University of Torino – Department of Oncology Giorgio V. Scagliotti University of Torino...

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Adjuvant Therapy for Early Stage Lung Cancer

Giorgio V. ScagliottiUniversity of Torino

Department of [email protected]

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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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ogy Prospective Adjuvant Trials testing Biomarkers

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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ogy Prospective Adjuvant Trials testing Biomarkers

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




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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ogy ECOG 1505 – Efficacy Outcomes

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


Gefitinib x 2 yearsCDDP/VNR 4 cycles

Disease free survival

ChinaICTAN


Chemotherapy Chemotherapy followed by 6 or 12 months of icotinib


China 300 pts Stage II-IIIA

Icotinib versus placebo x 2 years(after chemotherapy)


Dana FarberMGH

92 ptsStage I-III

Afatinib 3 months versus 2 years(after chemotherapy)


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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

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