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Adjuvant Therapy for Early Stage Lung Cancer
Giorgio V. ScagliottiUniversity of Torino
Department of Oncologygiorgio.scagliotti@unito.it
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Adjuvant CT ± post-op RT, in operable NSCLC: two meta-analyses of individual patient data
NSCLC Meta-analyses Collaborative Group Lancet 2010; 375:1267
34 trials, 8447 patientsHR 0.86 (95 CI : 0.81-0.92)P<0.0001
13 trials, 2660 patientsHR 0.88 (95 CI : 0.81-0.97)P<0.009
4% benefit
4% benefit
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Adjuvant Chemotherapy in Early Stage NSCLC
• Accepted as the standard in node-positive curatively resected early stage NSCLC
• Remains controversial in node-negative early stage NSCLC (decisions based on tumor size)
• Cisplatin-based therapy considered the standard• Carboplatin often used but “unproven”• Most evidence-based regimen - cis/vinorelbine• ECOG 1505 - allowed other regimens all of which
were previously untested in the phase III setting
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Phase II of Cisplatin /Pemetrexed vs. Cisplatin/Vinorelbine (TREAT)
Cis/Vb N-67 Cis/Pem N-65Feasibility 75% 96%
Early termination of therapy 63% 22%
Grade 3-4 hematological toxicity 78% 11%
Grade 3-4 non-hematological toxicity
33% 31%
Dose Delivery (% Planned) Cis 66% Cis 90%
Vb 64% Pem 90%
p =.001; p<.0001
Kreuter M et al. Ann. Oncol. 24: 986–992, 2013
Stages IB-pT3N1
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Proportion of patients with early NSCLC surgically resected and treated with ACT
Booth C.M. et al. J. Clin.. Oncol. 2010; 28: 3472-3478
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Factors associated with referral to Medical Oncologists
• Decision associated to age (younger patients) and stage (II-III)
• Co-morbidity and post-operative length of stay not associated with initial referral but associated with the use of ACT in patients seen by medical oncologists
Kankesan J. et al. Curr. Oncol. 2013; 20:30-37
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Vinorelbine-Cisplatin Adjuvant Chemotherapy
Booth C.M. et al. J. Thorac. Oncol. 2012; 7:559-566
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Compliance and Toxicity of Adjuvant Chemotherapy
• In ACT the most evidence-based regimen is cisplatin/vinorelbine
• Weekly schedule of vinorelbine used in some of the phase III studies was associated with low compliance and significant toxicities.
• Discrepancies with routine clinical practice. • Carboplatin often used but “unproven”.• Need for studies testing alternative regimens and
schedules.
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ogy Hurdles in adjuvant studies in NSCLC
• Phase II “proof of concept” studies less applicable to adjuvant setting.
• In adjuvant studies overall response rate is NOT an endpoint.
• Survival is much longer and potentially impacted by additional lines of therapy at relapse.
• Quality of life issues and adverse events.• Early stage NSCLC are less frequently reported
than in other types of tumors (e.g. breast).
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ogy Adjuvant Trials
• Primary endpoint– Disease free survival vs. Overall survival?
• Cross over effect
– Disease free survival- 2 years? 3 years? – Event free survival
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Early Stage NSCLCNo Biomarker, Unselected Population
Survival Time
Patients cured with local regional therapy
Patients with residual micrometastases resistant to adjuvant therapy
patients with residual micrometastasessensitive to adjuvant therapy
Prbability
Predictive Factors
Prognostic Factors
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How Can We Improve Cure Rates for Early Stage NSCLC?
