Emerging Role of EGFR-Targeted Therapies and Radiation in Head and Neck Cancer
By John Song, MD1, Changhu Chen, MD, PhD2, David Raben, MD3 |
December 1, 2004
1Assistant Professor, Department of Otolaryngology
2Assistant Professor, Department of Radiation Oncology
3Associate Professor and Scientist, Tobacco Related Malignancy Program and Department of Radiation Oncology, University of Colorado Health Sciences Center, Aurora, Colorado
JENNIFER R. GRANDIS, MD and KENNETH A. FOON, MD
If EGFR inhibitors are to be relevant in the treatment of HNSCC, we need to determine exactly how they work. A key issue is whether EGFR expression is a relevant predictor of response; a cancer may not necessarily rely on EGFR signaling alone for its survival. In addition, the integrity of the EGFR-activated downstream intracellular signal transduction machinery may influence the response to these drugs. Recent experimental evidence suggests that cancer cells may escape growth inhibition by using alternative growth pathways or by constitutive activation of downstream signaling effectors.
Despite the promising preclinical findings seen with EGFR blockade in many epithelial malignancies, the clinical response in pretreated HNSCC patients receiving EGFR inhibitors has hovered at ~15%. Why haven't we observed a higher response when so many HNSCC cancers express EGFR? The current thought is that a host of molecular abnormalities play a role in determining head and neck carcinogenesis and biologic behavior. Therefore, similar histologic types notwithstanding, the activated cell survival pathways may vary among HNSCCs. Differences in activated EGFR-associated phosphoinositide-3-kinase (PI3K), MAPK, or STAT3 may account for the differences in tumor response to EGFR antagonists. This hypothesis can be partially addressed by a panel of correlative biomarker studies examining the association between the expression profiles of these molecules and the tumor response, along with other as of yet unknown proteins/genes, using tumor specimens of patients enrolled into prospective trials.
Understanding which HNSCC cancers will respond to EGFR inhibition may also relate to the expression and activity of the remaining family members of EGFR (erbB2-4). Also, the presence of exogenous EGF-related ligands may, in part, govern tumor response to anti-EGFR agents, and thus, dual or multiple blocking of other family members of EGFR may be required to achieve the desired effects.[ 46] Increased expression levels or mutations in downstream proteins such as Ras, Raf, PTEN, and Akt may also predict response, along with other as yet unknown proteins/genes, independent of EGFR expression, as shown in Figure 4.
Mutated Elements of the EGFR-Kinase Pathway in Tumors May Predict for Response to EGFR Inhibitors
An emerging issue is whether rash is predictive of response to EGFR inhibitors as well as survival. Across the board in phase II studies employing cetuximab(Drug information on cetuximab)-including a trial in patients with advanced HNSCC-patients who developed the acne-like rash survived longer than those who did not develop a rash, and the more intense the rash, the longer the survival. The findings from four phase II studies incorporating cetuximab, as presented by Saltz et al at ASCO 2003, suggests that skin rash may be an important surrogate predictor of efficacy.[ 47] Similar findings were seen in a phase II study in advanced HNSCC patients treated with gefitinib(Drug information on gefitinib) monotherapy.[ 28] This observation has not held up in stage IV lung cancer patients treated with gefitinib. Perhaps individualizing patient dosing to stimulate skin rash will be more closely evaluated in future clinical trials with EGFR inhibitors.
Recent experimental evidence suggests that cancer cells may escape growth inhibition by using alternative growth or angiogenic pathways. For example, resistance to anti-EGFR antibodies such as cetuximab and hR3 has been reported in A431 tumors in mice. Overexpression of vascular endothelial growth factor (VEGF) may have been a contributor to resistance through the upregulation of angiogenesis. Activation of the insulin-like growth factor receptor I contributed to continuous activation of the antiapoptotic PI3K-signaling pathway that blocked EGFR inhibitors such as gefitinib in human glioblastoma cells in vitro.
These observations, along with increasing evidence that superfluous growth pathways are active in neoplastic cells, form the basis for testing therapeutic strategies targeting multiple pathways. Indeed, preclinical studies have shown significant and sustained antitumor activity in vitro and in vivo by combining anti-EGFR agents with, for example, inhibitors of the cAMP-dependent protein kinase (type I PKA) or a VEGF antisense oligonucleotide. Other promising strategies have included concurrent blockage of the VEGF receptor (VEGFR) using PTK 787 and EGFR by PKI 166, both tyrosine kinase inhibitors directed at VEGFR and EGFR signaling respectively in a pancreatic model, and the combination of gefitinib with the anti-erbB2 antibody trastuzumab(Drug information on trastuzumab) (Herceptin). Figure 3 presents possible polytargeted scenarios against HNSCC.
