combined modality treatment for n2 disease · combined modality treatment for n2 disease dr clara...

The Christie NHS Foundation Trust

Combined modality treatment for N2 disease

Dr Clara Chan

Consultant in Clinical Oncology

8th March 2019


DISCLOSURE OF INTEREST

No disclosures.


Overview

• Background

• The evidence base

• Systemic treatment

• Radiotherapy

• Future directions/clinical trials


Background

• 25-30% of NSCLC pts have stage III disease

• Few locally advanced NSCLC patients are candidates

for surgery

• Survival is poor

• stage IIIA 10-25% 5 year survival

• Scope for improving local and distant control


Radical treatment options for N2 disease

• Surgery

• Radiotherapy alone

• Sequential chemo-radiotherapy

• Concurrent chemo-radiotherapy

• Trimodality treatment


Sequential chemoradiotherapy

• BMJ metanalysis 1995:

• hazard ratio of 0.87 in favour of combined treatment

• 13% reduction in the risk of death

• Absolute benefit of 4% at two years

• Heterogeneity in chemotherapy regimens and

radiotherapy schedules used


Concurrent chemoradiotherapy

• Auperin metanalysis

2010: • Concurrent CTRT

superior to sequential

• HR 0.83 overall survival

in favour of concurrent

• 4.5% survival benefit at

5 years

• Significantly higher

oesophagitis rate (HR

4.9)

• similar pneumonitis rate

Anne Aupérin et al. JCO 2010;28:2181-2190


Walter J. Curran, Jr et al. JNCI J Natl Cancer Inst 2011;103:1452-1460

Concurrent chemoradiotherapy

• RTOG 9410

• Concurrent CTRT

superior to sequential

• 5 yr survival 16% v

10% (p=0.046)

• Acute G3-5 toxicity

higher with concurrent

• Late toxic effects

similar


Patient selection

• Performance status

PS 0-1

• Co morbidities

• PET

Encompassable within radical field

• Mediastinal staging

• Brain imaging

• Pulmonary function testing

• FEV1 > 40%

• KCO >40%

• Age


Which chemotherapy?

• Platinum based chemo with 3rd generation drugs

• Taxol/Gemcitabine/Vinorelbine (reduced doses)

• Cisplatin/Etoposide (full dose)

• Emerging role for Carboplatin/Paclitaxel

• No benefit of Pemetrexed in concurrent setting (PROCLAIM trial)

• No evidence to support the use of TKI in the

concurrent setting

Vokes JCO 2002, Hanna JCO 2008, Santana-Devilla JCO 2015

Senan, JCO 2016


? More systemic treatment

• Concurrent CTRT optimises local control but

distant spread is still a major problem

• Further systemic treatment to optimise treatment

of distant disease


? More systemic treatment

• No benefit to induction chemotherapy

• CALGB 39801 (Vokes, JCO 2007)

• No benefit to consolidation chemotherapy

• HOG 01-24 (Hanna, JCO 2008)

• KCSG-LU05-04 (Ahn, JCO 2015)

Consolidation Immunotherapy -PACIFIC

• Unresectable, Stage III NSCLC

without progression after definitive

platinum-based cCRT (≥2 cycles)

• 18 years or older

• WHO PS score 0 or 1

• If available, archived pre-cCRT

tumor tissue for PD-L1 testing*

All-comers population

(i.e. irrespective of PD-L1 status)

N=713 randomized

Durvalumab10 mg/kg q2w for

up to 12 months

N=476

Placebo

for up to 12 months

N=237

2:1 randomization,

stratified by age, sex,

and smoking history

R

1–42 days

post-cCRT

Antonia S, et al. NEJM 2017; 377:1919–29;

Antonia S, et al. NEJM 2018; 379:2342-2350

PFS HR = 0.52 95% CI, 0.42–0.65

P<0.001

Antonia S, et al. NEJM 2017; 377:1919–29

OS HR = 0.68 99.73% CI, 0.469–0.997†

P=0.00251

Antonia S, et al. NEJM 2018; 379:2342-2350


Radiotherapy planning

• RT commences D1 chemotherapy

• RT planning scan done asap

• Motion management

• 4D CT

• Respiratory gating/Breath hold

• Advanced RT techniques

• IMRT

• IGRT


4D CT


Intensity Modulated RadiotherapyIMRT

• Improved conformity

• Avoidance of radiosensitive structures eg spinal cord

• Retreatments

• Large volumes


• Sequential CTRT

• 60-66Gy/30-33# OD

• 55Gy/20# OD

• 54Gy/36# TDS (CHART)

• Concurrent CTRT

• 60-66 Gy in 30-33 fractions OD

What RT?


