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Imclone’s Erbitux BMS-099 trial was not powered to show overall survival and expectations for conclusive data remain low, Dr Eric Rowinsky, executive vice president and chief medical officer told Pharmawire.

Erbitux is a monoclonal antibody currently approved to treat head and neck cancer and colon cancer. It is also being tested for use in non-small cell lung cancer (NSCLC), with key trial results expected at the upcoming American Society of Clinical Oncology conference in Chicago. The drug is co-marketed in the U.S. with Bristol-Myers Squibb and Germany’s Merck KgaA.

Although the company will have OS data for the BMS-099 trial in 2H08, ”expectations are low because it really takes a lot of patients to show statistical power.” The trial recruited 660 patients, and previously failed to meet its endpoint of progression free survival (PFS), Rowinsky added.

Furthermore, the FDA does not consider PFS as endpoint in lung cancer trials, and an improvement in PFS will not likely garner approval, he added. The only trial powered for OS is the FLEX trial, but Imclone will include the BMS-099 trial as part of its submission to the FDA.

The FLEX trial is Imclone’s pivotal trial, which measures OS. ”Nothing is short of survival in lung cancer...to be beneficial for patients,” said Rowinsky.

Although the FDA approved Avastin for breast cancer based on a benefit in PFS, a competing industry executive said OS remains the only logical endpoint for approval in lung cancer, given the cost implications of this drug.

Although Genentech’s Avastin has seen bleeding risk in squamous cell patients, Rowinsky said Imclone is not just going after squamous cell patients, but all patients in non-small cell lung cancer (NSCLC). When asked whether a 4-week survival benefit would be enough, physicians interviewed by this news service were disappointed with Erbitux’s modest 6-week survival benefit in metastatic colorectal cancer (mCRC), Rowinsky said ”you’ve got to start somewhere. We don’t have too many drugs right now for lung cancer.”

”If you accept a drug with one-month survival, if the company can do further work and find a KRAS mutation influence, they can make further progress in being able to channel that drug to patients who will better respond,” Rowinsky said.

The competing industry executive said the FDA will consider two things for approval - the overall survival data and the toxicity profile. If the data is very compelling, the agency might not refer Imclone’s submission to the ODAC. He noted that if the data is ambiguous and if the other trials, apart from FLEX, are negative or neutral, the FDA will likely refer it to the ODAC - where a negative trial has more weight.

Similar to the Avastin’s recent approval in breast cancer, even though it was voted down 5-4 by the FDA advisory committee, it was approved. He speculated that the approval was based on subsequent data by Roche which was not disclosed publicly. ”We don’t know the arrows in BMS and Imclone’s quivers. We need to look at the FLEX study. ”It’s a reference trial, and if the data is 4-weeks or higher, it will be blockbuster territory for this drug,” the competing executive said.

However, the only hindrance may be the drug’s toxicity profile, which will be known at the company’s June 1 Plenary Session at the American Society of Clinical Oncology (ASCO). The agency will also consider ”morbidity management,” and not just the overall survival benefit in weeks. There can be several trials that disagree based on the differences in patient selection, the industry executive added.

There is also a subtle difference between the FDA acceptance for an NDA versus sNDA, he said. In a worse case scenario that it is not approved, physicians may opt to use the drug off-label in lung cancer, as it is already on the market for metastatic colorectal cancer (mCRC), the industry executive noted. The FDA may give Erbitux a first-line registration or line extension, based on the data.

If there is a high profile side-effect for Erbitux, that is similar to Avastin’s bleeding risk in squamous patients, this will result in a morbidity problem with added costs for Imclone, the industry executive said. Genentech’s Tarceva, currently approved in second and third-line NSCLC, has seen flat sales due to a side-effect of rash - which is seen in 30% of patients. However, the rash has been taken as an indicator of the drug’s efficacy, and more rash means more binding of the EGFR kinase, he said. All EGFR drugs cause some degree of rash, and Erbitux - being a monoclonal antibody and not a small molecule like Tarceva - may cause even more rash, he noted.

”Erbitux is not without problems. Rash is a big issue for the patients, if it’s second degree or higher,” the competing industry executive said. Dual-inhibition of pathways may also be another problem, as Amgen’s EGFR-inhibitor Vectibix and VEGF-drug Avastin led to faster cancer progression in metastatic colorectal cancer. He added that Vectibix is an inferior product to Erbitux, as the reason relates primarily to the drug’s binding and off-target activity.

It will come down to a function of strong marketing. ”The odds are although Avastin showed bleeding in squamous patients, it will still have the dominant position in lung cancer for awhile,” he said. There will be a steep road uphill for any compound that wants to break into frontline NSCLC. Erbitux will probably focus on squamous cell patients, the industry executive added.

When asked why Imclone did not decide to run a trial with one squamous arm, and one non-squamous arm to see what the exact differences are between these two groups, Rowinsky said it is a ”dangerous” suggestion. He disputed this idea and said Imclone is not looking to make a division between use in squamous and non-squamous patients. FLEX has a primary endpoint of OS for all patients with NSCLC.

There is an unmet medical need because of Avastin’s deficiency in squamous, but ”our trial is not focused on squamous and is powered for all patients,” said Rowinsky. But Imclone will be looking at squamous and non-squamous data histologically to determine in a prospective fashion what the effect is.

The number of squamous patients in the FLEX trial are around 20-30%. However, the trial is not powered for squamous cell patients, ”unless there is a major effect,” said Rowinsky. ”We will be presenting subtype information, but the trial and goals are really [to] get the drug approved.”

Imclone has a current market cap of USD 3.73bn.

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