la chemioterapia. razionale, efficacia e futuro alessandro ......palmanova 24 maggio 2017. lung...

La chemioterapia.Razionale, efficacia e futuro

Alessandro Follador

Palmanova 24 maggio 2017

Lung cancer is a complex disease

Travis; JTO 2015


Pao, Lancet Oncol 2011


31

25

17

7

3

22

22

44

1UnkwnonKRASEGFR sensitizingALKMETHER2ROS1BRAFRETEGFR otherNTRK1; PI3KCA; MEK>1 Mutation

Adapted from Tsao; JTO 2016

majority of patients do not haveactionable mutations/driver oncogenes


Tracking the Evolution of Non–Small-Cell Lung Cancer, Jamal-Hanjani, NEJM 2017

Squamous

Adenocarcinoma


Somatic mutation frequencies observedin exomes from 3.083 tumour

Lawrence; Nature 2103


• genetic changes, different pathways

• relationships with surrounding stromal cells

• specific target(s)

• mechanisms of resistance

• not easy to reproduce in preclinical studies

Epidemiology

Incidenza e proporzione sul totale dei tumori (esclusi i carcinomi della cute)

Cause di morte tumorali più frequenti e proporzione sul totale dei decessi oncologici

Airtum, I numeri del cancro in Italia 2016

Epidemiology

Airtum, I numeri del cancro in Italia 2016

Numero di nuovi tumori stimati per l’anno 2016 nelle singole Regioni italiane per le principali sedi tumorali, per il totale (esclusi gli epiteliomi)

Opzioni di trattamento

SurgeryRadiotherapy

Systemic therapy

• Conventional cytotoxic chemotherapies

• monoclonal antibodies/Tki/ /intracellular pathways/ other

mechanisms involved in cell functioning

• Antiangiogenic drugs/ targeting vascular endothelial

growth factor

• Immune checkpoint inhibitors:anti PD-1 or PD-L1

Supportive drugs

Antiemetics

Granulocyte-colony stimulating factors

Antibiotics

Bisphosphonates

Theoretical bases for chemotherapy

Pharmacokinetics [what happens to a drug]

Absorption – Distribution – Metabolism – ExcretionDetermining the dosing frequency, interactions…

Pharmacodynamics [the pharmaceutical effects on the patient]

target and the mechanism of action of the drug tumor response as a pharmacodynamic effect

Cytotoxic therapy

CT disrupts basic cellular processes

CT works because cancer cells have developed greater dependencies on these processes than normal cells

All CTs are targeted agents.We just lack a clear understanding of their targets in cells.


• Skipper–Schabel–Wilcox log-kill model 1964

• Goldie-Coldman hypotheses 1973

• Gompertzian model

• Norton-Simon hypothesis 1988


Detectable tumors are at least 10^9 cells

Tumor cells acquire spontaneous mutations

Despite response [PR or CR], resistant clone expands

Give multiple drugs at once or cycle non-crossresistant regimens


Combination chemotherapy

• maximal cell kill with "acceptable" toxicity

• close to the maximum tolerated dose

• drug-free breaks in between cures to recover from the treatment-related toxicities

• synergistic model(s)

• prevent and/or slow the development of resistance

sCombination chemotherapy

Clinical trial(s)

Phase 0: pharmacokinetic and pharmacodynamic properties of a new drug/ preclinical toxicology studies; mechanism of action, relationships between the pharmacokinetics and pharmacodymics, biomarker assay

Phase I: dose finding

Phase II: activity

Phase III: efficacy and safety

Phase IIIb-IV: post-marketing surveillance

Chemotherapy in NSCLC

Non-small Cell Lung Cancer Collaborative Group BMJ 1995

…We also need studies to determine whether particular molecular characteristics of tumors identify subsets of patients likely to benefit from chemotherapy..

Chemotherapy vs no treatment, stage IV

~ 19000 stage IV patient pairs

median OS9.3 vs 2.0 months, p < 0.0001

David; JTO 2016

Adjuvant

LACE Pooled Analysis \ Pignon, JCO 2008

overall HR of death 0.89 (95% CI, 0.82- 0.96)

5-year absolute benefit 5.4%

LA-NSCLC: chemoradiotherapy

Auperin; JCO 2010

1st line NSCLC/Sq wt

Novello, Annals of Oncology 2016

1st line NSCLC/NSq wt


2nd line NSCLC/Sq wt


2nd line NSCLC/NSq EGFR+


Driver di scelta per trattamento

Performance status, age, comorbidities

Histologic subtype: NSCLC NonSq / NSCLC Sq

Molecular testing: molecular profiling to find driver event• EGFR [activating mutations: ex19 del or ex 21 (L858R)]*

• ALK\ROS1 [ALK fusion oncogene ALK-EML4, rearrangement ROS1]

• BRAF V600e [mutation]

