State of the art: Standard of care for resectable NSCLC Adjuvant chemotherapy Is there a place for neo Adjuvant chemotherapy?

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1 ESMO Preceptorship Programme NSCLC Singapore dec 2016 State of the art: Standard of care for resectable NSCLC Adjuvant chemotherapy Is there a place for neo Adjuvant chemotherapy? Pr Jaafar BENNOUNA Université de Nantes France Institut de Cancérologie de l Ouest Nantes

2 COI Disclosure Advisory Boards and Symposium presentations Astra-Zeneca Boehringer-Ingelheim Lilly Roche BMS

3 The MRC 1995 meta analysisfor the beginningof the story 14 randomized trials : 4357 patients 1st group : alkylating agents containing regimen riskof death: + 15 % survival: -5 % at5 y. 2cnd group : UFT based chemo. non conclusive results decreasein the riskof death 3rd group : cisplatin based chemo. Non-smallCellLung Cancer Collaborative Group -BMJ 1995

4 MRC 1995 meta analysis (3rd group : CDDP based chemo.) 8 randomizedphase III trials pts Surgery vs surgery + cisplatin-based chemo. Absolutebenefitfromchemo. of 5 % at5 years Not statistically significant: HR: 0.87 [95% CI: ] (p=0.08) These findings prompted renewed interest of postoperative chemotherapy in completely resected NSCLC. Only trials with cisplatin-based chemotherapy Non-smallCellLung Cancer Collaborative Group -BMJ 1995

5 meta analysis 11 randomized trials : 5716 patients 6 randomized trials : 2003 patients In these trials, adjuvant chemotherapy yielded a survival advantage over surgery alone(hr 0.872). In a subset analysis, both cisplatin-based chemo. (HR, 0.891) and single-agent therapy with UFT (HR 0.799) were found to yield a significant survival benefit. UFT single agent-based adjuvant chemotherapy in Japan. Mostlyearlystages(T1,T2,N0)andadenocarcinoma84% HR0.74( ) Hotta K, et al. J Clin Oncol2004 ; Hamada C, et al. J Clin Oncol2005

6 2010 : Adjuvant chemo., with or without postoperative radiotherapy, in operable NSCLC: two meta analyses of individual patient data 1 st meta-analysis:surgery+ctversussurgery 34trials:8447patients absolute increase in survival of 4% at 5 y. (from 60%to64%) HR0.86( ) 2cnd meta-analysis: surgery + RT-CT versus surgery + RT 13trials:2660patients absolute increase in survival of 4% at 5 y. (from 29%to33%). HR0.88( ) NSCLC Meta-analyses Collaborative Group. Lancet 2010

7 Effect of adjuvant treatment according to the type of chemotherapy NSCLC Meta-analyses Collaborative Group. Lancet 2010

8 7 major adjuvant studiesin NSCLC study n stage chemotherapy comments CALGB IB paclitaxel + carboplatin vs obs No Survival benefit with paclitaxel + carboplatin for stage IB Kato H 999 I UFT vs obs Survival benefit for stage IB only (T2N0) IALT 1867 I IIIA platin-based Chemo. vs obs Survival benefit at 5 y. Not maintained > 5 y. increase in noncancer deaths in the CT arm. ALPI 1209 I IIIA MVP vsobs No survival benefit of CT at 5 years BLT 381 I IIIA platin-based chemo. vs obs No survival benefit with adjuvant CT ANITA 798 I IIIA vinorelbine+ cisplatinvsobs Survival benefit of CT at 5 and 7 y for stage II and IIIA JBR IB- II vinorelbine + cisplatin vs obs Significant survival benefit at 5 years for stage II Benefit maintained after 9 years. * TNM V and VI classification Strauss G M et al. J Clin Oncol 2008 ; Kato H, et al. N Engl J Med 2004 ; Arriagada R, et al. N Engl J Med 2004 ; Scagliotti GV, et al. J Natl CancerInst2003;WallerD,etal.EurJCardiThoacSurg2004;WintonT,etal.NEnglJMed2005;DouillardJY,etal.LancetOncol2006

