current strategies for adjuvant therapy: ongoing and future trial research
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Current Strategies for Adjuvant Therapy:
Ongoing and Future Trial Research
Tracey Evans, MDAbramson Cancer Center
University of Pennsylvania, Philadelphia
Current Status of Adjuvant Chemotherapy in NSCLC
It is STANDARD OF CARE
How did we get here?
Early Adjuvant Trials in NSCLC
No benefitBusulfan + Cyclophosphamide
726Girling 1985No benefitCCNU + Hydrea865Shields 1982No benefitCyclophosphamide +
MTX417Shields 1977
No benefitCyclophosphamide IV + IP
909Shields 1974
No benefit higher
recurrence in treatment
arm
Cyclophosphamide IV189Brunner 1973
No benefitCyclophosphamide orally
502Miller 1971No benefitNitrogen mustard IV +
IP1192Slack 1970
No benefitCyclophosphamide IV1035Higgins 1969
No benefitNitrogen mustard IV + IP
1002Hughes 1962
ResultsChemotherapy# ptsInvestigator
Limitations of Earlier Adjuvant Trials
• Regimens with marginal activity in advanced NSCLC
• Inclusion of patients with compromised PS and multiple co-morbidities
• Difficulty administering systemic therapy in the post-op setting
• Inadequate power/overly ambitious survival endpoints
BMJ Meta-analysis: Adjuvant Cisplatin-based Chemotherapy
Overall Survival
at risk Months706 590 462 371 295 206Surgery+CT
Surgery 688 548 433 353 258 177
Survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
1.00.9
0 12 24 36 48 60
Surgery 316 688298 706
Events Total Surgery+CT
Survival benefit with cisplatin-based chemotherapy:
3% at 2 years, 5% at 5 years
BMJ 311:899-901, 1995.
IALT Schema
Surgically resected non-small cell lung cancer
Observation
Cisplatin 300-400mg/m2 over 3-4 cycles
with
Etoposide, vinorelbine, vinblastine, or vindesine
Within 60 days post-op
Randomize
Radiation optional, predetermined by N stage for each center
IALT Results
Chemo (932) No Chemo (935)5 yr OS 44.5% 40.4%
5 yr DFS 39.4% 34.3%MS 50.8 mos 44.4 mosMDFS 40.2 mos30.5 mos
NEJM 350; 351-60, 2004.
935 775 619 520 447 372 282 208 125932 780 650 550 487 399 300 208 133
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5 6 7 8 years
chemotherapy: 578 deaths - 495 deaths before 5 years - 83 deaths after 5 years
control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years
HR: 0.91 (0.81-1.02, P = 0.10)
Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.
IALT: 7.5-Year Median Follow-Up
NCIC-BR10
Select inclusion criteria:
•Stage IB-II NSCLC
•Complete surgical resection
•N=482
RANDOMIZE
Vinorelbine, IV, 25 mg/m2, weekly 16 wk
Cisplatin, 50 mg/m2, d 1, 8 q 4 wk 4 cycles
No chemotherapy
Overall Survival by Treatment Arm
Absolute improvement in 5 yr OS = 11% (67% vs. 56%); benefit persists at 9+ yrs
Vincent, Butts et al, 2009.
All Patients
Absolute improvement in 5 yr OS = 15% (69% vs. 54%) Winton et al. NEJM 2005.
HR 0.695 yr: 69% vs 54%MST 94 m vs 73 m
5 yr: 67% vs 56%MST 94m vs 72m
At RiskObservationVinorelbine
Stratified Log-Rank: p=0.04HR: 0.780(0.613, 0.993)
'
Observation Vinorelbine
Perc
enta
ge
0
20
40
60
80
100
0
240242
3
155182
6
117135
9Time(Years)
5867
12
912
15
00
NCIC-CTG JBR.10Elderly Analysis
• Elderly received less chemotherapy overall• Toxicity differences not seen in this trial by age
group• Adjuvant chemotherapy should be offered to the fit
elderly
Pepe, J Clin Oncol Vol 25: 1553-1561, 2007.
