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Lung Cancer Trials Advance EGFR-Testing Hypothesis for Iressa and Tarceva, Though Questions Remain

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By Turna Ray

Two studies published last month in the New England Journal of Medicine provide support for establishing lung cancer patients' status for mutations in the epidermal growth factor receptor prior to treatment with tyrosine kinase inhibitors, such as Iressa and Tarceva.

An editorial reviewing the two studies, by Adi Gazdar of the University of Texas' Southwestern Medical Center, concluded that while both "suggest that first-line tyrosine kinase therapy should be considered for carefully selected subgroups" of NSCLC patients of East Asian and non-East Asian origin, the studies leave many unanswered questions — such as the ability of TK-inhibitors to impact overall survival and the feasibility of extrapolating study results from an East Asian population to Western patients .

In Mok et al., researchers from various East Asian institutions and AstraZeneca conducted a Phase III trial of more than 1,200 previously untreated East Asian patients with advanced pulmonary adenocarcinoma, who were nonsmokers or former light smokers, and randomized them to receive gefitinib (AstraZeneca's Iressa) or carboplatin plus paclitaxel. In this study, researchers found that in 261 patients who were EGFR-mutation positive, progression-free survival was longer for those receiving Iressa than those treated with the carboplatin-paclitaxel regimen. The study received funding from AstraZeneca.

In addition, a non-randomized study by Rosell et al. screened 2,105 lung cancer patients in 129 institutions in Spain for EGFR mutations. Those positive for EGFR mutations were given erlotinib (Genentech/OSI's Tarceva). The researchers reported an improvement from previous studies in median progression-free survival (14 months) and median overall survival (27 months) in the 217 patients who were treated with Tarceva.

According to Gazdar's editorial, these two studies, like other previously published studies, suggest "that EGFR mutations represent favorable prognostic markers of survival and are predictive of tumor shrinkage, but the evidence that they can predict a differential effect of tyrosine kinase inhibitors on survival is incomplete."

Japanese researchers in 2006 published a study in Clinical Cancer Research which suggested EGFR-mutation testing may be used to identify best responders to NSCLC treatments Iressa and Tarceva. However, although the study found that by using EGFR mutation testing to guide treatment improved progression-free survival in NSCLC patients, improvements in overall survival were statistically insignificant [see PGx Reporter 07-12-2006].

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A study published last year in the Journal of Clinical Oncology reported that lung cancer patients with certain EGFR mutations, when treated with Iressa, had a better response rate and an improved time-to-tumor growth than when treated with chemotherapy [see PGx Reporter 05-29-2008].

In his analysis, Gazdar highlights that both studies showed "significant increases" in rates of response and progression-free survival in patients whose tumors had EGFR mutations, and showed that toxic effects associated with therapy were "modest and well tolerated."

However, in Gazdar's view, several questions must be answered before the findings of the randomized East Asian trial (Mok et al.) can be extrapolated to a Western population, including whether Iressa can substitute for Tarceva with comparable efficacy. The main problem with the randomized East Asian trial by Mok et al. is that it failed to show an improvement in overall survival, Gazdar said.

In cancer treatment, "the major end point for benefit is overall patient survival," Gazdar told Pharmacogenomics Reporter. "Progression-free survival may be a desirable endpoint, but it is not the best."

Since "there was no improvement in [overall] survival in the randomized trial [by Mok et al.]," Gazdar questions in his editorial whether it is necessary to perform mutational analyses in selected subpopulations, or if they can be treated empirically. Also, Gazdar questions whether the lack of a difference in overall survival in the East Asian study suggests that "the order of drug administration may not be important, as long as patients who do not have a response can cross over to the other" treatment arm.

"Despite these unanswered questions, the studies by Rosell et al. and Mok et al. and other reports suggest that first-line tyrosine kinase therapy should be considered for carefully selected subgroups of patients of East Asian and non–East Asian origin who have non–small-cell lung cancer," Gazdar concludes.

These study results come a month after AstraZeneca formed a collaboration with DxS to market its TheraScreen EGFR29 Mutation Kit in Europe as a companion diagnostic for Iressa [see PGx Reporter 08-05-2009]. However, the Rx/Dx deal does not extend to the US market, where Iressa is currently indicated for the treatment of locally advanced or metastatic NSCLC in patients who have previously received chemotherapy.

"There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival," Iressa's label states. The company provides the drug in the US through an access program. In 2004, AstraZeneca informed the US Food and Drug Administration that a large randomized study, called ISEL, failed to demonstrate a survival advantage for Iressa in NSCLC patients. Based on these findings, the FDA did not take the drug off the market but restricted any new patients from taking Iressa.