9 IALT : randomizedphase III study(n=1,867) Stage I (36 %) ; II (24 %) ; IIIA (40 %) Pneumonectomy (35 %) ; squamous histology(46 %) ; adjuvant radiotherapy(31 %) ArriagadaR, et al. N EnglJ Med 2004 ArriagadaR, et al. J Clin Oncol2010

10 IALT : randomizedphase III study(n=1,867) Significantbenefitof cisplatin-basedct at5 y. HR 0.86 (p=0.03) ; +4.1 % at5 years, An updatedanalysiswaslaterpublishedat7.5 y. HR 0.91 ; p= ArriagadaR, et al. N EnglJ Med 2004 ArriagadaR, et al. J Clin Oncol2010 An excess of non-cancer related deaths was noticed in the chemotherapy arm with time Long FU isneededto reallyevaluatethe benefitof ajuvantct

11 IALT : randomizedphase III study(n=1,867) According to the author, all test for interaction are negative, not allowing p values among groups A different analysis on stage published by Strauss et al showed a significant p value for stage III only (p=0.035) (Hematol Oncol ClinNAm , ) The study was initially calculated on 3000 pts and therefore lacks power for subgroup analysis ArriagadaR, et al. N EnglJ Med 2004 ArriagadaR, et al. J Clin Oncol2010

12 CALGB 9633 : A randomized phase III study (n=344) Stage IB only; Lobectomy (89 %) ; squamoushistology(39 %) Compliance(paclitaxel+ carboplatinarm) : 4 cycles (85 %) ; 55 % (full dose) Overall population Tumor 4 cm Adjuvant chemotherapyisnot the standard of care for all patients withstage IB NSCLC Strauss G M et al. JCO 2008

13 JBR10 : A randomized phase III study (n=482) Stage IB (45 %) ; IIA (15 %) ; IIB (40 %) ; pneumonectomy(23 %) Chemoarm : vinorelbineweekly25 mg/m² + cisplatin50 mg/m² d1,d8 (4 cycles d1,d28) The medianfollow-up was9.3 yearswitha confirmedbenefit, stillconfinedto stage II For stage IB and size 4 cm ; HR 0.66 ( ) Overall survival: stage II Overall survival: stage IB WintonT, et al. N EnglJ Med 2005 ; ButtsCA, et al. J Clin Oncol2010

14 ANITA trial : A randomized phase III study (n=840) Stage IB (35 %) ; II (30 %) ; IIIA (35 %) ; lobectomy(58 %) ; Squamoushistology(59 %) Chemo arm: vinorelbine weekly 30 mg/m² + cisplatin 100 mg/m² d1(4 cycles d1,d28) Compliance: Median% planneddose: CDDP 76%, VNR 56% OBS. NVB + CDDP mos P- value HR 0.80 [ ] % benefitin OS 1 years years years years +8.4 Douillard JY et al. Lancet Oncol. 2006

15 ANITA trial : survival according to lymph nodes status N0 status N1 status N2 status OBS. CT OBS. CT OBS. CT mos mos mos Douillard JY et al. Lancet Oncol. 2006

16 ANITA trial : Conclusion Significant improvement in survival with adjuvant vinorelbine/cisplatin StageIB:nodifferenceat5-years StageII:+12.6%at5-years StageIIIA:+16.4%at5-years The effect of vinorelbine/cisplatin is demonstrated in stage II and IIIAbutnotinIB Douillard JY et al. Lancet Oncol. 2006

17 LACE meta analysis LACE meta analysis LACE vinorelbine meta analysis Population Patients with completely resected NSCLC Inclusion criteria Included studies Patients characteristics Main objective CDDP-based vs Obs CDDP-based + PORT vs PORT 5 studies included ALPI, BLT, IALT, JBR10, ANITA n= 4,584 IA: 8%, IB: 30%, II: 35%, III: 27% Overall Survival of CDDP-based regimens NVB + CDDP vs Obs NVB + CDDP + PORT vs PORT 4 studies included BLT, IALT, JBR10, ANITA n= 1,888 IA: 2%, IB: 34%, II: 38%, III: 26% OverallSurvivalof VNR + CDDP regimens PORT= post-operativert Pignon JP, et al. JCO 2008; Douillard JY, et al., JTO 2010