Age (N) HR OS(Chemo vs obs)
CI p
≤65 (327)
0.77 [0.54-1.09] 0.14
>65 (155)
0.61 [0.38-0.98] 0.04
>75 (23) 2.35 [0.84-6.58] 0.09
CALGB 9633: RCT of Adjuvant Chemotherapy in Stage IB NSCLC
T2N0MOstage IB NSCLC
COMPLETESURGICAL RESECTION
ADJUVANT CHEMOTHERAPY
Paclitaxel, 200 mg/m2
Carboplatin, AUC=6 mg/ml x min
4 cycles over 12 weeks
OBSERVATIONrandomization within 4 to 8 wks of resection
STRATIFIEDsquamous vs otherpoorly differentiated vs othermediastinoscopy: yes vs no Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant chemotherapy in stage IB
non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.
Overall Survival: THEN AND NOW
ASCO: 2004 ASCO: 2006
HR=0.62; 90% CI: 0.44-0.89; P=0.01
HR=0.80; 90% CI: 0.60-1.07; P=0.10
Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.
0 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty
ObservationChemo
0 1 2 3 4 5 6 7 8 9 0 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty
ObservationChemo
0 1 2 3 4 5 6 7 8 9
Disease-Free Survival: Then and Now
ASCO: 2004 ASCO: 2006
HR=0.69; 90% CI: 0.51-0.92; P=0.02
HR=0.74; 90% CI: 0.57-0.96; P=0.03
Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.
0 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty
ObservationChemo
0 1 2 3 4 5 6 7 8 9 0 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty
ObservationChemo
LACE* Meta-analysis• 5 trials including 4,584 patients• Median follow-up: 5.1 years (3.1 – 5.9)• 80% male • Median age 59 years, 9% > 70 years old • Pathological Stage: IA: 8%, IB: 30%, II: 35%, III: 27%• Surgery: 31% pneumonectomy• Histology: 49% squamous cell, 39% adenocarcinoma, 12% other
*Lung Adjuvant Cisplatin Evaluation Pignon Proc ASCO 2006 abs 7008.
Pignon J et al. JCO 2008;26:3552-3559.
The absolute effect of chemotherapy at 5 years was a decrease of 6.9% for lung cancer death and an increase of 1.4% for non–lung cancer death.
LACE Meta-analysis
Overall Survival (%) Disease-free Survival (%)
Overall Survival (%)
LACE Meta-analysis
P=.005 P<.001
0.89 (0.82-0.96)
0.84 (0.78-0.91)
Pignon J et al. JCO 2008;26:3552-3559.
NCCN Guidelines
Controversies
• Which regimen?– Cisplatin vs Carboplatin?
• Stage IB?
• Predictive/prognostic biomarkers?
• Post-operative XRT (PORT)?
Which regimen?
Regimens: LACE Meta-analysis
• Cisplatin/vinorelbine: regimen for 41% LACE pts– Regimen for Anita and JBR10– 86% patients received >300mg/m2 cisplatin– 13% of IA’s cis/vinorelbine vs. 43% other stages
• Drugs used with cisplatin other studies– IALT: vinorelbine, vindesine, vinblastin, etoposide– BLT: vinorelbine, vindesine, mitomycin/vindesine,
mitomycin/ifosfamide– ALPI: vindesine/mitomycin
.04
.02
.10
.09
Extrapolating Stage IV: Not Vinorelbine?
Survival Time (Mos.)
Cum
ulat
ive
Prob
abili
ty1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30 33
DocetaxelCisplatin
VinorelbineCisplatin
P = 0.044(adjusted log-rank)
Fossella FV et al. JCO 22, 2003.
Schiller et al. NEJM.2002; 346:92-98.
Extrapolating Stage IV: It’s all the Same?
Ardizzoni A et al. JNCI J Natl Cancer Inst 2007;99:847-857.
Extrapolating stage IV: Cisplatin ≠ Carboplatin:
Response Rate
Extrapolating Stage IV: Cisplatin ≠ Carboplatin:
Overall Survival
Ardizzoni A et al. JNCI J Natl Cancer Inst 2007;99:847-857.
Randomized Phase 2 Trial on Refinement of Early Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed
(CPx) vs. Cisplatin and Vinorelbine (CVb) - TREAT
M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M.
