KRAS identification, TOGA trial results make 2009 a big year for gastrointestinal cancer research

A HemOnc Today Editorial Board member discusses important gastrointestinal news from 2009.

David H. Ilson, MD, is attending physician at Memorial Sloan-Kettering Cancer Center and a member of the HemOnc Today Editorial Board Gastrointestinal Cancers section. HemOnc Today recently spoke with him about developments in gastrointestinal oncology in 2009 and about data presented at this year’s Gastrointestinal Cancers Symposium.

The revision of cetuximab’s prescribing label for KRAS mutations was voted into HemOnc Today’s Top Stories of 2009. Why was this story such an important milestone in gastrointestinal oncology?

The identification of KRAS as the most predictive marker in colon cancer for benefit of cetuximab (Erbitux, ImClone) was a critical development. Increasingly, we have seen that most targeted agents appear to benefit only a relatively small number of patients. Targeted agents are expensive and they have associated toxicities, so there is an increasing focus on personalizing therapy.

KRAS turned out not only to be an accurate predictor, but also to be a very commonly occurring marker. If you identify a marker in 5% of patients, it is not likely to be clinically relevant. KRAS mutations are present in about 40% of patients with colon cancer, and it is clear from phase-2 and phase-3 trials that if a patient has KRAS mutation that cetuximab adds no benefit, either as a single agent or in combination with chemotherapy. Only patients with KRAS wild-type status should be eligible for cetuximab as a single agent or in combination with chemotherapy in first-, second- or third-line treatment. Data also support the same approach with panitumumab (Vectibix, Amgen.)

The results of the TOGA trial made a big impact at this year’s ASCO Annual Meeting. What was the significance of these results?

The TOGA trial is the most important study of the last year in esophagogastric adenocarcinoma. The phase-3 study identified for the first time that there is a benefit to adding a targeted agent to systemic chemotherapy in esophagogastric adenocarcinoma. Combining trastuzumab (Herceptin, Genentech) with capecitabine/cisplatin or 5-FU/cisplatin improved PFS and OS, and anti-tumor response compared with chemotherapy alone in HER-2–positive patients.

It is a similar issue as with cetuximab and KRAS status: Identifying a subgroup of patients that will benefit from a novel therapy. In HER-2–positive breast cancer, trastuzumab is active as a single agent, improves outcome in combination with chemotherapy and results in a significant survival improvement when used in the adjuvant setting.

David H. Ilson

Based on the TOGA results, we have a new era in gastric cancer. We need to test all patients with esophagogastric adenocarcinoma for HER-2 overexpression. HER-2–positive patients are candidates to receive trastuzumab as part of their chemotherapy in advanced disease. This has established a new standard of care and given us a lot of hope that targeted agents will play a role in treating this disease.

The next step in development is to move trastuzumab into adjuvant treatment of HER-2 esophageal and gastric cancers. I am happy to report that we are opening, through the RTOG, a randomized trial evaluating the contribution of trastuzumab to preoperative chemotherapy and radiation into HER-2–positive esophageal and GE junction adenocarcinomas (RTOG protocol 1010).

Quality-of-life results from the TOGA trial were just presented at the Gastrointestinal Cancers Symposium in Orlando. What was the significance of these data?

The quality-of-life results showed that there was no detrimental effect to adding trastuzumab to combination chemotherapy. Many of us hope that when we see a higher response rate and better PFS with a drug that it will automatically translate into superior quality of life. We did not see improvements in quality of life, but adding trastuzumab did not cause a negative impact on quality of life either.

One of the reasons we did not see improvement is because this chemotherapy has inherent toxicities. However, the data support that adding this agent improves survival, response and PFS, which are all important endpoints to validate the use of a new agent in advanced disease. The fact that quality of life was not impacted in a negative way indicates that the drug added no toxicity and that it can be incorporated into chemotherapy regimens in HER-2–positive patients with confidence.

What were some of the other important trial data presented at the Gastrointestinal Cancers Symposium this year?

There were a number of important studies that were presented this year across many subspecialties.

In gastric cancer, the most important trials were surgical trials. An important study from Japan by Kitagawa and colleagues looked at the surgical management of early stage T1 gastric cancer, and a companion study from Korea by Park and colleagues looked at the outcome of endoscopic mucosal resection for early stage gastric cancer. The take-home message from the Kitagawa study is that sentinel node mapping in T1 gastric cancers is quite sensitive and accurate in identifying patients who can potentially get a lesser operation (for more on this study, turn to page 19). The study by Park validated the use of endoscopic mucosal resection in very early stage T1 gastric cancers with very favorable long-term outcome results.

