Highlights in the Management of NSCL cancer, June 13-14, 2008, Domus Sessoriana, Rome Italy...

Highlights in the Management of NSCL cancer

June 13-14, 2008, , Domus Sessoriana, Rome ItalyDomus Sessoriana, Rome Italy

Pierosandro TagliaferriUniversità Magna Græcia di CatanzaroCentro OncologicoFondazione Tommaso Campanella

Optimal use of inhibitors of the EGF-R pathways


EGF Receptor Signal Transduction Pathway


EGFR as a Molecular TargetMember of erbB family of

receptor tyrosine kinases•EGFR (ErbB1), HER2/Neu (ErbB2), HER3 EGFR (ErbB1), HER2/Neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4)(ErbB3) and HER4 (ErbB4)

Overexpressed in various solid tumors

•Overexpression has been correlated with poor Overexpression has been correlated with poor prognosis.prognosis.

EGFR signaling is implicated in angiogenesis, proliferation, and inhibition of apoptosis.

The HER Family of Receptors

HER1/EGFRerbB1

HER2erbB2neu

EGFTGF-a

AmphiregulinBetacellulin

HB-EGFEpiregulin Heregulins

NRG2NRG3

HeregulinsBetacellulin

Cysteine-rich

domains

Tyrosine-kinase

domainsHER3erbB3

HER4erbB4

Ligands:

Salomon D, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.Woodburn J. Pharmacol Ther. 1999;82:241-250.

HER1/EGFR Targeted HER1/EGFR Targeted TherapyTherapy

Slamon DJ, Leyland-Jones B, Shak S, et al. N Engl J Med. 2001;344:783-792; Noonberg SB, Benz CC. Drugs. 2000;59:753-767; Mendelsohn J, Baselga J. Oncogene. 2000;19:6550-6565; Raymond E, Faivre S, Armann JP. Drugs. 2000;60(Suppl 1):15-23; Arteaga C. J Clin Oncol. 2001;19:32s-40s; Pedersen MW, Meltom M, Damstrup L, et al. Ann Oncol. 2001;12:745-760.

Anti-HER1/EGFR-blocking antibodies

Anti-ligand-blocking

antibodies

TKinhibitors Ligand–toxin

conjugates Antibody–toxinconjugates

P

P P

P

EGFR Expression in Various Carcinomas

Tumour EGFR Expression Rate

Colon 25 % - 77 %Breast 14 % - 91 %

Lung Cancer 40 % - 80 %

(Non small cell)

Pancreatic 30 % - 50 %

Head & Neck 80 % - 95 %

Ovarian 35 % - 70 %


HER1/EGFR Targeted Therapy Neutralizing Monoclonal Antibody

• Cetuximab (Erbitux), Panitumumab (Vectibix), Matuzumab−Competitive inhibitor−Prevents dimerization

Tyrosine Kinase Inhibitors• Gefitinib (Iressa), Erlotinib (Tarceva)

−Reversible inhibitors• Lapatinib

−Dual EGFR/erbB2 irreversible inhibitor






A, EGFR phosphorylates erbB3 to activate PI3K/Akt signaling in gefitinib/erlotinib ^ sensitive NSCLCs. In such cancers, following gefitinib/erlotinib treatment, EGFR, erbB3, and Akt phosphorylations are turned off.


B, gefitinib/erlotinib are unable to inhibit EGFR phosphorylation in the presence of EGFR T790M. EGFR signaling persists in the presence of gefitinib/erlotinib, leading to persistent erbB3 and Akt phosphorylation.


C, METcan also activate PI3K/Akt signaling through erbB3. In NSCLCs with MET amplification, gefitinib/erlotinib can still inhibit EGFR phosphorylation but not erbB3 phosphorylation.This leads to persistent activation of PI3K/Akt signaling via erbB3 in an EGFR-independent manner


D, other potential mechanisms of gefitinib/erlotinib resistance.These potential mechanisms include alternative ways of maintaining PI3K/Akt signaling, such as by an oncogenic PIK3CA or by other receptor tyrosine kinases that could activate PI3K/Akt signaling in an erbB3-independent fashion


Concrete data…….


J Clin Oncol 26:2442-2449. © 2008


J Clin Oncol 26:2442-2449. © 2008

First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.


N Engl J Med 2005;353:123-32.

BR-21


ConclusionsErlotinib can prolong survival in patients with non–small-cell lung cancer after first-line or second-line chemotherapy.

N Engl J Med 2005;353:123-32


N Engl J Med 2005;353:133-44


N Engl J Med 2005;353:133-44


ResultsIn univariate analyses, survival was longer in the erlotinib group than in the placebo group when EGFR was expressed (hazard ratio for death, 0.68; P=0.02) or there was a high number of copies of EGFR (hazard ratio, 0.44; P=0.008). In multivariate analyses, adenocarcinoma (P=0.01), never having smoked (P<0.001), and expression of EGFR (P=0.03) were associated with an objective response. In multivariate analysis, survival after treatment with erlotinib was not influenced by the status of EGFR expression, the number of EGFR copies, or EGFR mutation.