Thomas on behalf of the TREAT investigators
LACE-Metaanalysis NCIC-JBR .10No treatment 9% 4.5%Treatment incomplete 24 %
(≤ 2 cycles)50%
(< 4 cycles)• early death or progression 9% 5%• toxicity 34% 13%• patient refusal 35% 29%Therapy delay 55%Dose reductions 77%
Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005; Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009.
TREAT Rationale:• Adjuvant CTX: mainly Cisplatin / Vinorelbine • Need: reduction of toxicity, improvement of dose delivery & compliance• Cisplatin / Pemetrexed in thoracic malignancies: high dose intensity, low toxicities
Rationale: Dose delivery: Adjuvant CTX
TREAT: Design
Cisplatin / Vinorelbine (CVrb)
Cisplatin / Pemetrexed (CPx)
50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4
75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4
R0Winton et al., N Engl J Med (2005) 352: 258
Inclusion • NSCLC stages IB, IIA, IIB, T3N1M0 • ≤ 42 days postoperative, R0, systematic LN-dissection • ECOG 0, 1 • amenable to Cisplatin treatment
Stratification • Center • Nodal status (N0 versus N1) • Surgical procedure (lobectomy versus pneumonectomy)
Study conduct:• Study concept 2005, Inclusion 10/2006-12/2009 (16 sites,
132 patients)• Treatment until 2/2010, primary endpoint analysis 12/2010
Primary endpoint:Clinical Feasibility considered promising if > 80%• No death due to cancer, toxicity, comorbidity• No Non-acceptance by patients leading to premature
withdrawal• No observation of DLT
Neutropenia grade 4 > 7 d Neutropenia grade 3/4 with fever/infection Thrombocytopenia grade 4 > 7 d Thrombocytopenia any grade with bleeding Non-hematologic toxicity grade 3/4 related to CTX
Secondary endpoints:Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of
relapse
TREAT: Conduct / Endpoints
Characteristics CPx(n=67)
CVb(n=65)
Total(n=132)
Age (years [range]) 58 [40-73] 60 [38-74] 59 [38-74]Gender (%)• male • female
7228
77 23
7426
Smoking status (%)• Smoker • Ex-smoker• Non-smoker • Not available
336160
26711.5 1.5
29664 1
Stage (%)IB 37 38 38IIA 12 8 10IIB 46 48 47T3N1 5 6 5
TREAT: Characteristics
Characteristics CPx(n=67)
CVb(n=65)
Total(n=132)
Surgical procedures (%)Lobectomy 84 82 83Pneumonectomy 12 15 14Complex resections 4 3 3
Histology (%)Squamous cell carcinoma 45 42 43Non-squamous 55 58 57• Adenocarcinoma 37 44 41• Large cell carcinoma 9 9 9• Mixed cell carcinoma 9 5 7
TREAT : Characteristics
CPx CVb
Feasibility rate (%) 95.5
(CI 87.5-99.1)75.4
(CI 63.1-85.2)Death (%) 1.5 3.1Withdrawal of consent (%) 0 6.2DLT (%) 3.0 15.4
Reasons for DLT (events) * patients (n=2) patients (n=10)G4 neutropenia >7d 0 4G4 thrombocytopenia >7d 0 0G3/4 febrile neutropenia 1 5Thrombocytopenia with bleeding 0 0
G3/4 non-hematologic toxicity 2 1
Results: Primary Endpoint - Feasibility
* multiple reasons possible
p = 0.0010
EOT CPx CVbRegular EOT (%) 77.6 36.9
Earlier termination of therapy (%) 22.4 63.1
Reasons for earlier termination (events)*
patients (n=15)
patients (n=41)
• Unacceptable toxicity according to protocol** 4 19
• Unacceptable toxicity perceived by patient 6 7• Relapse of disease 0 2• Withdrawal of consent 0 4• Death (therapy related) 1 (0) 2 (0)• Non-compliance to protocol 0 2• Medical decision by investigator 4 5• Major protocol violation 0 1• Other reasons 0 4
Results: End of Therapy
*multiple reasons possible**delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity
Toxicity CPx CVbMean Number(AE / SAE) 6.8 / 0.3 6.9 / 0.2
HematologicToxicity G3/4 (%) 10.5 76.5
Non-hematologic Toxicity G3/4 (%) 33 31
Hematologic Toxicity (%) G3/4 G3/4
Anemia 0 1.5Thrombocytopenia 0 0
Neutropenia 9 69Febrile Neutropenia 1.5 6
TREAT: Toxicity
p<0.0001
p=0.7988
TREAT: Time to Treatment Failure
TtTF:Time from surgery to withdrawal due to • AE• progression /
relapse / death• failure to return
to therapy• refusal of treatment
/ withdrawal of consent
p<0.001W
ithdr
awal
pro
babi
lity
• CPx safe and feasible less toxicity compared to CVb superior dose delivery compared to CVb high dose density (mg/m2/week)
• Dose delivery failure in CVb mostly due to Vb (delivery d15, d22)
• Efficacy: longer follow up to be awaited
TREAT: Conclusions
E1505 Chemotherapy Regimens
• Therapy to start 6-12 weeks post-operatively– Investigator Choice of Chemo - 4 cycles (12
wks)• Cisplatin/Vinorelbine
– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d• Cisplatin/Docetaxel
– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d• Cisplatin/Gemcitabine
– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d• Cisplatin/Pemetrexed
– Cis 75 mg/m2 d 1; Pem 500 mg/m2 d 1 Q 21 d
• Bevacizumab 15 mg/kg q 21 days x 12 months
ECOG 1505: Adjuvant Bevacizumab
RANDOM IZE
STRATIFIED:
StageHistologyGenderChemo regimen*
ChemotherapyX 4 cycles
ELIGIBLE:
Resected IB^-IIIA
Squamous Allowed!³ LobectomyNo prior chemoNo planned XRTNo h/o CVA/TIANo ATE w/in 1 yr
Chemotherapyx 4 cyclesPlusBevacizumabX 1 year
^ Now revised to exclude IB < 4cmCompleted accrual/study closed Sept 20, 2013
ECOG 4599: Overall Survival
0.0
0.2
0.4
0.6
0.8
1.0
Prop
orti
on S
urvi
ving
0 6 42 4818 3012 24 36Months
HR=0.80; P=0.013
BV/PC 12.3 moPC 10.3 mo
Median Survival
1-year survival51% vs. 44%
2-year survival23% vs. 15%
Sandler, et al. NEJM. 355;24. Dec 14 2006.
Stage IB
LACE Meta-analysis: Stage Effects
CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin + vinorelbine (13% of stage IA patients versus ~43% for other stages)
Stage IA 102 / 347 1.41 [0.96;2.09]
Stage IB 509 / 1371 0.92 [0.78;1.10]
Stage II 880 / 1616 0.83 [0.73;0.95]
Stage III 865 / 1247 0.83 [0.73;0.95]
CategoryNo. Deaths
/ No. EnteredHazard ratio
(Chemotherapy / Control) HR [95% CI]
Test for trend: p = 0.051Chemotherapy better | Control better
0.5 1.0 1.5 2.0 2.5
Stage IA 102 / 347 1.41 [0.96;2.09]
Stage IB 509 / 1371 0.92 [0.78;1.10]
Stage II 880 / 1616 0.83 [0.73;0.95]
Stage III 865 / 1247 0.83 [0.73;0.95]
CategoryNo. Deaths
/ No. EnteredHazard ratio
(Chemotherapy / Control) HR [95% CI]
Test for trend: p = 0.051Chemotherapy better | Control better
0.5 1.0 1.5 2.0 2.5
Stage-Specific Hazard RatiosRecent Adjuvant Trials
Trial IB II IIIAIALT 0.95 0.93 0.79BR-10 0.94 0.59 N/AANITA 1.10 0.71 0.69CALGB 0.8 N/A N/ALACE 0.92 0.83 0.83
Negative Positive
Indeterminate Not studied
Stage-Specific Hazard RatiosRecent Adjuvant Trials
Trial IB < 4 cm IB > 4 cm
II IIIA
IALT 0.95 0.93 0.79BR-10 1.73 0.66 0.59 N/AANITA 1.10 0.71 0.69CALGB 1.02 0.66 N/A N/ALACE 1.41* 0.91* 0.83 0.83
Negative Positive
Indeterminate Not studied* Using 3 cm as cut off
UICC6 T/M Descriptor Proposed T/M N0 N1 N2 N3
T1 (< 2 cm) T1a IA IIA IIIA IIIB
T1 (> 2-3 cm) T1b IA IIA IIIA IIIB
T2 ( 3 to < 5 cm) T2a IB IIA IIIA IIIB
T2 (>5-7) T2b IIA IIB IIIA IIIB
T2 (> 7 cm) T3 IIB IIIA IIIA IIIB
T3 invasion T3 IIB IIIA IIIA IIIB
T4 (same lobe nodules) T3 IIB IIIA IIIA IIIB
T4 (extension) T4 IIIA IIIA IIIB IIIB
