CHEMOTHERAPY IN ADVANCED NSCLC

“If you have a long-distance patient with an advanced NSCLC, think it over before to treat him

with chemotherapy.........”

HANSEN, “personal communication” at European School of Oncology, 198............

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Quali affermazione condivido circa la CT nel NSCLC

24 / 30 Cross-tab label

1. Nessun sostanziale progresso negli ultimi anni

2. L'importante è separare NSCLC da SCLC, la specifica istologia del NSCLC non ha molto peso nella scelta terapeutica

3. Stiamo andando verso terapie diversificate a seconda dell' istologia anche nel caso del NSCLC

4. Il PS gioca ancora un ruolo fondamentale

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ANY EVOLUTION IN CHEMOTHERAPY OF NSCLC ?

In any case :

There is an increasing number of abstr. about NSCLC in international meetings compared to

SCLC : any progress in that disease ?

THE POINTS:

➲ What we know➲ Role of CDDP and del CBDCA➲ “two drugs” vs “three drugs”➲ Manteinance therapy➲ 2nd and 3rd line therapy➲ The matter of histology ➲ The compromised PS➲ Chemotherapy in elderly

WHAT WE KNOW:

➲ So called “third generation” regimens have substantially similar efficacy

➲ Different toxicity in different regimens➲ CDDP probably better than CBDCA

Similar results with CDDP + DCT,PCT, Gem and CBDCA+ PCT

➲ RR 24 - 30%➲ ONE YEAR S 37 - 39%➲ MEDIAN OS 8,6 – 9,1 m.

DIFFERENT TOXICITY

➲More G4 leucop.:CDDP+DCT,VNB,GEM➲More G4 thrombocytop.: CDDP+GEM➲Better haemathologic.tol.: CBDCA+PCT➲More alopecia: CDDP+DCT, CBDCA+PCT➲CDDP more neurologic tox. than CBDCA➲CDDP more emesis➲Nephrotoxicity of CDDP➲Use different regimens in different clinical setting......

Efficacy similar but not identical (1)

➲ OS: HR favours Gem (0.90): 1 year absolute benefit 3,9% - 2 years 2,6%

➲ MS: 9 vs. 8,2 months➲ PFS: HR favours Gem (0.88): 1 year

absolute benefit 4,2%➲ Med. PFS: 5,1 vs. 4,4 months ➲ Le Chevalier, Lung Cancer 2005, 47:69-

80

Efficacy similar but not identical (2)

CDDP+ “new drugs”: quite similar efficacyGEM and DTC containing regimen : better control

of diseasePTC containing regimen: significant increase of PDF.Grossi 12th World Conference on Lung Cancer

Better CDDP or CBDCA? (1)

Cis-Platin vs Carboplatin based chemotharapy in first-line treatment of advanced NSCLC : an

individual patient data Meta-Analysis

(A.Ardizzoni et al. J.Natl Cancer Inst 2007; 99: 847-57)

Better CDDP or CBDCA ? (2)toxicity

➲ Similar on WBC➲ Similar on HB➲ More on Platelets (CBDCA)➲ More gastrointestinal (CDDP)➲ More neurologic (CDDP)

Better CDDP or CBDCA ? (3)efficacy

➲ RR > CDDP : 30% vs 24% ( P < 0.001)➲ Risk of Death > CBDCA ( HR 1.07 vs 1.15)

(P = NS)➲ > Risk of death (CBDCA) for non-squamous

patients (HR 1.12, P = 0.02) when CDPP is combined with “new drugs”

Better CDDP or CBDCA ? (4)

➲ “Given the palliative nature of CT in adv. NSCLC and unquestionable pratical advantage of CBDCA in terms of ease of administartion, it could be argued that the small benefit achieved with CDDP relative to CBDCA, does not justify its preferential use in clinical pratice”

➲ CDDP the European winner➲ CBDCA the American winner

Better CDDP or CBDCA ? (5)

“ if the results of this meta-analysis may still support the use of CBDCA-based regimens in the

palliative treatment of pts. with very advanced disease and/or poor PS, CDDP regimens may well be preferable in pts. whose PS is good and whose

disease is less adv. (i.e. Oligomet. IV or III stage)”“CDDP should be remain the reference platinum

agent for NSCLC at least in adv. disease with good prognosis and in those with earlier disease”

Better CDDP or CBDCA ? (6)

CDDP BASED REGIMENS WITH “NEW DRUGS” COULD BE THE STANDARD THERAPY

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WHAT THE OPTIMAL DURATION OF CHEMOTHERAPY?

SMITH I.E. et al. (J.C.O. 2001)

➲ Regimen : MVP➲ Duration : 3 vs 6 months➲ MST : 6 vs 7 months➲ 1 year survival : 22 vs 25%➲ Improvement symptoms : 67 vs 68%➲ COMMENTS : > fatigue, nausea and

vomiting, = survival

Socisky M.A. et al. (J.C.O. 2002)

➲ Regimen : CBDCA + PCT➲ Duration : 4 cycles vs >PD➲ MST : 6.6 vs 8.5 months➲ 1 year survival : 28 vs 34 %➲ Similar QOL➲ No adv. for prolonged treat.

Von Plessen C. et al.

➲ Regimen : CDDP + VNR➲ Duration : 3 vs 6 cycles ➲ MST : 28 vs 32 weeks➲ 1 year survival : 25 vs 25%➲ QOL : similar ➲ No adv in RR and OS for 6 cycles

Park JO et al. (J.C.O. 2007)

➲ Regimen : CDDP + “3rd gen. Drugs”➲ Duration : 4 vs 6 cycles ➲ MST : 15.9 vs 14.9 months➲ 1 year survival : 62.4 vs 59%➲ QOL : similar➲ Better TTP for 6 cycles

Conclusions about duration,more chemoterapy :

➲ Possible increase of TTP➲ More toxicity➲ Decrease of QOL➲ No better Survival➲ No better OS

(Soon, Yu Yang et al. 12th World conference on Lung Cancer 2007)

Three or two drugs in CDDP containing regimens ?