ConclusionsAmong patients with non–small-cell lung cancer who receive erlotinib, the presence of an EGFR mutation may increase responsiveness to the agent, but it is not indicative of a survival benefit.

N Engl J Med 2005;353:133-44


N Engl J Med 2005;353:133-44(supplementary data)

June 13-14, 2008, , Domus Sessoriana, Rome Domus Sessoriana, Rome ItalyItaly

Efficacy of erlotinib in patients (pts) with advanced non-small-cell lung cancer (NSCLC) relative to clinical characteristics: Subset analyses from the TRUST study.

These data confirm the results of the phase III BR.21 study, i.e. a wide range of pt subgroups can derive a clinical benefit from erlotinib. No differences were found in DCR between pts treated in 2nd and 3rd line but some subgroups may derive a greater survival benefit when receiving erlotinib 2nd line. These data indicate that pts should not be excluded from receiving erlotinib based on clinical characteristics.

S. G. Allan, L. Bosquee, A. Franke, R. Pirker, G. V. Scagliotti, on behalf of the TRUST investigatorsJ Clin Oncol 26: 2008 (May 20 suppl; abstr 8081)


In INTEREST, gefitinib demonstrated: a) non-inferior overall survival (OS)b) more favorable tolerability and c) improved QoL vs docetaxel in advanced pretreated NSCLC.


Molecular and clinical subgroup analyses from a phase III trial comparing gefitinib with docetaxel in previously treated non-small cell lung cancer (INTEREST).

Gefitinib survival effect was not restricted to certain subgroups. Some subgroups had equally better outcomes compared to the overall population on both treatments. No clinical factors or biomarker appeared to be predictive of a greater gefitinib survival effect over docetaxel.

J. Douillard, V. Hirsh, T. S. Mok, M. A. Socinski, C. Watkins, E. Lowe, A. Armour, E. S. Kim J Clin Oncol 26: 2008 (May 20 suppl; abstr 8001^)







FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC).

R. Pirker, A. Szczesna, J. von Pawel, M. Krzakowski, R. Ramlau, K. Park, U. Gatzemeier, E. Bajeta, M. Emig, J. R. Pereira

J Clin Oncol 26: 2008 (May 20 suppl; abstr 3)



Patients with EGFR-detectable advanced NSCLC

Rand

omiz

e

ARM A: cetuximab (400 mg/m2 initial dose, then 250 mg/m2/wk) plus Cisplatin (80 mg/m2 d1) and Vinorelbine (25 mg/m2 d1, d8) and cetuximab maintenance

ARM B: Cisplatin (80 mg/m2 d1) and Vinorelbine (25 mg/m2 d1, d8)

Randomization was stratified by ECOG performance status (0/1 vs 2) and tumor stage (wet IIIb vs IV)



MedianOS (mo)Arm A

MedianOS (mo)Arm B

HR [95% CI] p-value

All (n=1125) 11.3 10.1 0.871 [0.762- 0.996] 0.0441

Caucasians (n=945)

10.5 9.1 0.800 [0.692-0.924] 0.0025

with AC (n=412)

12.0 10.2 0.809 [0.644-1.016] 0.0673

with SCC (n=347)

10.2 8.9 0.794 [0.626-1.007] 0.0567

Asians (n=121)

17.6 20.4 1.179 [0.730- 1.905] 0.4992



Cetuximab plus CV demonstrated superior survival over CV alone in patients with advanced EGFR-detectable NSCLC. There was a remarkable difference between the outcome of Asian and Caucasian patients. This is the first study to demonstrate a survival benefit of an EGFR-targeted agent in combination with platinum-based chemotherapy in advanced first-line NSCLC irrespective of histology and confirms the clinical relevance of cetuximab in NSCLC.


N Engl J Med. 2008 Mar 13;358(11):1109-17.

The new england journal of medicine

IgE Antibodies Binding to Cetuximab in Serum Samples from 76 Case Subjects and 462 Control Subjects.Results are shown according to whether the treating physician reported a hypersensitivity reaction (HSR) to cetuximab or no HSR reaction. Results are also shown for pretreatment serum samples from control subjects and from subjects who had not received cetuximab. The horizontal lines indicate geometric Mean values for the positive results. Values with multiplication signs indicate the number of negative values for each symbol.


N Engl J Med. 2008 Mar 13;358(11):1109-17.

N Engl J Med. 2008 Mar 13;358(11):1109-17.

Conclusions: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy.

The antibodies were specific for galactose-α-1,3-galactose.

N Engl J Med. 2008 Mar 13;358(11):1109-17.



Conclusions•Activating mutations(Exon 19 in frame deletions and exon 21 L858R) cause “addiction” to the EGFR, sensitivity to small kinase-inhibitors (SKI) in upfront treatment and have fauvorable prognostic weight

•Available results do not allow the identification of patient subgorups which should not be treated with SKI.

•Data are sometimes poor, derived from retrospective analysis and there is etergeneity in the molecular technologies. Consensus for standardized approaches is in progress of development.

•Cetuximab addition to chemotherapy (cisplatin-vinorelbin) produces a small but significant effect on the OS in first line treatment.

•New predictive criteria are eagerly awaited for a rational use of SKI e Cetuximab in NSCLC.

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