M1 (ipsilateral Lung) T4 IIIA IIIA IIIB IIIB
T4 (pleural effusion) M1a IV IV IV IV
M1 (contralateral lung) M1a IV IV IV IV
M1 (distant) M1b IV IV IV IV
New Staging System (IASLC ’07)
Staging alteration
Prognostic/Predictive Biomarkers
• Using prognostic data to treat fewer patients who are probably cured, more who are probably not
• Using predictive data to treat only those likely to benefit with drugs most likely to work
ERCC-1• DNA repair mechanisms important for
resistance to cisplatin• Excision repair cross-complementation
group 1 (ERCC1) enzyme plays rate-limiting role in the nucleotide excision repair pathway
ERCC-1 Negative
ERCC-1 Positive
IALT: ERCC-1 Survival
Olaussen et al, NEJM 2006; 355: 983-991
Prospective Biomarker NSCLC Studies
Stage Therapy BiomarkerSWOG 0720 I (>2cm) +/- chemo
(cis/gemcitabine)
ERCC1/RRM1
ITACA I-IIIA cis/pemetrexed ERCC1/TSTASTE I-IIIA cis/erlotinib ERCC1/EGFR
mutSCAT I-IIIA Platinum/
docetaxelBRCA1/RAP80
• Evaluation of 16 commercially available ERCC1 antibiodies could not distinguish between active and inactive ERCC1 isoforms.
8F1 antibody in IALT data set
Friboulet, et al, NEJM 2013; 368: 1101-1110.
Erlotinib
CDDP-Pemetrexed
Observation
ERCC1-
ERCC1+
EGFR wt
Experimental ArmCustomized
Control ArmCDDP - pemetrexed
EGFRmutated
TASTE: TAilored Post-Surgical Therapy in Early stage NSCLC:
Non-squamous cell NSCLC stage II and IIIA (non-N2)
[TITLE]
Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting
Spanish Customized Adjuvant Treatment (SCAT)
Resected NSCLCpN1/pN2
Control
Experimental
Q 1 BRCA1
Q 2,3 BRCA1
Q 4 BRCA1
Docetaxel/Cisplatin
Gemcitabine/Cisplatin
Docetaxel/Cisplatin
Docetaxel
RANDOMIZE
StratificationAge (</>65)Histology (squam vs non-squam)Extent of surgery (lobe vs pneumo)Nodal involvement (pN1/pN2)
PORT mandatory N2
3
1
BRCA1: mismatch repair pathway, High levels sensitize to apoptosis by antimicrotubulin agents (taxanes) and inhibit apoptosis with platinum
[TITLE]
Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.
[TITLE]
Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.
[TITLE]
Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.
RRMI > 40.5AND
ERCC1> 66.0
Active Monitoring
All Others (RRM1< 40.5 OR ERCC1 < 66.0 )
Cisplatin-Gemcitabine
S0720: Biomarker-directed Adjuvant Therapy of Stage I
NSCLC
Assignment
Good Prognosis Less benefit from Chemotherapy
Poor Prognosis More benefit from Chemotherapy
Primary Endpoint = Feasibilty (>75% of patients assigned)
High
Low
TS
TS
Low
Low
High
High
Profile 4
Profile 3
Profile 2
Profile 1
Taxane
Pemetrexed
Cis/Gem
Cis/Pem
Control*
Control*
Control*
Control*High/Low ERCC1 & TS selected according to median level of mRNA expression in historical series ; * Control arm – Investigator choice of a DDP-based doublet
ERCC1
ITACA* : Pharmacogenomic-Driven Adjuvant Study Assessing ERCC1 &
TS
* International TAilored Chemotherapy Adjuvant Trial
• Completely resected stage II-IIIA• Primary endpoint: overall survival• Secondary endpoints: recurrence free
survival, therapeutic compliance, toxicity profile, comparative evaluation of ERCC1 and TS mRNA vs protein
• Plan for 700 pts (90% power to detect 30% improvement in survival)
• As of ASCO 2011 annual meeting, 180 patients enrolled from 24 institutions (mostly Italy and Germany)
ITACA Pharmacogenomic-Driven Adjuvant Study Assessing ERCC1 &
TS
Novello et al, 2011 ASCO Annual Meeting, abstract e17514.