More radiotherapy?

• Greater local control correlates with improved

survival

• Modern RT techniques allow dose escalation

• Recent RTOG 0617 study

• No defined role for dose escalation


RTOG 0617

• Higher dose arm:

• Greater risk of locoregional failure

• Poorer survival

Lo

ca

l P

rog

ressio

n R

ate

(%

)

0

25

50

75

100

Months since Randomization

0 3 6 9 12 15 18

Patients at RiskStandardHigh dose

213206

205197

187170

165134

137105

113 80

85 62

Fail

6581

HR=1.37 (0.99, 1.89)

Total

213206

p=0.0319

Standard (60 Gy)High dose (74 Gy)

Su

rviv

al R

ate

(%

)

0

25

50

75

100

Months since Randomization

0 3 6 9 12 15 18

Patients at RiskStandardHigh dose

213206

207197

190178

177159

161135

141112

108 87

Dead

90117

Total

213206

HR=1.56 (1.19, 2.06) p=0.0007

Standard (60 Gy)High dose (74 Gy)


Chemoradiotherapy – summary

• Gold standard: Concurrent platinum based CTRT

• No consensus on chemo regimen

• Modern RT techniques allow better sparing of normal

tissue

• For patients with > 1% PD-L1 expression,

maintenance Durvalumab now standard of care

• For patients unsuitable for concurrent treatment,

sequential CTRT or radiotherapy alone

• No benefit to radiotherapy dose escalation with

conventional fractionation


What combination of treatment is best for potentially resectable N2

disease?


EORTC 08941 – overall survival

Van Meerberck et al, J Natl Cancer Inst 2007;99:442-50

The Christie NHS Foundation TrustAlbain, Lancet. 2009 Aug 1;374(9687):379-86


SAKK 16/00

Pless et al, Lancet 2015


Potentially resectable N2 disease –summary

• Trimodality treatment may have a role in selected

operable cases

• No survival benefit to surgery over definitive CTRT

• Uncertain benefit of induction CTRT versus chemotherapy

• Importance of

• Team working/MDT decision

• Local surgical expertise (avoid pneumonectomies)


Have we made progress in inoperable stage III NSCLC?

CAUTION! Will Rodger phenomenon

Median survival(months)

2 yrssurvival

RT 10 15%

CT → RT 14 30%

CTRT

prePET erapostPET era

1724-26

35%Up to 60%


Future directions

• Individualised treatment

• Personalised RT dose

• Combinations with novel agents

• Proton therapy


ADSCaNA Randomised Phase II study of Accelerated, Dose escalated, Sequential

Chemo-radiotherapy in Non-Small Cell Lung Cancer


CONCORDEPlatform study of novel agents in COmbinatioN with

COnventional RaDiothErapy in locally advanced disease


PACIFIC-2

A phase III placebo controlled study of Durvalumab + RCTfollowed by Durvalumab maintenance for unresectable stage III NSCLC

R

PD

PDKey patient inclusion criteria

• Unresectable stage III NSCLC

• ECOG 0-1

• No progression after

chemoradiotherapy (≥2 cycles of

platinum based and ≥50 Gy)

(n=300)CRT 60Gy + Placebo

---Placebo maintenance

CRT 60Gy + Durvalumab

--- Durvalumab maintenance

Primary endpoint

PFS, ORRNCT03519971


Take home messages

• Concurrent platinum based chemoradiotherapy remains

gold standard for inoperable N2 disease

• Overall survival benefit to consolidation Durvalumab

• No benefit to radiotherapy dose escalation

• Trimodality treatment may be appropriate in selected

operable cases

• Improved RT techniques may allow greater

individualisation of treatment in the future


Consolidation Pembrolizumab Following CCRT for Unresectable Stage III NSCLC: LUN 14-179