Gazdar told Pharmacogenomics Reporter that EGFR testing in the NSCLC setting is currently "patchy at best," and treatment decisions are usually guided by clinico-pathological features of the patient.

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He noted that while several ongoing clinical trials are looking to answer the missing links supporting EGFR testing prior to treating lung cancer patients with tyrosine kinase inhibitors, "some of the questions are very broad and we may need time before we get the answers."

Mok et al.

In Mok et al., researchers reported nearly 25 percent of patients on Iressa versus 7 percent of those treated with the carboplatin-paclitaxel regimen experienced progression-free survival rates of one year.

"The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin–paclitaxel, with respect to progression-free survival in the intention-to-treat population," the study authors stated in the article.

For the 261 patients who were EGFR-mutation positive, progression-free survival was "significantly longer" for those receiving Iressa, whereas those who were EGFR-mutation negative experienced longer progression-free survival on the carboplatin-paclitaxel regimen.

Patients treated with Iressa most commonly experienced rash or acne (66.2 percent) and diarrhea (46.6 percent). Those in the carboplatin-paclitaxel arm commonly experienced neurotoxic effects (69.9 percent), neutropenia (67.1 percent), and alopecia (58.4 percent).

"Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia," the researcher concluded. "The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib."

In his review, however, Gazdar takes issue with the researchers' lack of discussion of gefitinib's lack of effect on overall survival in the EGFR-mutated population.

"Responses to the tyrosine kinase inhibitor were almost entirely limited to the mutation-positive group, whereas mutation-negative patients benefited from chemotherapy," Gazdar notes. "However, overall survival, perhaps the most important endpoint in cancer treatment, was not improved by gefitinib, for reasons not discussed by the authors."

The study authors and AstraZeneca did not respond to questions regarding this study prior to deadline.

Rosell et al.

In Rosell et al., researchers from various institutions in Spain screened more than 2,000 lung cancer patients from April 2005 through November 2008 and treated EGFR-mutation positive patients with Tarceva. The researches looked at 350 patients whose tumors were EGFR-mutation positive and analyzed the association between their tumors and response to treatment.

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EGFR mutations were more frequent in non-smoking women (69.7 percent) and in those with adenocarcinomas (80.9 percent). In mutation-positive patients, researchers identified deletions in exon 19 in 62.2 percent of patients and L858R in 37.8 percent of patients.

"Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively," the researchers reported. "The adjusted hazard ratios for the duration of progression-free survival were 2.94 for men; 1.92 for the presence of the L858R mutation, as compared with a deletion in exon 19; and 1.68 for the presence of the L858R mutation in paired serum DNA, as compared with the absence of the mutation."

Patients treated with Tarceva commonly experienced mild rashes and diarrhea. In 7.4 percent of patients, grade 3 cutaneous toxic effects, and in 3.7 percent, grade 3 diarrhea were recorded.

"Screening for EGFR mutations is warranted in women with lung cancer, in those who have never smoked, and in those with nonsquamous tumors," the study authors conclude. "Large-scale screening of patients for EGFR mutations, with subsequent customization of erlotinib, is feasible and improves the outcome."

However, in his analysis, Gazdar cautions that while "the vast majority of EGFR mutations are either a deletion of a conserved sequence in exon 19 or a single point mutation in exon 21 (L858R)," the association between mutations and responsiveness to tyrosine kinase inhibitors is more complex than previously envisioned and confounded by findings suggesting increased gene copy number, possibly the copy number of HER2, "correlate better" with overall survival.

"Not all EGFR mutations are equal, and some, especially insertion mutations in exon 20, confer intrinsic resistance on tumor cells," Gazdar notes in his editorial. "A further confounder was the finding that activating mutations in the downstream KRAS gene (usually mutually exclusive with EGFR mutations) also conferred intrinsic resistance."

EGFR mutation T790 M and amplification of overexpression of the MET gene contribute to eventual resistance in NSCLC patients who initially respond to tyrosine kinase inhibitors, he notes.

Rosell et al. did not report "significant differences in progression-free survival according to performance status, age, first-line therapy versus second-line or third-line therapy, smoking history, or type of mutation." Median overall survival was 28.0 months for patients receiving first-line treatment with Tarceva and 27.0 months for those receiving it as second-line treatment. The study does not discuss the resistance to treatment.

Study authors did not respond to questions about this study ahead of press time.