Neoadjuvant Therapy for Resectable and Borderline Resectable ...
State‐of‐the‐art: Standard of care for resectable ...€¦ · chest wall (including the...
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State‐of‐the‐art: Standard of care for resectable NSCLCAdjuvant chemotherapyIs there a place for neo-adjuvant chemotherapy?
ESMO Preceptorship Programme NSCLC – Singapore 15 November 2017
Pr Jaafar BENNOUNA✓ Université de Nantes - France✓ University Hospital of Nantes ✓ (Thoracic Unit - Innovation and Care in Oncology)
COI Disclosure
Advisory Boards and Symposium presentations
✓ Astra-Zeneca✓ Boehringer-Ingelheim✓ Lilly✓ Roche✓ BMS
From Brierley JD, et al. ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017)
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
UICC TNM 8
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.
Histopathologic features
Kris MG, et al. ASCO Guideline. J Clin Oncol 2017
ESMO Guidelines (Postmus PE, et al. Ann Oncol 2017)
Treatment for patients with loco-regional NSCLC
The MRC 1995 meta-analysis
Non-small Cell Lung Cancer Collaborative Group - BMJ 1995
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
Only trials with cisplatin-based chemotherapy
8 randomized phase III trials - 1394 pts
Surgery vs surgery + cisplatin-based chemo.
Absolute benefit from chemo. of 5 % at 5 years
Not statistically significant:
✓ HR: 0.87 [95% CI: 0.74-1.02] (p=0.08)
These findings prompted renewed interest of
postoperative chemotherapy in completely
resected NSCLC.
MRC 1995 meta-analysis (3rd group : CDDP-based chemo.)
NSCLC Meta-analyses Collaborative Group. Lancet 2010
2010 : Adjuvant chemo., with or without postoperative radiotherapy, in operableNSCLC: two meta-analyses of individual patient data
▪ 1st 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 (0.81 – 0.92)
▪ 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 (0.81 – 0.97)
NSCLC Meta-analyses Collaborative Group. Lancet 2010
Effect of adjuvant treatmentaccording to the type ofchemotherapy
From ASCO Guidelines 2017Felip E, et al. J Clin Oncol 2010Ou W, et al. J Thorac Oncol 2010
study n stage chemotherapy comments
CALGB 9633 344 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 10 482 IB - II vinorelbine + cisplatin vs obs Significant survival benefit at 5 years for stage II
Benefit maintained after 9 years.
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
7 major adjuvant studies in NSCLC
* TNM V and VI classification
Arriagada R, et al. N Engl J Med 2004Arriagada R, et al. J Clin Oncol 2010
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 2004Arriagada R, et al. J Clin Oncol 2010
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=0.10
2004 2010
▪ 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
Strauss G M et al. J Clin Oncol 2008
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
Winton T, et al. N Engl J Med 2005 ; Butts CA, et al. J Clin Oncol 2010
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 (0.39 – 1.14)
Overall survival : stage II Overall survival : stage IB
Overall Survival Disease Specific Survival
Pepe C, et al. J Clin Oncol 2007
Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National CancerInstitute of Canada and Intergroup Study JBR.10
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)
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%
Douillard JY et al. Lancet Oncol 2006
OBS. NVB + CDDP
mOS 43.7 mo. 65.7 mo.
P-value
0.017
HR 0.80 [0.66 - 0.96]
% benefit in OS
1 years +3.1
2 years +5.1
5 years +8.6
7 years +8.4
ANITA trial : survival according to lymph nodes status
N0 status N1 status N2 status
OBS. CT
mOS 99.6 95.5
OBS. CT
mOS 31.2 65.7
OBS. CT
mOS 20.0 32.6
Douillard JY et al. Lancet Oncol 2006
LACEmeta-analysis
LACE vinorelbinemeta-analysis
Population Patients with completely resected NSCLC
Inclusion criteriaCDDP-based vs Obs
CDDP-based + PORT vs PORT
NVB + CDDP vs Obs
NVB + CDDP + PORT vs PORT
Included studies5 studies included
ALPI, BLT, IALT, JBR10, ANITA
4 studies included
BLT, IALT, JBR10, ANITA
Patients characteristicsn= 4,584
IA: 8%, IB: 30%, II: 35%, III: 27%
n= 1,888
IA: 2%, IB: 34%, II: 38%, III: 26%
Main objectiveOverall Survival of
CDDP-based regimens
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
LACE meta-analysis
LACE LACE NAVELBINE
• 5 trials• Absolute survival benefit of 5.3% at 5-years
• 4 trials• Absolute survival benefit of 8.9% at 5-years
LACE meta-analysis
Pignon JP, et al. J Clin Oncol 2008; Douillard JY, et al. , J Thorac Oncol 2010
LACE meta-analysis : according to TNM stage
LACE NAVELBINELACE
Detrimental effect for stage I
Pignon JP, et al. J Clin Oncol 2008; Douillard JY, et al. , J Thorac Oncol 2010
✓ 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)
Predicted outcome of 100 patients treated with surgery and adjuvant chemotherapy
Kris MG, et al. ASCO Guideline. J Clin Oncol 2017
▪ Vinorelbine plus cislatin improve overall and disease-free survivals ofpatients with resected NSCLC stage II and IIIA
▪ Vinorelbine 30 mg/m² associated with cisplatin 320 to 400 mg/m² are therecommended doses
▪ What about the other cisplatin-doublets ?