Presented By Greg Durm at 2018 ASCO Annual Meeting

N=92

The ETOP NICOLAS phase II trial with Nivolumab

� Interim safety analysis

Pneumonitis-free rate of grade≥3 at 3 months post-RT

Assumption: 70% of the events occur within the 3 months

n=21 (O’Brien-Fleming approach)

Success Rule: NO events

Hierarchical design: IF safety proven ��

• Key-secondary efficacy evaluation: 1-year PFS

Hs0: PFS0≤45% vs Hs1: PFS1>60%

n=74 (1-sided alpha=5%, power=83%).

Sequential administration of chemo-RT

was allowed before amendment for

efficacy

Slide courtesy of Prof. Solange PetersASCO 2018 - ETOP NICOLAS trial

The Christie NHS Foundation TrustNCT03102242

Concurrent chemoradiation

60Gy/30fx+ Carbo/paclitaxel weekly

Consolidation

Carbo/paclitaxel x

2

+ Adjuvant ATEZO

for 1 year

Unresectable Stage IIIA/IIIB

ATEZO 1200mg q 3 weeks x 4

Restaging post 2 and 4 cycles

Primary endpoint: Disease control rate at week 12

N=63

ALLIANCE Phase II Induction/Adjuvant Atezolizumab


1:1

Concurrent chemoradiationstage III NSCLC

RT dose: 59.4-66.6 Gy

Cisplatin/Etoposide,

Carboplatin/Paclitaxel or

Cisplatin/Pemetrexed

Consolidation chemo allowed (x2)

PET scan post treatment

mandatoryNIVO 3mg/kg x12 q 2 weeks

+ IPI 1 mg/kg x 4 q 6 weeks

NIVO 480mg q 4 weeks x 6

NCT03285321

N=108Primary endpoint: PFSSecondary endpoints: OS, TTDM, Safety

BTCRC LUN16 - 081


T2-4 N0-3 M0

Primary tumor

diameter > 4 cm

SUVmax > 5.0

Eligible for

radical treatment

(RT only, seq or conc)

RegisterDose

Planning

Start dose

66 Gy

in 24 fractions

<72 Gy Dose

escalation

not possible

> 72 Gy Dose

escalation

possible

RANDOMISED

radiotherapy

to tolerance

RT

Homogeneous

Boost

(Arm A)

RT

inhomogeneous

Boost 50% SUVmax

(Arm B)

Proceed with treatment plan for Arm A

(boost entire primary tumour)

-If primary tumour dose < 72 Gy

=> patient treated up to this dose level (no

randomization)

- If primary tumour dose ≥ 72 Gy

⇒ patient is randomized between Arm A and Arm B

Primary endpoint: LPFS at 1 year

PET boost- ARTFORCE

MLD 20 GyMed envelope and heart 76 GyBrachial Plexus 79 GySpinal Cord 53 Gy Oesophagus: V36 < 80%.


RTOG-EORTC randomised phase II study in stage III NSCLC with

EGFR TK mutations or EML4- ALK fusion gene

†Per treating physician’s discretion, a choice of the following chemotherapy regimens:

Cisplatin and etoposide every 4 weeks for 2 cycles

Paclitaxel and carboplatin weekly for 6 weeks followed by 2 cycles of consolidation

Pemetrexed 500 mg/m2 and carboplatin AUC-5 every 3 weeks for a maximum of 4 cycles

Patients with EGFR TK or EML4-ALK fusion arrangement (done at a CLIA certified lab) will be enrolled

† Concurrent chemotherapy

and radiation 64 Gy

Ra

nd

om

ise

Crizotinib 250mg/bid for 12 weeks

Ra

nd

om

ise


and radiation 64 Gy


and radiation 64 Gy


and radiation 64 Gy

Eriotinib 150mg/day for 12 weeks

EGFR +

ALK +

Weight loss ≤5%

Weight loss >5%

EGFR +

Weight loss ≤5%

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