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Originally published as JCO Early Release 10.1200/JCO.2003.04.001 on May 14 2003 © 2003 American Society for Clinical Oncology
Gefitinib in Recurrent Non–Small-Cell Lung Cancer: An IDEAL Trial?Division of Hematology & Oncology Vanderbilt-Ingram Comprehensive Cancer Center Vanderbilt University School of Medicine Nashville, TN IN 1962, Stanley Cohen isolated a novel protein from the submaxillary gland of mice that promoted accelerated eruption of incisors and eyelid opening in newborn animals.1 Nearly 25 years later, Cohen received a Nobel Prize for the discovery of what we now know as epidermal growth factor (EGF). In the intervening four decades, the importance of EGF and its family of related receptors to carcinogenesis and cancer therapy has become increasingly apparent.2 Drugs that interfere with the EGF signaling pathway are now widely viewed as potentially therapeutic and, quite possibly, as chemopreventive agents.3,4 Gefitinib (Iressa; AstraZeneca, Wilmington, DE) is a synthetic anilinoquinazoline capable of inhibiting the EGF receptor (EGFR) tyrosine kinase in vitro at nanomolar concentrations.5 Orally administered gefitinib inhibited tumor growth in mice bearing a range of human tumor-derived xenografts in a dose-dependent manner.5 In phase I trials, gefitinib was well tolerated at doses above that required to achieve antitumor activity in preclinical studies, and antitumor activity was observed in patients with non–small-cell lung cancer (NSCLC).6–8 On the basis of these preclinical and clinical data, phase II trials of single-agent gefitinib were undertaken in individuals with recurrent NSCLC. The results of one of these trials, known as Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL-1), are reported in this issue of the Journal of Clinical Oncology.9 The patients enrolled in IDEAL-1 all had recurrent or refractory NSCLC, a performance status of 0 to 2, a life expectancy of ≥ 12 weeks, and had experienced treatment failure after one or two prior chemotherapy regimens that included a platinum agent. They were randomly assigned to receive 250 or 500 mg of gefitinib daily. The two cohorts were well balanced for all known prognostic factors. Impressively, objective tumor responses were observed in approximately 20% of patients and tumor-related symptoms improved in nearly 40% of patients, often within days of starting gefitinib therapy. Symptomatic improvement was most common in responding patients and those with stable disease. Significant toxicities were uncommon, with acne-like rash and diarrhea the only side effects of consequence. Median survivals were 7.6 and 8.0 months, with 1-year survival rates of 35% and 29% at the 250- and 500-mg dose levels, respectively. Although these data are derived from an uncontrolled phase II trial, the results are nonetheless noteworthy. First and foremost, some tumors shrank with the use of a drug commonly characterized as cytostatic. Few cytotoxic chemotherapy drugs are capable of effecting the same degree of tumor regression in recurrent NSCLC.10 The response rate, duration of response, and the median survival observed with gefitinib are all similar to results achieved with docetaxel,11 the only drug approved by the United States Food and Drug Administration for second-line treatment of NSCLC. Given the impressive redundancy of the signaling pathways present in most epithelial cancers, any tumor shrinkage after inhibition of a single signaling network in a notoriously virulent malignancy such as lung cancer has to be considered surprising. Indeed, because of the potential for compensation, it has been widely assumed that interruption of a single signaling network or a transforming molecule would not be effective in late-stage disease. For example, a significant proportion of human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancers do not shrink in response to trastuzumab; those that do shrink eventually relapse,12 strongly indicating the presence of de novo or acquired mechanisms of drug resistance. The antitumor effect of HER receptor network inhibitors such as gefitinib and trastuzumab requires the subversion of key postreceptor signaling pathways, cell cycle progression, and antiapoptosis regulatory molecules that mediate the transforming effects of this signaling network. These postreceptor pathways are shared with, and receive simultaneous input from, heterologous receptor networks.13 Consequently, blockade of one receptor signaling pathway may be overcome through compensatory activation of a separate aberrant signaling program in the same tumor cell. For example, overexpression of the insulin-like growth factor 1 receptor can abrogate the antitumor effect of trastuzumab as well as inhibitors of EGFR tyrosine kinase.14,15 Similarly, loss of the phosphatase and tensin (PTEN) homolog in human tumor cell lines leads to phosphatidylinositol-3 kinase and Akt hyperactivity and results in relative resistance to gefitinib.16 In the latter study, resistance to gefitinib was reversed on reconstitution of phosphatase and tensin homolog and inhibition of Akt. Parenthetically, one might predict that mutations in K-ras, a frequent abnormality in NSCLC,17 may also counteract the efficacy of gefitinib by enhancing EGFR-independent signaling to mitogen-activated protein kinase, a key EGFR signal transducer. As these data indicate, advanced cancers are endowed with multiple aberrant signaling networks that can potentially counteract the blockade of EGFR function, making the IDEAL-1 results all the more impressive. In addition, the close association of tumor response and symptom improvement provides further evidence of the activity of gefitinib in NSCLC. Finally, the ease of gefitinib administration coupled with its favorable toxicity profile make this agent an extremely attractive treatment option for NSCLC patients with recurrent disease. There are, however, several unresolved issues. For example, gefitinib is said to be a targeted therapy by virtue of its selective inhibition of the EGFR tyrosine kinase. No attempt was made to determine EGFR status as a condition of participation in the IDEAL-1 trial, nor were any downstream transducers of this pathway assessed