'Tragedy' Not to Use EGFR Inhibitors in EGRF+ NSCLC

Zosia Chustecka

July 15, 2011

July 15, 2011 (Amsterdam, the Netherlands) — More and more data are accumulating to support the treatment of patients with nonsmall-cell lung cancer (NSCLC) testing epidermal growth-factor receptor–positive (EGFR+) with one of the EGFR tyrosine kinase inhibitor drugs: erlotinib (Tarceva, Astellas Pharma US, Inc, and Genentech, Inc) or gefitinib (Iressa, AstraZeneca). So much so, that "it would be a tragedy" to not treat such a patient with such a drug, says Edward Kim, MD, PhD, assistant professor of medicine and director of clinical operations at the University of Texas M.D. Anderson Cancer Center in Houston.

This involves obtaining and testing tumor tissue, which can be problematic, but "I don't think that we can accept a status unknown anymore," Dr. Kim commented here at the 14th World Conference on Lung Cancer (WCLC).

After long years of little progress, lung cancer is now going through a "spring of hope," Dr. Kim declared. There are now several targeted drugs that are offering improved outcomes, he noted. In addition to EGFR mutations and EGFR inhibitors, there is also crizotinib-targeting ALK rearrangement, and new data presented at the meeting suggest that cetuximab (Erbitux, Eli Lilly and Bristol-Myers Squibb) appears to home in on tumors showing high EGFR expression, although Dr. Kim commented that this information needs to be validated prospectively.

All this calls for lung tumor tissue to be obtained and analyzed, and Dr. Kim hopes that this will be happening routinely in the not-too-distant future. Breast oncologists already receive this sort of information before they start treatment (eg, on hormonal status and whether the tumor is human epidermal growth factor receptor–positive, and thus amenable to targeted therapy with trastuzumab [Herceptin, Genentech]), he commented. "If we had that sort of info up front, it would change everything," he said.

New Data Show Doubling of Progression-Free Survival

The new data presented here at the meeting included the European Randomised Trial of Tarceva vs Chemotherapy (EURTAC), which is the first in Western patients to test erlotinib as first-line treatment in patients with EGFR+ NSCLC. The trial was stopped early after showing benefit: Erlotinib nearly doubled progression-free survival when compared with chemotherapy.

"Although a growing body of evidence has been emerging about this type of lung cancer, almost all of the studies have been conducted in Asian patients — a group that historically has had significantly different results to NSCLC therapy compared to Western populations," commented lead investigator Radj Gervais, MD, from the Centre François Baclesse in Caen, France.

In addition, the proportion of patients with NSCLC with these mutations is different. According to Roche, manufacturer of erlotinib, EGFR+ tumors are found in up to 10% of Western patients and up to 30% of Asian patients with NSCLC. Roche supported EURTAC, as well as a similar study in Asian patients known as OPTIMAL, both of which are exploring the use of erlotinib as first-line therapy.

In EURTAC, erlotinib showed a significant improvement over chemotherapy, with a better tolerability profile, Dr. Gervais reported. Progression-free survival was 9.4 months in the erlotinib group compared with 5.2 months in the chemotherapy group (hazard ratio, 0.37; P < .0001). There was also a trend toward improved overall survival (22.9 months with erlotinib vs 18.8 months with chemotherapy), although this difference was not significant (hazard ratio, 0.80; P = .42).

"We now have results for the use of erlotinib first-line for both Asian and Western EGFR-mutation-positive patients with NSCLC, so we can carry this knowledge into our daily practice," Dr. Gervais concluded.

"This was a long-awaited study and important study" commented Tony Mok, MD, professor of clinical oncology at the Chinese University of Hong Kong, who discussed the results at the recent American Society of Clinical Oncology annual meeting, where the EURTAC results were first presented.

Dr. Mok drew parallels between this study and the Iressa Pan-Asia Study (IPASS) that he headed, using gefitinib in Asian patients. IPASS showed a median progression-free survival of 9.5 months with gefitinib, and EURTAC showed a median progression-free survival of 9.7 months with erlotinib, he noted.

These are the 2 most important studies in this field, he suggested, and they both support the use of these targeted agents in a first-line setting.

Speaking at the WCLC meeting, Martin Edelman, MD, from the University of Maryland Greenebaum Cancer Center in Baltimore, was in agreement. "EGFR+ patients should be offered treatment with EGFR [tyrosine kinase inhibitor] drugs early on in the course of their disease (ie, first-line therapy)."

However, he added that these drugs are also reasonable second-line and third-line options, as there is "some evidence of benefit" in patients who have good performance status, he said.

"But we need a reality check here," Dr. Edelman declared. In advanced NSCLC EGFR+ disease, very few patients have durable responses, he commented, pointing out that progression-free survival is still only 9 to 12 months, and overall survival is 2 to 2.5 years. "So we still have a long way to go," he said.

In addition, another discussant brought up the high price of these drugs. Erlotinib costs $94,638 per quality life-year gained, pointed out Primo Lara Jr, MD, from the University of California–Davis Cancer Center, but the confidence intervals around the markers of benefit with this drug are large, he noted. The high cost has been an issue in some countries that review cost-effectiveness. Canada decided that eroltinib in advanced NSCLC was "marginally cost-effective," but the United Kingdom accepted it only after a price reduction, and rejected it for maintenance use because of the lack of cost-effectiveness in this setting.