• Better risk stratification to guide selection of neo-adjuvant & adjuvant therapy– Develop novel options for high-risk patients
• Tailoring chemotherapy based on individual molecular markers– ERCC1, BRCA1, RRM1, TS, genomic alterations
• Integration of targeted agents
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Prognostic classifier in radically resected stage I non-squamous NSCLC
Kratz J.R. et al. Lancet 2012; 379:823
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Prognostic classifier in radically resected stage I non-squamous NSCLC
Kaiser validation cohortN= 420
Chinese validation cohort N=471
Kratz J.R. et al. Lancet 2012; 379:823
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Risk Stratification
Screening:R0 resectionNon-squamous NSCLCPathologic stage IN = 1,500
RandomizationN=700
Observed for OSN=350
Excluded
• 4 cycles cisplatin+ vinorelbine
• Routine CT scans• DFS• OS
• Routine CT scans• DFS• OS
PervenioTM Lung RSTesting
High RiskN~750
Intermediate RiskN~375
Low RiskN~375
ChemotherapyN=350
ObservationN=350
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Early Stage NSCLC Predictive Biomarkers
Reference Marker Trial N Marker HR for Survival (P Value)Fouret 2009[1] MSH2 IALT 768 Negative
Positive0.76 (.03)1.12 (.48)
Olaussen 2006[2]
ERCC1 IALT 761 NegativePositive
0.65 (.002)1.14 (.40)
Filipits 2007[3] p27Kip1 IALT 778 NegativePositive
0.66 (.006) 1.09 (.54)
Tsao 2007[4] p53 JBR.10 253 PositiveNegative
0.54 (.02)1.40 (.26)
Seve 2007[5] β-tubulin III JBR.10 265 PositiveNegative
0.64 (.07)1.00
Pirker 2007[6] ERCC1/p27Kip1 IALT 778 Both negativeBoth positive
0.52 (95% CI: 0.36-0.74) 1.27 (95% CI: 0.87-1.84)
Fouret 2009[1] MSH2/ERCC1 IALT 658 Both negativeBoth positive
0.65 (.01)1.30 (.19)
1. Fouret P, et al. ASCO 2009. Abstract CRA7502. 2. Olaussen KA, et al. N Engl J Med. 2006;355:983-991. 3. Filipits M, et al. J Clin Oncol. 2007;25:2735-2740. 4. Tsao MS, et al. J Clin Oncol. 2007;25:5240-5247. 5. Seve P, et al. Clin Cancer Res. 2007;13:994-999. 6. Pirker R, et al. J Thoracic Oncol. 2007;2:S397-S398.
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Trial Stage Biomarkers
SWOG 0720 I ERCC1/RRM1
ITACA II-III ERCC1/TS
SCAT II-IIIA BRCA1
MAGRIT IB-IIIA MAGE-A3
TASTE II-IIIA ERCC1/EGFR mut
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Trial Stage Therapy Marker
SWOG 0720 I ± Chemotherapy (cis/gem) ERCC1/RRM1
ITACA II-III Cisplatin/Pemetrexed ERCC1/TS
SCAT II-IIIA Platinum/Docetaxel BRCA1
MAGRIT IB-IIIA MAGE A3 Vaccine MAGE-A3
TASTE II-IIIA Erlotinib vs CDDP Pem ERCC1/EGFR mut
RADIANT IB-IIIA Erlotinib vs Placebo EGFR FISH or IHC+
SELECT I and I N0 Erlotinib EGFR mutation
GACT II-IIIA N+ Gefitinib vs CDDP Vinorelbine EGFR mutation
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ogy Breast Cancer Associated (BRCA) gene 1
• Preclinical and retrospective studies initially suggested a predictive role for BRCA1 with regard to cisplatin response1-5
• Phase III trial in stage IV NSCLC using BRCA1 and RAP80 expression levels showed a ↓ OS in the experimental arm compared to the control arm 6
• IALT - no association between BRCA1 expression (IHC) and cisplatin response7
1. Taron M et al. Hum Mol Genet 2004;13;2443-9, 2. Papadaki C et al. J Thorac Oncol 2012;7; 663-71, 3. Rosell R et al, PLoS ONE 2009;4. e5133, 4. Su C et al. Med Oncol 2001;28;1411-7, 5. Bartolucci R et al, Clin Lung Cancer 2009; 10;47-52, 6. Moran T et al. J Clin Oncol, 2013;31; LBA8002, 7. Pierceall WE et al. Ann Oncol 2012; 23; 2245-52
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Customized BRCA1 Adjuvant Treatment in Stage II-III NSCLC (SCAT)
Resected NSCLC R0pN1 / pN2
Q 2 & 3 BRCA1
Q 4 BRCA1
Gem/Cis
Docetaxel
Docetaxel/Cis
Q 1 BRCA1
Planned number of patients: 432 (amended)
CT should be started before 8 weeks after surgery
PORT in N2 patients
CONTROL
EXPERIMENTAL
Docetaxel/Cis
Statification factors: - Stage: N1 vs. N2- Age <65 vs > 65 y - Histology: Non-SCC vs. SCC - Type of resection: Lobectomy vs Pneumonectomy
Eudract: 2007-000067-15NCTgov: 00478699
1
:
3
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SCAT - Overall survival
HR=0,86 (0,59-1,27)
Massuti B. et al. Proc. ASCO 2015
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Phase III trial of customized adjuvant chemotherapy after resection in NSCLC with lymphnode metastases
• Study hypothesis : absolute improvement of 20% in experimental group with a 80% power
• The study failed to show a significant benefit from treatment customization but a prolonged FU time is needed to conclude in favor of a completely negative study (current FU 28 months)
• The study does not support the hypothesis of cisplatin- resistance in high BRCA1 tumors and cisplatin- based CT remains the standard
• The study suggest a differential activity of the 2 explored doublets in low BRCA1 tumors but be careful about subgroup analyses
• Dose reductions? Treatment compliance in the elderly patients?
