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Imclone’s cancer drug Erbitux and the use of KRAS as a biomarker in lung cancer needs further validation, according to physicians interviewed by Pharmawire. Although promising, larger studies need to be conducted to refine the use of this biomarker as a way of selecting patients for treatment with this drug. As Erbitux has significant side-effects such as skin toxicities and rash, it is important to only use it in patients who will benefit from the drug’s use.
A challenge to clinicians seeking to treat lung cancer is the accurate measurement of epidermal growth factor receptor (EGFR) activity, which is known to play a role in cancer.
Erbitux, which binds to and inhibits EGFR is only beneficial in patients whose cancer is linked to an increase in this receptor. The importance of enrolling the appropriate patients is only recently being recognized as a significant factor in determining who is most likely to benefit from a treatment. If patients are being enrolled in programs that do not target the appropriate receptors, thereby deceasing the likelihood of benefit, clinical trials will be less likely to produce results that demonstrate a drug’s advantages to the FDA, industry executives explained.
Initial trials with Erbitux only elected to recruit patients who expressed EGFR as detected by immunohistochemistry (IHC), a technique that measures the amount of a specific protein, under the assumption that patients with greater amounts of the protein would be the most likely to respond. ”But we barked up the wrong tree. The IHC tool that allowed us to identify the target was not really a good tool,” said Dr Eric Rowinsky, chief medical officer at Imclone. He added that in trials testing Erbitux in the metastatic colorectal cancer setting, the IHC technique proved insufficient in patient screening as well.
The FLEX trial is screening for patients that demonstrate IHC evidence of EGFR expression, said Dr Frederico Cappuzzo, a medical oncologist at the Istituto Clinico Humanitas IRCCS in Italy. He commented that the use of IHC to measure levels of EGFR, as in the FLEX trial, is too subjective and that the FISH analysis is more sensitive. FISH (fluorescent in situ hybridization) is a technique that measures gene amplification or copy number. ”Patients that are EGFR positive by FISH analysis have been shown to have better progression-free survival.”
Dr Philip Bonomi, an oncologist at Rush University Medical Center added ”there is relatively little info about EGFR mutations and efficacy of Erbitux, but the evidence which is available suggests that EGFR mutations do not have predictive value.”
Mutations within EGFR have been correlated with differential response rates to kinase inhibitors such as AstraZeneca’s Iressa and Genentech and OSI Pharmaceutical’s Tarceva, but there is no role for EGFR mutations in the efficacy of Erbitux in lung cancer, said Cappuzzo.
EGFR mutations are predominately found in patients who are non-smokers, and the majority of tumors in lung cancer patients are smoking related, Rowinsky explained.
In response to whether Imclone screened out smokers in the FLEX trial, Rowinsky said initially that most patients in the FLEX trial are non-smokers. However, he later emphasized via e-mail that “the FLEX trial was not limited to non-smokers, did not screen out smokers, and that most of the patients in the trial are not non-smokers.”
It was only a recent finding that non-smokers have a higher likelihood of response to EGFR drugs, he said in the interview, and although there will be study data at the upcoming American Society of Clinical Oncology (ASCO), the company’s major pivotal study, the FLEX trial, was formulated prior to our understanding of Erbitux’s effect on the smoker/non smoker status, he said.
Bonomi raised the point that Erbitux is less effective in colorectal cancer patients with KRAS mutations. KRAS, which is turned on by EGFR, is involved in cell growth. In cancerous cells, mutated KRAS is stuck in the “on” position, which means it no longer communicates with EGFR, thereby rendering Erbitux ineffective.
Rowinsky said 15-25% of lung cancer patients have the KRAS mutation. “If you can take those patients out of your trials...you’d avoid treating people who don’t respond,” said Rowinsky. Imclone is currently aiming to do that in metastatic colorectal cancer (mCRC), but it is too early to do in lung cancer. “We would presume it would likely be similar,” Rowinsky added.
Since KRAS as a biomarker in lung cancer is yet to be fully accepted by the scientific community, the FLEX trial is designed to select patients based upon EGFR status but not KRAS status. Physicians are not currently using the KRAS biomarker in lung cancer, and when asked why, Rowinsky said it is because there is no data with KRAS in lung cancer. ”This data does not exist so far for lung cancer,” said Rowlinsky, but the company will be presenting data on the KRAS mutation in first-line mCRC patients at the company’s June 1 Plenary Session at ASCO.
Up until now, the EGFR assays have been insensitive, said Dr Gordon Parry, VP clinical research & development oncology at Monogram Biosciences. Sub-classification of patients would be helpful, and the key is matching the drug with the target to find the activation state and levels of drug response. ”Personalized medicine will be very important in terms of cost-benefit to patients,” he added.
There are 2/10 patients in lung cancer who will have a very good response. The challenge now remains in identifying those patients. ”We have done that with metastatic colorectal cancer, and we now aim to do the same in lung cancer,” said Rowinsky.
A competing drug, Genentech’s Avastin, seems to work effectively regardless of KRAS mutations. A spokesperson for Genentech said data has been published which suggests Avastin is effective regardless of mutations in the KRAS gene and that the survival benefit of Avastin plus chemotherapy for mCRC is not associated with mutations in genes, such as KRAS, p53 and b-raf.
Imclone on the other hand, is conducting studies to see if overall studies determine if KRAS and other biomarkers truly do predict as well in lung cancer as they do in colon cancer. The company will look at the biological samples from the studies, and conduct the same extrapolations similar to the work done in mCRC.
”Those studies are still in progress, with data hopefully very soon,” he said. But another hurdle may be that the sample collection with lung cancer patients will be a lot harder than from colorectal cancer patients, some physicians believed.
The company has come a long way in learning which patients are likely to better respond to this therapy. “This has great ramifications, as we could avoid treating certain patients and avoid needless toxicities,” Rowinsky said.
Physicians believe KRAS is a highly promising biomarker if it can be validated in larger studies. “If physicians can start treating patients who will respond earlier on, this can really channel a greater benefit. That is the spirit of personalized medicine, but the challenge now remains in identifying those specific patients,” concluded Rowinsky.
Imclone has a current market cap of USD 3.72bn.
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