Combined modality treatment for N2 disease · Combined modality treatment for N2 disease Dr Clara...

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Combined modality treatment for N2 disease

Dr Clara Chan

Consultant in Clinical Oncology

8th March 2019

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DISCLOSURE OF INTEREST

No disclosures.

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Overview

• Background

• The evidence base

• Systemic treatment

• Radiotherapy

• Future directions/clinical trials

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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

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Radical treatment options for N2 disease

• Surgery

• Radiotherapy alone

• Sequential chemo-radiotherapy

• Concurrent chemo-radiotherapy

• Trimodality treatment

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Radical treatment options for N2 disease

• Surgery

• Radiotherapy alone

• Sequential chemo-radiotherapy

• Concurrent chemo-radiotherapy

• Trimodality treatment

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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

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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

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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

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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

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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

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? 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

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? 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

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Radiotherapy planning

• RT commences D1 chemotherapy

• RT planning scan done asap

• Motion management

• 4D CT

• Respiratory gating/Breath hold

• Advanced RT techniques

• IMRT

• IGRT

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4D CT

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Intensity Modulated RadiotherapyIMRT

• Improved conformity

• Avoidance of radiosensitive structures eg spinal cord

• Retreatments

• Large volumes

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• 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?

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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

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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)

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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

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What combination of treatment is best for potentially resectable N2

disease?

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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

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SAKK 16/00

Pless et al, Lancet 2015

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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)

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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%

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Future directions

• Individualised treatment

• Personalised RT dose

• Combinations with novel agents

• Proton therapy

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

Chemo-radiotherapy in Non-Small Cell Lung Cancer

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CONCORDEPlatform study of novel agents in COmbinatioN with

COnventional RaDiothErapy in locally advanced disease

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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

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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

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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

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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

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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

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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%.

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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

† Concurrent chemotherapy

and radiation 64 Gy

† Concurrent chemotherapy

and radiation 64 Gy

† Concurrent chemotherapy

and radiation 64 Gy

Eriotinib 150mg/day for 12 weeks

EGFR +

ALK +

Weight loss ≤5%

Weight loss >5%

EGFR +

Weight loss ≤5%