CHICAGO - With positive results of the Phase III FLEX study in hand - showing an overall survival benefit for Erbitux in first-line non-small cell lung cancer - Bristol-Myers Squibb and partner ImClone are discussing with FDA their plans to use the data as the basis of a supplemental BLA filing, Bristol told "The Pink Sheet" DAILY.

The Merck KGaA-sponsored First-line in Lung cancer with ErbituX trial, which added Erbitux (cetuximab) to standard platinum-based chemotherapy, is scheduled for June 1 as a late-breaking, plenary presentation at the American Society of Clinical Oncology annual meeting in Chicago. Merck is Bristol/ImClone's international partner on the drug.

According to ImClone Exec VP Eric Rowinsky, the firms' intention is to submit an sBLA for the epidermal growth factor receptor inhibitor in first-line NSCLC later this year.

More than 1,000 patients with stage IIIB or IV NSCLC were randomized in the FLEX study to receive Erbitux plus platinum-based chemotherapy or chemotherapy alone. Median overall survival was prolonged for those in the combination arm by 1.2 months compared with those receiving chemotherapy alone (11.3 months versus 10.1 months).

The sponsors herald FLEX as a significant advancement and the first time an anti-EGFR targeted therapy improved survival with initial treatment of NSCLC. But the positive results stand in stark contrast to findings of an earlier Bristol-sponsored trial in first-line NSCLC.

In Bristol's BMS-99 study in first-line advanced metastatic NSCLC, released in July 2007, cetuximab missed the endpoint of improvement in progression-free survival (¹ Also see "Erbitux Misses Primary Endpoint As First-Line Treatment In Phase III NSCLC Trial" - Pink Sheet, 12 July, 2007.). Cetuximab was studied in combination with carboplatin and a taxane versus a taxane/carboplatin combination in more than 600 patients. Data on overall survival from the BMS-99 trial are still pending, Bristol told said in an interview.

Progression-free survival was a secondary endpoint in FLEX. The PFS findings were presented at a June 1 plenary session, but Bristol said they do not show a statistically significant difference at this time.

Bristol maintains that although the two studies are in the same setting, the patient populations and eligibility criteria are different, and that because one was designed for PFS and one for OS, they cannot be compared.

Still, going from a study that failed to demonstrate an improvement in PFS to a study showing an improvement in overall survival is quite a coup for a drug developer.

Beyond the 1.2 month improvement in overall survival in the total population, subgroup analysis of FLEX indicates slightly greater efficacy in different patient populations and, importantly, across all histological subtypes.

"Preliminary results of a prespecified subgroup analysis suggest a greater benefit in Caucasian patients independent of histology and a general better prognosis in Asians," the abstract adds. Caucasian patients, who represented 84 percent of the trial population, experienced a significant increase of 1.4 months in overall survival. Those with adenocarcinoma who received Erbitux had an overall survival of 1.8 months, Merck noted.

The FLEX trial included patients with all histological subtypes, including adenocarcinoma and squamous cell carcinoma, as well as ECOG-2 patients who have a much worse prognosis than patients with a better performance status.

"Since 94 percent of patients in the Erbitux plus chemotherapy arm had stage IV mestastatic NSCLC and 17 percent had performance status 2, these data are not only robust, but also very meaningful for the everyday clinical reality in the treatment of first-line NSCLC," Merck Exec VP Wolfgang Wein said in a prepared statement.

Erbitux was well-tolerated in the trial with "managed and expected" side effects.

Erbitux is approved for treatment of metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens, and as a single agent for mCRC in patients intolerant to irinotecan. North American net sales rose 17 percent to $187.5 million in the first quarter on positive clinical data and increased promotional efforts with co-marketer Bristol, ImClone reported April 24 (² Also see "North American Erbitux Sales Up 17 Percent In First Quarter" - Pink Sheet, 24 April, 2008.).

FLEX is not Erbitux's only appearance in the plenary session at ASCO: also expected is a presentation of data on KRAS mutation status and efficacy from the Phase III CRYSTAL trial in first-line treatment of CRC with FOLFIRI.

-Lauren Smith (lauren.smith@elsevier.com)

FLEX Shows Erbitux’s Strength With Survival Benefit In NSCLC

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