as a potential predictor of response. Because the overwhelming majority of NSCLC tumors express or overexpress EGFR or one of its ligands,18,19 it might be argued that measurement of EGFR was not necessary. Moreover, unlike trastuzumab, for which efficacy is limited to tumors with gene-amplified HER2,3,12 gefitinib does not require the presence of EGFR gene amplification or overexpression.5 In fact, preclinical studies indicate that gefitinib can produce growth arrest in tumors expressing a wide range of EGFR levels.5,20 Thus, although knowledge of the EGFR status of the IDEAL patients might have proved interesting, EGFR expression as determined by current methods does not appear to represent a valid predictor of gefitinib activity. It has been proposed that an assay of activated (phosphorylated) EGFR will be predictive of response to EGFR inhibitors. However, without assessment of the inhibition of this phosphorylation in vivo in response to gefitinib, the predictive value of this assay in pretreatment tumor material alone will be limited. The lack of a measurable target for this so-called targeted therapy presents a clinical conundrum. Should clinical development of gefitinib be halted until a predictive molecular marker is identified? Without a specific molecular marker of activity, akin to using HER2 assessment for trastuzumab therapy, it will be difficult to enrich study populations with patients prone to responding to gefitinib. As we await identification of a useful molecular marker, it may be necessary to use clinical markers to help accomplish this goal. Such an approach is not new and might prove more acceptable if there were a plausible biologic rationale for using a particular clinical parameter. In the IDEAL-1 trial, response to gefitinib was associated with good performance status, prior immuno- or hormonal therapy, female sex, and adenocarcinoma histology. At first glance, some of these results seem contradictory to what we know—or at least what we think we know—about the drug and the EGFR pathway. For example, high EGFR expression is more common in squamous carcinomas than in adenocarcinomas,21 indicating that an EGFR-targeted therapy should work better in the former. Yet, this was not the case in IDEAL-1. How might we explain this? In contrast to squamous carcinomas, adenocarcinomas of the lung are more likely to coexpress both EGFR and high levels of HER2.22 Gefitinib is active against HER2-overexpressing tumor cell lines,23,24 which raises the possibility that the responses in adenocarcinoma might be related to the association of this histology with HER2 expression. In other words, the potential for formation of EGFR-HER2 heterodimers in response to EGFR ligand stimulation may be more pronounced in adenocarcinomas. EGFR-HER2 heterodimers induce a stronger and more sustained proliferative signal than EGFR homodimers.2 Interestingly, lung cancers that coexpress EGFR and HER2 appear to possess a more virulent clinical behavior.25 Thus, in contrast to the authors’ assertion that adenocarcinomas may be more sensitive to gefitinib because of their "slow growth" (a view counter to clinical experience), we propose that adenocarcinomas may be more vulnerable to the disruption of the EGFR pathway because of their greater reliance on this signaling network for growth and survival. Because bronchioloalveolar carcinomas have even higher coexpression of both EGFR and HER2 than adenocarcinomas, one might anticipate a high response to gefitinib in this histology as well.21 In addition to histology, the authors found that that female sex and prior hormonal therapy were associated with a higher response to gefitinib. These findings may also have a plausible biologic explanation. Although the exact role of estrogen and progesterone in the development of lung cancer in women is a matter of debate,26 these hormones can upregulate EGFR in normal tissues.27,28 Furthermore, activation of steroid receptors results in increased transcription of EGFR ligands.2 If steroid hormones impact EGFR function in NSCLC, and preliminary data indicate that they may,29,30 sex-related differences in estrogen or progesterone may account for the observed sex differences in gefitinib response. Although purely speculative, the ability of these clinical factors to predict for gefitinib response could be assessed in future trials. Phase III trials combining gefitinib with chemotherapy in advanced NSCLC have been completed.31,32 Disappointingly, these trials showed no survival benefit for the combination compared to chemotherapy alone, even though their design was based on sound preclinical data. Some experts have suggested that the phase III data indicate that the concomitant administration of chemotherapy and EGFR tyrosine kinase inhibitors may be antagonistic, and that sequential use of these drugs is a more appropriate strategy. We suggest that our inability to select patients properly and the phenomenon of unrecognized molecular heterogeneity33 are alternative explanations for the negative results. In any case, it seems self-evident that future trials with gefitinib (and other so-called targeted therapies) should be conducted with appropriate correlative studies in diagnostic tumor tissue whenever possible. Ideally, frozen tumor material should be retrieved from patients enrolled in future trials that employ EGFR inhibitors. These tissues can be subjected to modern cDNA array and proteomics-based approaches and the data generated from these studies correlated with clinical response.34 It is conceivable that a novel set of RNAs or proteins will provide a molecular signature to identify patients likely to benefit from an EGFR-targeted treatment. The lack of a predictive molecular marker, however, should not slow additional clinical development of gefitinib. Clinical markers of gefitinib activity, such as those noted in the IDEAL-1 trial, offer a reasonable, near-term strategy for enriching study populations. These trials are needed to help define the IDEAL candidate for gefitinib therapy. "A box turtle on a fence post didn’t get there by accident!" R.M.H. to D.H.J., circa 1955 REFERENCES
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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