Eric Van Cutsem, MD, PhD
Safety results for regorafenib (Stivarga) in metastatic colorectal cancer (mCRC) were recently verified in the large phase IIIb CONSIGN study of more than 2800 patients from 188 sites worldwide.
The multikinase inhibitor was found to have similar adverse events (AEs) as seen in the preceding phase III CORRECT trial, with 80% of patients experiencing grade 3 or higher AEs, including hypertension, hand-foot skin reaction, fatigue, diarrhea, and hypophosphatemia. Progression-free survival (PFS), a secondary endpoint, was improved in patients with mCRC who received regorafenib versus placebo, with an estimated PFS rate of 2.7 months (95% CI, 2.6–2.7).
Despite the high percentage of grade ≥3 AEs, the consistency of the safety findings across the CORRECT and CONSIGN studies are encouraging, said lead CONSIGN author Eric Van Cutsem, MD, PhD, University Hospitals Gasthuisberg/Leuven. OncLive
sat down with Van Cutsem during the 2015 World Congress on Gastrointestinal Cancer to learn more on the management of these toxicities and the continuing advance of precision medicine in mCRC.OncLive: What was the goal of the CONSIGN study? Dr Van Cutsem:
CONSIGN was a phase IIIb, nonrandomized study where patients with chemorefractory mCRC were treated with regorafenib at the standard dose. It was designed as a result of the CORRECT study, which was a randomized study of regorafenib that showed that the agent improved survival. We wanted to examine a larger data set with a greater number of patients. There were 2800 patients included in the study. The primary goal was to look at safety and to learn more about how to improve the tolerance to this drug.What were the most significant findings from the study?
An important finding was that there were no new safety concerns. The toxicity was identical to what we saw in the more restrictive CORRECT study. Between 40% and 50% of patients needed some dose modifications due to toxicities. The most frequent toxicities that were grade 3 or more were hypertension, fatigue, and hand-foot skin reaction, but that was consistent to what we saw in the previous CORRECT study.
We also found that PFS was in range of the previous studies in the larger cohort of patients. Moreover, we examined PFS in patients with KRAS
mutant and wild-type tumors, which was also similar.What are the next steps following this study?
We plan to do an even more in-depth analysis and look at subgroups within mCRC. Sometimes, physicians have concerns with the label dose of 60 mg and many are using a lower dose of 20 mg, so we want to investigate that further.
Another next step is to look at how we can better manage patients early to prevent and treat hand-foot skin reaction and educate oncologists on these practices.What do oncologists need to know about managing hand-foot skin reaction?
There are some easy recommendations that clinicians can inform patients of to help manage and prevent hand-foot skin reaction. Wearing good shoes can make a big difference. Early intervention is also important. If there are signs of hand-foot skin reaction, it is important to treat them quickly and with local creams. It is also important that oncologists are aware that this toxicity can occur early. Sometimes, they think it will go away and then it only gets more severe. It can cause blisters that make it difficult to function and can be painful.Overall, what emerging research in colorectal cancer do you envision will have the most potential?
We are moving toward precision medicine. We are not yet there, but 2015 is the year of several new subgroups in colorectal cancer. These include HER2, which is found in approximately 5% of patients and is a target for trastuzumab (Herceptin) and lapatinib (Tykerb). Another subgroup we have recently discovered is the microsatellite instability tumors. These are targets for the checkpoint inhibitors, and we have now seen some interesting data with the anti-PD-1 antibodies.
Moreover, 6% to 8% of patients also have the BRAF
mutation. The combination of the BRAF inhibitor dabrafenib (Tafinlar), the MEK inhibitor trametinib, (Mekinist), and the EGRF antibody panitumumab (Vectibix) has resulted in a 30% objective response in BRAF
-mutated patients which lasts for a reasonable amount of time.