ABORDAJE TERAPÉUTICO DEL CÁNCER MICROCÍTICO DE PULMÓN

Rosario García CampeloServicio de Oncología Médica

Complejo Hospitalario Universitario A Coruña

SCLC accounts for approximately 18.31% (female) and 13.68% (male) of all lung cancers in 2003

SCLC and NSCLC

Wahbah et al. Ann Diagnostic Pathol 2007; 11: 89–96.

LAS CIFRAS DEL CÁNCER EN ESPAÑA

ENFERMEDAD RARA O HÚERFANA:

incidencia < 0.05%

4177 CMP anuales en España28.000 muertes anuales en el mundo

7ª causa de mortalidad por cáncer en el mundoEs el 3er subtipo histológico más frecuente de cáncer de pulmón

NO ES RARO…PERO SÍ PROBABLEMENTE HUÉRFANO…

SMALL CELL LUNG CANCER SURVIVAL

Median survival without treatmentLS: 4 monthsES: 2 months

Extensive StageLimited Stage

Govindan, JCO 2006

Median survival with treatmentLD 16 monthsED 9 months

5 YS men: 7.5%

5 YS female: 12%

5 YS male: 3.5%

5 YS female: 5%

My main objectives today

STATE OF THE ART

AND SOME FUTURE PERSPECTIVES…

U.S National Cancer Institute Levels of EvidenceHow do we change our clinical practice?

Study Design

Randomized controlled trials

Non-randomized controlled trials

Population based consecutive series

Consecutive case series

Non- consecutive case series

+

-

Meta-analysis

LIMITED STAGE:Progress in treatment

Standard combinations

Platinum combinations

• Cisplatin – Etoposide (PE)

• Carboplatin – Etoposide (CE)

• Ifosfamida – carboplatin – Etoposide (ICE)

• Cisplatin- Epirubicin

Anthracyclines combinations

• CTX- adria - VCR (CAV)

• Adria – CTX – etoposide (ACE)

Platinum vs Anthracycline combinationsRandomized trials

Author CT N Median Survival(months)

All LS ES

2 y survival (%)

All LS ES

SundstromJC0 02

CEV

PE

218

218

7.8

10.2

9.7

14.5

6.5

8.4

6

14

8

25

1

4

p 0.0004 0.001 NS 0.0004 0.001 NS

BakaBJC 08

ACE

PE

139

141

10.1

10.7

11.8

12.6

8.8

7.8

14

12

21

17

0

3

P 0.76 0.67 0.78 0.76 0.67 0.7

Meta-analysis of cisplatin vs non cisplatin randomized clinical trials

Pujol et al. B J Cancer 2000

Survival: Increased of 4.4% of 1 yearSurvival

20% mortalityResponse: Increase of 9%No differences in toxicity

CIS OR CARBO…

.

Rossi A et al. JCO 2012;30:1692-1698

The choice of a platinum compound for1st line should take into account• Expected toxicity profile• Age• Patient´s organ function• Patient´s comorbilities

¿Cisplatino o carboplatino en enfermedad limitada?

Cisplatino -etoposido vs Carboplatino-etoposido + radioterapia concurrente en pacientes > 65 añosEstudio de Cohorte SEER-Medicare

• Objetivo 1º: Supervivencia

• Edad mediana 72 (66-81

• 611 pacientes

– Cis-etoposido: 229 pacientes

– Carbo-etoposido: 382 pacientes

• # CSS: Cause Specific Survival

16.03 m/22.8%

15.01m/25.21%

mCSS#/ 5 años

13.7m/10.51%B:CE

13.3m/10.11%A:PE

mSG/ 5 años

Kim E. ASCO 14

Resultados

Is radiotherapy necessary?Two meta-analysis

Pignon et al (NEJM 1992) evaluated 13 randomized trials:

Thoracic Radiotherapy in LS-SCLC: an absolute benefit in overallsurvival of 5.4% at 3 years and a 14% reduction in mortality.

Warde and Payne (JCO 1992) evaluated 11 randomized trials:

The addition or RT to Chemotherapy showed an overall survivalbenefit of 5.4% at 2 years.

Chemo-TRT

“The sequence”

Autor Sequence N patients MS(meses)

2Y survival (%) P

Gregor, 1997 Concurrent

Sequential335

14

15

26

23

No significant

Lebeau, 1999 Concurrent

Alternante

82

74

13.5

14

NR

NR

No significant

Takada 2002 Concurrent

Sequential

114

114

27.2

19.7

5a23.7

18.3

SignificantP= 0.02

Chemo-TRT“The moment”

Author “Timing” N patients

MS(month

s)

2 year Survival

(%)

StatisticalSignification

Perry, 1987 EarlyLateNone

125145129

13.114.613.6

15258

Advantage for arms with RT, No differences in timing.