Vinorelbine + cisplatin in adjuvant setting
Pignon JP, et al. J Clin Oncol 2008; Douillard JY, et al. , J Thorac Oncol 2010
E1505 Chemotherapy Subset Analysis in Early-Stage,Resected NSCLC
▪ E1505: randomized phase III study evaluated bevacizumab plus cisplatin-baseddoublet 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: 0.82-1.19; P = .90) orDFS (HR: 0.99; 95% CI: 0.86-1.15; P = .95)[3]
✓ Trial stopped early for futility
Wakelee HA, et al. ASCO 2016. Abstract 8507.
E1505 Chemotherapy Subset Analysis in Early-Stage,Resected NSCLC
Wakelee HA, et al. ASCO 2016. Abstract 8507.
OS not significantly different between chemotherapy groups
E1505 AEs
Grade ≥ 3 AEs, %
Squamous (n = 422) Nonsquamous (n = 1078)
V (n = 127)
D(n = 140)
G(n = 149)
V (n = 241)
D(n = 199)
G(n = 132)
P (n = 485)
Anemia 12 3 15 12 3 7 4
Febrile neutropenia 9 6 1 15 7 2 0
Neutropenia 54 39 41 58 40 44 12
Thrombocytopenia 3 2 23 3 2 12 1
Fatigue 15 17 12 15 13 9 9
Diarrhea 6 9 1 5 10 2 1
Nausea 8 15 11 11 11 5 8
Vomiting 6 12 5 6 7 3 5
Dehydration 12 12 7 10 11 2 3
Hypertension 17 14 19 17 12 18 25
Thromboembolism 6 2 5 6 4 9 3
WORST DEGREE 85 80 82 83 74 83 64
Wakelee HA, et al. ASCO 2016. Abstract 8507.
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
▪ Pts 18-74 yrs, with completelyresected pathologic stage II-IIIA(N1-N2) NSCLC and centrallyconfirmed EGFR activatingmutation (exon 19 del or exon21 L858R);
▪ ECOG PS 0-1▪ (N = 222)
Gefitinib 250 mg/day for up to 2 yrs(n = 111)
Vinorelbine 25 mg/m2 on Days 1, 8 + Cisplatin 75 mg/m2 on Day 1every 3 wks for up to 4 cycles
(n = 111)
Stratified by EGFR mutation, N stage
Wu YL, et al. ASCO 2017. Abstract 8500.
▪ Primary endpoint: DFS▪ Secondary endpoints: 3-yr DFS, 5-yr DFS, OS, 5-yr OS, safety, HRQoL, exploratory biomarker analyses
Gefitinib vs VNR-Cis✓ Median DFS (months) 28.7 vs 18
- HR 0.60 (0.42 – 87) ; p=0.005✓ 3-yr DFS rate, % 34 vs 27
23 patients were not treated in chemo. Arm
ADJUVANT: Phase III Trial Evaluating Gefitinib vs Vinorelbine/Cisplatin in Completely Resected Stage II-IIIA (N1-N2) NSCLC With EGFR Activating Mutations
Wu YL, et al. ASCO 2017. Abstract 8500.
Is there a place for neo-adjuvant chemotherapy ?
n Stage Phase III Overall Survival
Depierre A, et al (MIP91)
J Clin Oncol 2002355 I, II, IIIA pre-op CT vs surgery
no differenceexcept for stage I,II
Gilligan D, et al (MRCLU22)
Lancet 2007519 I,II,III pre-op CT vs surgery no difference
Pisters KM, et al (SWOG 9900)
J Clin Oncol 2010354 IB, II, IIIA pre-op CT vs surgery no difference
Scagliotti GV, et al (2012)
J Clin Oncol 2011270 IB, II, IIIA
pre-op CT vs surgery no difference
except for stage IIB, IIIA
Westeel V, et al (IFCT 0002)
Eur J Cancer 2013528 I, II pre-op CT vs peri-op CT no difference
Felip E, et al (NATCH)
J Clin Oncol 2010624
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
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 %)
Felip E, et al. J Clin Oncol 2010
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 %)”.
130 98 77 53 34 23
131 95 71 54 37 25
85 68 54 38 26 17
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0 1 2 3 4 5 6years
At risk:
Surgery
Adj CT
Preop CT
DFS in PR/CR to preop CT vs adj CT vs 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%
Adj CT
Surgery
Preop CT (PR/CR)
Felip E, et al. J Clin Oncol 2010
Meta-analysis: pre-operative chemotherapyversus surgery alone
Pre-operative chemotherapy versus surgery alone
Scagliotti GV, et al. J Clin Oncol 2011
▪ 2,200 patients▪ 10 studies
Pre-operative chemotherapy for NSCLCMeta-analysis of individual participant data
Burdett S, et al. Lancet 2014
▪ Stage IB to IIIA▪ 15 randomized controlled trials▪ 2,385 patients▪ HR 0.87 (0.78 – 0.96)
Pre-operative chemotherapy for NSCLCMeta-analysis of individual participant data
Burdett S, et al. Lancet 2014
▪ The absolute survival improvement at 5 years was 5 % (40 % to 45 %)
Pre-operative chemotherapy for NSCLCMeta-analysis of individual participant data
Burdett S, et al. Lancet 2014
Forest plot of the interactions betweenthe effect of preoperative chemotherapyon survival and covariates
No evidence of a difference in the effecton survival by▪ chemotherapy regimen▪ number of drugs▪ platinum agent used
▪ age▪ sex▪ performance status▪ histology▪ clinical stage
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)
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 inpatients 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)
ESMO Guidelines
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 isnot 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 paramountimportance 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 byadjuvant 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 experiencedcentres [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)
Resectable stage III NSCLC