combined modality treatment for n2 disease · combined modality treatment for n2 disease dr clara...
TRANSCRIPT
The Christie NHS Foundation Trust
Combined modality treatment for N2 disease
Dr Clara Chan
Consultant in Clinical Oncology
8th March 2019
The Christie NHS Foundation Trust
DISCLOSURE OF INTEREST
No disclosures.
The Christie NHS Foundation Trust
Overview
• Background
• The evidence base
• Systemic treatment
• Radiotherapy
• Future directions/clinical trials
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
The Christie NHS Foundation Trust
Radical treatment options for N2 disease
• Surgery
• Radiotherapy alone
• Sequential chemo-radiotherapy
• Concurrent chemo-radiotherapy
• Trimodality treatment
The Christie NHS Foundation Trust
Radical treatment options for N2 disease
• Surgery
• Radiotherapy alone
• Sequential chemo-radiotherapy
• Concurrent chemo-radiotherapy
• Trimodality treatment
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
? 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
The Christie NHS Foundation Trust
? 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
The Christie NHS Foundation Trust
Radiotherapy planning
• RT commences D1 chemotherapy
• RT planning scan done asap
• Motion management
• 4D CT
• Respiratory gating/Breath hold
• Advanced RT techniques
• IMRT
• IGRT
The Christie NHS Foundation Trust
4D CT
The Christie NHS Foundation Trust
Intensity Modulated RadiotherapyIMRT
• Improved conformity
• Avoidance of radiosensitive structures eg spinal cord
• Retreatments
• Large volumes
The Christie NHS Foundation Trust
• 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?
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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)
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
What combination of treatment is best for potentially resectable N2
disease?
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
SAKK 16/00
Pless et al, Lancet 2015
The Christie NHS Foundation Trust
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)
The Christie NHS Foundation Trust
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%
The Christie NHS Foundation Trust
Future directions
• Individualised treatment
• Personalised RT dose
• Combinations with novel agents
• Proton therapy
The Christie NHS Foundation Trust
ADSCaNA Randomised Phase II study of Accelerated, Dose escalated, Sequential
Chemo-radiotherapy in Non-Small Cell Lung Cancer
The Christie NHS Foundation Trust
CONCORDEPlatform study of novel agents in COmbinatioN with
COnventional RaDiothErapy in locally advanced disease
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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
The Christie NHS Foundation Trust
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%.
The Christie NHS Foundation Trust
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%