An alternative method that might prevent the development of resistance to EGFR blockade would be to administer single agents with dual inhibitory action toward EGFR and VEGFR signaling. ZD6474 represents such an agent. It is a small-molecule inhibitor of KDR/VEGFR-2 tyrosine kinase activity and of a variety of other tyrosine and serine-threonine kinases including those activated by EGFR. In animals bearing human colon cancer xenografts with acquired resistance to gefitinib or cetuximab, ZD6474 administration resulted in significant tumor growth inhibition. Tumor cells resistant to cetuximab or gefitinib exhibited a marked increase in activated MAPK, cyclooxygenase- 2, and VEGF compared with the control GEO cells. These data indicate that inhibition of VEGF signaling has potential as an anticancer strategy, even in tumors that are resistant to EGF inhibitors.
Another attractive approach applicable to the treatment of HNSCC might include the combination of two molecules acting on different domains of EGFR. Gefitinib plus cetuximab provided supra-additive cancer growth inhibition on the high EGFR-expressing A431 tumor in vitro and in vivo (P < .05) . In this particular model, 25 mg/kg of gefitinib plus cetuximab resulted in a 90% growth inhibition and induced complete remissions in 3 out of 10 tumors, and 50 mg/kg of gefitinib plus cetuximab resulted in 100% complete remission. This suggests that hindering both the extracellular and intracellular activation sites of EGFR may prevent the cancer cell from overriding a specific blockade.
Because other EGFR family members may play a role in HNSCC, preventing coupling of, for example, erbB2 to EGFR (or erbB1) might prevent redundant signaling from overriding or bypassing EGFR blockade. In this regard, 2C4-which binds to a different portion of the extracellular domain than trastuzumab (Herceptin) and prevents the receptor from dimerizing with other erbB family members- is under investigation and appears active irrespective of EGFR status.[57,58] Further studies assessing the role of 2C4 in polytargeted therapy against HNSCC are ongoing.
One of the concerns recently raised is the potential antagonistic effects that might be seen with concurrent administration of TKIs and chemotherapy. Several clinical trials combining TKIs with chemotherapy in the treatment of advanced lung cancer failed to show a survival benefit over chemotherapy alone.[59,60] It is unclear whether there are differences in interactions with antibodies vs TKIs and chemotherapy and whether the type of chemotherapy dictates synergy or antagonism.
An early report by the Lung Cancer CetuximAb Study (LUCAS), presented at ASCO 2003, evaluated the response rate of the combination of cetuximab plus cisplatin(Drug information on cisplatin)/vinorelbine or of the same chemotherapy alone as first-line treatment in patients with EGFR-positive stage IIIB/IV NSCLC. The overall response rates were 50% (nine partial responses, eight confirmed; seven cases of stable disease; and two cases of progressive disease) in arm A and 29% (five partial responses, three confirmed; six cases of stable disease; and six cases of progressive disease) in arm B. The trial continues to accrue patients with the intent of recruiting a total of 40 patients per arm. It will be interesting to see if these response rates hold up with mature follow-up. Limited information is available on sequencing issues using EGFR inhibitors and radiation, and this is an area that warrants further preclinical and clinical investigation.
In this review, we have tried to provide a review of the emerging role of targeted therapies in HNSCC. The goal of targeted therapy should include the development and testing of agents with selective activity against HNSCC and low systemic toxicity. Ideally, a molecular target in HNSCC meets the following criteria: (1) it drives tumor growth, (2) it demonstrates reversible function by pharmacologic inhibition, (3) its inhibition is tolerated by normal cells, and (4) effects on it are measurable in tumor tissue.
We are clearly establishing new ground in the fight against HNSCC with the introduction of drugs that attack specific parts of the cancer cell growth pathways. Despite the gains achieved with concurrent chemoradiotherapy, the toxicities can be daunting at times. Thus, the foundations established with EGFR inhibitors and radiotherapy should embolden oncology investigators to design clinical trials that incorporate combinations of targeted agents with different mechanisms of action. An additional task is to return to the laboratory and understand why EGFR inhibitors work, why they are active in EGFR-negative as well as EGFR-positive tumors, how to better predict response, and the optimal way to sequence these drugs with radiation. Advancement in these areas will lead to optimal stratification or selection of patients based on tumor or serum markers, for testing promising novel multitargeted therapy regimens in clinical trials.
Financial Disclosure: Dr. Raben has received partial financial support for preclinical studies conducted through the University of Colorado Comprehensive Cancer Center from AstraZeneca.
CAROLYN SARTOR, MD
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