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ITACA Adjuvant Trial Pharmacogenomics: Yes or No?
Radically Resected II-IIIANo priorChemotherapy or Radiation Therapy prior surgery
Stratification Factors Pathological stage (II vs. III) Smoking status (current vs. former vs. never smoker)
ERCC1 and TS Assessment by RT-PCRERCC1 and TS Assessment by RT-PCR
HIGH ERCC1 & HIGH TSHIGH ERCC1 & HIGH TS
HIGH ERCC1 & LOW TSHIGH ERCC1 & LOW TS
LOW ERCC1 & HIGH TSLOW ERCC1 & HIGH TS
LOW ERCC1 & LOW TSLOW ERCC1 & LOW TS
DocetaxelDocetaxel
Standard ChemotherapyStandard Chemotherapy
PemetrexedPemetrexed
Standard ChemotherapyStandard Chemotherapy
Standard ChemotherapyStandard Chemotherapy
Standard ChemotherapyStandard Chemotherapy
Cispplatin/PemetrexedCispplatin/Pemetrexed
Cisplatin/GemcitabineCisplatin/Gemcitabine
R
R
R
RN= 700
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Novello S. et al. JTO suppl. Sept. 2015
ITACA - Treatment allocation by profile (N=761)
PROFILE 1 PROFILE 2 PROFILE 3 PROFILE 40
20
40
60
80
100
120
140
160
personalizedstandard
37.5% 11.6% 26.8% 24.2%
PROFILE1: ERCC1 low, TS lowPROFILE2: ERCC1 low, TS highPROFILE3: ERCC1 high, TS lowPROFILE4: ERCC1 high, TS high
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Preliminary Results of the International Tailored Chemotherapy Adjuvant Trial: the ITACA Trial – Silvia Novello
AE Personalized: n=375 Standard: n=386 p *
Grade >0 3-5 >0 3-5
Anemia 18.7 1.6 25.9 1.8 .019
Neutropenia 20.8 12.8 23.6 17.4 .048
Thrombocytopenia
12.3 3.5 17.9 7.3 .019
Nausea/Vomiting 24.0 3.5 30.8 4.1 .018
Cardiac 2.4 1.0 3.6 1.0 .406
GI 35.5 5.9 42.0 4.9 .058
Infections 12.0 1.9 11.7 2.6 .800
SAE leading to discontinuation 8.3 16.0 .002
ITACA -Major adverse events according to treatment (N=761)
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AE Tailored: n=143 Control: n=142 p *
Grade >0 3-5 >0 3-5Anemia 11.9 0.7 26.8 2.1 <.001
Neutropenia 13.3 7.7 25.4 16.9 .004
Thrombocytopenia
0.0 0.0 21.8 8.5 <.001
Nausea/Vomiting 14.0 0.0 31.7 4.9 <.001
Cardiac 0.7 0.0 5.6 0.7 .042
GI 24.5 0.7 44.4 5.6 <.001
Infections 8.4 1.4 16.2 5.6 .049
SAE leading to discontinuation 15.7 34.1 .001
ITACA -Major Adverse Events According to Treatment – Profile 1 (N= 285)
* p value for difference in distribution of SAE grade by treatment
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ALTERATION OF GENES INVOLVED IN DNA REPAIR
EPIGENETIC ALTERATIONSOF GENES INVOLVED IN
DNA REPAIR
Cancer as a disease of the genes
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Main pathways implicated in genome instability
• Mismatch repair
• Base and nucleotide excision repair
• Telomere maintenance
• Double-stand break repair
• De-regulated DNA replication
• Chromosome segregation
Barrell RA et al. Nature 2013; 501: 338
‘‘Mutational signature’’ reflecting the imprint of the type of DNA damage
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pStage IB-IIIAIB > 4 cm
All histologies
RANDOMIZE
Cisplatin – based Chemotherapy
Cisplatin – basedChemotherapy
+Bevacizumab: 15 mg/kg
followed byBevacizumab x 1 year
REGIMENS
Vinorelbine + CDDP
Docetaxel + CDDP
Gemcitabine + CDDP
Pemetrexed + CDDP
Wakelee, et al. J Clin Oncol 2011; 29 (suppl; abstr 7013)
ECOG 1505 : Adjuvant Chemotherapy: The Addition of Bevacizumab
85% power to detect a HR 0.79(26.5% OS advantage)N=1500
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Wakelee H. et al. JTO suppl. Sept. 2015
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New Approaches to Adjuvant Therapy
Can the therapeutic advances that have been made with molecularly targeted therapy and
immunotherapy in metastatic disease translate to increased cures in early stage
disease?
