The headline and this story have been updated to reflect that BMS and Lilly have submitted to the FDA retrospective analysis on Erbitux's efficacy in colorectal cancer patients with wild-type KRAS mutations, which the agency may use to update the drug label.
By Turna Ray
Seeking to establish the safety and efficacy of their colorectal cancer treatments Erbitux and Vectibix in patients with wild-type KRAS genes, sponsors Bristol-Myers Squibb and Amgen are hoping to convince the US Food and Drug Administration to update the drugs' labels to state that this patient subset derives more benefit from treatment with these drugs than from the standard of care.
Such a labeling change, emphasizing the subset of patients who would benefit, would be a departure from the current labels, which state that these drugs should not be used in patients with KRAS mutations.
At a presentation last week hosted by the New York Pharma Forum on the use of genomics data in drug development, Steven Averbuch, head of pharmacodiagnostics at BMS, suggested that the company is seeking a labeling change from the FDA to Erbitux's label that discusses the drug's efficacy in colorectal cancer patients with KRAS wild-type tumors.
In this regard, a BMS spokesperson told PGx Reporter that the company and its Erbitux marketing partner Lilly earlier this year submitted to the agency new retrospective survival analysis from the CRYSTAL trial, which randomized colorectal cancer patients to receive either Erbitux plus FOLFIRI chemotherapy in the first-line setting or just FOLFIRI. In that study, researchers led by Eric Van Cutsem of the University Hospital Gasthuisberg found that KRAS wild-type patients receiving Erbitux plus FOLFIRI had median overall survival of 23.5 months compared to 20 months when patients were given just chemotherapy. Patients with KRAS mutations did not see benefit from the Erbitux/chemo regimen in this study.
The agency has said it prefers sponsors conduct prospective clinical trials when establishing the efficacy and safety of a drug that requires the aid of a companion diagnostic to discern best responders. However, the FDA has also indicated that it will accept retrospective analysis in certain circumstances, such as when new pharmacogenomic data for a drug emerges in the post-market setting, as was the case with Erbitux and Vectibix. Qiagen, the developer of the KRAS companion diagnostic for the two drugs, has submitted prospective data to the FDA on the test.
Amgen, on the other hand, has said it is in the process of conducting a prospective study to try to prove that Vectibix-treated chemorefractory patients whose tumors express the wild-type KRAS gene survive longer than patients receiving just chemotherapy (PGx Reporter 2/9/2011). This study is necessary to confirm Vectibix's clinical benefit in metastatic colorectal cancer patients and to translate the FDA's 2006 accelerated approval for the drug to full regulatory approval.
Positive data from this trial could similarly result in FDA updating the label for Vectibix to inform doctors and patients of the drug's effect on KRAS wild-type tumors. Amgen did not respond to PGx Reporter's questions about the details and status of this trial ahead of press time.
If these studies are positive and result in a labeling change in which FDA states that patients with normal KRAS genes derive greater benefit from Erbitux and Vectibix compared to chemotherapy, it would provide more guidance for physicians prescribing these treatments.
Such labeling language could also increase the revenue potential for these drugs. Industry observers view the current labeling language, which emphasizes non-responders, as revenue limiting, whereas a focus on best responders in the label might give sponsors cause to increase the price of their drugs.
"At present, the extent of scientific knowledge related to the average safety and efficacy of potential drugs is typically much greater than knowledge on the underlying structure of drug responses in patient subpopulations, and on the existence of predictive biomarkers to identify the most appropriate patient subpopulations for treatment," wrote Mark Trusheim of the Massachusetts Institute of Technology and colleagues in Nature Reviews this month. "An economic knowledge gap also exists."
The study authors noted the post-marketing labeling update for Vectibix and Erbitux regarding the effect of the drugs in KRAS-mutated colorectal cancer tumors as an example of how the biological knowledge gap can become an economic disadvantage for pharma. "The post-approval application of companion diagnostics such as the KRAS mutation test, which predicted a lack of response to [Vectibix] and [Erbitux], may have reduced commercial revenues as the prices paid for the drugs have not increased commensurately with the improved efficacy rates in the selected subpopulation," Trusheim et al. wrote.
In 2009, the FDA issued a class labeling change for Erbitux (BMS/ImClone) and Vectibix (Amgen) to note that "retrospective analyses of metastatic colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13." In the labels for the two drugs, the agency states that colorectal cancer patients with these mutations should not receive these treatments.
In order to make the labeling change, the agency reviewed retrospective data from seven clinical trials, two involving Vectibix and five with Erbitux. The FDA decision followed an advisory committee meeting that discussed the conditions under which the FDA should accept retrospective data on genetic subpopulations from drug developers BMS and Amgen (PGx Reporter 7/22/2009).
Recently published studies indicate that the biology underlying which patients will and will not respond to these drugs involves far more than just KRAS mutation status. As such, it appears that the current labeling language for Vectibix and Erbitux doesn't contain enough information to reflect that complexity.
For example, it has been shown that KRAS mutations beyond those included in the current labeling play a role in colorectal cancer. Studies suggest that approximately 40 percent of colorectal cancer patients harbor a mutation in the KRAS gene, with 90 percent of these mutations occurring in codons 12 and 13 in exon 2 of the gene. Around 5 percent of KRAS mutations occur in codon 61, however, and a similar percentage of mutations show up in codon 146.
