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Cimavax EGF in NSCLC
Tania Crombet Ramos, MD, PhDNovember 2011
FIRST LINE THERAPY
EGFR inhibitors in first line
Multivariate analysis: Flex study
Trial/Patient Group EGFR Mut+,
n
Median PFS, Mos OS, MosGefitinibErlotinib
Chemo HR (95% CI) Gefitinib Erlotinib
Chemo
Selected by Clinical FactorsI-PASS[1,2] East Asian,
light/nonsmoker, adeno
261 9.8 6.4 0.48 (0.36-0.64)
21.6 21.9
First-SIGNAL[3] Korean, nonsmoker, adeno
42 8.4 6.7 0.61 (0.31-1.22)
30.6 26.5
Selected by Molecular parameterNEJ002[4] Japan,
EGFR mutant230 10.8 5.4 0.322
(0.236-0.438)27.7 26.6
WJTOG3405[5] Japan,EGFR mutant
172 9.2 6.3 0.49 (0.34-0.71)
30.9 Not reached
OPTIMAL[6] China,EGFR mutant
154 13.7 4.6 0.164 Not reached Not reached
Spain Spain, EGFR mutant
217 14.0 27.0
1. Mok TS, et al. N Engl J Med.
2009;361:947-957. 2. Yang CH, et al. ESMO 2010. Abstract LBA2. 3. Lee JS, et al. WCLC2009. Abstract PRS 4. 4. Inoue A, et al. ASCO 2011. Abstract 7519. 5. Mitsudomi T, et al. Lancet Oncol. 2010;12:121-128.
6. Zhou C, et al. ASCO 2011. Abstract 7520.
EGFR TKIs vs Chemotherapy as First-line Therapy
VACCINES IN FIRST LINE THERAPY???
•
TG4010 (Transgene SA, Illkirch, France) consists of a suspension of a recombinant modified vaccinia virus strain Ankara (MVA) that codes for the MUC1 tumour-associated antigen and interleukin 2.
CIMavax EGF trials in first line
Vaccine-CTP-Vaccine (Randomized study)
Phase III study in Europe (vaccination before CTP and then vaccination and CTP )
Investigator sponsored trial in IIIA NSCLC patients
MAINTENANCE THERAPY
R4‐6 cycles of chemo stop
Watch and wait
Continue same chemo
Continuation maintenance
Different chemo or another drug
Early second‐line therapy
4‐6 cycles of chemo stop
Watch and wait
Different chemo or another drug Switch maintenance
4‐6 cycles of chemo stop
Watch and wait
Options: bevacizumab, cetuximab, pemetrexed
Options: docetaxel, pemetrexed, erlotinib/gefitinib
Maintenance Therapy: Options After Platinum‐ Based Therapy With Non‐PD
R
R
Continuation Maintenance Trials
Study Yr Induction Therapy Maintenance Therapy Median PFS
Median OS
Main Grade 3/4 Toxicities
Brodowicz 2006 Gemcitabine 1250 mg/m2
Days 1, 8 + cisplatin 80 mg/m2
Day 1 q3w x 4
Gemcitabine 1250 mg/m2
Days 1, 8BSC
6.6 mos
5.0 mos(P < .001)
13.0 mos
11.0 mos
Maintenance gem: ANC 14.9%, plts 1.7%; blood transfusion 20% gemcitabine vs 6.3% BSC
Belani 2010 Gemcitabine 1000 mg/m2
Days 1, 8 + carboplatin AUC 5 Day 1 x 4
Gemcitabine 1000 mg/m2
Days 1,8
BSC
7.4 mos
7.7 mos(P = .575)
8.0 mos
9.3 mos(P = .838)
ANC 15% chemo, 2% BSC; plts 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC
Perol 2010 Gemcitabine 1250 mg/m2
Days 1, 8 + cisplatin 80 mg/m2
Day 1 x 4
Gemcitabine 1250 mg/m2
Days 1, 8
BSC
3.8 mos
1.9 mos(P <. 001)
NR
NR
At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6%
Paz-Ares 2011 Pemetrexed 500 mg/m2
Day 1 + cisplatin 75 mg/m2
Day 1 x 4
Pemetrexed 500 mg/m2
Day 1 BSC
4.1 mos
2.8 mos(P = .00006)
NR
NR
Fatigue:4.2% pem, 0.6% BSC, anemia: 4.5%, 0.6% BSC, ANC: 3.6% pem, 0 BSC
Fidias P, et al. J Clin Oncol. 2010;28:5116-5123.Paz-Ares LG, et al. ASCO 2011. CRA7510.