➲ Three drugs : more RR (23 vs 31%)➲ No survival adv.➲ More toxicity

(Delbaldo C et al JAMA 2004)

➲ Comella et al. JCO 2000: CDDD/VNR/GEM vs CDDP/GEM : MST > 3 months for 3 drugs regimen

➲ Three drugs better for neoadjuv ct ?

Manteinance therapy :1) until PD

2) Predefinite N° cycles➲ Ciuleanu T. (ASCO 2008) : manteinance

Therapy with Pemetrexed in IIIb IV stage NSCLC : better PFS and better preliminary OS in non- squamous

➲ Fidias P. (JCO 2009) : better PFS and NS improvement of OS when DCT administred immediately (max 6 cycles) vs delayed after front-line CDDP+ GEM ct

2nd line therapy : approved drugs

➲ CHEMOTHERAPY: Docetaxel, Pemetrexed➲ EGFR TKI THERAPY: Gefitinib, Erlotinib➲ 2nd line therapy end-points: Symptom

improvement, > TTP, > Disease Control, < Toxicity, > QOL VERY IMPORTANT TOPICS FOR 2nd LINE TREATMENT OF NSCLC

Shepherd F. (J.C.O. 2000)Docetaxel vs BSC

➲ Patients with PS 0 to 2 IIIb or IV stage after 1 or more CDDP containing regimens

➲ Docetaxel 75mg/mt2 better than 100mg/mt2➲ Median survival 7.5 vs 4.6 months➲ 1 year survival 37% vs 11%➲ At a dose of 75mg/mt2 benefits of

Docetaxel outweigh risks

Fossella F. (J.C.O. 2000)Docetaxel vs control (VNR or IFO)

➲ Patients previous failed CDDP containing regimens

➲ Docetaxel better than VNR or IFO control regimens

➲ Docetaxel 75mg/mt2 less toxic than 100➲ Previous exposure to Paclitaxel do not

decrease likelihood of response to Docetaxel➲ > efficacy in CDDP resistant vs refractory➲ > TTP and PFS at 26 w in Docetaxel group➲ OS non significant better

Docetaxel every 3w vs weekly(Meta-analysis)

Di Maio M. (J.C.O. 2007)

➲“ weekly Docetaxel shows similar efficacy compared to 3 weeks Docetaxel and represents an alternative for 2nd line treatment of advanced NSCLC”

Pemetrexed vs Docetaxel in 2nd lineHanna N. (J.C.O. 2004)

➲ Pemetrexed 500mg/mt2 vs Docet 75mg/mt2

➲ RR 9.1% vs 8.8% (NS)➲ Pemetrexed : less G 3- 4 neutropenia,

less febrile neutropenia, less hospitalization for febrile neutropenia, less G-CSF, less hospitalization for any drug-related AE

3rd line therapy ?

➲ DEFINITION : patients previosly treated with CDDP containing regimen and Docetaxel or Pemetrexed

➲ RR decreases with subsequent regimens of chemotherapy

➲ Not clear evidence suporting 3rd line ct➲ Role for “biological” ? Target !!! ➲ Importance of good PS and a low

toxicity profile

ONCE UPON A TIME THERE WAS..........

NSCLC vs SCLC

The matter of histology........

SQUAMOUS VS NON-

SQUAMOUS.....

“The differential efficacy of pemetrexed according to NSCLC Histology: a review of

two phase III studies” (Scagliotti, The Oncologist 2009)

➲ A predictive role for NSCLC histology➲ Differential efficacy of Pemetrexed➲ Survival advantage for Pemetrexed in non

squamous histology➲ Pemetrexed should be not recommended

for the treatment of squamous cell ca.➲ May be preferable to other agents for non

squamous NSCLC➲ A lower baseline TS expr. level may be an

explanation for the > activity of P in non squamous histology

And poor PS and elderly...?

➲ Have a statistical advantage a clinical significance ?

➲ Are the clinical trials well designed for elderly?

➲ In elderly monoct probably best ➲ CDDP containing ct could be considered in

> 70y good PS➲ Monoct standard in PS2

TAKE HOME MESSAGES

➲ COMBINATION CDDP + 3rd GENERATION DRUG IS 1st CHOICE IN NON ELDERLY GOOD PS (“bulky disease ?”)

➲ 3 DRUGS COMBINATION MORE ACTIVE BUT MORE TOXICITY

➲ GEMCITABINE BEST TTP➲ PEMETREXED BEST IN NON

SQUAMOUS➲ ELDERLY AND PS2 CONSIDER MONOCT

Quali affermazione condivido circa la CT nel NSCLC

➲ Nessun sostanziale progresso negli ultimi anni

➲ L'importante è separare NSCLC da SCLC, la specifica istologia del NSCLC non ha molto peso nella scelta terapeutica

➲ Stiamo andando verso terapie diversificate a seconda dell' istologia anche nel caso del NSCLC

➲ Il PS gioca ancora un ruolo fondamentale

25%

25%

25%

25%

Quali affermazione condivido circa la CT nel NSCLC

0 / 0 Cross-tab label

1. Nessun sostanziale progresso negli ultimi anni

2. L'importante è separare NSCLC da SCLC, la specifica istologia del NSCLC non ha molto peso nella scelta terapeutica

3. Stiamo andando verso terapie diversificate a seconda dell' istologia anche nel caso del NSCLC

4. Il PS gioca ancora un ruolo fondamentale