PD-L1 testing [expresion expression positive (≥50%, 1st line) and EGFR, ALK, ROS1 negative or unknown]

* 15% ex 21 (L861), ex8 (G719X, G719), ex 20 (S768I

1st line: EGFR M+

Mok; NEJM 2009

1st line: EGFR M+

Mok; NEJM 2009Rosell; Lancet 2012Sequist; JCO 2013

1st line: ALK +

Solomon, NEJM 2014

mPFS10.9 vs 7.0 months

Schiller, NEJM 2002Grossi; The Oncologist 2009

1st line: platinum doublets + 3rd gen

Odds ratios for response

Odds ratios for progression

Schiller, NEJM 2002


1st line: cis vs carbo vs platinum doublets

Ardizzoni; J Natl Cancer Inst 2007

1st line: paclitaxel + carboplatin + bevacizumab

Sandler; NEJM 2006

mOS 12.3 vs 10.3

mPFS 6.2 vs 4.5

1st line: istology NonSq

Scagliotti; JCO 2008

1st Line: elderly

Quoix; Lancet 2011

mOS 10.3 vs 6.2 months1year survival 44.5 vs 25.4 %Median age 77 yrs


Rossi; Lancet Oncol 2014

Maintenance

Ciuleanu; Lancet 2009Paz-Ares; JCO 2013

2nd line/Subsequent Systemic Therapy

Shepherd; J Clin Oncol 2000Nasser Hanna JCO 2004

1-00

0.75

0.50

0.25

0.00

0.05.010.015.020.0

SurvivalDistrib

utionfunctio

n

Pemetrezed (n=265)Docetaxel (n=276)

Hazard Ratio

MST8.3mo7.9mo

0.99(95%CI:0.8-1.20)

1-yr29.7%


Reck;Lancet Oncology 2014

docetaxel + nintedanib


Brahmer, NEJM 2015

nivolumab

1st line Platium doublets• overall response rate: 25 – 35%

• time to progression: 4 – 6 months

• median survival: 8–10 months

• 1-year survival rate: 30 – 40%; 2-year survival rate: 10 – 15%

• Cis/pem > efficacy & < toxicity (vs Cis/gem) in NonSq

• Cis/gem > efficacy (vs Cis/pem) in Sq

• Symptom control & > quality of life (vs best supportive care)

• single-agent therapy in select patients

• BSC for unfit patients OR ECOG performance status 3 – 4

Clinical issues

Valutazione della risposta ai trattamenti

Quality of LifeLung Cancer Symptom Scale (LCSS)EORTCFACT-L

Clinical Benefit

Patient Reported Outcomes

Palliative [supportive] care

Temel, NEJM 2010

Drug interaction

http://udine.terap.it/

Drug interaction: herbal medicine

http://udine.terap.it/

potentially negative effects

direct toxic effects

interactions with anticancer drugs

Renal & Hepatic Dysfunction/ Dose Adjustment

Hendrayana; Sci. Pharm. 2017

Cispaltin and antitumor immunomodulation

de Biasi Clin Cancer Res. 2014

Metronomica

Munzone & Colleoni Nat Rev Clin Oncol 2015

Old Drugs / New Packages

• Nanoparticle formulations: liposomes, polymeric micelles, protein-drug nanoparticles, and dendrimers

• Different pharmacokinetic properties

• Passive tumor targeting [permeability and retention effect]

• Different toxicity profiles and drug distribution

• Eliminate the need for using emulsifying excipients

• Active molecular tumor targeting, environment-sensitive drugrelease


Nanoparticle albumin-bound paclitaxel

Socinski, JCO 2012Shukuya; Lancet Oncol 2015

Nedaplatin


Antibody-drug conjugate

Local Therapy

…intrapericardic, intratecal, intrapleural hyperthermicchemotherapy, locoregional approach…

«alternative» drug / targets

Fillimore; Nature 2015Saxena; Oncologist 2015 Keith; Nature Reviews Clinical Oncology; 2013

Theoretical models

Benzekry, Semin Cancer Biol 2015

Combo PD-1/Chemoterapy

Langer , Lancet Oncology 2016

Keynote021

Conclusioni

Relevant part of the therapeutic armamentarium for lung cancers

Improves overall survival in adjuvant setting

Enhance curability in individuals with locoregional disease when combined with surgery or irradiation

Improves lung cancer symptoms, quality of life, time to progression and survival in palliative setting

Conclusioni

• Terapie di combinazione

• Strategia terapeutica

• Nuovi farmaci

• >> efficacia & << tossicità

• Biomarkers predittivi

Conclusioni

Virtually all patients with A-NSCLC will be consideredfor chemotherapy at some point in their illness

one – size – fits – all approach -> precision medicine

[email protected]

grazie per l’attenzione

la chemioterapia. razionale, efficacia e futuro alessandro ......palmanova 24 maggio 2017. lung...

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