As part of our coverage of the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, Cancer Network is speaking today with Leonard Saltz, MD, chief of the gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center, about some of the colorectal cancer research that is expected to be presented at the meeting.
—Interviewed by Leah Lawrence
Cancer Network: Thank you for speaking with us today, Dr. Saltz. A late-breaking abstract will be presented in the plenary session discussing chemotherapy plus bevacizumab or cetuximab in patients with metastatic colorectal cancer without KRAS mutations. Can you discuss why the results of this abstract will be important?
Dr. Saltz: This is a study that has taken a very long time to complete. It has really been a mammoth effort. I think that we are going to be learning a tremendous amount about treating colon cancer from this study. The specific information is a comparison of treatment with a standard cytotoxic chemotherapy backbone—either FOLFOX or FOLFIRI, investigators and patients were given their choice about that—with patients then randomized to receive either bevacizumab or cetuximab. This has only KRAS wild-type patients included, and, based on the technology available at the time, it is those patients that are exon 2 KRAS analyzed. We now understand that non-exon 2 KRAS mutations and NRAS mutations would also be relative contraindications to inclusion of patients and treatment with anti-EGFR therapies such as cetuximab. A later analysis will look at that subpopulation. This is basically going to answer the question: Is there a superiority to treating KRAS wild-type patients with an EGFR inhibitor upfront vs using bevacizumab, a VEGF inhibitor?
The study is the culmination of more than a decade of effort and involved the cooperative groups working together to answer a question that would not have been addressed outside of the cooperative group network, and I think that is very important in its own right. The study originally was asking the question of whether the combination of using anti-VEGF and anti-EGFR therapy together would be a useful thing to do. We have already gotten the answer that that was an inferior arm that was closed early. Also, when we started the study we did not know about KRAS for selectively, so that was a modification made in the study, and the data presented here are only those patients since KRAS genotyping became available—and only those patients that are KRAS wild-type.
Cancer Network: During the oral abstract session, you will be the discussant for two abstracts dealing with maintenance therapy. Why is this an important topic in colorectal cancer right now? How will these abstracts add to the clinical knowledge related to this topic?
Dr. Saltz: This is an interesting dichotomy and style here, because I think these are more relevant to European investigators, or at least more interesting to European investigators than to American investigators. Not that that should be the case, but I think it is.
American investigators and American clinicians have tended to be resistant to the idea of treatment breaks and maintenance therapy, and tended to push treatments to their toxicity levels; whereas, Europeans have been more interested in either stopping chemotherapy after a fixed period of time or in cutting back the therapy to a so-called maintenance therapy. The data to support this approach was first published in the Journal of Clinical Oncology back in 2006 by Christophe Tournigand in the OPTIMOX study, which showed that in patients being treated with frontline FOLFOX, if one made a plan to stop the oxaliplatin after the first 6 cycles and just continue with the 5-FU and leucovorin, with the option to bring oxaliplatin back in at a later date, that patients had lower toxicity, certainly lower drug expense, and the same long-term outcome in terms of duration of disease control and in terms of overall survival. We have known for a long time that we can drop oxaliplatin out of the mix early and that we should.
In the CAIRO 3 study, the question being addressed is, Should we stop everything? Should we simply drop chemotherapy after 4 months and observe? The answer is that there does appear to be a benefit in terms of continuing at least maintenance chemotherapy. I don’t find that terribly surprising or earth shattering. To some degree, I find this a confirmation of some earlier studies that have been presented including the OPTIMOX 2 study. For anyone who was considering stopping therapy cold turkey this will provide some data justifying that continuation of fluoropyrimidines plus bevacizumab has some advantages over observation.
The other study that is being presented is a trial looking at taking patents with fluoropyrimidine, oxaliplatin, and bevacizumab, and after 6 months, if they still have good disease control, randomizing them to stop therapy, to continue with bevacizumab alone, or continue with fluoropyrimidine. What we see is in this study, which is 840 patients and is split between three arms, the overall survival did not appear to be meaningfully different. The data are preliminary for that. The duration of disease control is about 2.5 months longer when bevacizumab and fluoropyrimidine are continued. Single-agent bevacizumab looks to be inferior to bevacizumab and fluoropyrimidine. It is a month better in terms of duration of disease control than doing nothing. In this essentially open-label study with investigator adjudicated progression, I wouldn’t make anything of a 1-month difference in duration of disease control. I don’t think it gives any support to single-agent bevacizumab. I don’t think that has any role in treatment of metastatic colorectal cancer. It does suggest that continuation of cytotoxic chemotherapy at a maintenance level has some benefit. It would be nice if the study had included a chemotherapy-only arm without continuation of bevacizumab, but we don’t have those data, and I doubt that we ever will. We will just have to make use of the information available. I think these studies are of interest. I think they will convince believers and not sway a whole lot of conversions from one approach to another. They will make for some interesting discussion in terms of treatment options.
Cancer Network: Last year at the Annual Meeting, there was a lot of excitement surrounding research on PD-1 and PDL-1 inhibition. Are these targets being explored at all in colorectal cancer research?
Dr. Saltz: We and others are starting to explore these immune checkpoint inhibitors in colorectal and other GI malignancies. We have been a little late to the party in GI oncology because preliminary evidence in phase I has been more exciting in some other areas. Whether that is going to turn out to be an issue or not is too early to say.
We clearly will see evidence of responses in GI malignancies but in terms of the numbers and percentages there won’t be enough volume at this meeting for us to have a sense yet of where these drugs are going to fit in. It is very possible that we may find that tumors with large amount of mutations (such as the hypermutated colorectal cancers we see with mismatched repair deficiency) may be more vulnerable to immune therapy because those tumors will have more foreign antigens that might be more readily recognized. There is also the possibility that we have to consider that there may be innate immune tolerance in the GI track which is necessary when you consider the degree of microbial colonization of the GI tract and when you consider that we need to have a situation where we don’t have immunological reactions to every foreign protein that we take in our diet. How that is going to color immune modulation therapy in GI malignancies is still too early to say.
Cancer Network: Are there any other abstracts or colorectal research that will be presented at this year’s meeting that you are looking forward to?
Dr. Saltz: There are a number of interesting looking things. It is very hard to tell from just the abstract how much we are going to learn at the meeting. I would emphasize that just reading the abstracts alone is not sufficient.
The overall theme of the meeting is very interesting in that there is an emphasis on evaluating value in cancer care. Discussants are specifically being asked to consider value and discuss benefit in its relevance and comparison to toxicity and to expense. It is really the first time that ASCO is taking a broad public position on considering financial toxicities and the overall expense of cancer treatment in comparison to the benefits being achieved by patients. I think that is going to make for a lot of interesting and challenging discussions. I think it is overdue, and I am encouraged that we are going to be having these conversations.
Cancer Network: Thank you again for taking a few minutes to speak with us today, Dr. Saltz.
Dr. Saltz: It has been my pleasure.