Phase III Study of Nintedanib Could Provide a New Option for mCRC, According to Expert

The LUME-Colon 1 phase III trial is comparing nintedanib with best supportive care for patients with mCRC following treatment with standard chemotherapy and biological agents. The primary endpoint of the study is progression-free survival (PFS) and overall survival (OS). The international trial has fully acrued 764 patients, with an estimated completion date of December 2016 (NCT02149108).

Grothey, department of Oncology at the Mayo Clinic in Rochester, is optimistic about the use of nintedanib for mCRC given promising early phase results and demonstrated benefits for non-small cell lung cancer (NSCLC), ovarian cancer, and renal cell carcinoma (RCC).TargetedOncspoke with Grother, to gain further insight into the future for nintedanib in mCRC and for more details on the LUME-Colon 1 trial.

TargetedOnc: Briefly explain the LUME trials and why they are important.

Grothey: The LUME trials are trials conducted with nintedanib, a multikinase inhibitor, which has activity against not only various different kinases involved in androgenises, but also tumor in proliferation, including VEGF receptor and and FGF.

In the LUME- Colon 1 study, nintedanib is being tested as a single-agent compared to placebo in the last-line in CRC. It is a double-blind, randomized phase III study of nintedanib plus best supportive care versus placebo plus BSC in patients with CRC. We'll hopefully see data later this year, and, if positive, it may provide a new treatment option for patients with metastatic CRC.

It is important to have more agents. The more agents we have with different mechanisms of action, the longer our patients will live. We have a whole portfolio of agents, but we know that if we have even more agents, and hopefully agents that are efficacious and not as toxic as other existing options, it will improve outcomes for our patients.

Can you give an overview and predictions for LUME-Colon 2?

LUME-Colon 2 is a trial that is going to be initiated very soon that will compare nintedanib to a nintedanib plus capecitabine combination in the later-line setting, trying to see whether there are some clinical synergies between fluoropyrimidine plus this new drug, nintedanib, for patients who have all had prior progression on fluoropyrimidine. So, it will see whether we can reutilize a drug in a later-line setting in combination with nintedanib and if that brings a better outcome than nintedanib alone. It's a randomized phase II comparison. 

Knowing what we've seen with anti-angiogenesis inhibitors like bevacizumab plus fluoropyrimidine, I actually strongly believe the trial will be positive for the combination if we don't see any expected toxicities. It makes a lot of sense to combine these two oral agents. This can really change the way we really utilize this combination in earlier lines of treatment.

What are the toxicities associated with nintedanib?

When you talk about nintedanib, the comparative we like to use is regorafenib (Stivarga). That is also a multikinase inhibitor against multiple angiogenesis and tumor proliferation kinases. Regorafenib is considered a potentially more toxic agent, with skin toxicities, fatigue, voice changes, etc. What we know from nintedanib so far, is that it is probably better tolerated than regorafenib. There's clearly less hand-foot skin reactions, and less hypertension, so if nintedanib shows a similar efficacy profile as regorafenib, it could actually potentially be a preferred option over regorafenib.

Again, this will have to play out in the clinical trials that we have, but so far nintedanib has shown to be quite well-tolerated in patients. They still fatigue, there's some skin reaction, but not to the extent that we've seen with regorafenib, for instance.

What do you see for the future of nintedanib? Do you have predictions regarding the patient population that it will benefit most?

I think the future of nintedanib could not be in the last-line setting, as it is the trial is being conducted, but potentially in combination with cytotoxic agents like capecitabine, TAS-102, and others to utilize a dual-approach toward cancer cells. And if it's not as toxic as other agents, it might be combinable. So LUME 2, for instance, is a study that will combine nintedanib plus capecitabine in a later line setting to see whether this combination might be used later in earlier lines of therapy, potentially as maintenance therapy, keeping in mind that nintedanib and capecitabine are both oral agents.

So if I can tell my patients that for first-line mCRC treatment we go for, lets say, four months of IV chemotherapy, it really tethers them to a clinical facility. But then we'll maintain the anti-tumor effect by giving you two pills at home. That would be a very nice, hopefully effective or convenient way for patients to get anti-cancer therapy.