Bekaii-Saab Discusses Sequencing and Emerging Combinations in mCRC

Tanios Bekaii-Saab, MD

While the optimal sequence of the oral multikinase inhibitor regorafenib (Stivarga) and the biologic agent TAS-102 (Lonsurf) for patients with metastatic colorectal cancer (mCRC) is still unclear, expert Tanios Bekaii-Saab, MD, explains that novel combinations with these agents are emerging in the field.

An ongoing phase II clinical trial is examining the combination of TAS-102 and the PD-1 inhibitor nivolumab (Opdivo) in patients with microsatellite-stable (MSS) refractory CRC (NCT02860546). The primary endpoint of the trial, which is expected to be completed in March 2018, is immune-related overall response rate.

During the 2017 OncLive^® State of the Science Summit on Gastrointestinal (GI) Malignancies, program chair Bekaii-Saab lectured on the current state of the field and the multiple agents available for patients.

In an interview during the meeting, Bekaii-Saab, a professor of Medicine at Mayo Clinic, discussed optimizing treatment for patients with mCRC in the relapse setting and combination regimens on the rise.

OncLive: You spoke on what to do at relapse for patients with mCRC. Can you summarize?

Saab: Our armamentarium in CRC keeps expanding, so options across multiple lines of therapies are becoming available to our patients that, overall, are helping quite significantly extend their survival. Therefore, it’s very important first to understand the concept of sequencing therapies and going from 1 line to the next. We have about 4 to 6, or 7, lines of therapy, depending on how you look at it and depending what is available. It becomes very important for us to understand how to sequence all of these therapies.

What do we do after 2 lines of therapy have gone by? In that setting, we have 2 agents that are available to us. They have both been looked at in phase III clinical trials. Those 2 agents are regorafenib and TAS-102. These are a little bit different, comparatively. For one, regorafenib is actually a biologic tyrosine kinase inhibitor that attacks multiple facets of the cancer and microenvironment. It’s also an oral agent. In a phase III study, it was shown to significantly improve the outcomes of patients versus placebo in terms of overall survival (OS), progression-free survival (PFS), and disease-control rate (DCR).

TAS-102 is more of a cytotoxic agent, and is more of an agent that is a traditional chemotherapeutic drug. It’s not 5-fluorouracil (5-FU); it’s actually for when 5-FU fails because of its molecular and chemical structure. TAS-102 is more of a traditional agent that seems to work. From what we see from the phase III studies compared with placebo, it significantly improves OS, PFS, and DCR.

The toxicities are a little bit different when you look at the 2 agents. Regorafenib leads, mostly, to hand-and-foot syndrome, fatigue, and hypertension. The TAS-102 mostly affects the blood counts like neutropenia and others. TAS-102 does have some toxicity that show up a little bit later—fatigue can just linger and build up over time. Patients can get more fatigued the longer they’re on the drug. The GI toxicities are minor; most of the toxicities are in the hematologic world.

Which drug should be administered first?

There are questions about which one should we use first. Do we start with regorafenib or TAS-102? There are not many studies that can give us guidance. They have never been compared head to head; I can guarantee you they will never be compared head to head. How can we draw our conclusions about how to best optimize the sequence?

There is no guidance, so we have to look at the data. When you look at the CORRECT study, which looked at regorafenib, there was no prior therapy with TAS-102 involved. However, it didn’t seem to matter how many lines of therapy you go through to see an improvement.

With TAS-102, there have been about 20% of patients who had previously received regorafenib, which did not seem to affect how well TAS-102 worked. That gives us the first motive that it seems to be reasonable to go with regorafenib before TAS-102. At least we have that data.

The other data comes from 2 separate studies in Asian populations: CONCUR and TERRA. CONCUR is a study that looked at regorafenib versus placebo, while TERRA looked at TAS-102 versus placebo. In Asia, there is less access to prior lines of therapy. Therefore, we have a snapshot of time with both TERRA and CONCUR about how well regorafenib and TAS-102 do over placebo with less-treated patients.

What these studies suggest is that, in CONCUR, if you move regorafenib up the line, less pre-exposed patients do actually better comparatively with historical controls. Those curves widen and widen earlier. With TAS-102, we don’t see that as much. It doesn’t matter where you place it, you still do equally well.

What do you do in your practice?

What I do is usually start with regorafenib first in most patients, except those who have a performance status of 2 or above. Those patients who have some liver function dysfunction—which is 3 to 5 times what you expect from normal—those patients we try to avoid starting with regorafenib. For those patients who have significant hematologic toxicities from their prior therapies, I shift them more to regorafenib.

In most of the patients, I hope to expose them to 2 lines of therapy, but you have to have more data that will teach us one or another about how to optimize the sequencing. Today, it seems to be a wash; data favors starting with regorafenib, and it’s mostly indirect so it really doesn’t have the power of a phase III randomized study. Ultimately, the goal has to be to sequence in a way that you expose patients to both—since both have a benefit in that patient population.

Aside from sequencing, what possible combinations could there be with either agent?

There are ways for us to start looking at expanding further beyond the question of, “Is it TAS-102 or regorafenib?” Frankly, we need to move beyond that point and think how to combine these agents. Do we combine them together? There may be a rationale to do that. Chemotherapy and VEGF inhibitors plus other targets may actually do well together when we move them up the line. Regorafenib plus chemotherapy is being looked at in the first-line setting.

TAS-102 is also being looked at up the line of therapy as a maintenance therapy combined with bevacizumab (Avastin). There’s also preclinical rationale to combine regorafenib with PD-1 inhibitors, for example, in MSS patients. These patients normally do not get any benefit from PD-1 inhibitors; there may be some interaction between regorafenib and immune cells that would make the cancer a little more visible. This is mostly preclinical data, and we are waiting for additional clinical work to unravel that combination for us.

There are these various combos and beyond that—at this point in time—there is not much that can be done with those 2 agents, other than place them in their clinical positioning. We will hopefully continue to explore further targets of interest and match them with targeted therapies.

You chaired this State of the Science Summit. What is the value of having this type of an event?

The community oncologist has to deal with 30 to 40 different cancers with hundreds of agents and, in a busy practice, it’s kind of tough to keep up with all of this. I can’t be as smart as them and have to do this; I’m just focused on 1 or 2 areas.

What this summits allows is a good summary in a few hours of all of the advances that are applicable to the community or are coming in GI cancers. It helps in local venues and regional venues to helps physicians who are not able to get access to that data in real time, and who are unable to travel to all of these meetings that we go to that are very specialized. We are going to take that data, digest it, and give it to them and help them apply it to the practice.

It also exposes them to some of the research that is coming, so that they understand. Most of the community physicians understand research. They want to refer their patients on a clinical trial, but there are so many trials out there. Some of the trials make sense and some of them may not. You’re going to learn a lot about what’s there, what’s coming, and what’s in the pipeline. That helps a lot of physicians in their own backyard understand progress and what’s applicable to their clinic today.