Stefano Iacobelli Università “G. D’Annunzio”- Chieti-Pescara

1. L’EVOLUZIONE CLINICO-SPERIMENTALE   DI CETUXIMAB Stefano Iacobelli Università “G. D’Annunzio”- Chieti-Pescara

2. Epidermal Growth Factor Receptor (HER) family Ligands

3. Mendelsohn’s hypothesis (1980) In cancer cells, EGFR promotes the cell signaling that leads to increased cell proliferation, angiogenesis, invasion, and metastasis. A mAb that inhibits EGFR function might block tumor growth “Experiments of nature” Circulating antibodies against receptors were known to produce stable physiological changes (diseases) in patients:

4. 225 Proliferazione Sopravvivenza 1980 John Mendelsohn, University of California, San Diego, discovered 225, a mouse monoclonal antibody that binds to and inactivates the Epidermal Growth Factor Receptor (EGFR) EGFR

5. A success story……… …with some initial flows

6. 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

7. 1983-1990 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. Sato JD, Mol Biol Med 1983, 1:511-4 Masui H, Cancer Res 1984, 44:1002-7 Kawamoto T, PNAS USA 1983, 80:1337-41 Masui H, Cancer Res 1986, 45:5592-8

8. A431 cells Control mAb anti-EGFR

9. 1991 A phase I clinical trial established the feasibility of administering 225 at doses that produced receptor-saturating levels in the blood, without inducing toxicity Divigi CR, J Natl Cancer Inst 1991, 83:97-104 …..but, as expected, patients developed anti-mouse antibody response ! !

10. 1993 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 1995 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 Goldstein NI, Clin Cancer Res 1995, 1:1311-8

11. 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

12. 1996-2001 Several tumor cell xenografts and phase I/II studies showed that C225 enhanced cytotoxicity of chemotherapy and radiotherapy Milas L, Cin Cancer Res 2000, 6:701-6 Perez-Soler, ASCO 1998, astract 1514 Beselga J, JCO 2000, 18:904-914 Prewett MC, Cin Cancer Res 2002, 8:994-1003

14. DLD-1 cells HT-29 cells

15. 2001 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 Saltz et al, abstract 7, 2001 ImClone submitted request for FDA approval Dec 2001 FDA rejected approval • Approximately half of the patients (94) studied had not failed the approved treatments for colon cancer • Important information about the safety and effectiveness of Erbitux in a portion of the remaining patients (102) was missing.

16. Martha Stewart September 30, 2004 “Martha Stewart Assigned to Prison in West Virginia." “Erbitux, a targeted therapy for colon cancer, might be forever known as the drug that led to Martha Stewart’s downfall.” Famous television presenter, author and magazine publisher 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..)

17. 2003 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 Cunninghan et al, abstract 1012, 2003 ImClone submitted a new request for FDA approval Feb 2004 FDA approved cetuximab “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.”

18. CETUXIMAB IN COLORECTAL CANCER Patients with irinotecan-refractory mCRC HR 0.54; p < 0.001 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)

19. FDA granted approval for Erbitux in wt k-Ras mCRC in monotherapy for mCRC in combination with RT for HNC in combination with Irinotecan for mCRC 12 Feb, 2004 1 Mar, 2006 2 Oct, 2007 17 Jul, 2009

20. 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

21. CETUXIMAB IN HEAD AND NECK CANCER HR 0.74; p = 0.03 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

22. Cetuximab Proliferazione Sopravvivenza k-RAS mutations affect cetuximab activity EGFR

23. Resistance to cetuximab: not only k-RAS mutations

24. 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): 1. - 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. 2. Carcinoma a cellule squamose del testa-collo - in combinazione con radioterapia per la malattialocalmente avanzata; - in combinazione con chemioterapia a base di platino nella malattia ricorrente e/o metastatica

25. PROSPETTIVE FUTURE Circa 200 studi clinici attivi Adjuvant, CRC First line, CRC Liver metastases, CRC Neoadjuvant, Rectum Second line, NSCLC Locally advanced, Esophagus

26. Almost all k-RAS mutations are in exon 2 codon 12 and 13 All these mutations activate k-RAS function

27. COLON CANCER: k-RAS MUTATIONS k-RAS mutations are in 40% of CRC

28. The CRYSTAL trial Cetuximab + FOLFIRI vs FOLFIRI in first line mCRC HR 0.93; p = NS HR 0.85; p = 0.048 Van Custen E, N Engl J Med 2009, 360: 1408-17 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).

29. The CRYSTAL trial Subgroup Analysis According to KRAS Mutation Status HR 0.68; p = 0.02 HR 0.84; p = NS Van Custen E, N Engl J Med 2009, 360: 1408-17 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

30. The OPUS trial Cetuximab + FOLFOX vs FOLFOX in first line mCRC No difference in PFS

31. 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)

32. CETUXIMAB and k-RAS MUTATIONS in CRC Karapetis CS, N Engl J Med 359:1757-65, 2008 (modificata)

33. NSCLC EGFR+ Median OS 10.1 months 11.3 months Hazard ratio for death 0·871 [95% CI 0·762–0·996]; p=0·044