EGFR MUTATION TESTING

January 8, 2010 — The targeted therapy gefitinib (Iressa, AstraZeneca) is not inferior to chemotherapy in terms of improving overall survival in pretreated patients with advanced nonsmall-cell lung cancer (NSCLC). However, there is also no evidence of a difference in overall survival between these 2 treatments.

These are among the new findings from the multinational 1466-patient clinical trial known as INTEREST (Iressa NSCLC Trial Evaluating Response and Survival Versus Taxotere), which were published online December 28 in the Journal of Clinical Oncology.

The study investigators also found that patients who tested positive for an epidermal growth factor receptor (EGFR) mutation had longer progression-free survival (hazard ratio, 0.16; 95% confidence interval, 0.05 - 0.49; P = .001) with gefitinib than with the chemotherapy docetaxel.

INTEREST is the third major trial to show that EGFR mutation predicts benefit with EGFR tyrosine kinase inhibitors (TKIs), which are much less toxic than chemotherapy, writes Ramaswamy Govindan, MD, in an editorial accompanying the new results.

"Taken together, the three recent representative studies (INTEREST, IPASS [IRESSA Pan-Asia Study], and SATURN) underscore the fact that the presence of EGFR [tyrosine kinase] mutation best identifies those who would derive the most benefit, as measured by [progression-free survival]," writes Dr. Govindan, who is from the Alvin J. Siteman Cancer Center at Washington University School of Medicine in St. Louis, Missouri.

Other biomarker tests in NCSLC, including that for KRAS mutations, have not been consistently predictive of the benefit from EGFR [tyrosine kinase] inhibition, adds Dr. Govindan.

Although EGFR mutation is clearly the best biomarker for predicting progression-free survival benefit with the TKIs, which also include erlotinib (Tarceva, Genentech/OSI Pharmaceuticals), this finding needs to be placed in its proper context, said H. Jack West, MD, a lung cancer expert approached for comment by Medscape Oncology. Dr. West is from the Swedish Cancer Institute in Seattle, Washington.

"These data don't say that everyone with NSCLC needs to be tested for the mutation," said Dr. West, who explained that heavy smokers or those with squamous cell carcinomas are very unlikely to have the mutation.

"The most suitable candidates for testing are never-smokers or those with a remote smoking history with an adenocarcinoma," he noted.

However, even when patient context is clarified, it is not yet clear how the testing changes clinical practice, Dr. West explained.

EGFR Testing Has "Very Real" Barriers

Dr. West endorses testing patients for the EGFR tyrosine kinase mutation. "If feasible, it is desirable to test for this," he said, explaining, as an example, that patients who do not have the mutation should definitely not receive an EGFR TKI as a first-line therapy.

He also believes that the use of the testing is "actively evolving" and that "practice patterns are probably changing quarterly."

"It has changed my practice," Dr. West added.

"EGFR-mutation testing tells us that someone with a mutation is highly likely to have a dramatic and often long-lasting response to an EGFR TKI whenever they get it," Dr. West has written in his Medscape blog, Blowing Smoke.

However, the testing is often not feasible because of "very real barriers," Dr. West said.

"There are a limited number of labs that perform the test, and it can take 3 to 4 weeks to get results," Dr. West said, adding that most patients with lung cancer and their clinicians are "uneasy" about delaying the start of therapy for that long.

Also, initial lung biopsies often do not yield sufficient tissue for testing, necessitating another biopsy, said Dr. West. In the IPASS trial, only one third of patients had biopsied tissue suitable for the testing, he noted.

In INTEREST, only 297 of the 1466 patients had tissue assessable for the test, and 44 of them (15%) were EGFR-mutation positive.

EGFR TKIs Should Ultimately Be Used in Most Patients Anyway

Dr. West also declared that, in NSCLC patients, chemotherapy — and not the EGFR TKIs — is the "well-established standard of care as first-line therapy in North America."

"There is still no evidence that people live longer with an upfront TKI," he added, citing the IPASS results and other data.

However, Dr. West also noted that there is no "penalty" in terms of overall survival when giving it as a second-line instead of first-line therapy, he added, citing the results of a recent Spanish study of erlotinib.

Still, Dr. Govindan believes there is a case for the upfront use of EGFR TKI.

"Does it really matter whether we give EGFR TKIs earlier (front-line/maintenance) in the course of the disease or later (in the second- or third-line setting)?" he asks in his editorial.

Dr. Govindan goes on to suggest that sequence does matter because, in patients with an EGFR mutation, it is "hard to make the case for delaying a therapy that is dramatically effective, convenient, and well tolerated compared with more toxic intravenous cyctoxic chemotherapy."

But Dr. West says that an EGFR TKI will offer the same quality-of-life benefits to an NSCLC patient eventually as a second-line therapy. "There is no evidence of what is the best sequence," he reiterated.

Despite his objections, Dr. West offers an EGFR TKI to all NSCLC patients who progress, even those who do not test positive for the EGFR mutation.

"Being EGFR wildtype, however, does NOT mean that someone will get no benefit from an EGFR TKI," he writes in Blowing Smoke.

The results of IPASS, Dr. West writes, strongly suggest that these wildtype patients will not receive a "major and prolonged benefit, but they are in the large proportion of patients who may experience a minor response or prolonged stable disease that translates to a survival benefit in the range of a few months."

The INTEREST trial was supported by AstraZeneca. Dr. Govindan reports being a consultant/advisor to Genentech Lilly Oncology and AstraZeneca, and receiving honoraria from the same companies. Dr. West has disclosed no relevant financial relationships.

J Clin Oncol. Published online December 28, 2009. Abstract, Abstract