvant NCI-C study High btubiii 265 good quality analyses o reduced response and survival when treated with anti- microtubule cytotoxics (vincas( and taxanes) o high btubiii: poorer survival after surgery alone, corrected with adj cis-vinorelbine o low btubiii: better survival, not infuenced by adj cis- vinorelbine

47 Locally advanced NSCLC #7054 RRM1 predictive value Ribonucleotide Reductase M1 regulatory unit o one of the molecular targets of Gemcitabine

48 Locally advanced NSCLC #7054 RRM1 predictive value Ribonucleotide Reductase M1 regulatory unit o one of the molecular targets of Gemcitabine Prospective study RRM1 expression in pre-therapy biopsies of patients treated with Carbo-Gem When grouping CR/PR (n=12) vs SD (n=14) o RRM1 associated with response (P=0027)(

49 Metabolic pathways for self-potentiation of Gemcitabine nucleotides DNA = inhibitory reaction Gemcitabine triphosphate Gemcitabine diphosphate dctp deoxycytidine triphosphate dcdp deoxycytidine diphosphate 1 RRM1 CDP cytidine diphosphate 1 2 Gemcitabine monophosphate 2 Gemcitabine dfdump difluorodeoxyuridine monophosphate dfdu difluorodeoxyuridine metabolism/excretion excretion Inhibition of ribonucleotide reductase leads to lower intracellular levels of natural deoxycytidine nucleotides Subsequent upregulation of deoxycytidine kinase leads to higher level of gemcitabine nucleotides

50 > adjuvant therapy The history The true start: IALT Current studies / recent findings The current LLCG guidelines The future Conclusion

51 > adjuvant chemotherapy here to stay Surgery essential part of the treatment Level I evidence in favour of adjuvant chemotherapy o several positive RCTs o all except one with Cisplatin o 2 meta-analyses analyses o HR 089 (P=0012;( P=0004) o 1 patient based meta-analysis analysis o HR 089 (P=0005)( for Cisplatin o In different stages: stage IB < stages II / resected IIIA

52 > adjuvant chemotherapy here to stay To be started in well recovered patients,, and <6 weeks post- surgery o cisplatin-based based, cumulative dose up to 300 mg/m 2 o doublet combination with a 3 rd generation cytotoxic agent o carboplatin alternative if specific toxiciy is a concern (eg renal funcion, neuropathy) o not feasible in quite some patients Many ways to move forward o revival of postoperative clinical trials

53 Thank you for your kind attention Leuven, Gothic Town Hall (1448)