Today we are speaking with Dr. Leonard Saltz about the advances in treatment for colorectal cancer, as well as ongoing developments to find new and better therapies to treat this type of cancer. Dr. Saltz is head of the gastrointestinal oncology unit and a colorectal cancer specialist at the Memorial Sloan-Kettering Cancer Center in New York City, where he treats patients and develops new treatment strategies and drugs for colorectal cancer.
—Interviewed by Anna Azvolinsky, PhD
Cancer Network: There have been several new therapies that have become available for advanced colorectal cancer in the last year; could you highlight these for us?
Dr. Saltz: Sure, I think we can say that there are three changes that have occurred in our treatment paradigm and treatment guidelines for colorectal cancer during the past year. The simplest is a study that looked at whether continuation of bevacizumab (Avastin) as the second-line treatment after it has been used in a first-line regimen is effective and safe. The outcome of the so-called TML study that investigated that question was that there was a statistically significant, but unfortunately modest, improvement in overall survival, with a median improvement of 1.4 months, which works out to be 42 days, when one continues bevacizumab in the second line. This outcome was far less than had been speculated by some registry studies that had gotten a lot of play previously. It is not zero, but it is pretty modest. At the same time, new data were presented on a drug called aflibercept (Zaltrap), which was studied in the second line, and it had a 1.4-month survival benefit when used in that setting. The third agent that came along is regorafenib (Stivarga). This is an oral agent that is a tyrosine kinase inhibitor that was studied compared to placebo in patients who had exhausted standard therapy but were still in good performance status and good physical shape. The study showed that that agent also had a 1.4-month survival benefit over placebo when used in that setting. So, we have a number of new maneuvers. They are all working more or less around the vascular endothelial growth target, or VEGF target, and they have all added modestly to the effectiveness of therapy.
Cancer Network: One of the issues with new therapies is their cost burden. You wrote an op-ed in the New York Times late last year about the newly approved colorectal cancer drug aflibercept, which had only an incremental benefit but came with a huge price tag. The company that makes the drug ended up lowering the price of the drug. What are the main issues with these really costly new drugs, and who ends up paying for them?
Dr. Saltz: Of course, everybody ends up paying for these drugs because the cost is distributed throughout our society. I think it is important to emphasize that virtually all new drugs that have come on the market in the past 10 to 15 years have been egregiously overpriced. It is not necessarily fair to single out one drug. The issue with aflibercept was that, as I mentioned previously, parallel data became available suggesting that either continuation of bevacizumab or use of aflibercept in second-line therapy could offer the same 1.4-month survival benefit. There are of course some limitations of cross-study comparisons, but these data were fairly compelling, that these drugs, which worked along similar mechanisms, offered similar limited benefit. Bevacizumab is already very, very pricey, and I think way overpriced relative to the benefit patients derive from it. However, because the dose of bevacizumab used for colorectal cancer routinely is 5 mg/kg and the company marketed aflibercept on the basis of comparison with a 10 mg/kg dose of bevacizumab—this was by their own discussion, that was their decision, and they came out with a price that was more than double of bevacizumab. So, you now had two strategies that were alternative to each other, but one was more than twice the price. And in the absence of any apparent benefit, it seemed inappropriate to use the more expensive agent.
Cancer Network: So, what was the result, the company lowered the price of the drug?
Dr. Saltz: Well, that has been a little bit complicated. It is not clear to me that they truly lowered the price. What they did was they said to me and many other people who are thought leaders in this field in direct personal conversation that they were offering a 50% discount across the board to everybody. What Peter Bach, my colleague and coauthor on the New York Times piece, pointed out to them is that this would not have an impact on CMS (Centers for Medicare and Medicaid Services) patients, would not have an impact on the long-term average sale price, and in effect was a windfall for a prescribing physician or organization because whatever discount was offered could not be passed onto the patient. I think it is also important to understand that while there was movement on the topic, there was not a major change in price and the way it was represented to us was not the way it actually played out.