18 LACE meta analysis 5 trials Absolute survival benefit of 5.3% at 5-years 4 trials Absolute survival benefit of 8.9% at 5-years LACE LACE NAVELBINE Pignon JP, et al. JCO 2008; Douillard JY, et al., JTO 2010

19 LACE meta analysis : according to trials LACE LACE NAVELBINE Pignon JP, et al. JCO 2008; Douillard JY, et al., JTO 2010

20 LACE meta analysis : according to TNM stage LACE LACE NAVELBINE Detrimental effect for stage I Pignon JP, et al. JCO 2008; Douillard JY, et al., JTO 2010

21 Vinorelbine + cisplatin in adjuvant setting Vinorelbine plus cislatin improve overall and disease-free survivals of patients with resected NSCLC Vinorelbine 30 mg/m² associated with cisplatin 320 to 400 mg/m² are the recommended doses What about the other cisplatin-doublets?

22 E1505 Chemotherapy Subset Analysis in Early Stage, Resected NSCLC E1505: randomized phase III study evaluated bevacizumab plus cisplatin-based doublet chemotherapy in early stage resected NSCLC(n=1501) Cisplatin partners: vinorelbine (n=377), docetaxel (n=343), gemcitabine (n=283), pemetrexed(n=497) Bevacizumab addition failed to improve OS (HR: 0.99; 95% CI: ; P =.90) or DFS(HR:0.99;95%CI: ;P=.95) [3] Trial stopped early for futility Wakelee HA, et al. ASCO Abstract 8507.

23 E1505 Chemotherapy Subset Analysis in Early Stage, Resected NSCLC OS not significantly different between chemotherapy groups Wakelee HA, et al. ASCO Abstract 8507.

24 Squamous (n = 422) Nonsquamous (n = 1078) E1505 AEs Grade 3 AEs, % V (n = 127) D (n = 140) G (n = 149) V (n = 241) D (n = 199) G (n = 132) Anemia Febrile neutropenia Neutropenia Thrombocytopeni a Fatigue P (n = 485) Diarrhea Nausea Vomiting Dehydration Hypertension Thromboembolis m Wakelee HA, et al. ASCO Abstract WORST DEGREE

25 E1505 Chemotherapy Subset Analysis: Conclusions OS and DFS by chemotherapy subset in pts receiving adjuvant cisplatinbased chemotherapy for early stage resected NSCLC are similar Toxicity profiles of chemotherapy agents similar to known profiles Neutropenia/febrile neutropenia occurred more frequently with vinorelbine and thrombocytopenia occurred more frequently with gemcitabine Grade 3 toxicity lower in pemetrexed (nonsquamous) group than in other chemotherapy groups(p <.001) Wakelee HA, et al. ASCO Abstract 8507.

26 «Adjuvant chemotherapy should be offered to patients with resected stage II and III [I,A] and can be considered in patients with resected stage IB disease and a primary tumor > 4cm[II,B]. Pre-existing comorbidities, time from surgery and post-operative recovery need to be taken into account in this decision in a multidisciplinary tumor board[v,a]. For adjuvant chemotherapy, a two-drug combination with cisplatin is preferable [I,A]. In randomised studies, the attempted cumulative cisplatin dose was up to 300mg/m², delivered in 3 to 4 cycles. The most frequently studied regimen is cisplatin-vinorelbine. In the current stage of knowledge, the choice of adjuvant chemotherapy should not be guided by molecular analysis such as, e.g. ERCC-1 or mutation testing[iv,b]»

27 Is there a place for neo adjuvant chemotherapy? n Stage Phase III Overall Survival DepierreA, et al J Clin Oncol I, II, IIIA pre-op CT vs surgery no difference except for stage I,II Gilligan D, et al (MRC) Lancet 2007 PistersKM, et al (SWOG 9900) J Clin Oncol I,II,III pre-op CT vs surgery no difference 354 IB, II, IIIA pre-op CT vs surgery no difference Scagliotti GV, et al (2012) J Clin Oncol IB, II, IIIA pre-op CT vs surgery no difference except for stage IIB, IIIA WesteelV, et al (IFCT 0002) EurJ Cancer I, II pre-op CT vs peri-op CT no difference FelipE, et al (NATCH) J Clin Oncol IA (>2cm), II, T3N1 pre-op CT vs post-op CT vs surgery no difference