Furthermore, anecdotal reports and studies have suggested that a small number of colorectal cancer patients harboring different types of KRAS mutations may actually derive benefit from Erbitux.
In a paper published last year in the Journal of the American Medical Association, researchers led by Wendy De Roock from the University of Leuven in Belgium conducted a retrospective analysis of patient outcomes in seven trials. De Roock et al. concluded that chemotherapy-refractory colorectal cancer patients with p.G13D-mutated tumors experienced longer overall and progression-free survival than patients with other KRAS-mutated tumors. Based on these findings, they recommended prospective validation of Erbitux's effect in patients with specific KRAS mutations.
Similarly, it has been shown that not all KRAS wild-type patients respond to Vetibix and Erbitux. Prior research suggests that as many as 40 percent of wild-type KRAS patients may not respond to anti-EGFR monoclonal antibodies, and, as such, other mutations need to be assessed in order to predict treatment response in this patient subset.
For example, a clinical trial by De Roock and colleagues published in Lancet Oncology last year showed that colorectal cancer patients with wild-type KRAS who had BRAF and NRAS mutations had a "significantly lower" response rate compared to those with wild-type KRAS and BRAF and NRAS wild types. In that study, around 8 percent of KRAS wild-type patients with BRAF mutations responded to Erbitux versus 38 percent of KRAS wild-type, BRAF wild-type patients. Similarly, nearly 8 percent of KRAS wild-type patients with NRAS mutations responded to Erbitux, compared to 38 percent of KRAS wild-type, NRAS wild-type patients.
Data from the CRYSTAL study involving Erbitux also found that patients whose tumors were wild-type for both KRAS and BRAF had better progression-free survival when treated with Erbitux/FOLFIRI compared to just FOLFIRI. Meanwhile, in the wild-type KRAS colorectal cancer population, BRAF V600E mutations are "an indication of poor prognosis," the study authors wrote.
In light of the growing body of knowledge on the influence of additional response markers on anti-EGFR monoclonal antibodies, there is already some suggestion that health regulators may want sponsors to look beyond KRAS when it comes to identifying best responders.
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At a meeting of FDA's Oncology Drugs Advisory Committee earlier this year to discuss the accelerated approval commitments of several oncology drugs, including Vectibix, panelists doubted that Amgen would be able to prove that KRAS wild-type patients lived longer when treated with Vectibix compared to chemotherapy in a new prospective study when past trials suggest limited survival benefit in this population.
Two Phase III trials – study 2005181 comparing Vectibix and FOLFIRI versus FOLFIRI alone in the second-line setting and study 20050203 looking at Vectibix and FOLFOX compared to FOLFOX alone in the first-line setting – showed that KRAS wild-type patients experienced longer periods without cancer progression after treatment with Vectibix compared to chemotherapy treatment. However, neither study showed that KRAS wild-type patients lived significantly longer when treated with Vectibix compared to those treated with chemotherapy. In study '203, KRAS wild-type patients receiving Vectibix in the first-line setting lived four months longer than those in the chemo arm; in the second-line '181 trial, patients on the Vectibix arm survived about two months longer than those receiving just FOLFIRI.
Although at the ODAC meeting some committee members, as well as Richard Pazdur, director of FDA's Office of Oncology Drug Products, expressed concern that Amgen had already received too many chances to prove that Vectibix treatment had some meaningful improvement in patient outcomes compared to standard treatments, the sponsor remains confident that a prospective study in wild-type KRAS patients will show the drug benefits this population. In the original trial that led to accelerated approval of Vectibix, patients in the chemotherapy arm whose cancer progressed were allowed to cross over into the Vectibix/chemotherapy combination arm — a fact that may have skewed the results, according to the firm.
Simultaneously, sponsors are also looking into biomarkers beyond KRAS that may influence patients' response to these drugs. Last year, Merck KGaA, Northern Ireland-based Almac Diagnostics, and the UK-based Medical Research Council announced they would analyze samples from the MRC COIN trial to "identify whether biomarkers apart from KRAS status alone further define which patients may benefit most from the addition of [Erbitux] to chemotherapy." Lilly has partnered with Merck KGaA in Europe to market Erbitux.
Similarly, in 2009 Amgen presented data from a study in which researchers from the company and elsewhere sequenced archival patient tumor samples from 288 patients for mutations in nine genes in the EGFR pathway: AKT1, BRAF, CTNNB1, EGFR, KRAS (exon 3), NRAS, PIK3CA, PTEN, and TP53. These samples had previously been analyzed for KRAS exon 2 mutations using allele-specific PCR developed by Qiagen subsidiary DxS. The study found that patients with NRAS mutations had limited response to Vectibix (PGx Reporter 7/29/2009).
These new findings pose regulatory and economic challenges for drug developers, however, if they have to run the validation studies necessary to add these mutations to an FDA-approved companion test.
Although the current labeling of Vectibix and Erbitux recommends genetic testing to discern patients' mutation status, no FDA-approved KRAS companion test yet exists for these treatments. Qiagen's KRAS mutation test, the companion diagnostic used by BMS and Amgen to analyze the mutation status of colorectal cancer patients in clinical trials for Erbitux and Vectibix, is still being reviewed by the agency for marketing approval.
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