ESMO Preceptorship Programme NSCLC Singapore 15 November 2017

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1 ESMO Preceptorship Programme NSCLC Singapore 15 November 2017 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 University Hospital of Nantes (Thoracic Unit - Innovation and Care in Oncology)

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

3 UICC TNM 8 T1a 1 cm ; T1b > 1 cm to 2 cm ; T1c > 2 cm to 3 cm T2a > 3 cm to 4 cm ; T2b > 4 cm to 5 cm or atelectasis/pneumonitis ; or involvement of main bronchus (no involvement of the carina) ; or visceral pleura invasion T3 > 5 cm to 7 cm or associated with separate tumour nodule(s) in the same lobe as the primary tumour; or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus) ; phrenic nerve ; parietal pericardium T4 > 7 cm tumour >7 cm in greatest dimension or associated with separate tumour nodule(s) in a different ipsilateral lobe than that of the primary tumour or invades any of the following structures: diaphragm, mediastinum, heart, great vessels ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017) From Brierley JD, et al.

4 Histopathologic features Histopathologic characteristics associated with poor prognosis, Perineural invasion, tumor necrosis, vascular invasion, and/or lymphatic invasion Presence of visceral pleural invasion (upstages tumors < 3 cm to pt2a). Micropapillary or solid: high risk Acinar, papillary, or invasive mucinous: intermediate risk Minimally invasive or lepidic: low risk. Kris MG, et al. ASCO Guideline. J Clin Oncol 2017

5 Treatment for patients with loco-regional NSCLC ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017)

6 The MRC 1995 meta-analysis 14 randomized trials : 4357 patients 1st group : alkylating agents-containing regimen risk of death : + 15 % survival : - 5 % at 5 y. 2cnd group : UFT-based chemo. HR 0.89 (p=0.30) in favour of CT non conclusive results 3rd group : cisplatin-based chemo. Non-small Cell Lung Cancer Collaborative Group - BMJ 1995

7 MRC 1995 meta-analysis (3rd group : CDDP-based chemo.) 8 randomized phase III trials pts Surgery vs surgery + cisplatin-based chemo. Absolute benefit from chemo. of 5 % at 5 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-small Cell Lung Cancer Collaborative Group - BMJ 1995

8 2010 : Adjuvant chemo., with or without postoperative radiotherapy, in operable NSCLC: two meta-analyses of individual patient data 1 st meta-analysis : surgery + CT versus surgery 34 trials : 8447 patients absolute increase in survival of 4% at 5 y. (from 60% to 64%) HR 0.86 ( ) 2cnd meta-analysis : surgery + RT-CT versus surgery + RT 13 trials : 2660 patients absolute increase in survival of 4% at 5 y. (from 29% to 33%). HR 0.88 ( ) NSCLC Meta-analyses Collaborative Group. Lancet 2010

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

10 From ASCO Guidelines 2017 Felip E, et al. J Clin Oncol 2010 Ou W, et al. J Thorac Oncol 2010

11 7 major adjuvant studies in 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 vs obs 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 + cisplatin vs obs 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 Cancer Inst 2003 ; Waller D, et al. Eur J Cardi Thoac Surg 2004 ; Winton T, et al. N Engl J Med 2005 ; Douillard JY, et al. Lancet Oncol 2006

12 IALT : randomized phase III study (n=1,867) Stage I (36 %) ; II (24 %) ; IIIA (40 %) Pneumonectomy (35 %) ; squamous histology (46 %) ; adjuvant radiotherapy (31 %) Arriagada R, et al. N Engl J Med 2004 Arriagada R, et al. J Clin Oncol 2010

13 IALT : randomized phase III study (n=1,867) Significant benefit of cisplatin-based CT at 5 y. HR 0.86 (p=0.03) ; +4.1 % at 5 years, An updated analysis was later published at 7.5 y. HR 0.91 ; p= An excess of non-cancer related deaths was noticed in the chemo. arm with time Long FU is needed to really evaluate the benefit of ajuvant CT Arriagada R, et al. N Engl J Med 2004 Arriagada R, et al. J Clin Oncol 2010

14 CALGB 9633 : A randomized phase III study (n=344) Stage IB only ; Lobectomy (89 %) ; squamous histology (39 %) Compliance (paclitaxel + carboplatin arm) : 4 cycles (85 %) ; 55 % (full dose) Overall population Tumor 4 cm Adjuvant chemotherapy is not the standard of care for all patients with stage IB NSCLC Strauss G M et al. J Clin Oncol 2008

