There has been quite a lot of discussion recently about the EGFR tyrosine kinase inhibitors (TKIs), erlotinib (Tarceva) and gefitinib (Iressa). Recently however the final results of the FLEX trial were published in The Lancet, bringing attention back to one of the antibodies against EGFR, cetuximab (Erbitux). Dr. West had previously written about the early presentation of results from this trial in a post after the ASCO meeting last year.
As a background, cetuximab is a monoclonal antibody that is given through the vein weekly. It has been shown to prolong life in combination with chemotherapy for patients with head and neck cancers, as well as for patients with colon cancers. The FLEX (First-Line ErbituX in lung cancer) study was a large randomized trial evaluating whether the combination of cetuximab with chemotherapy would prolong life for patients with NSCLC.
This study enrolled patients with NSCLC whose tumors showed staining by immunohistochemistry (IHC) for EGFR, even if it was only one tumor cell. Patients must have incurable NSCLC and could not have previously received chemotherapy. Of 1688 patients with tumors tested, 1442 demonstrated at least one cell positive for EGFR. 1125 patients were ultimately randomized to receive either six cycles of chemotherapy with cisplatin and vinorelbine (Navelbine) or the same chemotherapy with weekly Erbitux. Patients in the Erbitux arm who didn't show progression after six cycles then continued to receive it weekly until progressive disease or until they experienced toxicity requiring stopping the drug.
As would be expected, more patients receiving Erbitux experienced a significant rash than did patients receiving chemotherapy alone (10% vs <1%, respectively). Although diarrhea is not as common with EGFR antibodies as it is with the TKIs, still more patients receiving Erbitux experienced diarrhea (4% vs 2% without Erbitux).
Infusion-related allergic-type reactions are known to occur with antibody drugs, and in this study 3.5% of patients receiving cetuximab experienced an infusion reaction, compared with 1.2% of those receiving chemotherapy alone.
Importantly, 21.7% of patients receiving Erbitux with chemotherapy experienced a neutropenic fever, while only 15.5% did when receiving chemotherapy alone. These numbers are really higher than we'd expect to see for either standard chemo or chemo with Erbitux, and some have speculated that the definitions for neutropenic fever were possibly different than we'd use in other trials, or perhaps that more frequent clinic visits and lab checks led to more detection of this issue than we typically see.
The authors noted that measurements of quality of life did not differ between the two groups but acknowledged that the surveys used to measure this were only returned by a small number of patients overall, and that the data was ultimately difficult to interpret.
No difference was seen between the two groups in regards to progression-free survival, meaning the time it took for the cancer to start growing after starting chemotherapy. Some oncologists have questioned the trial because it's hard to explain why or how a treatment can improve overall survival without also improving progression-free survival.
Overall survival did improve with cetuximab added to cisplatin and vinorelbine. The average survival for patients receiving the three agents in combination was 11.3 months, compared to 10.1 months with chemotherapy alone. What does this mean? Patients receiving cetuximab with chemo lived 5 weeks longer than with chemo alone, on average. 47% of patients receiving cetuximab were alive at 1 year, while 42% of patients receiving chemo alone were alive at 1 year. It was noted that more patients on the chemo-alone arm went on to receive EGFR TKIs when cancer progressed, and this was particularly the case for Asian patients who were participating in the study.
The authors concluded that “cetuximab added to first-line platinum-based chemotherapy can be regarded as a new standard first-line treatment option for patients with EGFR-expressing advanced NSCLC”.
Although this was a well-conducted trial representing a truly international effort, I am not certain that the world is ready to embrace Erbitux for NSCLC just yet. What was not mentioned in the article was the tremendous cost associated with this drug. In an economic climate where everyone is recognizing that unparalleled expenditures will bankrupt the healthcare system, this is a crucial issue to bring to light. In his review last year after the abstract presentation at the American Society of Clinical Oncology annual meeting, Dr. Tom Lynch discussed this issue very frankly. He discussed a common measure of drug cost to benefit, termed the “cost per year of life gained”. This translates roughly into what the total cost of a treatment would need to be to gain a year’s benefit in a number of patients. Typically, the “generally accepted” cost per year of life gained ranges from $50,000 to $100,000. Oncology treatments are more expensive by nature, and oncologists tend to view $300,000 per year of life gained as an acceptable cost. In Dr. Lynch’s rough calculations last year, given the survival benefit of cetuximab, the use of this drug would cost $540,000--622,000 to accomplish the same outcome.
Cost is not the only issue to consider, and as an individual physician, I do not feel it is my place to make a patient-by-patient judgment in that regard. A five-week benefit is certainly statistically significant, and in the world of lung cancer, we are certainly very happy to see any possible gains in survival being made. That being said, one needs to also look at the issues about quality of life.
Although in this trial, quality of life was supposedly equal, the higher rates of rash, diarrhea, and very importantly neutropenic infection bring this into question. Although there was not an increased rate of death from neutropenic infections, it must be remembered that a neutropenic infection itself means hospitalization, possibly in the intensive care unit, IV antibiotics, diagnostic studies, and potentially other invasive procedures. Time in the hospital as opposed to home certainly in my book does NOT translate into an equal quality of life. When one in five patients treated ends up with a neutropenic infection, I question whether this is appropriate to consider when goals are palliative and not curative.
So what do we do with this information? It represents a step forward, but only a small step. Many people feel that the next step is to figure out a better way of predicting who will experience a significant survival benefit with the drug and who will not. In so doing, we could more selectively administer the drug, which could control its costs, and save someone who would not experience a benefit with the agent from the increase in toxicity.
This again harkens to the drumbeat in the headlines of “individualized medicine”. Is this drug for everyone? No. Would I be more excited about using it if we had better predictive markers of who would benefit? Yes. Recently it has been shown that for patients with colon cancer who have a mutation of K-Ras, there is no benefit with Erbitux. This is changing the application of Erbitux in colon cancer. It does not seem yet that the same prediction applies for NSCLC. Further studies need to be done to figure out what those markers will be for NSCLC.
My conclusion is that Erbitux shows promise when combined with chemotherapy for NSCLC, but it is not yet ready for “prime time”, and a more prudent course would be to do further studies.
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