Lenz Lends Insight on Therapeutic Approaches Shaking Up Third-Line CRC Treatment

Heinz-Josef Lenz, MD, FACP

A wave of novel third-line therapeutic options have shown promising efficacy in patients with colorectal cancer (CRC), according to Heinz-Josef Lenz, MD, FACP, and refined technologies capable of detecting circulating tumor DNA (ctDNA) have opened the door to novel targets and a stronger understanding of disease biology, allowing for more informed treatment decisions.

“In the third-line treatment setting for metastatic CRC, we are relying on the molecular subtyping of this disease because we understand that colon cancer is not just 1 disease. We already use the RAS mutation and we now use specific treatments for BRAFmutations,” said Lenz. “Another very interesting and important subgroup is those with HER2 overexpression and/or amplification. Several clinical trials [are examining] compounds [that are] showing very promising and exciting efficacy in this patient population.”

In an interview with OncLive during the virtual 2020 International Perspectives in Cancer on Gastrointestinal Cancer, Lenz, a professor of medicine, the J. Terrance Lanni Chair in Gastrointestinal Cancer Research, and co-director at the University of Southern California (USC) Center for Molecular Pathway and Drug Discovery at the USC Norris Comprehensive Cancer Center, discussed third-line treatment approaches that are generating excitement in CRC.

OncLive: Could you provide a brief overview of the current frontline treatment paradigm for CRC? How are these agents sequenced in practice?

Lenz: Several differentagents are available for metastatic CRC. The first line [approach] is pretty straight forward; we usually use a chemotherapy backbone with the targeted agents, depending on the molecular testing of the tumor. If they do [not have RAS or BRAF mutations], then we have the option to [use] EGFR inhibitors. If mutant, we usually use anti-VEGF treatments such as bevacizumab (Avastin) and that will determine the choice of our second-line treatment. In the United States, many of my colleagues start with FOLFOX/bevacizumab and, even in the wild-type setting, they continue to FOLFIRI/bevacizumab and that will also then determine the third-line choice.

If chemotherapy in the first- and second-line settings is not effective anymore, third-line options include, from the standard-of-care options, regorafenib and TAS-102 (trifluridine/tipiracil; Lonsurf). New developments have also been made, including chemotherapy and targeted agents, such as EGFR inhibitors.

Many clinical trials have suggested that when you use an EGFR inhibitor in the first line, these treatments showed some effect measured by response or progression-free survival (PFS) of about 6 months and, when you switch to an alternative regimen such asbevacizumab-based chemotherapy for about 4 months, there is a possibility that you lose the mechanism of resistance gained under EGFR pressure. If this is the case, data show that re-challenging with EGFR inhibitors show a response rate between 20% and 30%. The efficacy goes up if you can determine, with a liquid biopsy, that the mechanism of resistance is not present. Wild-type RAS and wild-type BRAF, in most cases, [are] the most frequent mechanism[s of] resistance. The question of when we should use regorafenib or TAS-102 [are still open]. Both drugs have very similar efficacy data measured by response or PFS and overall survival (OS); however, significant differences exist with regard to the safety profiles of these agents.

When we use regorafenib in earlier lines of treatment, we seem to increase the efficacy. More and more data suggest that, in young patients or those with better performance status, we should use regorafenib before TAS-102. We also have data suggesting that TAS-102 continues to be effective after regorafenib failure; that sequence seems to work.

The toxicity of regorafenib was a clinical challenge until the ReDOS manuscript published in the Lancet Oncologylast year showed that we don't need to start with the FDA-recommended dosage of 160 mg; we can start with 80 mg. If no toxicity is observed, we can go up to 120 mg [and then up to] 160 mg. This dosing approach shows high efficacy and avoids significant toxicity as well as delays of start of treatment. This approach is now being integrated into the National Comprehensive Cancer Network guidelines and it has been much easier to give regorafenib and monitor patients. I still see patients on a weekly basis because, interestingly, the toxicity for regorafenib are often seen within the first 3 or 4 weeks. After that, it is very rare that we will need to make dose modifications.

TAS-102 has fewer adverse effects (AE), so we can use it in patients with poor performance status without any quality-of-life issues or dose-limiting toxicity. One interesting AE that we see with TAS-102 is neutropenia. Our recent publication in the Annals of Oncology showed that neutropenia is a significant predictor of outcome of efficacy. We have some particular measurements [that can help inform] how we use and how we sequence regorafenib versus TAS-102.

What are some of the approaches that are being examined in the third-line setting?

One of the most exciting clinical trials recently presented was the trial examining regorafenib plus nivolumab in gastric and colon cancer. The data with this combination in patients with microsatellite stable disease showed very promising response rates in both CRC, at 36%, and gastric cancer, at 44%. I found it incredibly impressive how patients with gastric cancer who progressed on immune checkpoint inhibitors, they responded toregorafenib/immune checkpoint. This indicated that they can overcome resistance to an immune checkpoint therapy, which is a very important mechanism of action. The significance of anti-VEGF and immune checkpoint inhibitorsis a very important combination that should be further explored; this combination resulted in several additional clinical trials. This is only the beginning of understanding combination treatment.

