stefano iacobelli università “g. d’annunzio”- chieti-pescara l’evoluzione...
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Stefano IacobelliUniversità “G. D’Annunzio”- Chieti-Pescara
L’EVOLUZIONE CLINICO-SPERIMENTALE
DI CETUXIMAB
Epidermal Growth Factor Receptor (HER) family
Ligands
In cancer cells, EGFR promotes the cell signaling that leads to increased cell proliferation, angiogenesis, invasion, and metastasis.
Mendelsohn’s hypothesis (1980)
A mAb that inhibits EGFR function might block tumor growth
Circulating antibodies against receptors were known to produce stable physiological changes (diseases) in patients:
“Experiments of nature”
Disease Antibody target
Myasthenia gravis Acetylcholine receptor
Insulin resistant diabetes Insulin receptor
Thyroid dysfunction TSH receptor
ProliferazioneSopravvivenza
225
EG
FR
John Mendelsohn, University of California, San Diego, discovered 225, a mouse monoclonal antibody that binds to and inactivates the Epidermal Growth Factor Receptor (EGFR)
1980
A success story………
…with some initial flows
1982 The NCI Board of Scientific Counselors, Division of Cancer Treatment & Diagnosis (DCTD) created the
National Cooperative Drug Discovery Group (NCDDG) to discover new targeted anticancer
therapies.
The First NIH Public-Private Partnerships
225 become one of the NCDDG-developed agents
Academia = University of California
Industry = ImClone
Preclinical studies showed the ability of 225 to inhibit the growth of cultured EGFR-expressing tumor lines and to repress the in vivo growth of these tumor when grown as xenograft in nude mice.
1983-1990
Sato JD, Mol Biol Med 1983, 1:511-4
Masui H, Cancer Res 1984, 44:1002-7
Masui H, Cancer Res 1986, 45:5592-8
Kawamoto T, PNAS USA 1983, 80:1337-41
mAb anti-EGFR
Control
A431 cells
Divigi CR, J Natl Cancer Inst 1991, 83:97-104
A phase I clinical trial established the feasibility of administering 225 at doses that produced receptor-saturating levels in the blood, without inducing toxicity
1991
…..but, as expected, patients developed anti-mouse antibody response ! !
Other preclinical studies showed a therapeutic synergy combining 225 plus chemotherapy in several well-established human xenograft models
Beselga J, J Natl Cancer Inst 1993, 85:1327-1333
Fan Z, Cancer Res 1993, 53:4637-4642
1993
225 was chimerized with human IgG1 in its constant region. The chimeric antibody C-225 had a Kd 5-fold lower than 225 and showed a better antitumor activity in tumor xenograft
1995
Goldstein NI, Clin Cancer Res 1995, 1:1311-8
Treatment: i.p. injection of C255 twice weekly for 5 weeks. Started when tumors reached >150 mm3
Many of the animals treated with C225 were tumor free at the end of treatment
Several tumor cell xenografts and phase I/II studies showed that C225 enhanced cytotoxicity of chemotherapy and radiotherapy
1996-2001
Prewett MC, Cin Cancer Res 2002, 8:994-1003
Milas L, Cin Cancer Res 2000, 6:701-6
Perez-Soler, ASCO 1998, astract 1514
Beselga J, JCO 2000, 18:904-914
DLD-1 cells
HT-29 cells
ASCO Meeting: Saltz presented data of a phase II trial.In patients who were refractory to irinotecan the combination of cetuximab plus irinotecan achieved 17% PR and 31% SD
2001
ImClone submitted request for FDA approval
1. Approximately half of the patients (94) studied had not failed the approved treatments for colon cancer
2. Important information about the safety and effectiveness of Erbitux in a portion of the remaining patients (102) was missing.
Dec 2001 FDA rejected approval
Saltz et al, abstract 7, 2001
September 30, 2004“Martha Stewart Assigned to Prison in West Virginia."
Famous television presenter, author and magazine publisher
“Erbitux, a targeted therapy for colon cancer, might be forever known as the drug that led to Martha Stewart’s downfall.”
Martha Stewart
Stewart sold all 3,928 shares of her ImClone Systems stock on December 27, 2001. The day following her sale, the stock value fell 16%
Samuel Waksal, ImClone’s chief executive officer, and Peter Bacanovic, her brocker, were also arrested (inside trading..)