The next study that I thought was important looked retrospectively at patients with gastric cancer that have positive peritoneal cytology without any evidence of obvious metastatic disease at the time of laparoscopy. These results were presented by Mezhir and colleagues from Memorial Sloan-Kettering Cancer Center. The take-home message of this study was that patients with positive peritoneal cytology at laparoscopy behave like metastatic disease and should probably not be referred for immediate gastrectomy. However, patients that ultimately go on to get chemotherapy and convert to negative cytology on follow-up laparoscopy may have a better survival, and there may be a potential benefit for gastrectomy after a trial of chemotherapy. Initial gastrectomy, however, may not be warranted, as a significant number of these patients develop early disease progression on chemotherapy (for more, turn to page 20).

In neuroendocrine tumors, there were interesting oral presentations looking at the role of imaging and an update on the potential benefit of targeted agents in pancreatic neuroendocrine tumors.

The first of these studies was from Memorial Sloan-Kettering presented by Reidy and colleagues: A retrospective analysis that examined the utility of combining octreotide (Sandostatin, Novartis) scanning with conventional CT and MRI. Interestingly, this study demonstrated that octreotide scan did not add much beneficial information to staging. CT and MRI appeared to be equally sensitive in identifying metastatic disease, and octreotide scan only added additional information in 5% of patients. All of the patients that had positive findings on octreotide scan that were not evident on CT turned out to have asymptomatic bone metastases.

There also was an update of the sunitinib vs. placebo trial in pancreatic neuroendocrine cancers presented by Raymond and colleagues. The trial was closed early because there was a clear benefit for sunitinib compared with placebo in treating these patients. There was a significant improvement in PFS, response rate and OS, indicating that sunitinib is a promising new agent in the treatment of pancreatic neuroendocrine tumors (for more, turn to page 18).

What were some of the important trials involving colon cancer from the Gastrointestinal Cancers Symposium?

There were several important studies presented in the colon cancer arena. Three of the studies looked at adding EGFR receptor targeted antibodies to chemotherapy in first- and second-line treatment of metastatic colon cancer.

Van Cutsem and colleagues presented an update of the CRYSTAL trial results, which randomized patients with metastatic colon cancer to FOLFIRI vs. FOLFIRI plus cetuximab. Updated results indicate that, in KRAS wild-type patients, cetuximab combined with first-line FOLFIRI improved all clinical endpoints, including OS compared with chemotherapy alone.

A subanalysis also examined this treatment in patients with BRAF mutation. In this analysis, the researchers found that BRAF mutation is a significant prognostic factor. Regardless of treatment arm, patients with BRAF mutation (only present in patients with KRAS wild type) had significantly poorer response rates to chemotherapy, inferior PFS and significantly reduced OS. The effect of the addition of cetuximab to chemotherapy in patients with BRAF mutation could not be discerned due to the small number of patients treated.

Two other studies looked at the EGFR-receptor–targeted antibody panitumumab. The PRIME trial examined first-line use of panitumumab plus FOLFOX. This study showed that in KRAS wild-type patients, first-line FOLFOX plus cetuximab improved PFS, the primary endpoint of the trial. There was a significant trend toward improved response rate and improved OS with the addition of panitumumab, but neither reached statistical significance.

The second trial looked at FOLFIRI second-line after FOLFOX failures. This trial randomly assigned patients to FOLFIRI with or without panitumumab. Similar to the first-line trial, second-line panitumumab met its primary endpoint. It improved PFS from 3.9 months to 5.9 months, which was statistically significant, and there was also a significant improvement in response rate from 10% to 35% with the addition of cetuximab. A two-month improvement in OS did not reach statistical significance.

I think both of these studies indicate a benefit for panitumumab to improve PFS both in first- and second-line chemotherapy in KRAS wild-type colon cancer.

Is there any important data that gastrointestinal oncologists are looking forward to in 2010?

There are several trials to look forward to in 2010. One of the important trials is the AVANT study. We are hoping to see data from this trial assessing the role of bevacizumab in the adjuvant treatment of colon cancer. Unfortunately, given the negative results of the C-08 trial, which examined a similar question, we expect the AVANT data to be negative.

In addition, gastrointestinal oncologists are also still awaiting the comparative trials of capecitabine/oxaliplatin vs. FOLFOX in the adjuvant setting, which will also be part of the AVANT trial analysis.

AVAGAST is another important trial that we still await outcome results. It is a randomized trial of capecitabine/cisplatin with or without bevacizumab designed to see whether or not we can demonstrate a benefit for bevacizumab in combination chemotherapy in advanced esophagogastric cancer. The results of AVAGAST trial could potentially be practice changing.

There are also some other randomized trials of targeted agents in esophagogastric cancer examining the use of cetuximab in combination with chemotherapy. Data from CALGB Trial 80402 comparing three different chemotherapy regimens, all combined with cetuximab, in GE junction cancers is anxiously awaited.

Dr. Ilson has no direct financial interest in trastuzumab. – by Leah Lawrence