Agent/Control Arm N PFS Salvage Treatment,
%
OS
Fidias DocetaxelDelayed docetaxel
309 5.7 m HR: 0.632.7 m P < .001
63 12.3 m HR: 0.809.7 m P = .085
Ciuleanu PemetrexedPlacebo
663 4.0 m HR: 0.602.0 m P < .001
67 13.4 m HR: 0.7910.6 m P = .012
Capuzzo ErlotinibPlacebo
889 12.3 w HR: 0.7111.1 w P < .001
72 12.0 m HR: 0.8111.0 m P = .0088
Miller Erlotinib + bevacizumabPlacebo + bevacizumab
768 4.8 m HR: 0.723.8 m P = .0012
55.5 15.9 m HR: 0.913.9 m P = .2686
Perol ErlotinibObservation
310 2.9 m HR: 0.821.9 m P = .002
81.9 NA HR: 0.91NA NA
Zhang GefitinibPlacebo
296 4.8 m HR: 0.422.6 m P < .0001
58.8 18.7 m HR: 0.8416.9 m P = .2608
Summary of Switch Maintenance Trials
Agent/Control Arm N PFS Salvage Treatment,
%
OS
Fidias DocetaxelDelayed docetaxel
309 5.7 m HR: 0.632.7 m P < .001
63 12.3 m HR: 0.809.7 m P = .085
Ciuleanu PemetrexedPlacebo
663 4.0 m HR: 0.602.0 m P < .001
67 13.4 m HR: 0.7910.6 m P = .012
Capuzzo ErlotinibPlacebo
889 12.3 w HR: 0.7111.1 w P < .001
72 12.0 m HR: 0.8111.0 m P = .0088
Miller Erlotinib + bevacizumabPlacebo + bevacizumab
768 4.8 m HR: 0.723.8 m P = .0012
55.5 15.9 m HR: 0.913.9 m P = .2686
Perol ErlotinibObservation
310 2.9 m HR: 0.821.9 m P = .002
81.9 NA HR: 0.91NA NA
Zhang GefitinibPlacebo
296 4.8 m HR: 0.422.6 m P < .0001
58.8 18.7 m HR: 0.8416.9 m P = .2608
NeningerInclusion
CIMAVaxBSC
242109
11.88.57 p=0.013
NeningerDiagnosis
CIMAVaxBSC
242109
17.114.5
Summary of Switch Maintenance Trials
Issues to Consider Regarding Maintenance Therapy
The big questions about maintenance therapy are WHO to treat and WHEN to treat
If a patient achieves no response and remains symptomatic, is subsequent therapy “maintenance”
or “early second-line
therapy”?
If a patient achieves response and becomes asymptomatic, is “maintenance therapy”
always better than “watch and wait”?
Increasing toxicity
and cost.
Need a cost-effectiveness analysis
VACCINES AS MAINTENANCE THERAPY
Enrolment finished in June 2011!!!
•
Patients who achieve complete or partial response or stable disease and who remain stable for 1 month after stopping chemotherapy are randomized to belagenpumatucel-L or placebo once monthly for 18 months, with additional immunizations at 21 and 24 months.
