IDENTIFYING NSCLC PATIENTS WHO WILL RESPOND TO CETUXIMAB

July 6, 2011 (Amsterdam, the Netherlands) — A new approach to identifying patients with nonsmall-cell lung cancer (NSCLC) who are likely to respond to cetuximab (Erbitux) when used in combination with chemotherapy was reported here at the 14th World Conference on Lung Cancer (WCLC).
The finding comes from a new analysis of the FLEX study, which showed that adding cetuximab to first-line chemotherapy statistically significantly improved overall survival in patients with advanced NSCLC. The study was first presented in 2008, and was subsequently published in the Lancet (2009;373:1525-1531).
Lead author Robert Pirker, MD, from Vienna Medical University in Austria, said that since that time, his team has been researching various biomarkers to find one that would predict a good clinical outcome, and now they have one — high EGFR expression.
Patients with a high expression of EGFR in their tumors (31% of those tested) have a significantly better response to cetuximab plus chemotherapy that those with a low expression, Dr. Pirker reported.
Tumor EGFR expression was assessed prospectively with immunohistochemistry in 1121 patients (of 1125) participating in the FLEX study. The researchers then determined a cut-off point (200 or more on a scale of 0 to 300) for high EGFR expression, which was determined retrospectively according to response rates.
The analysis shows that patients with high EGFR expression fared better on cetuximab plus chemotherapy than on chemotherapy alone, regardless of histology. The median overall survival in this high-expression group treated with cetuximab plus chemotherapy was 12 months, compared with 9.6 months for patients treated with chemotherapy alone (hazard ratio, 0.73; P = .011). One-year survival was higher in the combination group than in the chemotherapy group (50% vs 37%), as was 2-year survival (24% vs 15%).
In contrast, the patients who had low EGFR expression showed no benefit from the addition of cetuximab to chemotherapy — the median overall survival was no different in the 2 groups.
Measuring EGFR expression in tumors allows the identification of NSCLC patients who are most likely to benefit from treatment with cetuximab in the first-line setting, Dr. Pirker concluded. "We have further improved outcome with this analysis," he added.
Dr. Pirker emphasized that this is "the first predictive biomarker for overall survival in advanced NSCLC."
In an interview with Medscape Medical News,henoted that the genotyping approach — which has led to erlotinib and gefitinib for first-line therapy in patients with EGFR mutations — has so far shown an improvement in progression-free survival, but not overall survival. However, experts have noted on many occasions that this is because of a high crossover in these trials and that, overall, these patients have better survival than is seen in historic controls.
"I do believe that this is such an improvement in survival — one that we have never seen before — that this finding should be available to our patients," Dr. Pirker noted at a WCLC press conference.
Needs Validation
However, Roy Herbst, MD, from the Yale Cancer Center in New Haven, Connecticut, who was moderating the press conference, told Medscape Medical News that the finding should be validated prospectively before it is incorporated into clinical practice. This sentiment was echoed in another session at the meeting. "More validation is needed; we have just heard about this finding," said Luis Paz-Ares, MD, PhD, chair of oncology at Seville University Hospital in Spain.
"This is a very important observation, and it definitely shows an efficacy difference," said Edward Kim, MD, assistant professor of medicine and director of clinical research operations at the University of Texas M.D. Anderson Cancer Center in Houston. "But this is a post hoc analysis, so it is hypothesis-generating," he said. "This needs prospective testing in a randomized clinical trial," he insisted.
When challenged by a member of the audience about whether such a trial would be ethical, given the survival advantage, Dr. Kim said the trial need not be large, but insisted that it is necessary. "This is an easy test to do," he said, "but it would not drive my decisions at the moment. It would not change my mind right now as to whether or not to use cetuximab."
Dr. Kim noted that there is another possible way of identifying patients likely to respond to cetuximab — the observation of a rash after the first cycle of therapy.
Dr. Herbst said that prospective validation is important, and noted that this biomarker of EGFR expression, with the same cut-off, has just been added in a new group of an ongoing American trial (SWOG 0819). This trial has enrolled 400 patients so far, but the goal is 1200. Results are expected in a couple of years, he said. "This will provide prospective confirmation," he explained.
This is an important clinical issue, Dr. Herbst noted.
So far, the research into genetic mutations has identified patients who benefit from mutation-targeted therapies, but the numbers have been small, he said. About 10% of all NSCLC patients harbor an EGFR mutation and would benefit from erlotinib (Tarceva); a further 4% to 5% of patients have an ALK rearrangement and would benefit from crizotinib (under development by Pfizer) "if and when this drug is approved and available," he said.
But what about all the remaining NSCLC patients, he asked.
This research offers a new approach, Dr. Herbst continued. This approach, using immunohistochemistry to measure EGFR expression, has identified about 30% of NSCLC patients who have high EGFR expression tumors and who are likely to respond well to first-line cetuximab added to chemotherapy, he said.
The FLEX study was sponsored by Merck KgaA, the manufacturer of cetuximab. Dr. Pirker reports serving on the speakers bureau for Pierre Fabre and Roche; and serving on the consultancy/advisory board of AstraZeneca, Boehringer Ingelheim, Merck-Serono, Pfizer, and Bristol-Myers Squibb. Dr. Herbst reports serving on the advisory committee for Amgen, Biothera, Genetics Squared, Med Trust, N of One, SynDevRx, Targeted Molecular Diagnostics, and Diatech. Dr. Kim reports serving on the speakers bureau for Bayer/Onyx, Genentech, and Boehringer Ingelheim; and receiving research support from Eli Lilly.
14th World Conference on Lung Cancer (WCLC): Abstract 1557. Presented July 4, 2011.