15 JBR10 : A randomized phase III study (n=482) Stage IB (45 %) ; IIA (15 %) ; IIB (40 %) ; pneumonectomy (23 %) Chemo arm : vinorelbine weekly 25 mg/m² + cisplatin 50 mg/m² d1,d8 (4 cycles d1,d28) The median follow-up was 9.3 years with a confirmed benefit, still confined to stage II For stage IB and size 4 cm ; HR 0.66 ( ) Overall survival : stage II Overall survival : stage IB Winton T, et al. N Engl J Med 2005 ; Butts CA, et al. J Clin Oncol 2010

16 Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National Cancer Institute of Canada and Intergroup Study JBR.10 Overall Survival Disease Specific Survival Adjuvant chemo : similar benefit according to age: > 65 y and < 65 y (data not shown) Loss of benefit for patients > 75 y (low number of patients) Pepe C, et al. J Clin Oncol 2007

17 ANITA trial : A randomized phase III study (n=840) Stage IB (35 %) ; II (30 %) ; IIIA (35 %) ; lobectomy (58 %) ; Squamous histology (59 %) Chemo arm: vinorelbine weekly 30 mg/m² + cisplatin 100 mg/m² d1(4 cycles d1,d28) Compliance: Median % planned dose: CDDP 76%, VNR 56% OBS. NVB + CDDP mos 43.7 mo mo. P- value HR 0.80 [ ] % benefit in OS 1 years years years years +8.4 Douillard JY et al. Lancet Oncol 2006

18 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

19 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% Overall Survival of VNR + CDDP regimens PORT= post-operative RT Pignon JP, et al. J Clin Oncol 2008; Douillard JY, et al., J Thorac Oncol 2010

20 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. J Clin Oncol 2008; Douillard JY, et al., J Thorac Oncol 2010

21 LACE meta-analysis : according to TNM stage LACE LACE NAVELBINE Detrimental effect for stage I Pignon JP, et al. J Clin Oncol 2008; Douillard JY, et al., J Thorac Oncol 2010

22 Predicted outcome of 100 patients treated with surgery and adjuvant chemotherapy group 1 (blue): those who die within 5 years whether they receive chemotherapy or not group 2 (gold): those who live without receiving chemotherapy group 3 (gray): those who live because of adjuvant chemotherapy (gray) group 4 (red): those who die because of chemotherapy (red) Kris MG, et al. ASCO Guideline. J Clin Oncol 2017

23 Vinorelbine + cisplatin in adjuvant setting Vinorelbine plus cislatin improve overall and disease-free survivals of patients with resected NSCLC stage II and IIIA Vinorelbine 30 mg/m² associated with cisplatin 320 to 400 mg/m² are the recommended doses What about the other cisplatin-doublets? Pignon JP, et al. J Clin Oncol 2008; Douillard JY, et al., J Thorac Oncol 2010

24 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.

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

26 Grade 3 AEs, % V (n = 127) Squamous (n = 422) Nonsquamous (n = 1078) D (n = 140) G (n = 149) V (n = 241) D (n = 199) G (n = 132) P (n = 485) E1505 AEs Anemia Febrile neutropenia Neutropenia Thrombocytopenia Fatigue Diarrhea Nausea Vomiting Dehydration Hypertension Thromboembolism WORST DEGREE Wakelee HA, et al. ASCO Abstract 8507.

27 ADJUVANT: Phase III Trial Evaluating Gefitinib vs Vinorelbine/Cisplatin in Completely Resected Stage II-IIIA (N1-N2) NSCLC With EGFR Activating Mutations Randomized, phase III trial Stratified by EGFR mutation, N stage Pts yrs, with completely resected pathologic stage II-IIIA (N1-N2) NSCLC and centrally confirmed EGFR activating mutation (exon 19 del or exon 21 L858R); ECOG PS 0-1 (N = 222) Gefitinib 250 mg/day for up to 2 yrs (n = 111) Vinorelbine 25 mg/m 2 on Days 1, 8 + Cisplatin 75 mg/m 2 on Day 1 every 3 wks for up to 4 cycles (n = 111) Primary endpoint: DFS Secondary endpoints: 3-yr DFS, 5-yr DFS, OS, 5-yr OS, safety, HRQoL, exploratory biomarker analyses Wu YL, et al. ASCO Abstract 8500.

28 ADJUVANT: Phase III Trial Evaluating Gefitinib vs Vinorelbine/Cisplatin in Completely Resected Stage II-IIIA (N1-N2) NSCLC With EGFR Activating Mutations Gefitinib vs VNR-Cis Median DFS (months) 28.7 vs 18 - HR 0.60 ( ) ; p= yr DFS rate, % 34 vs patients were not treated in chemo. Arm Wu YL, et al. ASCO Abstract 8500.

