Grothey Gives Insight on Nintedanib, Immunotherapy Activity in CRC

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.

OncLive: Can you tell us about the LUME-1 trial? What are the treatment options right now for patients with metastatic CRC?

Are there any toxicities that were seen with nintedanib?

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.Grothey: 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.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.

Will there be a specific cohort of patients who would benefit the most?

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.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.

Can you tell us about LUME-2?

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.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.

Can you tell us a little bit about left tumors versus right tumors in CRC?

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.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.

What kind of research needs to be done into this?

Are there any other breakthroughs in CRC that you're excited about?

The interesting thing that came out of ASCO this year was not only prognosis, but also the predictive factor, particularly with anti-EGFR antibodies. They do not seem to work well in right-sided tumors, even if you look for RAS or KRAS wild-type tumors, but they seem to work better in left-sided cancers. So whereas the angiogenesis inhibitors were kind of agnostic and worked in both sides, EGFR receptor antibodies did not seem to work in right-sided cancers. How this will influence our clinical decisions, guidelines potentially, and the future of clinical trials will remain to be seen. It's very clear that we need to at least use sidedness, and that's a word, as a stratification factor for clinical trials.There was data recently presented on what molecular factors are really driving the difference between right and left sides, with regards to prognosis and response to treatment, and I think we will get more data on exactly these factors. So until then, can we use sidedness as a decision factor for treatment choices? It's not the best we have, but I would like to see what the biology behind it is. We need to determine not just what's driving the tumor, but also something we haven't really appreciated as much, which is the interaction with the microbiome. The bacteria living in the colon on the left and right side are different, and we need to look at what the interaction is between colon tissue and the bacteria living inside off all of us.We all talk about immunotherapies. Every tumor type wants immunotherapy to work, and we have at least one subgroup of colorectal cancers, metastatic as well, which have shown to be immunogenic. In the hyper mutated MSI-high, or mismatch-repair deficient colon cancers where you have a lot of mutation load, we know that PD-1 antibodies actually do work in these patients. There are a lot of studies being conducted right now—in first, second, and third line settings, as a single agent, in combination with other immunotherapies, and with chemotherapy—that will target this population that make up only 4% to 5% of advanced colorectal cancers.

That leaves 95% of patients that still don't benefit from immunotherapy. We need to find a way to make these tumors immunogenic. There was recent data that was looking at a combination of cobimetinib (Cotellic) and atezolizumab (Tecentriq). This combination was interesting because in MSS tumors, which normally do not respond to immunotherapy and where atezolizumab has no activity and a MEK inhibitor should have no activity, the combination of cobimetinib and atezolizuma produced a 20% response rate. There seems to be ways to make non-immunogenic tumors immunogenic by driving lymphocytes into the tumor, and I think we're just scratching the surface with MEK inhibition as the only way to do this.

Where do you see the field of immunotherapy going in 5 or 10 years?

As immunotherapy moves further into this field, do you think that surgery and chemotherapy will still remain a mainstay?

Can we utilize this immunotherapy in the adjuvant setting? How can we use immunotherapy there to improve survival? There is going to be a trial open very soon that looks atezolizumab added to FOLFOX as adjuvant therapy in MSI-high colon cancers.In 5 or 10 years, we hopefully will have clearly established efficacy in various lines of treatment for single agent checkpoint inhibitors in MSI-high colon cancers. Hopefully we will have found a way to make MSS tumors immunogenic, which will thereby expand the numbers of patients that can benefit from immunotherapy.As long as I practice, I think we will probably still need surgery and chemotherapy and all the targeted agents. This will not go away. I think we will probably find synergisms in different patient populations for different treatments. Right now we're very much thinking about immunotherapy, and with all the new discoveries, we're very excited initially because we want to make things work. Like anti-angiogenesis 10 years ago, everyone was excited, and it has provided benefit for a lot of patients, but still most patients will still succumb to their advanced cancers.

Immunotherapy has the potential, I believe, in some patients, to induce cures. That's a very strong word, but not in the majority of patients. I think in 10 years we will look back and say "yes, we learned a lot and we moved things forward, but we are still waiting for the cure for more patients." So we'll still need chemotherapy, and we'll still have the goal for most patients to extend duration as much as possible.