•
The primary end point is OS, with planned accrual of 700 patients. •
Completion of the study is expected in 2011
SECOND LINE THERAPY
Second line Therapy
Cimavax in primary care attentionFrom inclusion From diagnose
Mean(months)
Median(months)
CimaVax EGFCimaVax EGF 10.2410.24 7.107.10
Docetaxel Pemetrexed Erlotinib Gefitinib EGF EGF EGF
Line of therapy 2nd 2nd 2nd
& 3rd 2nd 3rd 2nd 2nd 2nd/3rd
Study design Phase III Phase III Phase III Phase III Phase II EAP Phase IV
Overall RR (%) 7.1 9.1 9 8.2
Median survival (mos) 7.5 8.3 6.7 5.6 6.47 7.10 5.3
One-year survival (%) 37 29.7 31 NA 30 36.8 24.5
Overall survival Phase II &E(n= 80) & Expanded Access Program (n=120)
Funciones de supervivencia
SURV
3020100
Sup
ervi
venc
ia a
cum
1.2
1.0
.8
.6
.4
.2
0.0
Función de supervive
ncia
Censurado
Mean(months)
Median(months)
CimaVax EGFCimaVax EGF 12.7312.73 6.476.47
controlcontrol 8.528.52 5.335.33
Overall survival after diagnosis in pts with PS=3
Resumen del procesamiento de los casos
43 21 22 51.2%Nº total Nº de eventos Nº Porcentaje
Censurado
Medias y medianas del tiempo de supervivencia
15.624 2.015 11.675 19.573 12.200 4.746 2.897 21.503Estimación Error típico Límite inferior
Límitesuperior
Intervalo de confianza al95%
Estimación Error típico Límite inferiorLímite
superior
Intervalo de confianza al95%
Mediaa Mediana
La estimación se limita al mayor tiempo de supervivencia si se ha censurado.a.
UNFIT PATIENTS
OPTIMAL DURATION OF VACCINATION
Patients receiving long‐term vaccination
Safety and Immunogenicity Doses Patients Related
Adverse events
AEFrequency
1 ‐8 77 99 22 %
9‐14 68 147 20 %
15‐27 44 182 20 %
28 or more14 93 15 %
NO CUMULATIVE TOXICITY!!!!
GAR Probability with repeated doses
Effect of prolonged immunization
Comparaciones globales
29.754 1 .000
36.269 1 .000
36.190 1 .000
Log Rank (Mantel-Cox)Breslow (GeneralizedWilcoxon)Tarone-Ware
Chi-cuadrado gl Sig.
Prueba de igualdad de distribuciones de supervivencia paradiferentes niveles de Dosis segun CRD codificada.
Medias y medianas del tiempo de supervivencia
5.691 .796 4.130 7.251 3.167 .316 2.547 3.78611.007 1.237 8.584 13.431 9.100 .765 7.601 10.5997.291 .754 5.812 8.769 5.067 .647 3.798 6.335
Dosis segunCRD codificada0-56 or moreGlobal
Estimación Error típico Límite inferiorLímite
superior
Intervalo de confianza al95%
Estimación Error típico Límite inferiorLímite
superior
Intervalo de confianza al95%
Mediaa Mediana
La estimación se limita al mayor tiempo de supervivencia si se ha censurado.a.
Resumen del procesamiento de los casos
149 82 67 45.0%51 19 32 62.7%
200 101 99 49.5%
Dosis segunCRD codificada0-56 or moreGlobal
Nº total Nº de eventos Nº PorcentajeCensurado
Riely et al Clin Can Res 13:5150, 2007
Racotumumab Phase III TrialNSCLC III A, IIIB, IV or recurrent after at least 1 year of curative intent
in CR/PR/SD after standard 1st
lineRandomization (1:1) Stratification
Control
If no PD: monthly visits
for 1 year, then
bimonthly.
PD
Follow‐
Up every 3 months: NLs & survival
Inject every 2 weeks x 5, then monthly.
PDNo Next Line:Continue Vaccination.
Next line (NL):Continuing the
vaccine concurrent o
with the next line.
If PS >
3, toxicity, pt. refusal, IDMC indication:
Patient Off Vaccine
Vaccine
•Lat Am. Vs. India + Asia
•Sex
•(IIIA+dry IIIB) vs. (recurrent/ wet IIIB +
IV)
•Response to 1st line: OR vs. SD.
Only stop vaccine when PS≥3 ,toxicity,patients request
Study Design
Total patients :1082
3 interim analyses:
¼
(190) events
2/4 (379)events
¾(569)events
758 events total
Randomized,openlabel,Multicenter
CIMAVax EGF
•
Monotherapy in pts with high [EGF]•
V-CTP-V
•
CTP+ Vac
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
CIMAVax EGF