Cancer Network: Switching to biomarkers, could you update us on any new thinking on KRAS testing for colorectal cancer?
Dr. Saltz: As I think most oncologists have been aware of for some time, evidence became available starting around 2007, 2008 that the mutation status of the KRAS gene in the tumor was critical to whether or not EGFR (epidermal growth factor receptor) agents, such as cetuximab or panitumumab, could be effective. It is now understood that if there is a mutation in exon 2 of KRAS that those drugs should not be used because they will not work. There was some interesting evidence that came out of Dr. Tejpar's group in Belgium that suggested that the G13D mutation was biologically different and more sensitive than the codon 12 mutations that make up the majority of the KRAS mutations. So, there was some question of whether people with a KRAS mutation that was exon 13 should still be treated with these agents. I think that it is important to understand that that would be an off-label use—the drugs are only registered for KRAS wild-type individuals, and secondly, there was a newer publication in the Journal of Clinical Oncology in the past couple of months that took a detailed look at large databases of patients treated with anti-EGFR agents, and specifically with panitumumab, and found that the outcomes were not affected by whether it was codon 12 or codon 13 that was mutated. Basically, the initial information that if there is a KRAS mutation in exon 2, which includes both the codon 12 and 13 mutations, that those patients do not benefit and should not be treated with anti-EGFR agents remains the current recommendation and remains appropriate practice.
Cancer Network: Is there a drug, test, or screening method that you see as having had a very major impact on colorectal incidence or survival in the last few years?
Dr. Saltz: Well, I wish that we could say yes. I think we have seen a lot of interesting ideas, lots of small incremental steps, but in terms of something that is going to have a major impact, I don't think we have identified that yet. I think that as we think about drug development for colorectal cancer, we had our brief golden age from 1996 to 2003 when after a 39-year period where there was nothing but 5-fluorouracil, we had a series of drugs come along—irinotecan, cytoplatin, capecitabine, bevacizumab, cetuximab, and then ultimately panitumumab. Then we had a relative dry spell since then. The new agents that have come along, aflibercept and regorafenib, are really modest variations on the themes already available and have not opened up a new paradigm or made a major impact in treatment. I think we are still looking for that next big advance.
Cancer Network: In terms of that research, to look for these big advances, could you highlight a major question in terms of the biology of colorectal cancer that needs to be addressed to better either diagnosis or treatment of colorectal cancer?
Dr. Saltz: I think we have come to understand that as with all common tumors, colorectal cancer is really many, many different diseases—hundreds if not thousands of different variants. We have always understood that some patients respond well to a particular therapy and some respond poorly, but what we haven't been able to do well is characterize why that is the case. I think that where I would like to see the field going in the near-term future is a better understanding of the different subtypes of the disease that may respond better to or be more refractory to specific therapies. So that rather than simply throwing every treatment at every patient, we could make intelligent decisions and say, "this is a therapy that has a high probability of success" and "this is a therapy that for all practical purposes will not be useful," and make treatment decisions on that basis. Ultimately, what we are really missing is an understanding of the actionable mutations in colorectal cancer. We have seen situations like in non–small-cell lung cancer where specific EGFR mutations create a vulnerability to drugs like erlotinib or ALK mutations to drugs like crizotinib, but we have not found those actionable mutations in colorectal cancer. We thought we had something in terms of the BRAF mutation, but in fact the trial of the BRAF inhibitor vemurafenib by itself was ineffective in BRAF-mutated colorectal cancer. We are looking at strategies now that might augment that, and I hope that the combination or use of multiple targeted agents and rationally designed therapies for specific mutational profiles and identification of specific treatable subgroups is going to change the way we treat this disease. We will just have to see how that plays out over the next few years.
Cancer Network: Thank you so much for joining us today, Dr. Saltz.
Dr. Saltz: Thank you.