Caso clinico prima linea

• Donna, 50 anni ricoverata in U.O. Pneumologia

• Fumatrice (20 sig/die da 30 anni)

• PS: 1

• Sintomi: tosse e dispnea da sforzo

• Comorbidità: ipertensione ben controllata

Caso clinico prima linea

• RX torace: lesioni nodulari bilaterali

• EO: linfonodo sopraclaveare destro di circa 2.0 cm

• TC Total-Body con mdc: tumefazione linfonodale sopraclaveare destra 1.7 cm. Multiple lesioni eteroplasiche polmonari periferiche bilaterali, di cui la maggiore di 3 cm al lobo inferiore di destra, linfoadenopatie mediastiniche e retrocarenali (max 3 cm)

• PET total body: iperaccumulo a livello della regione sopraclaveare destra (SUV 8.9), delle multiple lesioni polmonari bilaterali (SUV max 12.5), e a livello madiastinico (SUV 10.7)

cT4 N3 M1a – STADIO IV

Caso clinico prima linea

• Broncoscopia con brushing e BAL: non alterazioni della canalizzazione bilateralmente fino al limite della visione endoscopica, in rapporto all’ubicazione periferica delle lesioni.

Brushing: negativo BAL: positivo per carcinoma NOS

Per decidere un trattamento di prima linea più appropriato è mandatorio determinare l’istotipo e lo stato mutazionale di EGFR.

E’ necessario:• asportare il linfonodo sopraclaveare

destro oppure • effettuare un ago aspirato dello stesso

oppure• ripetere la broncoscopia con il tentativo di un agobiopsia transbronchiale?

Caso clinico prima linea: Quesito 1

Caso clinico prima linea: Risposta

Quesito 1

• Asportazione linfonodo sopraclaveare destro:

adenocarcinoma con EGFR non mutato

non-squamousnon-squamous squamoussquamous

?????? ?????? ??????

NSCLCNSCLC

considerconsider

gefitinibgefitinib

EGFR mut+EGFR mut+

First-line approach in advanced NSCLC

EGFR wt or unknownEGFR wt or unknown

EGFR-TKIs and EGFR Mutations First-Line Randomized Phase III Studies

Study Entry Criteria and Therapy (no.pts)

HR for PFS(EGFR mut +)

HR for OS(EGFR mut +)

IPASSMok NEJM 2009

Asiatic, never- & light –smokers, adenocarcinoma(EGFR mut + 59.7%)GEF (609) vs. CBDCA+PAC (608)

0.48 (0.36-0.66)

0.91 *(0.76-1.10)

*overall population

First – SIGNALProc. IASLC2009

Adenocarcinoma, Never-smokers(EGFR mut + 44%)GEF (159) vs. CDDP+GEM (150)

0.61(0.30-1.22)

0.82(0.35-1.92)

NEJ002MaemondoNEJM 2010

EGFR Mutation + (all)GEF (98) vs. CBDCA+PAC (96)

0.30(0.22-0.41)

GEF 30.5 mosCT 23.6 mos

P = 0.31

WJTOG3405Mitsudomi Lancet Oncol 2010

EGFR Mutation + (all)GEF (86) vs. CDDP+DOC (86)

0.49(0.34-0.71)

NA

EURTAC (EU) EGFR Mutation + (all)ERL vs. Platinum-based chemo

? ongoing ? ongoing

OPTIMAL (China)

EGFR Mutation + (all)ERL vs. CBDCA+GEM

? ongoing ? ongoing

Quale terapia di prima linea?

• Cisplatino + Pemetrexed

• Carboplatino + Paclitaxel + Bevacizumab

• Cisplatino + Gemcitabina + Bevacizumab

Caso clinico prima linea: Quesito 2

non-squamousnon-squamous squamoussquamous

JMDBJMDBHR 0.81HR 0.81

subset beva-eligible subset beva-eligible ECOG HR 0.80ECOG HR 0.80AVAiL HR 0.98AVAiL HR 0.98

cisplatin-cisplatin-

pemetrexedpemetrexed

doublet +doublet +

bevacizumabbevacizumab

platinumplatinum

doubletdoublet

NSCLCNSCLC

considerconsider

gefitinibgefitinib

EGFR mut+EGFR mut+

*Beva-eligible: *Beva-eligible: non-squamous, no gr non-squamous, no gr 2 haemoptysis, no invasion of major vessels,2 haemoptysis, no invasion of major vessels,no cavitation, no uncontrolled hypertension, no recent history of thrombosis, no cavitation, no uncontrolled hypertension, no recent history of thrombosis, no hemorrhagic disorders, no recent anticoagulationno hemorrhagic disorders, no recent anticoagulation

First-line approach in advanced NSCLC

EGFR wt or unknownEGFR wt or unknown

JMDB (ADK)* E4599 (ADK)° AVAiL (NSQ)^

(CDDP+PEM) (CBDCA+PAC+BEV) (CDDP+GEM+BEV)

OR (%)

PFS (mos)

OS (mos)

Female OS (NSQ mos)

G3/4 Toxicity (%) (NSQ)

Neutropenia

FN

PLT

Hypertension

Any G Alopecia

Outcomes in Adenocarcinoma histology

31.9 35 34.6-37.8

5.5 6.6 6.5-6.7

12.6 14.2 13.4-13.6

13.8 13.3 NR

15.1 25.5 36-40

1.3 5.2 2.0

4.1 1.6 23-27

NR 7.0 6-9

11.9 NR NR52% (Scagliotti JCO 2002) 10%

*Scagliotti JCO 2008; Scagliotti Oncologist 2009°Sandler NEJM 2006; Sandler JTO 2010^Reck JCO 2009; Reck Ann Oncol 2010

S130: Pem/Carbo S130: Pem/Carbo Pem Pem vs.vs. Pac/Carbo + Bev Pac/Carbo + Bev Bev Bev

Arm B:

360 Randomized Patients

Stratification factors:

•Disease stage

• Performance status

•Gender

RANDOMIZE

Pemetrexed 500 mg/m2

Carboplatin AUC 6q 21 days X 4 cycles*

Paclitaxel 200 mg/m2

Carboplatin AUC 6Bevacizumab 15 mg/kgq 21 days X 4 cycles*

Arm A:

Pemetrexed 500 mg/m2

q 21 days until PD or treatment discontinuation

Bevacizumab 15 mg/kgq 21 days until PD or

treatment discontinuation

*In both treatment arms, patients with CR, PR, or SD after 4 cycles of induction therapy continue on to maintenance therapy.

Induction Therapy Maintenance Therapy

Zinner R, Saxman S, Peng G, et al. Randomized, Open-Label Study of Pemetrexed/Carboplatin Followed by Maintenance Pemetrexed Versus Paclitaxel/Carboplatin/Bevacizumab Followed by Maintenance Bevacizumab in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) of Nonsquamous Histology. ASCO - Chicago, IL, Jun 4-8, 2010 – JCO 28, abstr. TPS290.

Primary endpoint: PFS without G4 toxicity, HR=0.75, N=360