Murray, 1993 EarlyLate

155153

20.015.0

4033

Significant

Jeremic, 1997 EarlyLate

5251

3426

7153

Significant

Work, 1997 EarlyLate

99100

10.512.0

2019

No significant

Spiro 2006 EarlyLate

13.715.1

No significant

Fried, D. B. et al. J Clin Oncol; 22:4837-4845 2004

Two-year overall survival risk ratio forest plot for early v late thoracic radiation therapy (RT)

“Early vs Late” Thoracic Radiation

Meta-análisis

TRTThe fractionation

Autor Fraccionamiento Nº pacientes MS

(meses) Supervivencia

(%) Significación estadística

Turrisi, 1999

Fraccionada No fraccionada (en 1º ciclo)

211

206

23

19

2 años 47 41

5 años 26 16

Significativo

Bonner, 1999 Schild 2003

Fraccionada No fraccionada (en 4º ciclo)

130

132

20.4

20.5

45

47

22 21

No significativo

HF-RT vs RT

Conclusión: Si la radioterapia comienza de forma temprana, el hiperfraccionamientopuede ser beneficioso en supervivencia.Pero si la radioterapia comienza de forma tardía, probablemente el hiperfraccionamiento no es beneficioso

HOW IMPORTANT IS THE SER CONCEPT

The time from the start of any treatment to the end of chest

irradiation

(A) The survival at 5 years as a function of the start of any treatment and the end of radiotherapy (SER).

Dirk De Ruysscher et al. JCO 2006;24:1057-1063

Spiro et al. J Clin Oncol 2006

El beneficio de la Radioterapiatemprana sólo existe en aquellos estudios en los que se administran

todos los ciclos de la quimioterapia programada

Study N CT CT-RT RR MS 2y S

Bogart 2004 63 T To CaE/70Gy 92% 22 48%

Miller 2007 65 TToE CaE/70Gy 81% 20 35%

Schild 2007 76 PE PE/60Gy - 22 46%

CT-TRT

The dose

Prophylactic cranial irradiation

Auperin et al. NEJM 1999

16% reduction in mortality

5.4% increase in 3 year survival rate

PCI decreases cumulative incidence of brainmetastasis in 25.3%

PCI significant increases the rate of diseasefree survival and disease free of brain mets.

Benefit observed in LS patients with CR or PR

Standard vs higher dose PCI in SCLC-LSPCI at 25 Gy should remain the standard of care in limited-stage SCLC.

Le Pechoux et al. Lancet Oncol 2009

OS DFS

Local relapseBrain met incidence

Pignon – NEJM 1992 * Turrisi –NEJM 1999 * Auperin –NEJM 1999 * Warde – JCO 1992*Fried – JCO 204 * Perry – NEJM 1987 * Pujol – BJC 2000 * Macaux – Lung Can 2000

1960 SCLC chemo-sensitive

1987 Perry: CT-RT > QT

Turrisi: Hf-RT (45Gy) > RT

1992

1999

Pignon / Warde: CT-RT > QT

Auperin: Holocranial RT

Pujol: CDDP > no-CDDP

CDDP-VP16 remains gold standard 2000

2004 Fried: Early RT > Late RT with HF-RT

LD-SCLC

18-23mo2-4 mo

Some conclusions for the daily practice

QT: Platinum-etoposide

Concomitant QT+RT better than sequential

Early RT: as soon as posible…better outcomesin the first 30 days

RT: dose, HF-RT??? Early RT > Late RT with HF-RT

PCI improves survival

Extensive Stage SCLCTHE LAST 10 or 20 YEARS SUMMARY…

SCLC is highly sensitive to chemotherapy and radiotherapy

Despite the high chemosensitivity, median survival remainspoor for patients with ES ranges only from 7 to 11 months

Platinum-etoposide is the standard of care in first linetreatment since the 1980s• ORR: 50-60%

• Median Survival: 9-12 months

• Topotecan is the standard of care in second-line therapy

SOME AND RELEVANT QUESTIONS in the 1st line setting…

What is the best 1st line regimen?

Is there a role for dose-intensive chemotherapy?

Is there a role for maintenance chemotherapy?

Is there a role for antiangiogenic agents?

Is there a role for inmunotherapy treatments?

Is there a role for preventive brain irradiation ?

Is there a role for thoracic radiotherapy?

CIS OR CARBO…

.

