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Eli Lilly’s (NYSE:LLY) cancer drug Erbitux (cetuximab) has demonstrated such a marginal clinical benefit in non-small cell lung cancer (NSCLC) that neither FDA rejection nor approval is likely to change current prescription habits in the US market, physicians told Pharmawire. Further patient stratification based upon genetic analysis is required to increase the survival benefit of the agent, they noted.
The European Union rejected the drug’s prospects to expand into lung cancer last month. Merck KGaA, which markets Erbitux in Europe, has stated that it plans to appeal the decision. The drug is also facing delays in the US, as partners Bristol-Myers Squibb (NYSE: BMY) and Eli Lilly (NYSE: LLY) withdrew their supplemental biologics license applications earlier this year, after FDA concerns with manufacturing and controls concerns, but they will eventually it.
Only the Phase III FLEX study showed a statistically significant benefit in overall survival (OS), whereas the BMS099 and LUCAS trials did not. Patients given chemotherapy plus Erbitux in the FLEX trial survived longer than those in the chemotherapy-alone group, with a median survival rate of 11.3 months vs 10.1 months. There was no statistical difference in progression-free survival (PFS).
Conclusive evidence has demonstrated that patients harboring an activating EGFR gene mutation have a better response to EGFR-tyrosine kinase inhibitors such as Genentech’s Tarceva and AstraZeneca’s Iressa.
Erbitux could be useful if a patient’s mutational status were known, said Dr Manlio Mencoboni, head of the medical oncology unit at Villa Scassi Hospital in Italy. Recently published studies have demonstrated that Erbitux can be a good agent for patients who are deemed responders based on the characteristic rash associated with Erbitux and other EGFR inhibitors.
Mencoboni said it is likely that the FDA will view the data submission package in the same light as the EMEA. Additional mutational status analysis is needed to be scientifically considered and this is an economic consideration too, he said. Appropriate selection of patients for Erbitux should increase the survival benefit. Knowing only the EGFR mutational status without further genetic determinants is not the best strategy, he said.
A spokesperson for Eli Lilly said she was not aware of any additional trials involving Erbitux in NSCLC, when asked whether the company will be conducting further trials for subgroup analysis based on EGFR expression. However, she noted that the company’s ownership of the drug is still fairly new.
Regulators, doctors take ‘hard look’ at data
The EMEA’s rejection of Erbitux was a surprise because the trial was positive from a regulatory point of view, as the FLEX trial met its primary endpoint, said Dr Federico Cappuzzo, a medical oncologist at the Istituto Clinico Humanitas IRCCS in Italy. There is a global strategy to restrict the use of an expensive drug unless there is a clear benefit and there is no evidence of such a benefit in any subgroup with Erbitux, he said. For the FDA, demonstrating a survival benefit is important and there is a benefit with Erbitux, he said. However, the benefit is so marginal that even if it is approved it will not have significant adoption.
Despite the EU rejection, Cappuzzo said that his treatment strategy will not change as he was never confident in the drug and will not miss its use.
”I am not surprised that the regulatory agencies are taking a hard look at the magnitude of the FLEX trial and the absence of a benefit in the BMS trial,” said Dr Nathan Pennell, an oncologist who specializes in the treatment of thoracic malignancies with a focus on lung cancer at the Taussig Cancer Center, Cleveland Clinic.
Until physicians have a consistent subgroup of patients who are clearly going to benefit from using Erbitux, this drug will face limited clinical uptake, Pennell said. ”Not many people are using Erbitux right now. It’s part of the NCCN [National Comprehensive Cancer Network] guidelines, so physicians can consider using it. But I haven’t used it myself.”
Dr Harry Raftopoulos, a lung cancer specialist at the Monter Cancer Center, North Shore-LIJ Health System, also voiced a similar opinion, and said even if Erbitux receives approval in lung cancer, he does not intend to use it.
”If approved, the main difference is that it allows for marketing. There will be some physicians who will prescribe it, but the benefits seem to be very low,” said Raftopoulos.
