Marshall, John L. MD
ASCO 2012 will be noted for important results, both positive and negative, in the world of GI cancers.
JOHN L. MARSHALL, MD...Image Tools
Several important new therapies and treatment strategies emerged in the colorectal cancer scientific world. The overriding theme was one of novel VEGF and targeted therapy inhibitors playing a role in first-, second- and third-line metastatic colorectal cancer.
In first-line therapy, we recognized that a strategy of maintenance therapy has emerged after initial combination chemotherapy. This strategy developed as a means to manage the cumulative neurotoxicity seen with oxaliplatin, but is one that could be used with irinotecan-based therapy as well.
The current therapies utilized in maintenance therapy include fluorouracil (5-FU) alone, capecitabine, bevacizumab, or combinations of these treatments. Based on a study known as MACRO from a couple of years ago, a new study called DREAM was presented at this year's ASCO meeting (Abstract LBA3500). The DREAM study randomized patients with frontline metastatic colorectal cancer to two different maintenance approaches. One maintenance approach utilized bevacizumab alone and the alternate arm combined bevacizumab with erlotinib.
It is important to note that erlotinib had been tested in refractory colon cancer and other settings in combination with chemotherapy in the past and had not demonstrated positive benefit. In this particular study, there was no enrichment for K-RAS wild-type either as it is unclear how K-RAS would interface and interact with erlotinib. Nonetheless the study was positive for the combination arm demonstrating a small 1.4-month improvement in progression-free urvival in the patients receiving the dual combination.
This study raises many issues for me: a need to revisit many of our assumptions around oral tyrosine kinase inhibitor EGFR agents; our disdain for combining EGFR and VEGF in front line; and optimizing maintenance approaches utilizing novel therapies and novel combinations. Of the many studies that were presented, this one actually got my attention the most as it opens many new doors for future drug development and basic biology understanding.
Second-Line Metastatic Colon Cancer
In second-line metastatic colon cancer, several agents emerged. The new agent aflibercept has been demonstrated to show a survival advantage in patients in second-line metastatic colon in a randomized clinical trial comparing FOLFIRI to FOLFIRI plus aflibercept. At this year's ASCO meeting, this data was further updated showing that in patients who have had prior bevacizumab, the benefit was seen in that group as well (Abstract 3505).
This concept of maintaining antiangiogenic inhibition or VEGF inhibition into the second line was further supported by a clinical trial know as the TML study which was a well-designed study focused on the concept of bevacizumab beyond progression (Abstract CRA3503).
In this clinical trial, investigators were given the option of whatever frontline chemotherapy they wished in combination with bevacizumab, and then in second line, patients were randomized to whatever second-line chemotherapy was desired plus or minus bevacizumab.
This trial also demonstrated a 1.4-month improvement in progression-free and overall survival, and suggests that maintaining a VEGF inhibition through to second line would be of benefit.
This point, of course, is controversial, as prior studies had shown the magnitude of benefit of bevacizumab beyond progression to be even greater than in this randomized trial, and further points out that randomized clinical trials, while our best tool to measure impact, often underestimate the impact of therapies in selected populations. Nonetheless I think this establishes the role of bevacizumab beyond progression or some VEGF inhibition beyond progression for patients with metastatic colon cancer.
The last area is refractory disease, where new studies were presented showing in one case the benefit of regorafenib in the refractory setting (Abstract 3502), and unfortunately in another trial, perifosine failed to benefit (Abstract LBA3501). Regorafenib will likely gain approval for patients with metastatic colon cancer in the United States very soon as a result of this trial of the first oral multi-targeted tyrosine kinase inhibitor in colon cancer.
One of the targets is antiangiogenesis for this agent, suggesting continuation of antiangiogenic therapy into now the third line for patients. In summary, the primary therapeutic studies presented support the use of biologics throughout the lines of therapy and bring to the table new agents for the treatment of this disease.
Non-Colorectal GI Cancer
Non-colorectal GI cancer was likewise a very busy place at ASCO. Unfortunately we did not gain the same positive impact that was seen in colorectal cancer.
For example, the REAL3 trial was a randomized clinical trial of epirubicin, oxaliplatin, and capecitabine, plus or minus panitumumab in advanced esophagogastric cancer (Abstract LBA4000). Unfortunately this trial was quite negative with no benefit seen from the addition of panitumumab. This is, of course, frustrating particularly given the fact that trastuzumab, another EGFR-targeting agent, was positive.
The result of this trial makes us take a step back in combining panitumumab or other EGFR-targeted agents with chemotherapy. One hypothesis is that panitumumab and EGFR monoclonal antibodies do not interface well with capecitabine as it has been seen in other colorectal studies, but this is hypothesis-generating.
Another interesting adjuvant clinical trial randomized patients with adenocarcinomas of the stomach between simple 5-FU-leucovorin versus a complex multi-agent regimen, including irinotecan, docetaxel cisplatin, and unfortunately, 5-FU-leucovorin performed just as well as the multi-drug cocktails (Abstract LBA4001).
This reminds me of the story in colorectal cancer where essentially fluoropyrimidines are the only thing that seem to work in the adjuvant setting, whereas other drugs that are active in the metastatic setting do not appear to play an important role in the adjuvant setting, Clearly we have much to learn about the biology of adjuvant gastrointestinal cancers. Finally an interesting study in anal cancer is the maturation study known as ACT II comparing mitomycin and cisplatin (Abstract 4004). Earlier presentations of this data suggested that mitomycin performed better than cisplatin, but the update that was presented at ASCO this year demonstrated that as more time progressed, the complete response rate and overall outcomes of cisplatin-containing recipes were equivalent to those with mitomycin. Basically this study showed that either cisplatin or mitomycin is a valid choice in combination with fluoropyrimidine in the treatment of anal cancer in combination with radiation.
Other new agents were brought forward in a non-colon GI cancers, but to date have not matured to a point where they are ready to move forward to the clinic.
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© 2012 Lippincott Williams & Wilkins, Inc.