Indication for First-Line Use

Erlotinib is currently approved for second-line use after chemotherapy has failed, but an application for first-line use, on the basis of the EURTAC results, has now been filed by Roche.

Gefitinib is already approved for first-line use, on the basis of the IPASS results, in more than 60 countries worldwide, including Asia and Europe. The drug is not available in the United States, however, and the manufacturer has said that it will not pursue approval in the United States.

The US labeling for gefitinib dates back to 2005, when the Iressa Survival Evaluation in Lung Cancer (ISEL) study showed no survival benefit in NSCLC, and use of the drug was restricted to patients who were already taking the drug. No new patients were to be put on this drug, the label emphasized.

Since then, however, a number of trials, including IPASS, have shown a benefit from gefitinib in the subgroup of patients who have EGFR+ mutations, and these new data have been accepted by regulatory authorities worldwide. The FDA, however, is "likely to require an additional randomised controlled study in EGFR-positive patients" that would link the results from IPASS to the US population, the company explained in a recent statement, adding: "AstraZeneca believes that such a study would not be viable within an acceptable timeframe and therefore does not plan to pursue approval in the US."

Astra Zeneca told Medscape Medical News that the patent for gefitinib expires in between 2017 and 2019, varying by geographical region.

"Clinicians in the US cannot get hold of gefitinib," commented Mark Kris, MD, chief of thoracic oncology at the Memorial Sloan Kettering Cancer Center, New York City, "and this is a great shame." It is always useful to have another drug in the same class to try in patients who do not respond or who cannot tolerate the first one, and there is some evidence to suggest that gefitinib may be better tolerated than erlotinib, Dr. Kris told Medscape Medical News.

Effect on Overall Survival?

None of the studies with EGFR inhibitors in patients with EGFR+ NSCLC has shown a statistically significant improvement in overall survival, but this is mainly because of the high crossover effect, say experts. Any patient in the control group who progresses is immediately offered the targeted therapy, confounding the outcomes.

Although the survival data are not there, as yet, there is a sense that these patients are doing better overall, and comparisons with historic controls suggest a survival advantage. "All of the patients in these trials are doing well," Roy Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center in New Haven, Connecticut, told Medscape Medical News.

However, there is a complication here, in that having the EGFR+ mutation in itself confers some survival advantage, Dr. Herbst noted. Asked to speculate on the magnitude of the improvement seen with the new drugs, Dr. Herbst said that historically, patients with advanced NSCLC treated with chemotherapy had a median overall survival of around 8 to 9 months. Now, patients with EGFR mutations treated with erlotinib have a median overall survival of around 18 to 20 months, he said. However, some patients respond very well and can live for several years, he added, noting that he has a few patients who are still alive at 8 to 9 years.

Resistance Is a Problem

One important problem, however, is the development of resistance to these agents. In the end, every patient develops resistance to these agents, commented Dr. Herbst. The median time to developing resistance is about a year, but some patients become resistant within 2 to 3 months, whereas others continue to respond to the drug for 6 to 7 years.

Research efforts are focusing on how to overcome this resistance, and one hopeful strategy is the development of an irreversible EGFR inhibitor, such as PF-299804 (from Pfizer), Dr. Herbst commented.

New data on this drug were presented here by Michael Boyer, MD, from the Sydney Cancer Centre, Camperdown, Australia, from a phase 2 study comparing PF299804 with erlotinib in patients with advanced NSCLC who had progressed after at least 1 course of chemotherapy. The investigational drug showed superior progression-free survival (12.4 months vs 8.3 months with erlotinib; hazard ratio, 0.66; P = .012) and a trend toward better overall survival, although this was not significant. The most common adverse effects were diarrhea and rash. On the basis of the results of this study, Pfizer is now conducting a phase 3 trial (known as ARCHER) with this drug.

Dr. Edelman has disclosed acting as a consultant for Lilly, Genentech, OSI, and Bristol-Myers Squibb and receiving research support from Bristol-Myers Squibb and Tragara. Dr. Lara has disclosed acting as a consultant for Pfizer, Novartis, Genentech, Sanofi-Aventis, Avco, and Exelixis and receiving research support from Pfizer, GlaxoSmithKline, and Genentech. Dr. Mok has disclosed acting in a consultancy or advisory role for Astra Zeneca, AVEO, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Serono, Pfizer, Roche, and Taiho; receiving honoraria from AstraZeneca, AVEO, Boehringer Ingelheim, Lilly, Pfizer, and Roche; and receiving research funding from AstraZeneca. Dr. Boyer has disclosed acting as a consultant to Boehringer Ingelheim and receiving research support from Merck, Bristol-Myers Squibb, MedImmune, ArQule, and Pfizer. Dr. Kris reports acting as a consultant to Boehringer Ingelheim, Pfizer, and Chugai.

14th World Conference on Lung Cancer (WCLC): Abstracts 733, 745. Presented July 4, 2011.

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