Final IPASS Data Back EGFR Testing Before NSCLC Treatment

Janis C. Kelly

June 23, 2011

June 23, 2011 — Clinicians should check epidermal growth-factor receptor (EGFR) biomarker status before starting nonsmall-cell lung cancer (NSCLC) patients on gefitinib (Iressa), researchers report in a study published online June 13 in the Journal of Clinical Oncology.

That advice, based on final results from the landmark Iressa Pan-Asia Study (IPASS), supports current recommendations from the American Society of Clinical Oncology that patients with advanced NSCLC who are candidates for the first-line EGFR tyrosine kinase inhibitors erlotinib (Tarceva) and gefitinib (Iressa) be tested for EGFR mutation status.

IPASS coauthor Sumitra Thongprasert, MD, from the Division of Medical Oncology at Chiangmai University in Thailand, told Medscape Medical News that "the most important point of the final overall survival analysis is that molecular markers like EGFR mutation are the most important selection criteria for the treatment of NSCLC with gefitinib. It is definite that EGFR mutation testing should be done before initiating treatment with gefitinib as first-line treatment for NSCLC."

The IPASS trial randomized 1217 NSCLC patients to open-label first-line treatment with gefitinib or with carboplatin/paclitaxel. The researchers analyzed biomarkers including EGFR mutation, EGFR gene copy number, and EGFR protein expression.

The final results showed no significant difference in overall survival between treatments or between patients with or without an EGFR mutation. However, two thirds of those with the EGFR mutation randomized to carboplatin/paclitaxel subsequently crossed over to gefitinib, which might be why the treatment-related differences in progression-free survival seen in the subgroup with EGFR mutations were not seen for overall survival.

With gefitinib, progression-free survival was significantly longer if the patients had both high EGFR gene copy numbers and EGFR mutations. With carboplatin/paclitaxel, progression-free survival was longer if the patients had high EGFR gene copy numbers but no EGFR mutation.

"In the first-line setting, gefitinib should not be used in preference to doublet chemotherapy in patients with negative mutation status," the authors write.

They conclude that "EGFR mutations are the strongest predictive biomarker for progression-free survival and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis)."

[This is] the largest and most important correlative study reported for any NSCLC trial to date.

In an accompanying editorial, Frances A. Shepherd, MD, notes that "frequently there is criticism of molecular correlative studies that are performed retrospectively in clinical trials (even when preplanned and designed prospectively), given that in advanced NSCLC studies, samples are available in only one quarter to one third of patients. This also was true for IPASS, but it is important to point out that molecular results were available for more than 400 patients, making this the largest and most important correlative study reported for any NSCLC trial to date.

"Indeed, the EGFR mutation results were so powerful for progression-free survival that statistically significant and clinically important qualitative interaction (benefit in mutation-positive and harm in wild-type EGFR) could be demonstrated (interaction < .001). The same was true for EGFR copy (interaction P = .043)." Dr. Sheppard writes.

Progression-Free Rather Than Overall Survival?

Dr. Shepherd, who is chair of the National Cancer Institute of Canada Clinical Trials Group Lung Cancer Site and is a member of the Clinical Studies Resource Centre at the Ontario Cancer Institute, in Toronto, suggests that the IPASS results should not only change clinical practice, but should trigger a shift in how new lung cancer drugs are dealt with by regulatory authorities.

"The dramatic, statistically significant, and clinically important difference in the molecular subset results seen for progression-free but not overall survival in the IPASS study raises the controversial issue of the appropriate clinical trial end point for molecularly targeted agents," Dr. Shepherd explains. In IPASS, the high crossover rates and commercial availability of both chemotherapy and EGFR tyrosine kinase inhibitors probably obscured overall survival differences.

"This issue is of particular relevance for registration studies and suggests that the time has come to approve new agents for lung cancer based on progression-free rather than overall survival, as is the case for some other tumor types," Dr. Shepherd concludes.

Dr. Thongprasert reports serving as a consultant or advisor for AstraZeneca, Novartis, and Pfizer; receiving honoraria from AstraZeneca and Eli Lilly; and receiving research funding from AstraZeneca, Roche, Pfizer, and Sanofi-Aventis. Dr. Shepherd reports serving as a consultant or advisor for AstraZeneca and Roche; owning stock in AstraZeneca; and receiving honoraria from AstraZeneca and Roche.

J Clin Oncol. Published online June 13, 2011. Abstract, Editorial


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