Originally published June 6.
By Turna Ray
CHICAGO — Roche subsidiary Genentech is in discussions with the US Food and Drug Administration about launching the non-small cell lung cancer drug Tarceva as a first-line treatment for patients with EGFR-mutated tumors. If Tarceva is launched in this indication, it will serve as an example of the use of a pharmacogenomics strategy to successfully grow a drug's market size.
Data presented at the American Society of Clinical Oncology's annual meeting here this week showed that NSCLC patients with EGFR mutations who received Tarceva lived twice as long without disease progression compared to patients who received platinum-based chemotherapy, which is currently the standard of care for first-line NSCLC therapy.
"Roche has applied to the European Medicines Agency to extend the current EU label for Tarceva to include first-line use in people with advanced EGFR-activating mutation-positive NSCLC," Genentech said in a statement. "Discussions are ongoing with the FDA regarding a submission that will include the use of a companion diagnostic test to help identify patients with activating EGFR mutations who are appropriate candidates for Tarceva."
Tarceva, marketed by Genentech and Astellas, is approved in the US as a maintenance treatment for patients with advanced-stage NSCLC that has not advanced after initial treatment with certain chemotherapy agents. The drug is also indicated in the second- and third-line setting to treat advanced NSCLC that has spread after receiving one chemotherapy regimen.
If Genentech receives approval for Tarceva in the first-line setting, it could substantially expand the market for the drug, since its other indications in chemo-experienced, later-stage NSCLC would remain — a scenario that bucks conventional wisdom that PGx strategies can only shrink the market size for a drug.
Based on the data presented at ASCO, "we plan to submit an application [to FDA] for a label extension to include first-line use in people with EGFR activating mutation-positive advanced NSCLC in 2011," a Genentech spokesperson told PGx Reporter.
Genentech doesn't break sales down by indication, but the spokesperson said that Tarceva sales in 2010 were 1.3 billion Swiss Francs ($1.6 billion), including the drug's indications in lung and pancreatic cancer. It is estimated that between 10 percent and 30 percent of people with advanced NSCLC are EGFR-activating mutation-positive; however the size of the subset differs in Asian and Caucasian populations.
EURTAC
Rafael Rosel of the Spanish Lung Cancer Group at the Catalan Institute of Oncology in Barcelona, Spain, presented data at ASCO on the European Randomized Trial of Tarceva vs. Chemotherapy, or EURTAC.
The multi-center, prospective Phase III trial screened 1,275 Caucasian NSCLC patients for EGFR mutations from February 2007 to January 2011 and then randomized 174 patients to receive either Tarceva or platinum-based chemotherapy. The researchers used Sanger sequencing followed by Applied Biosystems' TaqMan assay and GeneScan analysis software to identify patients' EGFR mutations.
In the trial, Tarceva nearly doubled median progression-free survival compared to chemotherapy — 9.7 months compared to 5.2 months. Patients in the Tarceva arm also had a 63 percent reduced risk of their cancer progressing compared to those in the chemotherapy arm. The study was stopped early after it met its primary endpoint.
The most common adverse events patients experienced with Tarceva were rash, diarrhea, and elevations in liver enzymes. Serious Grade 3 or 4 adverse events that occurred more often in Tarceva-treated patients than in chemotherapy-treated patients included rash, diarrhea, and alanine transaminase elevation. One patient receiving Tarceva died during the trial.
"The EURTAC study met its primary endpoint at the interim analysis," Rosel et al. concluded in the abstract of their presentation. "Erlotinib as first-line treatment for advanced NSCLC patients with EGFR mutations improves [progression-free survival], with acceptable toxicity, compared to platinum-based chemotherapy."
Registration Trial
According to an independent researcher who reviewed the EURTAC trial at ASCO, there is a good chance that the findings from the study — along with similar findings from another Phase III study in Asian patients with NSCLC, called OPTIMAL — will be sufficient to seek FDA approval for Tarceva as a treatment for EGFR-mutated first-line lung cancer treatment.
Tony Mok of the Chinese University in Hong Kong said in his presentation at the meeting that EURTAC's study design — namely, the fact that it was a large, randomized study that established the gene mutations of patients by both sequencing and genotyping in order to conduct prospective analysis via a quick test turnaround — was a positive from a regulatory standpoint.
Although the agency has accepted retrospective analysis to update drug labeling with PGx information, as in the case of colorectal cancer drugs Vectibix and Erbitux, the FDA prefers prospective collection and analysis of PGx data in randomized drug trials.
Mok also noted as a good sign the fact that progression-free survival seen in EGFR-mutated NSCLC patients in the EURTAC trial was similar to the pivotal IPASS study, through which AstraZeneca successfully launched Iressa in EGFR-mutated NSCLC patients in European markets. In the IPASS study, AstraZeneca reported an average progression-free survival in EGFR-mutated lung cancer patients of 9.5 months, whereas the PFS for a similar patient population in EURTAC was 9.7 months.
With this data, "there is a good chance that this drug will be available for first-line usage" in the US and in Europe, Mok said.
The Genentech spokesperson said the company submitted an application to the EMA last year to extend the label for Tarceva to include first-line use in people with advanced NSCLC with EGFR-activating mutations. The submission was based on published Phase III data from the OPTIMAL study.
Mok noted, however, that many EGFR inhibitors are being studied in EGFR-mutated NSCLC, so companies will likely need to figure out how these drugs provide differential benefits to patients in order to distinguish them in the marketplace.
An example of another new NSCLC PGx drug being developed in patients with EGFR mutations is Boehringer Ingelheim's afatinib, or BIBW2992.
At ASCO this week, Boehringer presented data from a Phase Ib trial combining the investigational drug with Erbitux in 22 NSCLC patients with EGFR mutations who have developed resistance to a reversible tyrosine kinase inhibitor. In that study, researchers observed a tumor size reduction of up to 76 percent over a treatment period of up to five months.
Pfizer is also developing an EGFR inhibitor for NSCLC. The compound, PF-00299804, is intended for patients with advanced NSCLC with wild-type KRAS who have failed at least one prior chemotherapy regimen and prior treatment with erlotinib.
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