28 The NATCH trial Pre operative chemo. vs surgery Adjuvant chemo. vs surgery In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment. FelipE, et al. J Clin Oncol2010

29 Meta analysis: pre operative chemotherapy versus surgery alone Pre operative chemotherapy versus surgery alone 2,200 patients 10 studies ScagliottiGV, et al. J Clin Oncol2011

30 Pre operative chemotherapy for NSCLC Meta analysis of individual participant data Stage IB to IIIA 15 randomized controlled trials 2,385 patients HR 0.87 ( ) BurdettS, et al. Lancet 2014

31 Pre operative chemotherapy for NSCLC Meta analysis of individual participant data The absolutesurvivalimprovementat5 yearswas5 %(40% to 45 %) BurdettS, et al. Lancet 2014

32 Pre operative chemotherapy for NSCLC Meta analysis of individual participant data Forest plot of the interactions between the effect of preoperative chemotherapy on survival and covariates Noevidenceofadifferenceintheeffect on survival by chemotherapy regimen number of drugs platinum agent used age sex performance status histology clinical stage BurdettS, et al. Lancet 2014

33 In view of the equivalence of neo-adjuvant and adjuvant chemotherapy for overall survival, the consistent results and broad evidence base support adjuvant chemotherapy as the timing of choice[i, A].

34 What is the role of surgery for stage IIIA? n Stage Phase III Albain KS, et al INT T1 T3 N2 CDDP/VP16 x 2 + RT 45 Gy, thensurgery, and CDDP/VP16 x 2 CDDP/VP16 x 2 + RT 45 Gy, thenrt 16 Gy, thencddp/vp16 x 2 No statistical difference between both arms An unplanned exploratory analyses showed survival advantage for patients who underwent lobectomy Albain KS, et al. Lancet 2009

35 What is the role of surgery for stage IIIA? n Stage Phase III Van MeerbeeckJP, et al EORTC IIIA-N2 Cisplatin-based chemo. then surgery Cisplatin-based chemo. then RT 60 gy Unresectable disease at diagnosis Induction chemotherapy : ORR 61% 167 patients were allocated to resection and 165 to radiotherapy. Results : surgical resection did not improve overall survival compared with radiotherapy. Radiotherapy should be considered the preferred locoregional treatment for these patients. Van MeerbeeckJP, et al. J NatlCancer Inst2007

36 Neo adjuvant chemo. or neo adjuvant CT RT? n Stage Phase III SAKK 16/ Stage IIIA N2 Docetaxel/cisplatinx 3, thenradiotherapyfollowedby surgery Docetaxel/cisplatin x 3 then surgery Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. Authors suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. PlessM, et al. Lancet 2015

37 incidental IIIA(N2)(unforeseen N2) Recommendation: If, despite adequate mediastinal staging procedures, N2 disease is only documented intra-operatively, surgery should be followed by adjuvant chemotherapy [I, A]. In case of complete resection, addition of post-operative radiotherapy is not routinely recommended, but may be an option following individual risk assessment[v, C].

38 Potentially resectable IIIA(N2) disease(pre-operative diagnosis of IIIA-N2) several options: induction CT followed by surgery, induction CT/RT followed by surgery, or concurrent definitive CT/RT [I, A]. No recommendation can yet be made; however, an experienced multidisciplinary team is of paramount importance in any complex multi-modality treatment strategy decision. If induction chemotherapy alone is given preoperatively, postoperative radiotherapy is not standard treatment but may be an option based on critical evaluation of locoregional relapse risks[iv, C].

39 In potentially resectable superior sulcus tumours, concurrent chemoradiotherapy induction followed by definitive surgery is the treatment of choice [III, A]. The same strategy may be applied for potentially resectable T3 or T4 central tumours in highly selected cases and experienced centres[iii, B]. In both situations, surgery should be carriedoutwithin4weeksaftertheendofradiotherapy[iii,b].