Rossi A et al. JCO 2012;30:1692-1698

4 RCT32% LD 68% SDNo differences in RR, PFS and OS

The choice of a platinum compound for1st line should take into account• Expected toxicity profile• Age• Patient´s organ function• Patient´s comorbilities

Have we found any way to improveplatinum-etoposide results?

Compare new platinum regimens toplatinum etoposide

• Irinotecan- Platinum

• Topotecan- Platinum

• Pemetrexed- Platinum

• Amrubicin-Platinum

JCOG 9511

Noda et al NEJM 2002

North American/Australian study

Hanna et al. JCO 2006

Platinum-Irinotecan vs Platinum-Etoposide

Irino 60mg/m2 d1,8,15P 60mg/m2 d1

Q4 weeks x 6 cycles

E 100mg/m2 days 1 to 3P 80mg/m2 day 1

Q3 weeks x 6 cycles

RANDOMIZATION

RANDOMIZATION

Irino 65mg/m2 d1,8P 30mg/m2 d1 and 8Q3 weeks x 4 cycles

E 120mg/m2 days 1 to 3P 60mg/m2 day 1

Q3 weeks x 4 cycles

Platinum-Irinotecan vs Platinum-Etoposide

Noda et al, NEJM 2002 Hanna et al, JCO 2006

S0124: A randomized Phase III trial of Cisplatin+Irinotecan vsCisplatin+ Etoposide in patients with SCLC ED

Lara et al. JCO 2009

MA Irinotecan/Platium vs Etoposide/Platinum

Shao et al. J Thorac Oncol 2012

RR: no difference

OS:better IP

PFS: No difference

Oral Topotecan-Platinum vs Platinum-Etoposide

Eckardt et al, JCO 2006

IV Topotecan/cisplatin vscisplatin/etoposide

Fink TH et al. J Thorac Oncol 2012

Phase III study of Pemetrexed plus Carboplatin vs Etoposideplus Carboplatin in patients with SCLC ED. GALES/JMHO Trial

Socinski et al. JCO 2009

Satouchi M et al. JCO 2014;32:1262-1268

Is there a role for dose- intensity chemotherapy?

43 published papers: There is no evidence that thetreatment of SCLC can be improved by increasing the

dose intensity, peak dose, or total dose of chemotherapy, so intensification strategy should be

probably abandoned

Criveralli et al. The Oncologist 2007

MA RESULTS OF INTENSIFIED CHEMOTHERAPY IN SCLC

Rossi et al. Cancer Treat Rev 2013

7505: Study Design

STAD-1 TRIAL

Morabito et al. ASCO 2015

No Difference Between the PFS and OS

Morabito et al. ASCO 2015

Is there a role for maintenance therapy?

ECOG e7593 Phase III trial: Topotecan vs Observation after Cisplatin Etoposide (Schiller etal JCO 2001)

FNCLCC cleo04–IFCT 00-01 Phase III trial Thalidomide vs Observation after Cisplatin-Etoposide (Pujol et al JCO 2007)

BR20 Phase II trial: Vandetanib vs placebo after complete or partial response toinduction chemotherapy with or without radiation therapy (Arnold et al JCO 2007)

EORTC BR.12: Prospective, Randomized, Double-Blind, Placebo-Controlled Trial ofMarimastat After Response to First-Line Chemotherapy in Patients With Small-Cell LungCancer (Shepherd et al JCO 2002)

ECOG E1500: A Randomized Phase II trial of two dose levels of Temsirolimus in Patientswith Extensive Stage Small Cell Lung Cancer who have responding or stable disease afterinduction chemotherapy (Panda et al JTO 2007)

NEGATIVE TRIALS

Rossi et al Lung Cancer, Volume 70, Issue 2, 2010, 119 - 128

MAINTENANCE OR CONSOLIDATION THERAPY: MA

3,688 patients, 11 RCTs employingchemotherapy, 6 interferons, and 4 otherbiological agents

The maintenance or the consolidationapproach failed to improve theoutcomes of SCLC.