Dr Karen Reckamp, assistant professor in the Medical Oncology & Therapeutics Research unit at City of Hope in Duarte, California, said the drug’s initial perception by the medical community was not positive, so its recent rejection by the European regulatory agency does not change her views on this drug. ”The drug’s use never really increased. I think its use is still incredibly low,” she said.
”Nobody believes in that result for the FLEX trial,” said Dr Silvia Novello, an oncologist from the University of Torino.
She added that ”in our minds, there is no Erbitux for our patients.” The drug has to be combined with a chemotherapy backbone that is not the standard of care, and coupled with the drug’s toxicity profile, it is impossible for the drug to be used in a large group of patients, Novello said. She agreed that it will probably take the company a long time before resubmitting a new application in the US.
In addition to the problem of the chemotherapy combination, Novello noted that the percentage of patients on Erbitux in the FLEX trial who reported febrile neutropenia – or an abnormally low white blood cell count – is also a concern. ”You can’t do a first-line therapy that [has such a high rate of] febrile neutropenia, when 50% of patients will request and undergo a second-line therapy,” Novello said.
Additionally, it is not possible to administer cisplatin at the doses used in the FLEX trial, said Mencoboni. For most patients, there would be too many toxicities, he explained.
Vinorelbine plus cisplatin is not the standard of care in the EU nor in the US, Novello said, adding that the drug’s toxicity profile is important.
Asked whether treatment with Erbitux is worthwhile, in light of the mediocre one-month survival benefit, Dr Pasi Janne, assistant professor of medicine at Harvard Medical School, said unfortunately none of the current therapies cure lung cancer. Physicians just have to make sure that the chosen course of therapy is actually associated with a reasonable quality of life, he said.
If the toxicities are terrible, even though there is an incremental increase in life, these are questions that will have to be discussed with patients individually, Janne said.
Dr Chandra Belani, deputy director of the Penn State Hershey Cancer Institute and the lead investigator of Lilly’s Alimta maintenance study, said Erbitux also has issues with its pharmacological formulation. The FDA wanted to see if the drug manufactured in the US was comparable with the formulation used in the EU. The company will have to show the equivalent pharmacokinetics between the EU and US formulations.
”I think that the data is modest,” Belani said, adding that the drug would probably beneficial if clinicians can target a specific group of patients. Data presented at ASCO, for instance, suggested that KRAS mutations matter, he said.
Genetic mutations yield few clues
Neither EGFR nor KRAS mutations are a predictor to response to Erbitux. KRAS mutations are a lot less prevalent in lung cancer, so there is only a limited subset of patients to pull data from. ”This marker hasn’t been shown to be predictive,” said Reckamp.
Dr Chao Huang, an oncologist specializing in lung cancer and head and neck cancer at the University of Kansas Medical Center, said although the approximate one month median survival is not really exciting, the study requires a look into particular patient subsets.
There does not seem to be a correlation between KRAS mutation and response, Huang said. ”So that’s very different from the results seen in colorectal cancer [CRC]. In lung cancer, KRAS doesn’t seem to tell us which patients respond better,” he said.
KRAS is not panning out as a predictive marker for Erbitux like it is in CRC, and there is also limited data, agreed Dr Shirish Gadgeel, associate professor at the Karmanos Cancer Institute at Wayne State University.
Oncology groups such as the Southwest Oncology Group are now looking at EGFR expression and response to Erbitux. Its study looks at gene amplificiation with FISH to detect EGFR over-expression to see if patients respond better to Erbitux based on these markers.
For EGFR expression analysis, IHC and FISH are standard tests. The EGFR mutational analysis is a more specialized test. While any hospital should be able to perform those tests, EGFR testing is not routine. ”Those tests cost money, and sometimes insurance may not cover that,” Huang said.
The problem with tests is the availability of tissue. ”We usually just do a fine needle aspiration test to collect a tissue sample from the patient,” said Huang. Sometimes, there is not enough cells or tissue left to conduct a FISH or IHC test. Clinicians may not have enough tissue sample available to do additional testing to see if EGFR or RAS mutation is present before making treatment decisions. There is also the question of whether oncologists need to re-biopsy some patients.
In the future, more routine testing, such as FISH and EGFR expression, should be conducted, Huang said.
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