HER2-Amplification Possible Negative Predictive Biomarker for Anti-EGFR Antibodies in mCRC

Kanwal Raghav, MD

Kanwal Raghav, MD

Colorectal cancer (CRC) patients that express amplified HER2 genes may be resistant to standard-of care therapy, says Kanwal Raghav, MD.

In an interview withTargeted Oncology, Raghav, assistant professor, GI medical oncology, the University of Texas MD Anderson Cancer Center, discusses the the role of HER2-amplification, and an upcoming trial looking at trastuzumab (Herceptin) and pertuzumab (Perjeta) against CRC standard of care siltuximab (Sylvant) and panitumumab (Vectibix) in patients who exhibit the the gene.

TARGETED ONCOLOGY:What role does HER2 amplification play as a biomarker for anti-EGFR antibody therapy in mCRC?

Raghav:Increasingly, we are recognizing that colon cancer is not just one disease. It's a compendium of smaller subsets. Our study focuses on one of these distinct subsets, and all of these subsets have some sort of characteristics. This subset is characterized by the amplification of the gene HER2. This amplification is seen very commonly in breast cancer and gastric cancer. Actually, there are drugs that can target this gene.

Our interest in this subset of colon cancer stems from the fact that you have potentially active drugs that can target this subset. We looked at our group of patient that had HER2 amplifications, and then there were others that didn't have them, and what we tried to do is see the difference between these two. Pre-clinically, we know that these patients that have this gene amplification are resistant to anti-EGFR monoclonal antibodies, specifically siltuximab and panitumumab, which are currently the standard of care in colon cancer.

When you have this gene, these patients don't respond. So when we looked at our group, we took patients who had received this anti-EGFR monoclonal antibodies with chemotherapy, and we found that the HER2-amplified patients did not respond at all. The progression-free survival in this group was less than 3 months, compared to 8 to 9 months in patients who were not HER2-amplified.

We strongly believe that this is a negative predictive biomarker for anti-EGFR chemotherapy, which is very interesting because if you can do this testing routinely in your patients who are RAS-wild type, you can save giving them a highly-toxic standard of care, which doesn't work. You can also identify them for early enrollment to clinical trials with drugs that can target this gene, one of which is the SWOG 1613 trial, which is going to be a national trial, which we are in the process of launching. This will take all of these patients and randomize them into getting either trastuzumab and pertuzumab, which is a fairly well-tolerated regiment, against siltuximab irinotecan, which is the current standard of care.

We feel that this subset is very fascinating and that if this is successful, it could change the standard of care for this particular type of patients.

TARGETED ONCOLOGY:Are there any other types of regimens that you'd like to see studied in this subset?

Raghav:This is a small subset, so we cannot launch multiple studies. The reason why we took trastuzumab pertuzumab as a combination is that these two drugs in clinical studies have also shown response rates at least in a small number of patients, about 30% of patients who are completely refractory to other lines of therapy, which is amazing for colon cancer because the response rate in this population is about less than 5% in standard of care therapy, which is regorafenib and TAS102.

TARGETED ONCOLOGY:What are some of the biggest questions to answer in this subset right now?

Raghav:One of the chief questions is what the biology of these tumors are. What we know about this subset is we find this amplification only in patients who are RAS and RAF wild type, so these are two genes that we routinely test in colon cancer and in that group, it's about 8% prevalence. It would be really helpful to understand what is the clinical phenotype.

Questions include: Are these patients right-sided, are they left-sided, women, men, is there a particular metastatic site associated with these tumors, and overall what is the biology of the subset? Not just looking at the biomarker per se, but what the biomarker represents, because then you will be able to tease out who responds and who doesn't respond to these therapies.

TARGETED ONCOLOGY:There's been some data about left- and right-sided tumors, as you had mentioned. Can you speak to that?

Raghav:I'm not directly involved in that data, but it appears as though there is some predictive impact of right-sided and left-sided tumors with these anti-EGFR agents. At least from our abstract, if you put it together, then the answer is that if you can test this gene amplification, the you can definitely identify a subset that does not benefit from these therapies.

It's kind of important for patients in general, because anti-EGFR agents are not easy therapies. They have skin toxicities, which can be very distressing for some patients. On the other hand, drugs like trastuzumab and pertuzumab, which work against HER2 from the data that we have from breast cancer, are relatively non-toxic. If they can improve your survival by any number of months, then you haven't just gained survival, you've gained quality of life.

So how do you apply this data clinically, right? That's the question. We have patients with metastatic colorectal cancer that get tested for RAS mutations pretty much as standard of care.