A survival advantage is suggested formaintenance chemotherapy andinterferon-alpha, but its clinical impactneeds to be confirmed by furtherstudies

Author Drug/Target NPts

RR%

mPFSmonths

MSmonths

HornJCO 2009

ECOG –E3501 PE + BVZ 63 63.5 4.7 10.9

ReadyJCO 2011

CALGB 30306PI + BVZ 72 75 7.0 11.6

SpigelJ Thor Oncol 2009 CI + BVZ 51 84 9.1 12.1

Spigel et alJCO 2011

Phase II SALUTE

PE+BVZvsPE

52

50

48

58

5.5

4.4

9.4

10.9

Pujol et alAnn Oncol 2015

PE+BVZvsPE

75

80

5.3

5.5

11.1

13.3

Fase II/III trials of CT+ BVZ in ES- SCLC

REDIFINING THE ROLE OF RADIOTHERAPY IN ED SCLC

PCI in ES chemotherapy respondingpatients

Slotman et al. NEJM 2007

1 year S: 27.1% vs 13.3%

HR: 0.68 p0.003

MA of PCI in SCLC

Vianaa et al. J Bras Pneumol 2012

16 RCT collectively involving1,983 patients

Overall mortality was 4.4% lowerin the patients submitted to PCI,especially in those showing acomplete response afterinduction chemotherapy and inthose submitted to PCI after thattreatment, regardless of thestage of the disease

THORACIC RT: CREST TRIAL

Slotman et al. Lancet 2014

2-year overall survival was 13% vs 3% p=0.004

PFS at 6 months was 24% vs 7% p=0.001

Treatment paradigm for relapsed SCLC

Relapsed disease

NO

Refractory

BSC or active treatment

YES

Non-cross resistantchemotherapy

Paclitaxel, Irinotecan,Gem, Topotecan

Amrubicin

ResistantTFI <90 days

SensitiveTFI ≥90 days

Re-challengefirst-line

SensitiveTFI >6months

SensitiveTFI >3-6months

TopotecanOther

Performance status and Sensitivity to 1st line QT are significant prognostic factors for patients receiving second-line treatment

Kim et al. Cancer 2008

Survival according to PS Survival according to sensitivity

Single agent activity in relapsed SCLC

Agent No. of studies Total patients Response rates

Paclitaxel 2 41 29%-36%

Docetaxel 2 38 25%-30%

Vinorelbine 2 49 14%-31%

Irinotecan 3 91 16%-47%Topotecan for Injection

3 129 11%-33%

Gemcitabine 2 71 0%-12%

Ardizzoni A, Hansen H, Dombernowsky P, et al. J Clin Oncol. 1997;15:2090-2096; Depierre A, von Pawel J, Hans K, et al. Lung Cancer. 1997;18(suppl1). Abstract 126; DeVore RF, et al. Proc Am Soc Clin Oncol. 1998;17. Abstract 1736; Fernandez-Rodriguez, et al. Proc Am Soc Clin Oncol. 2001;20. Abstract 2883; Furuse K, Kubota K, Kawahara M, et al. Oncology. 1996;53:169-172; Hoang, et al. Proc Am Soc Clin Oncol. 2002; 21. Abstract 2690; Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Eur J Cancer. 1993;29A:1720-1722; Kurata T, et al. Proc Am Soc Clin Oncol. 2002;21.

Abstract 1350; Le Chevalier T, et al. Proc Am Soc Clin Oncol. 1997;16:450a; Masters G, et al. J Clin Oncol. 2003;21(8):1550-1555; Masuda N, et al. J Clin Oncol. 1992;10:1225-1229; Nakamura H, et al. Proc Am Soc Clin Oncol. 2001;20.

Abstract 2872; Smit EF, Fokkema E, Biesma B, et al. Br J Cancer. 1998;77:347-351; Smyth JF, Smith IE, Sessa C, et al. Eur J Cancer. 1994;30A:1058-1060.

Topotecan in relapsed SCLC

JCO 1999 V Pawel

IV Topotecanvs CAV

JCO 2006 O´Brien

JCO 2007 Eckardt

Oral Topotecan vs

BSC

IV Topotecan vs Oral Topotecan

Median survival p=0.795:

