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Amgen Lays Out Timeline for KRAS Mutation Studies to Dispel Perceptions of Unethical Rx Development

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By Turna Ray

This article was posted on Feb. 19.

Although Amgen researchers may have known that the company's colorectal cancer drug Vectibix would eventually have to be marketed with a response biomarker, the drug developer was uncertain about the impact of KRAS mutations on drug response until around the same time it received a negative decision from European regulators for the anti-EGFR monoclonal antibody, an Amgen official recently claimed.

When Vectibix received approval from the US Food and Drug Administration in 2006, "Amgen already knew the response rate was low," said Scott Patterson, Amgen's
executive director of medical sciences, at a meeting hosted by the Drug Information Agency in Bethesda, Md., this month. Amgen began collecting patient tissue samples from mid-2005 to early 2007, knowing it would "need those samples for a biomarker analysis.

"We weren't absolutely sure which biomarker it would be … There were many different hypotheses we were exploring," Patterson said.

Last year, at a conference hosted by the Partners HealthCare Center for Personalized Genetic Medicine, leading researchers and healthcare industry stakeholders questioned whether Amgen knew, well in advance of the negative regulatory decision by European regulators in May 2007, that patients with mutated KRAS genes would not respond to Vectibix. The fact that Amgen resubmitted its application so quickly to the European Medicines Agency with KRAS-related drug response data, about a month later, led some at the conference to assert that Amgen pursued the largest indication possible for Vectibix with US and European regulators knowing full well that a significant proportion of the colorectal cancer patients would not respond [see PGx Reporter 12-02-2009].

At the conference, some industry officials defended Amgen, from a business strategy perspective, for pursuing the broadest indication possible first, and then moving to KRAS mutation analysis, which would undoubtedly shrink the market size for the drug. Other officials from competing drug firms held that Amgen missed a critical market opportunity in delaying companion diagnostic development for Vectibix. If Amgen had tried to launch Vectibix with a companion test from the start, it would have differentiated the drug from ImClone/Bristol-Myers Squibb's Erbitux, which was leading the colorectal cancer testing market at the time.

Others suggested ethical wrongdoing on the part of Amgen. If the company pursued the broadest possible indication knowing that approximately 40 percent of the colorectal cancer population harboring KRAS mutations would not respond, then the company would be responsible for denying those unresponsive patients an alternative treatment which could have benefitted them, some pointed out.

At the DIA meeting, Patterson attempted to dispel the perception that Amgen behaved unethically in its development strategy for Vectibix. "Several issues clouded the picture of why, given that it was known for 20 years that KRAS was an oncogene, did we and others not immediately use KRAS as a negative selection biomarker," he said. According to Patterson, imperfect knowledge of human biology, evolving genetics research, and conflicting published literature on the role of KRAS mutations on anti-EGFR treatment response, restricted Amgen from moving more quickly toward identifying a validated response biomarker for the drug.

"There was a range of studies that indicated that the presence of mutant KRAS correlated with poor prognosis," Patterson said. "There were some studies that said that it wasn't a poor prognostic factor. But given these were single-arm studies, you can't discriminate between a negative selection predictive biomarker and one that is just a poor prognostic indicator."

Furthermore, there were xenograft models with KRAS mutations that were sensitive to anti-EGFR therapies. "So, one might imagine, 'Oops! We didn't quite understand human biology like we thought we did. Look what happened to the xenografts,'" Patterson said.

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There were also reports of patients with mutant KRAS tumors in single-arm studies who responded to anti-EGFR therapies, Patterson noted, which further confounded researchers' understanding of KRAS mutations and Vectibix response.

According to Patterson, the fact that the 2006 FDA label for Vectibix indicates that the drug is for colorectal cancer patients expressing EGFR shows that Amgen was working all along to pinpoint the right target in the EGFR pathway.

Although patients enrolled in the clinical studies that led to Vectibix's initial US approval were required to have immunohistochemical evidence of EGFR expression, "exploratory univariate analyses assessing the relationship between EGFR expression and progression-free survival did not suggest that the PFS benefit differed as a function of EGFR staining intensity or percentage of EGFR-expressing tumor cells," the 2006 label notes.

After collecting tissue samples for 18 months, from 2005 to 2007, Amgen "began exploratory sequence analysis looking at a range of somatic mutations in different genes," Patterson said.

Finally, in early 2007, Amgen began focusing on the link between KRAS mutations and Vectibix response in samples from a pivotal Phase III study used for the US approval of the drug. But right around the same time, the company was slapped with a not-approval determination for its European marketing application for Vectibix.

"We were about to embark on this testing, and we received that negative opinion at that time," Patterson maintained. "So we had an opportunity within a very limited window of time to complete this analysis."

Having resubmitted its marketing application within a month of EMEA's negative opinion, Amgen began a long march back to the US market, where the FDA in 2009 updated both Vectibix and Erbitux's label to recommend KRAS mutation testing ahead of drug administration.

At the American Society of Clinical Oncology's annual meeting in 2008, researchers reported results from a large, multinational prospective trial showing that patients with metastatic colorectal cancer whose tumor carries the wild-type version of the KRAS gene were much more likely than patients with the mutated form of the gene to benefit from Erbitux. The results from the study led Eric Van Cutsem, lead author and professor at the University Hospital Gasthuisberg in Leuven, Belgium, to recommend that “KRAS testing be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient" [see PGx Reporter 06-02-2008].

The presentation of this data resulted in similar recommendations in treatment guidelines issued by ASCO and the National Comprehensive Cancer Network.

The FDA's class labeling update for EGFR-inhibiting monoclonal antibodies for colorectal cancer treatment came one year after the EMEA recommended Erbitux and Vectibix be marketed in non-KRAS-mutated patients. The agency's action followed an advisory committee meeting that discussed the conditions under which the FDA should accept retrospective data on genetic subpopulations from drug developers ImClone and Amgen [see PGx Reporter 07-22-2009].

Ultimately, despite the ethical questions surrounding Amgen's development strategy, the company has been lauded for pursuing drug/diagnostic codevelopment strategy with DxS to develop a companion test kit for Vectibix. Furthermore, Vectibix has now secured a place in the sparsely populated pantheon of early personalized medicine success stories.

Private insurers are beginning to reimburse for the test. An advisory panel of the Centers for Medicare & Medicaid Services found KRAS testing clinically useful in Vectibix- and Erbitux-treated populations [see PGx Reporter 02-03-2010].

Amgen is continuing its clinical investigations into the link between KRAS mutations and Vectibix response.

The company in January presented results from two Phase III studies investigating the safety and efficacy of Vectibix in combination with chemotherapy in patients with non-mutated KRAS tumors in the first-line and second-line settings at ASCO's Gastrointestinal Cancers Symposium in Orlando, Fla. The results suggest that Vectibix in addition to chemotherapy improves the progression-free survival for patients with wild-type KRAS in the first-line setting, as well as PFS, overall survival, and response rate in this subset of patients as a second-line treatment [see PGx Reporter 01-27-2010].

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