The combination of TAS-102 plus bevacizumab (Avastin) is another interesting development. Recent data published in the Lancet Oncologyby Per Pfeiffer, MD, PhD, of Odense University Hospital, showed a significant improvement in both PFS and OS. As such, I have been using that combination more often in my practice because it's very well tolerated and has a promising efficacy profile which needs to be further evaluated in larger clinical trials. In the future, in the third-line setting, we may have more successful and effective combination treatments consisting of either regorafenib and immunotherapy or VEGF TKIs. [Also, of course, we also have] the combination of TAS-102 and bevacizumab. We should have more of an armamentarium for the treatment of this patient population.

Could you expand on how molecular subtyping is being used to inform strategies in the third-line setting?

An important trial to mention is HERACLES, which combined trastuzumab (Herceptin)with lapatinib (Tykerb), so an TKI with an antibody against HER2 in metastatic CRC. This approach showed a response rate of 36%, which is unheard of in a refractory setting; this percentage was actually much higher than any [observed in the] second-line setting [as well]. Interestingly, we are no longer using classic chemotherapy; we’re shifting to targeted agents, and we’re showing that we can have high efficacy and very little toxicity when we select patients appropriately.

These data led to the development of many different HER2-targeted agents improving the efficacy of inhibiting HER2, including antibodies, such as CW25, which binds to different epitopes of HER2 and can be effective, even in those who progress on trastuzumab.

The other compound is Daiichi Sanykoantibody-drug conjugate. We don't what level of overexpression or amplification is necessary to demonstrate the effect, because it just binds to the receptor and delivers a lethal payload of a cytotoxic agent. Multiple trials in different diseases, all trastuzumab-resistant, showed response rates from 30% to 50%, indicating that targeting this pathway is very promising. We now have 3 different ways to target and drug this pathway.

It’s important for my colleagues to understand that we need to look for HER2 overexpression and amplification. The rate of overexpression and amplification is higher in patients who received EGFR inhibitors, because one of the mechanisms of resistance is upregulation of HER2 and HER3. Up to 10% of left-sided colon cancers treated with EGFR inhibitors actually go on to develop overexpression of HER2. We have to watch out for these patients, which we can monitor in real time with a liquid biopsy.

Speaking of liquid biopsy, how is circulating tumor DNA currently being used to monitor responses and resistance within this patient population?

This is a technology that will change our paradigm and how we treat patients in the future; it allows us to perform real-time molecular monitoring, identify the molecular makeup of the tumor at the time of treatment, and catch the changes of molecular characteristics under treatment pressure, allowing us to identify the escape mechanism on a molecular level to the ongoing treatment. This not only allows us to understand why a treatment fails on a biological level, but [it might also allow us to] see potential new targets we can use to make better treatment decisions for our patients.

[The use of ctDNA] is becoming more standard in most academic centers and it is also increasingly being used in community practices; this should become a standard technology to use. It’s not only for patients with metastatic disease; large, ongoing studies are working to establish this technology to decide whether patients with stage II disease should undergo active treatment, or whether we should use chemotherapy or escalate to a more aggressive chemotherapy regimen in patients with stage III disease.

We will hear more about the use of refined technologies in detecting ctDNA because many research projects focus on the exosome RNA, the tumor RNA, and certain tumor cells to further increase this very impressive technological tool.

Could you shed light on the difference between left- versus right-sided colon cancer? How are genomic alterations influencing treatment with regard to tumor location?

The primary tumor location is a critical clinical factor needed to make prognostic and predictive decisions. My laboratory was actually one of the first in the world to identify that left- versus right-sided colon cancers have differential outcomes. We also discovered that left-sided tumors benefit more significantly from EGFR inhibition; this makes a lot of sense because right-sided colon cancer comes embryologically from the mid gut and left-sided tumors come from the end gut.

This goes along with different genetic activated pathways. We see many more mutations on the right side, and on the left, we see more chromosomal alterations, but also an activation of the HER1 and HER2 pathways. It becomes very easy to understand that the left-sided with upregulated EGFR pathway may be more sensitive to the inhibition. This is exactly what we show in all large, randomized, phase 3 studies comparing bevacizumab with cetuximab.

Right-sided tumors fare significantly worse prognostically; [we have seen a] 14-month difference in OS. This is important to remember when deciding what treatment to use for a particular patient. For those with tumors on the right side, we don't know what the benefits of targeted agents and antibodies are; there is certainly little or no benefit with EGFR therapy. Some data suggest that there may be increased response rate, but it does not translate into PFS and OS benefit. Even bevacizumab does not seem to be a very effective drug. It’s critical that we consider a triplet for patients with right-sided colon cancer. A modified FOLFOXIRI regimen in combination with bevacizumab is often used as a standard of care, if the overall performance stages of the patients allow it.