Axel Grothey, MD
Studies into nintedanib, both as a single agent and in combination with capecitabine (Xeloda) could add another drug to oncologists' armamentarium for colorectal cancer (CRC), according to Axel Grothey, MD.
In an interview with OncLive
, Grothey, Department of Oncology, Mayo Clinic, discusses both the LUME-1 and LUME-2 trials, the differences between left and right tumors in CRC, and how that information could potentially be used in diagnosis and treatment. He also looks toward the future of immunotherapies in CRC.
OncLive: Can you tell us about the LUME-1 trial? What are the treatment options right now for patients with metastatic CRC?
: First of all, it's important to have more agents. The more agents we have that are differing in their mechanism of action, the longer patients will live if we use them sequentially. We have chemotherapy drugs like 5-FU, we have targeted agents, we have angiogenesis inhibitors, we have regorafenib (Stivarga) we have TAS-102—we have a whole portfolio of agents. We know that if we have more agents, and agents that are hopefully efficacious and not as toxic as pre-existing options, it will improve outcomes for our patients.
Are there any toxicities that were seen with nintedanib?
When you talk about nintedanib, I think the comparator you really like to see is regorafenib. It's also a multikinase inhibitor, against multiple angiogenesis and tumor proliferation kinases, and regorafenib is considered a potentially more toxic agent, with skin toxicities, fatigue, voice changes, etc. What we know about nintedanib so far is that's it's probably better tolerated than regorafenib. There's clearly less hand-foot skin reaction and less hypertension. If nintedanib shows a similar efficacy profile as regorafenib, it could actually be a potentially preferred agent over regorafenib.
This will need to play out in the clinical trials that we have, but so far nintedanib appears to be quite well-tolerated in patients. There's still fatigue, there's some skin reaction, but not to the extent that we've been seeing from regorafenib, for instance.
Will there be a specific cohort of patients who would benefit the most?
It's more or less a question of, "Do we have a biomarker?" Thus, far we don't. There is ongoing translational research that will try to identify patients who benefit more or less, but right now it's really more for all comers. The future of nintedanib could not necessarily be as a single agent in the last-line setting as the clinical trial is being conducted, but potentially in combination with cytotoxic agents like capecitabine, to utilize a dual approach toward cancer cells. If it's not as toxic as other agents, it might be better combined with them.
LUME-2, for instance, is a study that will combine nintedanib plus capecitabine in a later-line setting to see whether this combination could be used earlier, or potentially as maintenance therapy. Both drugs are oral agents. If I can tell my patients that they will go on 4 months of IV chemotherapy, and then we can maintain the effect by giving them 2 pills at home, that would be a very nice and, hopefully, effective way for patients to get anti-cancer therapy.
Can you tell us about LUME-2?
LUME-2 is a trial that is going to be initiated very soon comparing nintedanib to nintedanib plus capecitabine in the later-line setting to see if there's some clinical significance in patients who have prior progression. We're seeing if we can reutilize a drug in a later setting in combination with nintedanib and have a better outcome than just with nintedanib alone. It's a randomized phase II comparison.
I do believe that knowing what we've seen with angiogenesis inhibitors, I strongly believe the trial will be positive for the combination as long as we don't see any unexpected toxicities, because it makes a lot of sense to combine these two oral agents. This could really change the way we really utilize this combination in earlier lines of treatment.
Can you tell us a little bit about left tumors versus right tumors in CRC?
Tumor side is interesting because in some ways I feel stupid that we hadn't seen it before, because it's so easy—right versus left. We don't need a molecular analysis or EXON sequencing. When you go back to clinical trials, we have known this for almost 20 years but we didn't really pay attention, but it also probably didn't have any clinical consequence. I think it's very clear that right-sided tumors have a poorer prognosis than left-sided tumors. So we really need to change the way we talk about colorectal cancer, left and right versus colon and rectal.