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The promising results from clinical trials with cetuximab in colorectal, head and neck, pancreatic, and non-small cell lung cancers (NSCLC) may also apply to other cancers that overexpress the epidermal growth factor receptor (EGFR). These include renal cell carcinoma, as well as esophageal, prostate, cervical, ovarian, and breast cancers.

"The studies demonstrate the promise of cetuximab when combined with cytotoxic chemotherapy for progressing patients with squamous cell carcinoma of the head and neck, pancreatic and lung cancers," reported Howard Hochster, MD, during a presentation at the 20^th annual meeting of the Chemotherapy Foundation. In all cases, the addition of cetuximab, an antibody directed at the external domain of EGFR, can restore chemosensitivity in a certain proportion of patients who present with progressive disease, Dr. Hochster stated.

Phase II/III Trial Results in Head and Neck Cancer
Cetuximab has shown activity in 2 phase II studies and a recently completed phase III trial of squamous cell carcinoma of the head and neck. In the phase II trials, patients whose tumors progressed with platinum-based chemotherapy achieved objective responses when cetuximab was added. In one phase II trial, there were 2 complete responses (CRs) and 12 partial responses (PRs), an objective response rate of approximately 15% in 96 patients (Baselga J et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):226a. Abstract 900). In the other phase II trial, 11% of the 78 patients achieved PR, 17% stable disease, and 28% clinical benefit (Kies MS et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):232a. Abstract 925). Notably, all but 1 of the 25 patients who responded developed a skin rash.

"Rash appears to be a predictor of both response and of survival," reported Dr. Hochster, noting that the acneiform complication is thought to be a result of EGFR blockade in the skin, where EGFR is prevalent. Although there is an imperfect association between skin rash and anti-tumor activity, he suggested that the general correlation indicates that the relative degree of EGFR blockade may be important in achieving an optimal response.

In a phase III study, 123 patients with recurrent or metastatic squamous cell carcinoma of the head and neck were randomized to either cetuximab or placebo in addition to cisplatin (Burtness BA et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):226a. Abstract 901). Twenty two percent of patients who received cisplatin plus the monoclonal antibody had a response versus 9% for those who received cisplatin plus placebo. Moreover, time to treatment failure was extended to 4.1 months in the cetuximab group versus 3.3 months in the placebo group. One-year survival rate was 35% in the cetuximab group versus 17% for those who received cisplatin alone. Although the difference in response did not reach statistical significance (P=.0508), the consistent clinical benefit and evidence of activity was encouraging (Table 1).

Source: From data presented by Howard Hochster, MD, at the Chemotherapy Foundation Symposium XX: Innovative Cancer Therapy for Tomorrow, November 13-16, 2002, New York, New York.

"The data tell us that C225 adds benefit in these patients," Dr. Hochster reported. He noted that responses in this study, like previous trials, were more likely in those with skin rash, and he called for larger trials in order to better document the clinical activity of C225 in this disease.

NSCLC and Pancreatic Cancer: Early Results
Although there is far less experience with NSCLC and pancreatic cancer, early results encourage further clinical study.

In NSCLC, the addition of cetuximab to docetaxel produced a PR rate of 26% in 30 patients who had progressed on single-agent docetaxel therapy (Kim ES et al. Proc Am Soc Clin Oncol. 2002:21(suppl 1):293a. Abstract 1168). An additional 26% achieved stable disease despite progression on docetaxel monotherapy.

In addition to skin rash, grade 3 and 4 toxicities included neutropenia and asthenia, but all these toxicities were considered manageable. According to Dr. Hochster, the apparent benefits in this challenging patient population are "worthy of additional study".

Cetuximab was also evaluated in 40 patients with metastatic or locally advanced pancreatic cancer in combination with gemcitabine chemotherapy (Abbruzzese JL et al. Proc Am Soc Clin Oncol. 2001;20(suppl 1):130a. Abstract 518). Of these, 12.5% achieved an objective response and 52% had stable disease. Although rash, fatigue, and nausea were observed, the only grade 3 or 4 toxicities that occurred in more than 10% of patients was neutropenia (20%) and thrombocytopenia (13%). In a patient population with an extremely poor prognosis, the response rates were considered encouraging when judged against historical controls.

"Compared to the previously published pivotal trial with gemcitabine [Burris HA et al. J Clin Oncol. 1997;15:2403-2413], the median time to progression was 105 days with [the addition of cetuximab] versus 67 days, and the median survival was 203 days compared to 170 days. The 1-year survival was 17.5% for those on cetuximab versus 9% in those who participated in the gemcitabine study," Dr. Hochster reported (Table 2).

Source: From data presented by Howard Hochster, MD, at the Chemotherapy Foundation Symposium XX: Innovative Cancer Therapy for Tomorrow, November 13-16, 2002, New York, New York.

Cetuximab: A Closer Look
Cetuximab is a chimeric, humanized IgG1 antibody. Typically, it is administered in an intravenous loading dose of 400 mg/m² followed by weekly outpatient infusions of 250 mg/m².

Cetuximab binds to the external ligand binding site of EGFR without stimulating the receptor. By doing so, it prevents the endogenous ligands epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha) from binding to the receptor. As a result, EGF and TGF-alpha cannot activate the tyrosine kinase of EGFR. This process would usually initiate a phosphorylation cascade, which would activate several proliferative signaling pathways. The binding affinity of cetuximab is approximately 10-fold higher than that of the natural ligands. Once bound to the receptor, cetuximab induces receptor internalization that blocks the downstream activities of the EGFR pathway.

The activity observed with cetuximab in advanced cancers is exciting because of the possibility that "even greater utility may be observed when [cetuximab] is used in patients not previously exposed to chemotherapy," according to Dr. Hochster. He anticipates continued progress with this agent in phase III studies that better define its clinical role.

Key Points In Focus:

The addition of cetuximab to a chemotherapy regimen on which patients with advanced head and neck, lung, or pancreatic cancers are already progressing, restores activity in an encouraging proportion of these treatment-resistant patients.
Skin rash is a common complication in patients receiving cetuximab. The correlation between rash and clinical benefit reinforces the importance of blocking EGFR (which is prevalent in the skin) for optimal clinical activity.
Cetuximab activity in advanced head and neck, lung, and pancreatic cancers encourages further clinical trials using it at earlier stages of disease. The data are encouraging, and clinical testing of cetuximab is expected to extend to other tumors associated with EGFR overexpres-sion, including those of the breast, esophagus and prostate.

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