CALGB 30506: Phase III Randomized Study of Adjuvant Chemotherapy vs. Observation in Patients with Stage I
NSCLCD. Harpole, PI
Stage I NSCLC (2-6 cm, node negative)N=1525
Primary Outcome:• Overall survival chemo vs observation• Collection of high-quality fresh frozen tissue for gene expression array generationSecondary• Evaluate selected genomic-based prognostic models using data from the patients randomized to observation after resection.• Rate of toxicity for different chemo regimens.• QOL and impact of chemo on QOL
Cisplatin with vinorelbine, gemcitabine, docetaxel, pemetrexed x 4 cycles
Observation
RANDOMIZE
Start date: 3/09Estimated completion: 1/2014
SELECT Trial: Phase II Trial of Adjuvant Erlotinib in Patients with Resected, Early Stage NSCLC with EGFR Mutations
PI L Sequist
Resected stage IA-IIIA NSCLC
Screen tumor for activating EGFR mutations (del_19, L858R)
Adjuvant erlotinib x 2 years
+/- adjuvant chemo
Enroll if: screen + or documented EGFR mutation positive –and-No evidence recurrence on baseline CT scans
Surveillance CT scans and CTC analysis q 6 mos x 3 years then q 12 mos x 2 years
Biopsy at recurrence, sequence EGFR gene for new mutations, FISH for EGFR and MET copy number
surveillance
SCREENING PHASE TREATMENT PHASE
N=100Primary Endpoint: Two year disease-free survival
SELECT*: First 36 Patients Characteristic Patients
(n=36)Percentage
Median age, years 63 Range, 43-82Sex Male 9 25% Female 27 75%Smoking Never 20 56% <=10 pack years 6 17% >10 pack years + current
10 28%
Ethnicity Non-Asian 32 89% Asian 4 11%
Surgically resected EGFR mutant Lung cancer with adjuvant Erlotinib Cancer Treatment
Neal et al, ASCO 2012, abstract 7010.
SELECT: Stage and Mutation Distribution
Stage EGFR Mutation
SELECT: Toxicities
ToxicityAny (%)
Grade 3 (%)
Grade 4 (%)
Rash * 89 17 -Diarrhea * 78 3 -Fatigue * 61 6 -Nausea/vomiting 39 - -Dry skin 39 - -Cough (unrelated except 1 gr 2) 42 3 -Nail changes 36 - -Dyspnea (unrelated) 28 - -Alopecia/Scalp irritation 25 - -Eye irritation 25 - -
(Any relationship, >25% frequency or grade 3+)
* Toxicities leading to dose reductions
SELECT: Toxicities (cont)
ToxicityAny (%)
Grade 3 (%)
Grade 4 (%)
Pruritis 19 3 -Mucositis 19 - -Transaminitis* 19 - -Hyperbilirubinemia* 17 3 -Anorexia/dysguesia 14 - -Nosebleed 14 - -Constipation 14 - -Neuropathy 14 - -Urticaria* 3 3 -Venous thrombosis (unrelated) 3 3 -Pneumonitis (none observed) - - -
(Any relationship, 10-25% frequency or grade 3+)
* Toxicities leading to dose reductions
SELECT: Treatment LengthTreatment duration and dose reductions
1 Travel precluded participation2 Diarrhea 3 Rash/Diarrhea4 Diarrhea/fatigue5 Prostate cancer radiotherapy
Mon
ths
on E
rlot
inib
6 Patient preference7 Rash8 Disease progression9 Patient preference10 Rash
Reasons for discontinuation
Disease Free Survival
Disease Free Survival, by Stage
Overall Survival
SELECT: Conclusions• Feasible, some patients required dose reduction or
discontinuation
• Primary endpoint of 2 year DFS > 86% met. • Observed 2 year DFS: 94%• Only one patient progressed while receiving adjuvant
erlotinib• Ten patients progressed ≥6 months after stopping adjuvant
erlotinib• 6 of 8 rebiopsies did not identify a TKI resistance mechanism
• All 5 evaluable patients were sensitive to further treatment with erlotinib
• Taken together, this suggests that adjuvant erlotinib has, at least, a cytostatic effect on micrometastatic disease