IV topotecan= 25.0 weeks

CAV =24.7 weeks

Median survival

Oral topotecan= 25.9 weeks

BSC alone=13.9 weeks

Median survival

Oral = 33.0 weeks

IV=35.0 weeks

Some other options for 2nd line setting

Taxol combinations

Author CT RR (%) MS/ TTPmonths

3-4 Toxicity

DómineASCO 01

Gemcitabina 1250 mg/m2 d 1 y 8Taxol: 175 mg/m2 d 1Cada 21 d

46S 56R 31

7.1/4.9 Np: 7.5% Tp 5% An 5%

Dongiovanni ASCO 04

Gemcitabina 1000 mg/m2 d 1 y 8Taxol: 80 mg/m2 d 1, 8 y 15Cada 21 d

26S 29R 20

4/3 Np: 26% Tp 25% Astenia 13%

MoriCanc Chem Ph 06

Taxol 100 mg/ m2 d 1 y 8Carbo AUC 2 d 1 y 8Cada 3 -4 semanas

69%S 83R 45

P< 0.001

6.8/3.87.8/10.85.3/3.9P< 0.00

NP 55%, Tp 35, Np 55%

Old combinations: Gemcitabine plus campthotecin analogues

Author CT RR (%) MS/TTPmonths

G 3-4 toxicity

Dómine, IASLC 03 Gemcitabina 1500 mg/m2CPT-11: 150 mg/m2

2 weeks

31S 38R 22

7.3/6 0%

Castellanos, IASLC 03

Gemcitabina 2000 mg/m2CPT-11: 175 mg/m2

2weeks

50 8.5/8 Np 14%

Agelaki, Oncology 04

Gemcitabina 1250 mg/m2 d 1 y 8

CPT-11: 300 mg/m2 d 8Cada 21 d

10 6/? Np: 29%, Tp: 13%, D: 10%

Rocha -LimaAnn Oncol 07

Gemcitabina 1000 mg/m2 d 1 y 8

CPT-11: 100 mg/m2 d 821 d

S 31R11

7.1/3.53.1/1.6

Np: 43%, Tp: 36%, D: 9%

OkanoWCLC 07

P1-225

Gemcitabina 1000 mg/m2 d 1 y 15

CPT-11: 175 mg/m2 d 1 y 15

28 d

39.3%14.4

S 14,4R 7.4

Np: 42% Tp: 3% D: 9%

Amrubicina in 2nd line setting

Onoda, S. et al. JCO 2006

MS: 10.3 m Refractory

MS: 11.6 m Sensitive

Relapsed SCLC: is Amrubicin better than topotecan?

Author Regimen ORR PFS(m)

OSm

EttingerJCO 2010Phase II

R

Amrubicin40mg/m2 iv

D1-3

21.3% 3.2 m 6.0m

JotteJCO 2011Phase II

S

AmrubicinTopotecan

44%15%

P 0.021

4.53.3

9.27.6

InoueJCO 2008Phase II

S&R

AmrubicinTopotecan

53% (S) 17%(R)

21% (S) 0%(R)

3.9 (S) 2.6 (R)3 (S) 1.5 (R)

9.9 (S) 5.3 (R)11.7 (S) 5.4 (R)

Von PawellJCO 2014Phase III

AmrubicinTopotecan

31.116.9

P 0.001

4.13.5

P 0.0182

7.5 7.9

P 0.170

Is there a role for targeted agents?

No…is time to optimism?

Target Agent Trial phase ActivityC-kit imatinib II No

EGFR gefitinib II No

Ras R115777 II No

VEGF Bevacizumab II +/-

Thalidomide III No

Vandetanib II No

Cediranib II No

Sorafenib II No

mTor Temsirolimus II/III No

Src Dasatinib II NA

Bcl-2 Oblimersen II No

Have we made any progress?

I have my own personal opinion and it’s not too positive …

Why son many failures?

Reasons for the failure

Wrong design of clinical trials

Wrong drugs

Wrong targets

Wrong doses

Unknown molecular mechanisms of the disease

…….

Some ideas for the future…

Define SCLC biology to identify new actionablemolecular targets

Increase the diversity of agents

To abandon empiricism in favor of molecularlybased clinical trial design.

IO agents may be a good option for the future…

Novel molecular targets in SCLCSome hope for the future…

Hedgehog/ Smoothened

Slide 6

Mutations in small cell lung cancer

Immunotherapy – The Beginning of the End for Cancer:<br />Transforming Cancer into Chronic Disease

Slide 3

Reck M et al. Ann Oncol 2013;24:75-83

Phase II Study of Ipilimumab in SCLC

Phased schedule shows trendfor improved OS

Phase III ongoing

Abstract No: 7502 Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028.

ORR 35% GOOD DURABILITY

Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. Abstract No: 7503

ORR 32,7%PROMISING ACTIVITY OVERALL IN PLATINUM REFRACTORYPDL-1 EXPRESSION DOESN´T SEEM PREDICTIVEDON´T FORGET THE TOXICITY OF THE COMBINATION…NO CHANGES IN OUR CLINICAL PRACTICE…FUTURE MAYBE!!!!

MEANWHILE…THE MA BASED EVIDENCE

First-Line CT Recommended CT vs BSC

Platinum-based regimens Platinum-based regimens are the standard

CDDP vs CBDCA No difference in ED (toxicity profile)

Platinum/ etoposide combinationPE should be consider estándar of care, specially in caucasians

Maintenance Is not recommended

ICHP and CSF use Data do not support the use of ICHP and CSF

PCI PCI is recommended in responding patients

Thoracic RT NO MA

Second- line CT Limited benefit of CT vs BSC