29 Is there a place for neo-adjuvant chemotherapy? n Stage Phase III Overall Survival Depierre A, et al (MIP91) J Clin Oncol I, II, IIIA pre-op CT vs surgery no difference except for stage I,II Gilligan D, et al (MRCLU22) Lancet 2007 Pisters KM, 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 Westeel V, et al (IFCT 0002) Eur J Cancer I, II pre-op CT vs peri-op CT no difference Felip E, et al (NATCH) J Clin Oncol IA (>2cm), II, T3N1 pre-op CT vs post-op CT vs surgery no difference 2 trials closed early after results of a benefit survival for postoperative CT

30 General comments regarding neo-ajuvant chemotherapy IFCT 0002 : Compliance for 4 cycles of chemotherapy (CT) Pre-operative (90.4 %) vs peri-operative (75.2 %) : p=0.001 MIP91 + IFCT0002 : survival rate of responders vs non responders 80 % vs 55.8 % (p=0.0007) Reccurence of patients in histologic CR (41/492) vs non histologic CR 2/41 (4.9 %) vs 193/299 (42.9 %)

31 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 (96 %) than adjuvant treatment (66 %). Felip E, et al. J Clin Oncol 2010

32 DFS in PR/CR to preop CT vs adj CT vs surgery At risk: Preop CT Adj CT Surgery Surgery Adj CT PR/CR to Preop CT (N=210) (N=210) (N= 106) 3-year DFS 42% 45% 59% 5-year EFS 34% 37% 51% Surgery Preop CT (PR/CR) Adj CT years Felip E, et al. J Clin Oncol 2010

33 Meta-analysis: pre-operative chemotherapy versus surgery alone Pre-operative chemotherapy versus surgery alone 2,200 patients 10 studies Scagliotti GV, et al. J Clin Oncol 2011

34 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 ( ) Burdett S, et al. Lancet 2014

35 Pre-operative chemotherapy for NSCLC Meta-analysis of individual participant data The absolute survival improvement at 5 years was 5 % (40 % to 45 %) Burdett S, et al. Lancet 2014

36 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 No evidence of a difference in the effect on survival by chemotherapy regimen number of drugs platinum agent used age sex performance status histology clinical stage Burdett S, et al. Lancet 2014

37 ESMO Guidelines Adjuvant ChT should be offered to patients with resected stage II and III NSCLC [I, A] and can be considered in patients with resected stage IB disease and a primary tumour>4 cm [II, B]. Pre-existing comorbidity, time from surgery and postoperative recovery need to be taken into account in this decision taken in a multidisciplinary tumour board [V, A]. For adjuvant ChT, a two-drug combination with cisplatin is preferable [I, A]. In randomised studies, the attempted cumulative cisplatin dose was up to 300 mg/m2, delivered in three to four cycles. The most frequently studied regimen is cisplatin vinorelbine. At the present time, the choice of adjuvant therapy should not be guided by molecular analyses, e.g. ERCC1 mutation testing [IV, B]. In the current state of knowledge, targeted agents should not be used in the adjuvant setting [II, A]. In view of the equivalence of neoadjuvant and adjuvant ChT for OS, the consistent results and broad evidence base support adjuvant ChT as the timing of choice [II, C]. (Neo)adjuvant anti-pd(l)-1 checkpoint inhibitors are currently being evaluated in addition to current standard of care. ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017)

38 ESMO Guidelines PORT in completely resected early-stage NSCLC is not recommended [I, A]. In case of R1 resection (positive resection margin, chest wall), PORT should be considered [IV, B]. Even if such patients were not included in RCTs, adjuvant ChT should be considered in patients with R1 resection of stage IB disease and a primary tumour > 4 cm, stage II and III [V, A]. In case both ChT and RT are administered post-surgery, RT should be administered after ChT [V, C]. ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017)

39 Resectable stage III NSCLC If single station N2 disease can be demonstrated by preoperative pathological nodal analysis, resection followed by adjuvant ChT, induction ChT followed by surgery or induction CRT followed by surgery are options. If induction ChT alone is given preoperatively, PORT is not standard treatment, but may be an option based on critical evaluation of locoregional relapse risks [IV, C]. In multi-station N2 or N3, concurrent definitive CRT is preferred [I, A]. An experienced multidisciplinary team is of paramount importance in any complex multimodality treatment strategy decision, including the role of surgery in these cases [IV, C]. If, despite adequate mediastinal staging procedures, N2 disease is only documented intra-operatively, surgery should be followed by adjuvant ChT [I, A]. In case of complete resection, addition of PORT is not routinely recommended, but may be an option following individual risk assessment [V, C]. In potentially resectable superior sulcus tumours, concurrent CRT 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 carried out within 4 weeks after the end of RT [III, B]. ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017)