• Based on the demonstrated role of EGFR TKIs in advanced NSCLC with EGFR mutations, this trial has been expanded to 100 patients total
RADIANT: Adjuvant Erlotinib in Resected NSCLC
Stage IB, II, or IIIA NSCLC*Complete surgical resectionAnd subsequent adjuvant chemoNo prior or concurrent neoadjuvant or adjuvant
N=945
Arm AErlotinib qd 2 years
Arm BPlacebo qd 2 years
RANDOMIZE
*Enriched Population: FISH and/or IHC (+)
•Primary endpoint: disease free survival•240 sites (US, Canada,Europe, Asia, Argentina) •Completed enrollment 4/2010•Interim results expected soon
2
1
BR 19: Adjuvant Trial of Gefitinib
in NSCLCStage IB, II, or IIIA NSCLCComplete surgical resectionNo prior or concurrent neoadjuvant or adjuvant N=1242
Modified 2004 to allow adjuvant ٭chemotherapy
Arm AGefitinib qd 2 years
Arm BPlacebo qd 2 years
CAN-NCIC-BR19, CTSU, ECOG-CAN-NCIC-BR19, SWOG-CAN-NCIC-BR19 Protocol. Clinical Trials (PDQ®). At: www.cancer.gov. Commenced October 2002.
RANDOMIZE٭
BR 19: Results
Arm BSC Gefitinib P valueNo 252 251Female 46% 46%Adenoca 59% 60%Stage IB 50% 53%MS NR 5.1 y 0.14
[HR1.24]DFS NR 4.2 0.15 [HR
1.22]• Trend toward impaired outcome for EGFR mutation pts receiving Gef [HR of OS: 1.5]
Goss et al, ASCO 2010, abstract LBA7005.
Vaccines
MAGE-A3 Antigen(melanoma antigen family A, 3)
• Truly tumor-specific–Not expressed on normal cells (RT-PCR)–Expressed by various tumor types
• Lung 35-50%• Bladder 35%• Head & Neck 49%• Melanoma 74%
• May be associated with poor prognosis(Bolli et al.,2002; Gure et al.,2005)
• Member of a large family of genes (portfolio)
MAGE A3 ASCI* Randomized Phase II
• stage pIB or pII were 2:1, double-blind, randomly assigned to postoperative MAGE-A3 vaccination or placebo.
• Vaccination was started >6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months.
• Other anti-cancer adjuvant therapy was not allowed.
• Primary endpoint was disease-free interval, other endpoints were recurrence rates at different times, and survival.
• N=182 * antigen-specific cancer immune therapeutic
Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.
Safety Status
• 182 patients / 1214 MAGE-A3 doses administered
• Overall well tolerated• Mild grade 1 or 2 • Local or systemic reactions, 48 hours
• 29 grade 3 or 4 adverse events in 21 patients
• Three grade 3 events, possibly related to treatment
• Leading to withdrawal of 2 patients – (local pain, COPD exacerbation)
• Median follow up 44 mos• Induction of anti-MAGE-A3 IgG antibody
response observed in >98% of pts immunized (8% pts with baseline anti-MAGE-A3 antibody response)
• T cell response in 41% immunized pts, 14% placebo
• No correlation of immune response and clinical outcome
MAGE-A3 Vaccine Phase II:Efficacy Endpoints Overview
Hazard Ratio 95% CI p
Disease-free interval
0.75 [0.46-1.23] 0.127
Disease-free survival
0.76 [0.48-1.21]
Overall survival
0.81 [0.47-1.40]
Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.
• Median follow up 44 mos• Induction of anti-AMGE-A3 IgG antibody
response observed in >98% of pts immunized (8% pts with baseline anti-MAGE-A3 antibody response)
• T cell response in 41% immunized pts, 14% placebo
• No correlation of immune response and clinical out
MAGE-A3 Vaccine Phase II:Efficacy Endpoints Overview
Hazard Ratio 95% CI p
Disease-free interval
0.75 [0.46-1.23] 0.127
Disease-free survival
0.76 [0.48-1.21]
Overall survival
0.81 [0.47-1.40]
Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.