ASCO Meeting: Cunninghan presented data of a phase II trial.In patients who were refractory to irinotecan the combination of cetuximab plus irinotecan achieved 17,9 % PR
2003
ImClone submitted a new request for FDA approval
Feb 2004 FDA approved cetuximab
Cunninghan et al, abstract 1012, 2003
“Erbitux is indicated, in combination with irinotecan, for the treatment of EGFR-expressing, mCRC in patients who are refractory to irinotecan-based chemotherapy. In addition, it is also approved for use as a single agent in the treatment of patients with EGFR-expressing, mCRC who are intolerant to irinotecan-based chemotherapy.”
Cunningham D, N Engl J Med 2004, 351: 337-45
The median TTP was longer in the combination-therapy (4.1 vs 1.5 months, P< 0.001)
CETUXIMAB IN COLORECTAL CANCER
HR 0.54; p < 0.001
Patients with irinotecan-refractory mCRC
FDA granted approval for Erbitux
12 Feb, 2004 1 Mar, 2006 2 Oct, 2007 17 Jul, 2009
in combination with Irinotecan for mCRC
in combination with RT for HNC
in monotherapy for mCRC
in wt k-Ras mCRC
CETUXIMAB IN COLORECTAL CANCER
Patients with mCRC refractory to irinotecan- and oxaliplatin-containing regimens.
HR 0.766; p = 0.0048
Cetuximab plus BSC prolonged OS (6.1 vs 4.6 months)
Jonker DJ, N Engl J Med 2007, 357: 2040-8
CETUXIMAB IN HEAD AND NECK CANCER
Cetuximab plus RT prolonged OS (49.0 vs 29.3 months)
Bonner JA, N Engl J Med 354: 567-578, 2006
Cetuximab plus platinum-based chemotherapy with fluorouracil
prolonged OS (10.1 vs 7.4 months)
Vermorken JB, N Engl J Med 359: 1116-27, 2008
HR 0.74; p = 0.03
ProliferazioneSopravvivenza
Cetuximab
EG
FR
k-RAS mutations affect cetuximab activity
Resistance to cetuximab: not only k-RAS mutations
Attuali indicazioni all’uso di Cetuximab (AIFA)
Carcinoma metastatico del colon-retto con espressione del recettore per il fattore di crescita epidermico (EGFR) e con gene KRAS non mutato (wild-type):
- in combinazione con chemioterapia a base di platino nella malattia ricorrente e/o metastatica
- in combinazione con chemioterapia;
- in monoterapia nei pazienti nei quali sia fallita la terapia a base di oxaliplatino e irinotecan o che siano intolleranti a irinotecan.
Carcinoma a cellule squamose del testa-collo
- in combinazione con radioterapia per la malattialocalmente avanzata;
1.
2.
Adjuvant, CRC
First line, CRC
Liver metastases, CRC
Neoadjuvant, Rectum
Second line, NSCLC
Locally advanced, Esophagus
PROSPETTIVE FUTURECirca 200 studi clinici attivi
Almost all k-RAS mutations are in exon 2 codon 12 and 13
All these mutations activate k-RAS function
COLON CANCER: k-RAS MUTATIONS
k-RAS mutations are in 40% of CRC
The CRYSTAL trial
The addition of cetuximab improved response rate and PFS.
Despite the statistically significant decrease in the risk of disease progression (HR, 0.85), the absolute benefit was modest (8,9 mo vs 8).
Cetuximab + FOLFIRI vs FOLFIRI in first line mCRC
HR 0.85; p = 0.048 HR 0.93; p = NS
Van Custen E, N Engl J Med 2009, 360: 1408-17
The CRYSTAL trialSubgroup Analysis According to KRAS Mutation Status
The benefit from the addition of cetuximab was greater (HR, 0.68) in patients with WT tumors.
In contrast, patients with KRAS mutant tumors had no benefit from the addition of the mAb
HR 0.68; p = 0.02 HR 0.84; p = NS
Van Custen E, N Engl J Med 2009, 360: 1408-17
The OPUS trial Cetuximab + FOLFOX vs FOLFOX in first line mCRC
No difference in PFS
The OPUS trial Subgroup Analysis According to KRAS Mutation Status
In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a lower risk of disease progression (HR 0.57; p 0.0163)
CETUXIMAB and k-RAS MUTATIONS in CRC
Karapetis CS, N Engl J Med 359:1757-65, 2008 (modificata)
11.3 monthsMedian OS
NSCLC EGFR+
10.1 months
Hazard ratio for death 0·871 [95% CI 0·762–0·996]; p=0·044