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