Louis M. Weiner, MD; Axel Grothey, MD


June 09, 2014

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Colorectal Cancer: A Plenary Presence

Louis M. Weiner, MD: Hello. I am Dr. Louis Weiner, Director of the Lombardi Comprehensive Cancer Center and Chair of the Department of Oncology at Georgetown University in Washington, DC.

Welcome to this edition of Medscape Oncology Insights in Gastrointestinal Cancer. Today we will highlight some of the presentations from the 2014 annual meeting of the American Society of Clinical Oncology (ASCO®). Joining me today is Dr. Axel Grothey, Professor of Oncology at Mayo Clinic College of Medicine, in Rochester, Minnesota.

This year the plenary session featured a study in colorectal cancer presented by Alan Venook.[1] We have been waiting for these results for quite some time. What have we learned? Axel, would you like to summarize the results of that study for us?

Axel Grothey, MD: I am more than happy to. This study took 10 years to complete, and much has changed during that time. This study showed that we underappreciated where we would be in the treatment of colorectal cancer in 2014. The study integrated 2 drugs, which were new in 2004. Bevacizumab and cetuximab were approved within 2 weeks of each other in 2004. The question was, which of these drugs is the better first-line therapy added to chemotherapy?

The study allowed investigators to choose FOLFOX (5-FU, oxaliplatin, and leucovorin) or FOLFIRI (leucovorin, 5-FU, and irinotecan) as the chemotherapy backbone. More than 70% of the patients (1150) received FOLFOX chemotherapy in the United States and were randomly assigned -- eventually in the "14th amendment version" of the study because things change over 10 years -- to bevacizumab or cetuximab in first-line therapy. The primary endpoint was overall survival. There is good news and bad news. The median overall survival was 29 and 29.9 months in the FOLFOX and FOLFIRI groups, respectively. There was no real difference between the groups.

This was a patient population with KRAS wild-type tumors and KRAS exon-2 wild-type tumors. The importance of the study is that it takes a little bit of the wind out of the sails of the study that we saw last year (the FIRE-3 study),[2] which was a German/Austrian trial comparing cetuximab and bevacizumab added to FOLFIRI. That study did not show any difference in response rate or progression-free survival. However, that study also had an interesting and unexplained (until now) finding of a difference in overall survival in favor of cetuximab, which became even larger when the refined patient population underwent more RAS testing[3] to eliminate patients with NRAS and KRAS mutations.

'All the Drugs' Plus Metastasectomy: Winning Strategy

Dr. Weiner: It is easy for us to minimize the advances that have been made over the past decade. In oncology, we tend to think about advances defined as the identification of active new drugs, and we often forget that what we are really trying to do is treat people with cancer and help them live longer and better lives. As I recall, the seminal study by Hurwitz,[4] published in 2004, showed that the combination of irinotecan, 5-FU, and leucovorin (IFL) plus bevacizumab was significantly superior to IFL alone, with an overall survival that was in the neighborhood of 20 months. Here we are, a decade later, with a median survival of 29 months, and in the interim there has been a good deal of work showing that patients who get all of the drugs do better than those who get only one or two of the drugs. How important has this been to the improvement in overall survival that we are seeing? And are there any other factors that we should be considering?

Dr. Grothey: Having access to all of the agents and using them in a strategic manner is important. In the past 10 years we have switched from distinct lines of therapy to identifying a continuum of care. This sounds like wordplay, but it is actually what we are doing. We are keeping patients' tumors under control for a longer period of time. I tell my patients in the palliative setting that "my goal is to keep you around as long as possible and with as good a quality of life as possible, using the least amount of treatment necessary to control the disease."

Dr. Weiner: Absolutely.

Dr. Grothey: One factor, then, is access to the drugs and knowing how to use them, when to use them, their strengths and weaknesses, toxicity management, duration of therapy, and 2 additional considerations. One is using liver surgeons to render patients free of disease, even if only for a short time, by resecting metastases. This is somewhat different from where we were 10 years ago, when we just started to recognize that this contributes to improved outcomes and adds to the effectiveness of our approaches.

The second significant event in the past 10 years was the KRAS story of 2008, when we learned to approach colorectal cancer in a different way. We started testing patients first and then giving a drug (similar to what we have been doing in breast cancer all along), refining the patients who can benefit, and eliminating patients who might even have a detrimental effect from therapy.

