This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
--------------------------------------------------------------------------------------------------------
Imclone’s Erbitux should not be used in Avastin-eligible patients in non-small cell lung cancer yet, Dr Thomas Lynch, associate professor of Medicine at Harvard Medical School, told Pharmawire. The drug should not be used as a single-agent, and should only be used in squamous-cell patients, he added. Squamous cell patients, a subset of lung cancer patients who are particularly difficult to treat because the tumor is located deep within the lungs are not treated with Avastin.
Erbitux, a monoclonal antibody, binds to and inhibits the EGFR (epidermal growth factor receptor), which can be responsible for uncontrolled cell growth in cancer. In order to select patients for treatment with Erbitux, it is necessary to ensure that an increase in EGFR is responsible for the cancer. FISH (Fluorescent in situ hybridization), is a technique that can be used to evaluate the number of copies of EGFR present in a patient, which if higher then normal, suggests that treatment with Erbitux would be effective.
KRAS is a gene that plays an important role in cell growth. KRAS, which is “turned on” by EGFR in a healthy patient, can be mutated and constantly active in some cancer patients, and acts to make cells grow even in the absence of signal from EGFR, rendering Erbitux ineffective. Therefore, it is also important to know if patients have a mutated form of KRAS before treatment with Erbitux is initiated.
In a discussion over the eagerly awaited FLEX trial results, Lynch, who provided a discussion on the results at the company’s Plenary presentation at the American Society of Clinical Oncology meeting in Chicago, said patients will need to be screened on a molecular basis through the use of biomarkers such as EGFR and KRAS in order to increase the median survival benefit to 2.5 months, instead of the current 1.2 median overall survival that was reported in the trial.
In colorectal cancer, patients that have the KRAS mutation do not respond to Erbitux. ”That may be the same case with lung cancer, which has a very high rate of KRAS mutation,” said Huang. The number of patients with mutated KRAS in lung cancer is roughly 10-20%, which is somewhat less than the number reported in colorectal cancer - which is 35-40%.
Dr Karen Reckamp, an assistant professor of medicine at City of Hope Cancer Center in Duarte, California, said Erbitux’s pricing is definitely a concern for physicians, and the key will be to find out which patients respond better.
Lynch estimated that a conservative estimate of the drug’s cost to patients would be USD 54,000. In order to make Erbitux more cost-effective to patients, the KRAS biomarker may play a role in the drug’s use in lung cancer. The drug was recently approved in Europe for use only in patients with wild-type KRAS in first-line metastatic colorectal cancer.
More data has to be conducted to select patients who will show a better response. However, this can only be done with adequate tissue samples from patients, to test for the KRAS association.
Over 500 lung cancer patient tissue samples have been collected from the FLEX trial, for a retrospective molecular analysis according to Dr Robert Pirker, lead investigator and professor of Clinical Oncology at the University of Vienna, Austria. The optimal trial to conduct in the future will be focused on predictive biomarkers, such as KRAS, to further patient selection, he added.
However, Pirker said it will be ”very difficult” to collect tissue samples. ”Sometimes you can’t ask patients anymore [for samples.] There are 166 centers, and it is very complicated.”
Physicians interviewed on-site at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) also agreed that sample collection may be harder to collect in lung cancer as compared to colorectal cancer, for which Erbitux is approved.
Approximately 50% of patients have advanced disease and cannot undergo surgery. Samples are easier to collect in patients with early stage disease, who get surgery but much harder in the metastatic setting, due to risks with biopsy.
Dr Chao Huang, a lung cancer specialist and professor at the University of Kansas Medical Center, said in early stage patients there is no problem with getting tissue since patients would have gotten surgery. ”Unfortunately, the majority of the patients, around 50-60% cannot get surgery.”
On the question of Erbitux versus Avastin in lung cancer, Pirker said the major difference is the different patient population in the FLEX trial. ”We also included centrally located tumours, and a much broader patient population.” The FLEX trial aimed to treat a representative lung cancer population, and therefore did not screen patients on histology, or location of the tumor origination. In trials for Avastin, Genentech elected to omit squamous-cell patients from trials, due to the fact that they are notoriously difficult to treat. He also added that there may be a combination of both Erbitux and Avastin in the future. ”FLEX is an important step forward.”
EGFR receptor expression was used in patient selection. ”At the time, I was arguing against using this in [patient] selection,” said Pirker. 85% of patients were positive for EGFR expression, and there is still discussion on what is the optimal EGFR receptor, he added.
The company prespecified subgroup analysis based on race and histology. ”We did not prespecify other subgroup analysis. We prespecified histology and ethnicity.” The trial showed an overall survival benefit for the total patient population. The subgroup populations are just more exploratory. The post-hoc subgroup analysis will be informative in guiding future trial design and possibly labeling by determining which patients should be excluded due to a lack of response.
Although the Asian patient population showed a worse response than Caucasians, there is no group which demonstrated a lower survival, and no statements can be made about certain subgroups.
When asked why Asians appeared to do worse on Erbitux and whether the results really make a strong care of increased use of Erbitux in some subsets, such as in Caucasians (although the FLEX trial showed a three month detriment in the Asian subgroup) Pirker said, ”there is no proof that Erbitux does not work in the Asian population.”
The trial was not powered to show differences in subgroups. The main difference bewteen Erbitux and Avastin is the FLEX trial recruited a much broader patient population compared to the patient population in the Avastin trial. There are also side-effects such as the problem of serious bleeding, compared to erbitux’s side-effect of rash which is manageable, he added.
”The rash was not a major problem at this trial,” said Pirker. Data from the company’s LUCUS trial suggested that there was a correlation between patient response and rash. Pirker said more research will be done to see which the rash is a prognostic biomarker for response.
The drug’s biggest hurdle seems to be pricing, and cost-effectiveness. However, Pirker believed that Erbitux should not see resistance in terms of reimbursement as the drug clearly shows an advantage.
Imclone has a current market cap of USD 3.77bn
--------------------------------------------------------------------------------------------------------
For more information or to inquire about a trial please email sales@pharmawire.com or call Americas: +1 212-500-1384 or Europe: + 44 (0)20 7059 6251