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Hurdles to be considered with molecular alterations
• Is the alteration equally present in early disease?
• Is the molecular alteration stable overtime?• Is the targeted treatment equally effective as
adjuvant (maintenance) treatment or should be reserved at relapse?
• Are long term toxicities tolerable?
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Adjuvant Therapy: Phase III Trials in patients with EGFR M+ Tumors
N Design Primary Endpoint
ALCHEMIST 410 ptsStage IB(>4cm-IIIA)
Erlotinib versus placebo x 2 years(after chemotherapy)
Overall Survival
ADAURA 700 ptsStage IB-IIIA
AZD9291 versus placebo x 3 years(after chemotherapy)
Disease Free survival
JapanWJOG6401L
230 ptsStage II-IIIA
Gefitinib x 2 yearsCDDP/VNR 4 cycles
Disease free survival at 5 years
ChinaCTONG1104
220 ptsStage II-IIIA
Gefitinib x 2 yearsCDDP/VNR 4 cycles
Disease free survival
ChinaICTAN
477 ptsStage II-IIIA
Chemotherapy Chemotherapy followed by 6 or 12 months of icotinib
Disease free survival
China 300 pts Stage II-IIIA
Icotinib versus placebo x 2 years(after chemotherapy)
Disease free survival
Dana FarberMGH
92 ptsStage I-III
Afatinib 3 months versus 2 years(after chemotherapy)
Disease free survival
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ALCHEMIST SchemaConsent & Register: A151216 Screening & Follow-up Protocol
Pre-op Cohort Post-op Cohort
CLIA-approved LAB• EGFR mutation test (sequencing)• ALK rearrangement (FISH)
• SOP-driven FF/FFPE• After resection, buffy coat
TCGA• Genomic sequencing• Transcriptome• Methylation
E4512: Erlotinib
A081105: Crizotinib
• Assess FFPE• buffy coat
Other Adjuvant Studies
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Lung Cancer Immunotherapy
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Vansteenkiste JF et al, ESMO 2014
Disappointing Results from MAGRIT
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Therapeutic Lead company Antibody type Affinity/K2 Reference Anti-PDL1
MPDL3280A Roche Engineered IgG1 (no ADCC) 0.4 nM Herbst et al.
ASCO 2013
MEDI-4736 AstraZeneca Modified IgG1 (no ADCC) Not available Stewart et al.
Cancer Res 2011
Anti-PD1
Nivolumab Bristol-Myers Squibb IgG4 2.6 nM Brahmer et al. J Clin Oncol 2010
MK3475 Merck & Co IgG4 (humanised) 29 pM Patnaik et al. ASCO 2012
AMP-224 GlaxoSmithKline PD-L2 IgG1 Fc fusion Not available Smothers et al.
Ann Oncol 2013
Pidilizumab (CT-011) CureTech IgG1 (humanised) Not available Armand et al.
J Clin Oncol 2013
ADCC, antigen-dependent cell-mediated cytotoxicity
Overview of PDL1 and PD1 inhibitors currently in development
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Adjuvant Immunotherapy
1. Will immune checkpoint inhibition be effective in the setting of minimal residual disease in which a nonexistent or immature tumor microenvironment may exists?
2. What influence, if any, does surgical resection and adjuvant
chemotherapy have on immune cells?
3. Who will benefit? a) Those with PD-L1 tumor expression b) Will benefit been seen across all stages of resectable
disease?
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PD-L1 Expression in Resected NSCLC
Author N Stage PD-L1 Prognosis
Velcheti2014
269 (Greece) 33 (Greece)
131 (Yale)11 (Yale)
I-IIIIV
I-IIIIV
25%36%37%36%
All patients PD-L1 associated with better survival
Kowanetz 2010
254 (adeno)37 (adeno)
139 (squamous)16 (squamous)
I-IIIa IIIb-IV
I-IIIa IIIb-IV
31%19%31%31%
?
Velcheti V et al. Lab Invest 94: 107-16, 2014; Kowanetz M et al. WCLC 2013 Abstract
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Conclusions
• Adjuvant cisplatin-based chemotherapy is the SOC in node-positive curatively resected early stage NSCLC
• The role of ACT in stage IA will be redefined in light of the new TNM staging system
• ECOG 1505 –The role of adjuvant bevacizumab not proven in a phase III study
• Specifically designed studies in selected subgroups of patients will define the role of targeted therapies
• The role of immunotherapy in this specific setting remains a matter of clinical trials