Dr. Weiner: An abstract[5] presented on Saturday in a poster session described in more detail the surgical metastasectomy strategies and their impact. It was a very important study in that it described the value of doing pulmonary and liver metastasectomies, and demonstrated similar outcomes and even some improved outcomes with ovarian but not with peritoneal metastasectomies. We are beginning to understand with more clarity the patient populations that might benefit.

Immunotherapy: Looking for the 'Big Win'

Dr. Weiner: I would like to return to the idea of stratifying patients effectively. As you know, I am fond of immunotherapy. We haven't had the "big win" in immunotherapy with the checkpoint inhibitors in colorectal cancer that we have seen in melanoma, kidney cancer, lung cancer, and other diseases that are being described at this year's meeting.

There was a fascinating presentation by Jerome Galon,[6] who did some wonderful work beginning in the 2000s, showing that the nature of immune infiltrates in cancers of the colon actually has a very important impact on defining prognosis. This is very important because we haven't had a major pharmaceutical advance in the adjuvant therapy of colorectal cancer for quite some time.

He describes an approach using the Immunoscore®. By looking at the type and density of lymphocyte infiltration and tumors, and developing strategies that can be applied across the board in multiple institutions, it is possible to stratify people at any given Dukes or TNM [tumor, nodes, metastases] stage and identify, perhaps with greater precision, the patients who are destined to relapse vs those who are destined to be cured. What is your thinking about that?

Dr. Grothey: Let me bounce it back to you. Do you believe that almost every cancer is potentially immunogenic?

Dr. Weiner: This is what I think: A cancer faces only one major threat as it is developing in a person's body, and that is the individual's immune system. The immune system is, essentially, the selection pressure that is driving survival mechanisms. The successful cancer cell has developed -- if you think about it -- a particular set of mechanisms that allow it to thrive in a given person, and that set of mechanisms becomes the Achilles heel of that cancer. If you can disable it, you ought to be able to effectively treat the cancer. We have found that in some cases, the PDL-1 and PD-1 axis is critical. It is not going to hold true for all cancers (such as colorectal) but it will for others, and the challenge before us is to identify the Achilles heel.

What I find fascinating in colorectal cancer is that the human immune system can recognize a colorectal cancer because sheets of T cells invade the cancers and have prognostic significance.

Dr. Grothey: You see a lot more lymphocytic infiltrate around the hypermutated microsatellite instability high-level tumors, which have a better prognosis, suggesting that the immune system might play a role.

We are working on developing immunotherapies, first in the palliative setting before we move into the adjuvant setting. I always wondered: How could we screen for agents that could skip the "palliative medicine test" and go into the adjuvant setting?

Dr. Weiner: That is a great question. The first thing we need to have is knowledge, and Dr. Galon's work and that of his colleagues have been critical and enabling. It has allowed us to identify that there is something happening immunologically that should be able to be manipulated to the benefit of our patients at some point in the future.

The challenge before us now is to dive down deeply and really understand the mechanisms that these cancer cells are employing to defeat that immune infiltrate, because people are still dying of cancer. Is it because the T cells weren't permitted access? Is it because the cancer no longer allowed itself to be recognized? Is it because of checkpoints that were erected? These are military analogies, to be truthful, but they have value, and if we can understand that, categorize it, catalog it, and develop strategies to defeat those specific mechanisms, we are going to make significant progress in the future.

CRC: Winning by Military (and Molecular) Tactics

Dr. Grothey: That is the future. What I find important at ASCO, in talking about other colorectal cancer studies that tie into what we have learned over the past year or so, is all-RAS testing. I highlight this because it is commonplace in Europe. It is not yet commonplace in America, and we have seen data during the past year related to panitumumab and now to cetuximab. Three trials[7,8,9] were presented here that did an all-RAS analysis (meaning that we are not just focusing on KRAS exon 2 mutations but also mutations in exon 3, 4 of KRAS, NRAS exon 2, 3, 4) and eliminated patients who had any mutations in the RAS DNA, because those patients don't benefit from epidermal growth factor receptor (EGFR) antibodies. They might even have a detrimental effect.

This excludes another 15%-17% of patients beyond the conventional KRAS wild-type definition. In Europe it is contraindicated to give an EGFR antibody if you don't have comprehensive RAS test results.

