EGFR-TK Mutations Underlie Majority of Responses to Gefitinib

NEW ORLEANS-Mutations in the epidermal growth factor receptor (EGFR) may predict for significant response to drugs targeted at this molecule in non-small-cell lung cancer (NSCLC), according to presentations at a special educational session of the American Society of Clinical Oncology 40th Annual Meeting ("EGFR Mutations Predict Response to Gefitinib(Drug information on gefitinib)-Now What?") The session was called after reports from several groups, dealing with small numbers of patients, that strong response to EFGR inhibition correlates with the presence of mutations in the receptor's tyrosine kinase (TK) domain. The results were discussed by Thomas Lynch, MD, of Massachusetts General Hospital (MGH) and Pasi Jänne, MD, PhD, of the Dana-Farber Cancer Institute. Carlos L. Arteaga, MD, of the Vanderbilt-Ingram Cancer Center at Nashville, Tennessee, provided a concluding discussion. Strong Responses to Gefitinib Dr. Lynch gave an update of published work (N Engl J Med 350:2129- 2139, 2004) in which 25 (9%) of 275 patients showed a strong response to single-agent gefitinib mesylate (Iressa), a small molecule inhibitor of the TK domain of the EGFR. Tumor samples from 10 of these patients have been assayed. All had been diagnosed with adenocarcinoma or bronchoalveolar carcinoma (BAC), and were never or former smokers. Eight of these 10 samples showed somatic mutations in this same TK domain, located in the ATP binding site. Such mutations were absent from seven nonresponders to gefitinib treatment. In addition, a survey of tumor material from 25 NSCLC patients not treated with gefitinib revealed two more cases of mutated TK domains in the EGFR. Dr. Lynch also cited in vitro work by Jeff Settleman, PhD, of the MGH Cancer Center. In cell lines, transfection of the mutated EGFRs into Cos-7 led to enhanced activation in response to EGF, as well as increased sensitivity to gefitinib; both phenomena are of direct relevance to the development of the cancer and the response to gefitinib. [Dr. Settleman's work was published online in Science July 29, 2004.] Dr. Lynch suggested that these relationships might justify sequencedependent dose modification protocols, in which mutation-negative patients would receive higher doses, while mutation-positive patients could possibly benefit from reductions if toxicity were proving problematic. He also urged first-line trials of EGFR inhibitors in mutation-positive NSCLC patients. Several clinical reports have shown that the frequency of strong responses to gefitinib is higher in women than in men, in Japanese vs Caucasian patients, in adenocarcinoma vs other histologies, and in nonsmokers vs former or current smokers. In a sequencing program of unselected NSCLC specimens, done in collaboration with Japanese researchers at Nagoya City University, Dr. Jänne and his colleagues found that the frequency of EGFR mutations "very much mirrored the population of patients that derive the greatest benefit, in terms of response, from gefitinib." In one striking example, 54% of women nonsmokers with adenocarcinomas had mutated EGFRs, compared with only 11% of women smokers with adenocarcinoma. In vitro analysis of NSCLC cell lines with the EGFR L858R mutation revealed increased sensitivity to gefitinib, compared with wild-type cell lines. In addition, Dr. Jänne and his colleagues showed that this enhanced sensitivity is accompanied by a dramatic increase in gefitinib-mediated apoptosis, suggesting that the mutant receptor is important for cell survival in NSCLC. Dr. Lynch urged first-line trials of EGFR inhibitors in mutation+ NSCLC patients Detailed analysis of individual patients who responded to gefitinib yielded results similar to those reported by Dr. Lynch; all seven patients with a strong response to gefitinib had EGFR mutations, while none was found in six patients progressing on gefitinib. "These comparisons are highly significant and, combined with the in vitro findings, suggest that the mutations in these patients are determinants of sensitivity to gefitinib," Dr. Jänne said. Finally, EGFR sequence analysis of 227 tumor blocks from the TRIBUTE trial, in which patients received chemotherapy with or without erlotinib (Tarceva), another small molecule EGFR-TK inhibitor, revealed that inclusion of erlotinib led to significantly greater response rates among the 29 patients with mutated receptors vs the 199 patients with wild-type EGFRs. These responses in patients with mutations have not yet translated into improved survival. He noted that survival was significantly longer in patients with mutated vs nonmutated cancers regardless of treatment, suggesting that mutations may not only predict response to EGFR inhibitors may but also be prognostic for survival. Underestimates? Dr. Arteaga pointed out that the estimates of mutation frequencies discussed above (about 10%) may be underestimates. In most cases, the entire gene was not sequenced; moreover, the use of material from paraffin(Drug information on paraffin)- embedded sections may entail lower detectability, since the quality and amount of DNA from such sources are not optimal. In addition, the use of diagnostic tumor material prior to the appearance of metastatic disease may mean that subsequent transformation events, including mutation of the EGFR, may not have been detected. Ongoing investigations should help to assess the relevance of these concerns. There is certainly no shortage of potential mechanisms through which these mutations can be transforming. The EGFR is only the first of a family of four receptors, erbB1 through erbB4, which form homodimers and heterodimers in responding to a variety of ligands. In principle, mutations could lead to enhanced downstream signaling through a variety of potential mechanisms, including: (1) constitutive receptor dimerization, especially in more active heterodimer combinations; (2) enhanced response to ligands; (3) more effective engagement with downstream pathways; and (4) less sensitivity to endocytosis and degradation. ATP mimetics such as gefitinib or erlotinib could be effective in countering several of these possibilities, especially if the EGFR mutation also confers enhanced affinity to the inhibitor. Possibility of Screening While the evidence for the relevance of EGFR mutations is convincing, Dr. Arteaga argued that wide screening for EGFR mutations is of limited utility at present. In addition to the question of the number of likely mutations, it is difficult to conceive of a test that could include them all with current technology, he said. In fact, mutational screening is not done in clinical laboratories at all, and remains very much a research- based enterprise. Practical matters such as tissue availability also remain problematic. "However," Dr. Arteaga said, "if surgical tissue was available and there was access for EGFR sequencing, there are good reasons why this should be done. These studies will inform further on the natural history of mutant EGFR lung cancers as well as potentially identify candidates for randomized adjuvant studies with EGFR inhibitors that are in early phases of development." This would be particularly true, he said, for certain classes of patients, such as nonsmoking women with adenocarcinoma, for whom the probability of EGFR mutations is approximately 50%. "For these patients," Dr. Arteaga told Oncology News International, "mutational screening, as well as entrance into clinical trials of firstline therapy with EGFR inhibitors, might well be a reasonable proposition, even at our current state of knowledge."