Resectable NSCLC
Surgery
Pathological stage IB, II, IIIA
N=2,270*
R
MAGE-A3 +AS15 Placebo
No chemotherapy
Chemotherapy
Up to 4 cyclesplatinum based chemotherapy
R
MAGE-A3 +AS15 Placebo
MAGRIT: Phase III
*MAGE-A3 as Adjuvant non-small cell LunG Cancer ImmunoTherapy
PEARL
• Randomized, double blind phase II study of PRAME (PReferentially Expressed Antigen of MElanoma Immunotherapy) after resection in NSCLC
• Recombinant PRAME protein combined with AS15 adjuvant system, 13 doses
• N= 220 , stage IA-T1b, IB, II, IIIA, PRAME positive (~30-40%)
• Open 6/13, primary endpoint DFS
Post-operative Radiation Therapy
Adjuvant Radiotherapy:Meta-analysis 1998
• Individual data from 9 randomized trials including 2128 patients
• Treatment details (staging, surgery, RT) highly variable among series
• PORT: better local control: 29% fewer local recurrences - 195 LR vs 276 LR for no RT
• Overall HR = 1.21 (1.08-1.34) ~ survival decrement of 7 % at two years (55% vs 48%)
• Increase risk greater for early stage patients(Stage I/II vs. III)
Lancet 25 July 1998.
PORT Meta-analysisSurvival Curves
Stewart et al Lancet 1998.
PORT – Results by Stage/Nodal Status
• No increased risk for patients with N2 disease
• Patients with the least to gain have the most to lose
Stewart et al Lancet 1998
PORT Meta-analysisMethodologic Flaws
• Variable and unspecified staging• Variable and unspecified interval between
resection and PORT• Inadequate RT
– Suboptimal doses; large fields– Poor treatment planning– Outmoded techniques (e.g.: use of low-energy photons
or 60Co for a substantial proportion of patients)• Inclusion of node negative patients• Unpublished data (2 of 9 studies)• Relatively short follow up (< 4 yrs)
Risks of PORT Modern Technology
• Retrospective review– 202 patients treated with surgery
and PORT for Stage II and III disease
– Median dose 55 Gy– Actuarial rate of death from
intercurrent disease was 13.5% compared to expected rate of 10%
Machtay et al JCO 2001.
ANITA - PORT Evaluation• PORT: 33% on obs, 22% on chemo• For all Chemo > XRT = chemo/XRT > 0• For N2 Chemo/XRT > chemo > XRT > 0
XRT No No Yes YesChemo No Yes No YesAll pts MST 26mo 93mo 50mo 46mo
N2 MST 13mo 24mo 23mo 47mo
Rosell, IASLC 11, Abs Pr3, 2005.
CT RTCTRTOBS
0.00
0.25
0.50
0.75
1.00
DURATION OF SURVIVAL (MONTHS)
0 20 40 60 80 100 120
IASLC 2005
ANITA TRIAL: N2 Disease – Influence of RT
Lally, B. E. et al. J Clin Oncol; 24:2998-3006 2006.
Plot of Overall Survival for N2 pts Stratified by Postoperative Radiotherapy
(PORT) use SEER Data
“Lung ART”P.I. Dr Cécile Le Pechoux
Completely resected N2 NSCLC
SURGERY
Conformal RT
No post-op RT
54 Gy/27-30 fxs
Primary end-point: DFS (Sample size: 700 patients)
Pre or post-op chemotherapy allowedConcomitant chemo not allowed
Sponsors: FNCLCC, IFCT, LARS-G, EORTC
Controversies• Which regimen?
– Cisplatin vs Carboplatin?Cisplatin with vinorelbine, gemcitabine, docetaxel, pemetrexed (non-squam), or
nab- paclitaxel, carboplatin regimens if not cis candidate
• Stage IB? If at least 4 cm. • Predictive/prognostic biomarkers?
Not ready for prime time, clinical trials ongoing
• Post-operative XRT (PORT)? Consider if N2 disease
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