Eli Lilly said last week that it received a complete response letter from the US Food and Drug Administration declining its application to market Erbitux as a first-line treatment for non-small cell lung cancer.
The company disclosed the decision as part of its first-quarter financial results on April 25.
"Lilly and its partner, Bristol-Myers Squibb, do not plan to resubmit the [First-Line Erbitux study, or] FLEX filing, but will continue to market Erbitux in the US for certain types of head and neck cancer and colorectal cancer," the company said in a statement.
According to a report from BioCentury, the FDA asked Lilly to submit data from another trial showing that Erbitux improves overall survival in NSCLC patients, and to submit data on a validated companion diagnostic that can predict which patients will benefit from the treatment.
For the NSCLC Erbitux marketing application, Lilly and BMS submitted data from the Phase III FLEX trial, which randomized patients to receive either Erbitux (cetuximab) plus cisplatin/vinorelbine versus just chemotherapy. In this study, patients in the Erbitux arm experienced overall survival for 11.3 months compared to 10.1 months for patients who just received chemotherapy. Patients eligible for the trial had to have at least one tumor cell stained positive for the EGFR protein; researchers determined EGFR status with Dako's immunohistochemistry test.
PGx Reporter was unable to get confirmation from FDA or from Lilly as to whether the agency asked for a validated companion test for Erbitux.
In Europe, after receiving a negative decision from the European Medicines Agency in 2009 for NSCLC, Lilly partner Merck last year resubmitted retrospective analysis looking at overall survival in the FLEX study when patients were stratified based on EGFR tumor expression levels. The analysis revealed that patients with high EGFR expression who received the Erbitux/chemo regimen survived an average of 12 months, while those in the chemotherapy-alone group lived only 9.6 months.
Researchers led by Robert Pirker of the Medical University of Vienna published these data in Lancet Oncology in November 2011.
It is unclear why this additional retrospective analysis from the FLEX trial was insufficient for the FDA. However, there is indication Erbitux's sponsors were looking at predictive markers, but the design of the FLEX trial didn't provide the level of evidence the agency wanted on predictive biomarkers.
In a presentation at the 2008 American Society of Clinical Oncology's Molecular Markers meeting, Pirker explained that the FLEX trial, designed in 2003, was seeking to define a survival advantage in patients with EGFR-expressing tumors treated with Erbitux and chemotherapy compared to just chemotherapy alone. The trial wasn't designed initially to gauge predictive markers of response, Pirker said at the meeting.
At the meeting, Pirker reflected that if he could do the FLEX trial over again, he would still use an IHC test but he wouldn't use EGFR expression as an inclusion criteria. FLEX researchers retrospectively collected tumor specimens from more than 500 patients, or about half the study participants enrolled in FLEX. They used Vysis's EGFR FISH test to gauge EGFR positivity, Qiagen/DxS's test to gauge EGFR mutations, and a qPCR platform to gauge KRAS mutations.
At the time, Pirker indicated that FISH testing was a challenge in lung cancer due to limited access to tissue samples. Furthermore, identifying predictive markers in NSCLC is further challenged by tumor heterogeneity.
However, as previously reported by PGx Reporter, none of Merck's biomarker evaluations in earlier investigations, including looking at the frequency of positive immunohistochemical staining cells, as well as KRAS and EGFR mutations, were predictive for treatment response (PGx Reporter 11/16/2011).
Separately, last year, Roche received a positive opinion from the EMA's Committee for Medicinal Products for Human Use to market Tarceva as a first-line treatment for NSCLC patients with EGFR mutations. The drug will be marketed with an EGFR mutation companion diagnostic that will run on Roche's Cobas 4800 System. Roche has said it is in discussions with US regulators about expanding Tarceva's use in the EGFR-mutated NSCLC population and is planning to file a marketing application with the FDA this year (PGx Reporter 7/27/2011).