About 2 weeks ago, the US Food and Drug Administration (FDA) approved panitumumab in combination with FOLFOX for KRAS wild-type tumors, and I was actually disappointed. Somehow, the FDA wasn't bold enough to demand RAS testing, probably acknowledging that a lot of physicians wouldn't even know what comprehensive RAS testing is.

Dr. Weiner: They wouldn't know what it means.

Dr. Grothey: Or where to get it, but it's the future; it is actually right now.

Dr. Weiner: It is going to help us guide therapy. Another set of abstracts that I was very impressed with were the studies looking at coordinated attack of the RAS/RAF signaling pathway to begin to replicate some of the exciting results achieved with drugs such as vemurafenib to treat melanoma. Do you want to talk about that a little?

Dr. Grothey: I am happy to. We have talked about this before. This is one of the more exciting new things, because we have heard about RAS testing before. There were a lot of "me-too" abstracts this year. It was a bit depressing. BRAF dysregulated tumors have a poor prognosis, and 5%-10% of patients with metastatic colorectal cancer have BRAF mutations.[10] They live less than half as long as patients with BRAF wild-type. This mutation is easily tested. The same mutation can be found in melanoma, and single-agent vemurafenib works quite well in melanoma for a while, but it is not a cure. Yet, it doesn't work at all in colon cancer, achieving perhaps a 1%-5% response rate.

Dr. Weiner: If you looked at those posters, it shows the degree of impact of the drug on phosphorylation of downstream targets, but it doesn't shut down the system nearly as well as it does in melanoma.

Dr. Grothey: We have the same mutation (potentially a driver mutation), but somehow colon cancer cells have redundant pathways and can activate pathways that eventually bypass the blockade. An effort is arising from some very decent preclinical work, using not just a single inhibitor but combinations of inhibitors such as BRAF and MEK, or BRAF and EGFR antibodies to shut down the pathway from top to bottom and side to side. This triple therapy has been quite promising and the data are intriguing. We have seen the responses in phase 1–level data, and the outcomes are intriguing enough for the US Intergroup to open a study in July that will randomize patients to this triple approach compared with a standard treatment. Hopefully we can demonstrate effectiveness. The FDA is on board, so hopefully we will find an improved strategy for BRAF-mutant tumors.

Dr. Weiner: That would be really exciting, and we look forward to seeing the results of that at ASCO 2016.

Dr. Grothey: Perhaps in 2017.

A Slow Year for Other GI Cancers

Dr. Weiner: Before we conclude our conversation, there are other gastrointestinal cancers. Can you think of any studies that caught your eye, particularly in pancreatic, gastric, or esophageal cancer?

Dr. Grothey: There were some negative trials. It wasn't a great year for noncolorectal gastrointestinal cancer. We saw highly anticipated data[11] for adjuvant sorafenib in hepatocellular carcinoma after resection, which were negative. Sorafenib works in a palliative setting but not in the adjuvant setting. The adjuvant setting is always tricky. We cannot always extrapolate from what works in the metastatic setting to adjuvant.

We saw data on first-line ramucirumab, which works in second-line therapy in combination with a taxane in esophageal cancers. In the first-line, large, randomized phase 2 trial adding ramucirumab to FOLFOX,[12] there were no differences in outcome. Pancreas cancer has gone through some evolution. We went from gemcitabine alone (which didn't help patients very much) to having 2 different, more intense, treatments, which have created new standards of care -- gemcitabine plus FOLFIRINOX, and paclitaxel plus FOLFIRINOX, and both regimens are clearly superior to gemcitabine alone. In our institution, we have a lot of experience with FOLFIRINOX. We modify FOLFIRINOX. We dropped the bolus, and the French investigators have now also dropped the bolus. It abrogates the need for growth factor in most patients, and we are seeing response rates. We see borderline resectable patients who clearly turn into resectable patients. We are changing how pancreas cancer is being treated, and hopefully we will see an uptick in survival for patients with metastatic pancreas cancer.

Dr. Weiner: At this point, we are learning that for the noncolon gastrointestinal cancers, we are where we were 10 years ago, in some ways, with colon cancers. We have tools that we didn't have before, and now we have to figure out how to use them to the benefit of our patients, and at the same time develop more effective therapies for our patients.

Dr. Grothey: Absolutely.

Dr. Weiner: Thank you, Axel. Thank you for joining us for Medscape Oncology Insights. This is Louis Weiner, reporting from ASCO 2014.


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