Tabernero Discusses Novel Antibody Mixture Sym004 and Emerging Trends in Colorectal Cancer

Josep Tabernero, MD, PhD

Treatment options for metastatic colorectal cancer (mCRC) have been rapidly expanding. Recently published data showed that TAS-102 (tipiracil hydrochloride) improved overall survival for refractory mCRC in the RECOURSE study. Ramucirumab (Cyramza), approved by the FDA last month in combination with FOLFIRI, is another promising option for mCRC in second-line, with study results showing that the agent extended overall and progression-free survival compared with FOLFIRI alone.

An investigational antibody mixture, Sym004, may offer yet another breakthrough for mCRC patients. Sym004, a mixture of two antibodies that bind to different regions of the extracellular domain of EGFR, was found to be clinically active in patients with advanced colorectal cancer who had become resistant to prior anti-EGFR therapies, according to a study recently published in Cancer Discovery.

The phase I study enrolled 62 patients. Twenty patients with advanced solid epithelial tumors were enrolled to the dose-escalation phase of the study and received different doses of Sym004, ranging from 0.4 mg/kg to 12 mg/kg, administered weekly. The remaining 42 patients had metastatic colorectal cancer and had previously been treated with anti-EGFR antibodies with brief responses, and were enrolled to the dose-expansion phase of the trial.

Of the patients in the dose-expansion cohort, five (13%) had a partial response, and overall, 17 (44%) had some degree of tumor shrinkage during treatment with Sym004. The overall disease-control rate, defined as partial responses plus stable disease, was 67%.

OncLive spoke with the lead author of the Sym004 study, Josep Tabernero, MD, PhD, head of the Medical Oncology Department at Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain. In the interview, Tabernero discusses Sym004’s potential in mCRC, as well as other emerging treatments and trends in the management of the disease.

OncLive: What is the biggest challenge in treating patients with advanced colorectal tumors?

Dr Tabernero: For patients with mCRC, EGFR inhibitors are effective for those with mutations that are not KRAS or NRAS. Unfortunately the patients develop resistance to multiple different mechanisms. But there are some patients that continue to be dependent on the EGFR signaling pathway.

How does Sym004 offer a solution to this problem?

One way to circumvent this resistance to EGFR inhibitors is to treat patients with a combination of two monoclonal antibodies targeting nonoverlapping EGFR epitopes like Sym004. The reason why these patients are still sensitive to a novel EGFR inhibitor, once becoming refractory to previous EGFR agents, is because with an antibody mixture we are targeting the receptor in different epitopes. We are producing a compound of the receptor plus two attached monoclonal antibodies. So this totals to a compound of 450 kilodaltons in size and weight. Once this compound gets internalized in the cell it is destroyed. There is no way recycling of the receptor can occur. With single monoclonal antibodies, usually the receptor is not fully validated and part of the receptor is recycled.

What is currently the standard of care for refractory patients and what are the typical outcomes for those patients?

When patients become resistant, we only have a few options. These include TAS-102, which is not yet approved but will probably be in the near future, and sorafenib. There is a need for new treatment options. The outcomes for these patients currently are not very good.

How does Sym004 compare to the anti-EGFR antibodies cetuximab and panitumumab?

We do not yet have a face-to-face comparison, but we can anticipate that this compound is more active. This is basically because patients that are refractory to cetuximab and panitumumab have responded to Sym004. We assume that if we have a face-to-face comparison, the arm with Sym004 is going to do better than the conventional EGFR antibodies.

What are the next steps in this research?

What we are doing right now is a randomized phase III study in the refractory setting administering Sym004 or the physician’s choice for this setting. This is often cetuximab, which we know in this setting is almost inactive. We hope that this is going to provide proof of efficacy in improving survival. This trial is ongoing and we anticipate having the preliminary results around the end of 2015. The next step would be gaining approval of the compound in the refractory setting.

With the level of activity we see, we are thinking of starting from the bottom of this compound and testing it in earlier settings of the disease for example in first-line or second-line treatment.

Outside of Sym004, what have been the biggest recent advances in metastatic colorectal cancer?

We have been trying to classify more and more colorectal cancers into different subtypes. We know that there are different subtypes of the disease that have completely different clinical outcome and molecular biology. The Colorectal Cancer Subtyping Consortium is doing this. We have four different well-defined subtypes: Cancer Stem Cell (CSC), 1 the immune or inflammatory subgroup; CSC 2, the epithelial cortical; CSC 3, epithelial metabolic; and CSC 4, the mesenchymal subtype. We have been granted permission by the European Commission to conduct clinical trials in particular populations of patients of metastatic colorectal cancer based on this gene expression signature. We are moving forward with the focus on precision medicine.

What other therapies do you see the most potential for in colorectal cancer?

We see opportunities for several PARP inhibitors for the metabolic subtype. We also see potential for immune checkpoint inhibitors and immune regulators for the CSC 1 group. New antigenic agents also have possibility in the CSC 4 mesenchymal subtype.

What impact do you think ramucirumab, which was recently FDA approved for metastatic colorectal cancer, will have?

I think it is an alternative option for second-line treatment. Ramucirumab is active in second line and also patients coming from the first line to the second line. The study looked at a huge population of patients, over 1000, and found an advantage with ramucirumab. The design of the clinical trial is much cleaner with ramucirumab than without. However, it does not mean that ramucirumab is superior but it is a good alternative second-line option.

Are there any other recent studies in colorectal cancer that you are excited about?

In the refractory setting, there is a study that was just published in The New England Journal of Medicine on TAS-102 that I found very interesting. It had an advantage in overall survival and I am interested to see what comes out of the research next.