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

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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