Molecular Markers Gaining Greater Influence in CRC Paradigm

Mohamed E. Salem, MD

The field of metastatic colorectal cancer (mCRC) is starting to shift away from a one-size-fits-all treatment approach due to the discovery and development of targeted therapies for patients with HER2 amplification, NTRK fusions, and BRAF mutations, said Mohamed E. Salem, MD.

“We’re moving toward an era of precision medicine and customized treatment, with which we hope to prolong survival and make colon cancer more of a chronic disease,” said Salem.

Most recently, updated results from the phase II MyPathway trial (NCT02091141) were published in Lancet Oncology, in which patients with refractory, HER2-amplified mCRC received the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta). Among all 57 patients who enrolled in the trial and were eligible for evaluation, there was 1 complete response (CR) and 17 partial responses, translating to a 32% objective response rate (ORR) among the entire study cohort.

Moreover, the combination was found to be well tolerated, with no treatment-related deaths reported. However, grade 3/4 treatment-related adverse events occurred in 21 patients, the most common of which were hypokalaemia and abdominal pain.

If the combination progresses in development, it has the potential to join an increasingly expanding armamentarium of targeted therapies, which currently include larotrectinib (Vitrakvi) for patients with NTRK fusion—positive cancer. Additionally, the regimen of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) for those with BRAF V600E—mutant mCRC has been granted a breakthrough therapy designation.

Apart from these markers, microsatellite instability-high (MSI-H) and microsatellite stable (MSS) status must also be considered, as the presence of MSI-H can indicate potential for immunotherapy.

OncLive: How has the field of mCRC changed in recent years?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Salem, a medical oncologist at Levine Cancer Institute, Atrium Health, highlighted ongoing research efforts to potentially improve survival in patients with mCRC.Salem: mCRC is a common disease. Until recently, we didn't have many treatment options available. Usually, we would give frontline FOLFOX or FOLFIRI plus a biologic agent to these patients. Once patients progressed on those regimens, we didn't have many options to offer them. In the last few years, we started to have more drugs. For example, regorafenib (Stivarga) was approved by the FDA in 2013. TAS-102 (trifluridine/tipiracil; Lonsurf) was FDA approved in 2014 and became available to patients who progressed on FOLFOX- and FOLFIRI-based regimens.

Another important aspect to remember is that we've started to understand the disease better. I used to tell my patients in the clinic that CRC is a family [disease], yet every patient has their own individual features that differentiate them from other [cases]. For example, we now know that right-sided CRC is biologically different from left-sided CRC. As such, choice of therapy will differ based on where the tumor arises.

What did the results of the MyPathway trial show?

CRC is also starting to be divided into patient subgroups. For example, MSI-H disease is sensitive to immunotherapy. Additionally, some of our patients have NTRK fusions and respond very well to NTRK inhibitors. We're also learning about BRAF-mutant CRC. We know that the combination of a MEK inhibitor, BRAF inhibitor, and EGFR inhibitor is linked to a better result than the use of traditional therapy. We also saw activity with an anti-HER2 agent in the refractory setting. Recently, results from the MyPathway trial were published in Lancet Oncology showing the activity of this agent.We're learning from breast cancer. In [that space], we learned about HER2 as a physiology and how to target it. With advances made in technology and the ability of next-generation sequencing, we are able to find HER2 overexpression in about 3% to 5% of patients. This is important, because we have drugs that can be used to target HER2-amplified tumors. A few years ago, the HERACLES trial was presented at the ASCO Annual Meeting and demonstrated the activity of anti-HER2 therapy in the refractory setting.

What other molecular abnormalities are we having difficulty understanding?

Following the results of the ReDOS trial, what are the next steps with regorafenib?

As I mentioned, a recent trial published in Lancet Oncology showed the activity of anti-HER2 therapy with trastuzumab and pertuzumab in patients with HER2-amplified tumors in the refractory setting. The response rate was about 32%. Moreover, 2% of patients achieved a CR. The disease control rate was about 40%. Although the sample size was small, there was a signal of activity. You have to keep in mind that the response rate in that setting is typically 1%. The fact that we saw a 40% disease control rate and a 32% ORR is very exciting. It also seems that there is an association between resistance to anti-EGFR therapy and RAS-wild type and HER2-amplified tumors.Immune therapy has shown very impressive activity in patients with MSI¬-H tumors. The problem is that the majority of patients have MSS disease. From what we’ve seen, there is not much activity with immunotherapy in this population. The next generation of trials are going to see how we can overcome that resistance and how we can make a “cold tumor” more sensitive to immunotherapy.Regorafenib has been around for a few years now. Until TAS-102 was approved by the FDA, we didn't have any phase III data showing efficacy in that setting. You have to put that in perspective. Regorafenib was used at a dose of 160 mg daily on a 3-weeks-on/1-week-off schedule. The problem was that the toxicity was frequent enough that physicians had to stop the drug. It took a while for us to learn how to use that drug.

We started to realize that starting at a lower dose made more sense. Some of us started using 80 mg to begin with. Some of my colleagues used 120 mg. The concern was whether a lower dose was as effective. I have to credit the investigators of the ReDOS trial, Tanios Bekaii-Saab, MD, of Mayo Clinic, and Axel Grothey, MD, of West Cancer Center. They took the initiative to see whether a lower dose would be as effective as the standard dose [in a clinical trial]. In this phase II trial, half of patients received the standard 160 mg of regorafenib, while the other half received 80 mg of regorafenib. Then, patients were escalated to 120 mg and then 160 mg based on patient tolerance.

The primary endpoint of the trial was the percentage of patients who were able to start cycle 3. The results showed that more patients in the dose-escalation arm were able to make it to cycle 3. This was a small phase II study that did not show statistical significance. However, the median survival was about 9 months in the dose-escalation arm and approximately 6 months in the standard arm. This gives us some assurance that a dose-escalation strategy might be a wise way to use that drug.

Could you provide some perspective on the IMblaze370 trial?

One very interesting element that came out of the ReDOS study was the quality of life (QoL) data, which favored the dose-escalation approach. Now, many oncologists start regorafenib at a lower dose, as the National Comprehensive Cancer Network guidelines have since adopted that strategy.The majority of our patients have MSS status. We know that immunotherapy is effective in MSI-H tumors. The question in this trial was whether we could overcome that resistance by adding a MEK inhibitor, thereby making MSS tumors more immunogenic. A phase I trial was presented a couple of years ago by Johanna Bendell, MD, of Sarah Cannon Research Institute, which showed very impressive results.

A phase III study was then conducted, in which investigators randomized patients to receive either the combination of atezolizumab (Tecentriq) and cobimetinib, atezolizumab alone, or regorafenib alone at a dose of 160 mg. Unfortunately, the study didn't meet its endpoint as there was no significant survival difference observed between the 3 arms. However, we learned a lot from the study. More than 300 patients were enrolled, so there are good data there. Now we can look to see if a subgroup of patients may have benefitted from the combination.

Unfortunately, none of the drugs we have in the metastatic setting will cure our patients. The only way we can move forward is by conducting more clinical trials. Every patient and provider should look for the best clinical trial available to them.

Meric-Bernstam F, Hurwitz H, Raghav K, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from the multicenter, open-label, phase 2a, multiple basket study [published online ahead of print March 8, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30904-5.